Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex disease that affects children and adolescents as well as adults. The etiology has not been established. While many pediatricians and other health-care providers are aware of ME/CFS, they often lack essential knowledge that is necessary for diagnosis and treatment. Many young patients experience symptoms for years before receiving a diagnosis. This primer, written by the International Writing Group for Pediatric ME/CFS, provides information necessary to understand, diagnose, and manage the symptoms of ME/CFS in children and adolescents. ME/CFS is characterized by overwhelming fatigue with a substantial loss of physical and mental stamina. Cardinal features are malaise and a worsening of symptoms following minimal physical or mental exertion. These post-exertional symptoms can persist for hours, days, or weeks and are not relieved by rest or sleep. Other symptoms include cognitive problems, unrefreshing or disturbed sleep, generalized or localized pain, lightheadedness, and additional symptoms in multiple organ systems. While some young patients can attend school, on a full or part-time basis, many others are wheelchair dependent, housebound, or bedbound. Prevalence estimates for pediatric ME/CFS vary from 0.1 to 0.5%. Because there is no diagnostic test for ME/CFS, diagnosis is purely clinical, based on the history and the exclusion of other fatiguing illnesses by physical examination and medical testing. Co-existing medical conditions including orthostatic intolerance (OI) are common. Successful management is based on determining the optimum balance of rest and activity to help prevent post-exertional symptom worsening. Medications are helpful to treat pain, insomnia, OI and other symptoms. The published literature on ME/CFS and specifically that describing the diagnosis and management of pediatric ME/CFS is very limited. Where published studies are lacking, recommendations are based on the clinical observations and practices of the authors.

Preface

Myalgic encephalomyelitis (ME), also known as chronic fatigue syndrome (CFS) or ME/CFS, affects children and adolescents as well as adults. This primer has been written to provide the information necessary to understand, diagnose, and manage the symptoms of ME/CFS in children and adolescents. Some information in this primer overlaps with information in a similar primer for adults “Chronic Fatigue Syndrome, Myalgic Encephalomyelitis, Primer for Clinical Practitioners” that was published under the sponsorships of the IACFS/ME and is available at www.iacfsme.org. This pediatric primer was developed to cover the many unique aspects of the diagnosis and management of pediatric ME/CFS.

The published literature on pediatric ME/CFS is modest. Many studies on ME/CFS have only enrolled adults. Where it has been helpful, we have sometimes cited studies in adults and this is explained in the text. Where published studies are lacking, our recommendations are based on the clinical expertise of experienced medical practitioners.

The text was developed by consensus of the members of International Writing Group for Pediatric ME/CFS who have made every effort to ensure that the information is accurate and up to date. Statements, opinions, and study results published in this primer are those of the authors and the studies cited. The recommendations contained in any part of this primer do not indicate an exclusive course of treatment or course of action. Nothing contained in this primer should serve as a substitute for the medical judgment of a treating provider.

Introduction and Overview

Pediatric myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex disease characterized by overwhelming fatigue and a substantial loss of physical and cognitive function. The etiology is uncertain and there is no curative treatment. The cardinal feature is a sensation of feeling ill (malaise) and worsening of symptoms following minimal physical or mental exertion. This post-exertional worsening can persist for hours, days, or weeks, and is not relieved by rest or sleep. Other symptoms include unrefreshing or disturbed sleep, cognitive impairment, and a multitude of immune, neurological, and autonomic symptoms. Orthostatic intolerance (OI) is a common co-morbid condition.

Significant pathophysiological changes found in ME/CFS show that it is an organic/physical illness. Secondary psychological symptoms can be present in some patients as occurs in many other chronic illnesses, but psychological factors have not been shown to be the cause.

Nomenclature

Myalgic Encephalomyelitis (ME) and chronic fatigue syndrome (CFS) were names given to two well-documented cluster outbreaks of a clinically similar illness in London, UK in 1955 and in NV, USA in 1984. Several different but overlapping case definitions have been published for ME and for CFS to aid in diagnosing sporadic cases. Research studies tend to use the term CFS because a case definition was written for this purpose (1). The name CFS has been criticized for trivializing the illness (2), and it can be confused with the non-specific term chronic fatigue, which is a common symptom in other illnesses. The World Health Organization classifies ME as a disease of the central nervous system, G93.3 (3).

Less common names for the illness include chronic fatigue immune dysfunction syndrome, myalgic encephalopathy and neuro-endocrine-immune dysfunction syndrome. In 2015 a new name, SEID and a new case definition were suggested (2). Currently the new name is under discussion and the new case definition has not yet been clinically validated. This publication will use the acronym ME/CFS.

Symptoms of ME/CFS sometimes follow an acute illness, such as influenza or infectious mononucleosis (4). If symptoms resolve within 6 months, the term post-infectious fatigue syndrome is used to describe the illness.

Epidemiology

Myalgic encephalomyelitis/chronic fatigue syndrome is globally endemic. Most cases are sporadic, but cluster outbreaks have occurred worldwide. In several outbreaks the illness has been prominent in schoolchildren (5, 6). In sporadic cases the disease is not thought to be transmitted by casual contact. ME/CFS affects all ages, races and socioeconomic groups. In sporadic ME/CFS, two peak ages of onset are seen, 11–19 years in young patients and 30–39 years in adults (7). Although adolescents are more likely than younger children to have ME/CFS, children as young as 2 years old have developed the illness (5, 8). In adolescents, approximately 3–4 times as many girls as boys have ME/CFS. There are less data on the sex ratio in younger children. Estimates of the prevalence of pediatric ME/CFS vary in different studies from 0.1 to 0.5% (9, 10). Research studies have shown that 84–91% of adult patients who satisfy diagnostic criteria for ME/CFS have not been diagnosed (11, 12). We are aware of one comparable study having been done in children and adolescents (13).

Presentation, Course of the Illness, Prognosis

Myalgic encephalomyelitis/chronic fatigue syndrome can begin suddenly, gradually, or with an abrupt increase in the intensity and frequency of milder chronic symptoms. There can be a history of repeated minor relapsing and remitting prodromal illnesses over the months or years preceding the onset. An acute onset of fever and viral-like symptoms is common, and the onset also can be marked by severe orthostatic symptoms. ME/CFS can follow a known illness such as infectious mononucleosis (4). A gradual onset is more common in younger children and can occur over months or years.

While all patients experience a substantial loss of physical and cognitive functioning, there is a wide spectrum of severity. Mildly affected young people might be able to attend school full-time or part-time, but they might have to limit sport and after-school activities and have frequent school absences. ME/CFS has been found to be the most common cause of long-term absence from school (9, 13–16). More severely affected young people can be wheelchair dependent, housebound, or bedbound. The more impaired might even have difficulty participating in home tutoring sessions. In young persons with ME/CFS, overall self-reported quality of life is often lower than in other illnesses such as diabetes, epilepsy, and cystic fibrosis (17, 18).

Symptoms often fluctuate significantly during the day and from day-to-day. Commonly, patients are slow to get moving upon awakening, with somewhat better function later in the day. Reduced ability to function after activity (physical, cognitive, emotional, orthostatic stress, or academic pressure)—often referred to as “a crash” by patients—with prolonged recovery is a feature. In girls, ME/CFS symptoms are often worse at or just before the menstrual period. The unpredictable level of function from day-to-day can interfere with planning ahead for school attendance, social outings, or family obligations.

The course of ME/CFS is very unpredictable but must often be measured in years, not weeks or months. Remissions and relapses are common. Relapses can be caused by overexertion, infectious illnesses or failure to recover from a “crash” (see above). Dramatic improvement sometimes occurs in the first 4 years, but slow improvement over time is more likely.

It is generally accepted that young people with ME/CFS have a more favorable prognosis than adults. There have been few studies with sufficient numbers and duration of follow-up to be confident of the findings, but factors such as severity of symptoms or age at onset have not been shown to be reliable predictors of long-term outcomes. In a follow-up study of nearly 700 young people the average duration of illness of those who report having “recovered” was 4–5 years with a range from 1 to 15 years. By 5 years, 60% reported recovery, and by 12 years, 88% reported recovery. Of those who reported recovery, about one-third admitted to modifying their activities to remain feeling well (19). Several other studies found that although many patients improved, 20–48% showed no improvement or actually had worse fatigue and physical impairment at follow-up times ranging from 2 to 13 years (20–22). Even among those who report having completely recovered, many describe persistent symptoms that are not reported by healthy individuals (20).

Feedback from young people indicated that an important determinant of their functioning as adults was the effort made to enable them to remain engaged in education. This might have followed relatively unconventional pathways but it enabled them to remain socially connected and to feel they were able to achieve their aspirations fully or in part. From this group, more than 95% were either studying or working part or fulltime (23).

Diagnosis

No valid, reliable, laboratory test that confirms the diagnosis is currently available. The diagnosis of ME/CFS is purely clinical and is based on the history and the exclusion of other fatiguing illnesses by physical examination and medical testing. Routine blood tests are usually normal. If the typical symptom pattern is not recognized, the diagnosis will be overlooked. The diagnosis depends on the patient’s symptoms meeting the criteria of one of several overlapping case definitions (1, 2, 24–27). Most of the case definitions were developed for adults and they can exclude some young people with ME/CFS. Some case definitions are also quite complex to use in primary care and some do not require the cardinal symptom of post-exertional exacerbation of symptoms to be present. We recommend the diagnostic criteria shown in Section “Clinical Diagnosis.”

Role of the Health Practitioner in Diagnosis and Management

Young people who appear to have ME/CFS should be evaluated by a physician. A comprehensive history, a thorough physical examination, and appropriate laboratory testing are necessary to make the diagnosis and to exclude other fatiguing illnesses. Co-morbid illnesses are common and require appropriate treatment (see Comorbid Medical Conditions). Some patients with an initial diagnosis of ME/CFS are later found to have a different treatable illness.

Establishing a diagnosis frequently provides the patient and parents much relief. Early diagnosis of ME/CFS can lessen the impact of the illness through timely support and intervention. The unequivocal advice for careful avoidance of overexertion can help to both avoid deterioration and facilitate improvement.

Since there is no medication or intervention which will cure ME/CFS, clinical care focuses on managing symptoms and improving function. A management plan might include:

• Educating the patient, the parents, the family, and the school about the illness (e.g., using handouts, see Appendices C–E).

• Guidance on determining the optimum balance of rest and activity to help prevent post-exertional symptom worsening.

• Advice on diet, social interactions, and education.

• The treatment of symptoms with non-pharmacological interventions and/or medications.

• Regular assessment of progress and watchfulness for the emergence of other illnesses.

The chronicity of ME/CFS signifies the need for continuing management and periodic re-evaluation. Regular monitoring can support the young patient and uncover a change of symptoms, or the emergence of a new illness. Young patients can do well when treated in a primary care setting, but given the complexity of this illness, appropriate referral to other health practitioners (preferably those familiar with ME/CFS) is often needed.

The health practitioner has an important role helping to ensure that the young patient receives the most appropriate schooling by educating the young person’s school personnel about the effect of the illness on scholastic performance, and providing appropriate documentation to education authorities.

Etiology and Pathophysiology

The underlying etiology of ME/CFS has not been established. Well-documented pathophysiological changes demonstrate that ME/CFS is a multisystem physical disease, not a psychological disorder. The wide variety of pathophysiological findings has led to multiple hypotheses for etiology. These include: infectious agents, immune dysfunction, autoimmune disorders, circulatory abnormalities, neuroendocrine disorders, metabolic disturbances, brain dysfunction, toxins, genetic susceptibility, abnormal gene expression, or a combination of any of these mechanisms.

Etiological Factors

There is evidence that several predisposing and precipitating factors can contribute to the illness, but evidence for perpetuating factors is limited.

Predisposing Factors

Being female is a predisposing factor in post-pubertal adolescents. The prevalence of ME/CFS is 3–4 times higher in adolescent girls than in boys (9, 28). There is less information on the sex ratio in younger children. Genetic factors may produce a susceptibility to the illness in some families. Studies have shown that in approximately 20% of patients, ME/CFS affects more than one family member and in 90% of them, the affected relatives were genetically related (29). The prevalence of ME/CFS was found to be 5.1% in the offspring of mothers with ME/CFS (29). Another study showed an excess relative risk for developing ME/CFS in first (2.7), second (2.3), and third (1.9) degree relatives (30). Twin studies have shown that the concordance rate for a ME/CFS-like illness was 55% in monozygotic twins and 19% in dizygotic twins (31). Approximately 60% of adolescents with ME/CFS have joint hypermobility, compared to approximately 20% of healthy adolescents (32). The mechanism by which this changes the risk of illness is not understood.

Precipitating Factors

Sporadic cases of ME/CFS can be preceded (triggered) by: a viral, bacterial, or parasitic infection, an immunization, significant physical or emotional trauma, overexertion, (“overtraining”) chronic sleep deprivation, exposure to a toxin, or an atypical adverse reaction to a medication. In some patients no precipitating factor can be identified.

Perpetuating Factors

It is difficult to determine factors that perpetuate the illness, although it has been suggested that factors that aggravate the illness can also contribute to its persistence. Few studies have investigated this issue. Aggravating factors include: failure to diagnose the illness promptly, resulting in poor management in the early stages of the illness, overexertion resulting in “crashes,” stress, inadequate sleep, and co-morbid conditions, such as OI.

Pathophysiological Basis for Symptoms

Despite the wide variability in precipitating factors and in pathophysiological findings, there appear to be some common underlying mechanisms behind the most prevalent symptoms.

Infection

Although sporadic cases are more common, ME/CFS can also occur in cluster outbreaks, suggesting an important etiologic role for microbial pathogens. This assumption is supported by the common pattern of an abrupt onset in association with flu-like symptoms in many sporadic cases. In the absence of evidence of persistent replication of an infectious agent, the main scientific debate currently centers around whether there is an occult active persistent infection or whether infectious agents have been cleared, but have triggered chronic symptoms due to a maladaptive host immunologic response.

Pediatric ME/CFS sometimes follows an acute infection, including most prominently Epstein-Barr virus (EBV). After monospot-positive infectious mononucleosis, 13%, 7%, and 4% of adolescents met criteria for ME/CFS at 6, 12, and 24 months after infection, respectively (4). As in adults, the most important factor associated with developing ME/CFS was the severity of the initial illness, as reflected by the number of days spent in bed with acute symptoms (33). Several other ubiquitous infectious agents or their antibodies have been found in patients with ME/CFS and their presence can influence symptom severity. Although individual cases of ME/CFS have been identified in association with B. burgdorferi, cytomegalovirus, human herpesvirus 6, Coxsackie virus, enterovirus, adenovirus, or parvovirus B19, a large Norwegian pediatric study did not identify a prominent etiologic role for any of these organisms (34).

Some studies in adult patients with ME/CFS report benefit from anti-viral treatment, suggestive of a viral pathophysiology, but other studies have not confirmed the efficacy of anti-viral treatment (35–37). We are not aware of studies of anti-viral agents in young patients.

Immune Dysfunction

Another prominent theory is that ME/CFS symptoms can be a consequence of a prolonged immunologic host response to infection. A limited number of immunological studies have been performed in pediatric patients. Studies in adults show immune system changes that are often inconsistent and tend to wax and wane over time (38). The most consistent immune responses are: immune activation, defective cell-mediated immunity, decreased natural killer cell (NK) cytotoxic activity that correlates with the severity of the illness (39, 40) and the occasional finding of low levels of autoantibodies including rheumatoid factor, anti-thyroid antibodies, anti-gliadin, anti-smooth muscle antibodies, and cold agglutinins in some patients. These immune responses are not unique to ME/CFS.

In pediatric patients, evidence of poor NK cell function is less robust than in adults (41), but few studies have been performed. Individual studies have reported cutaneous anergy (42), increased prevalence of autoantibodies (41), a beneficial response to intravenous immunoglobulin (IVIG) (42), increased rates of apoptosis in peripheral white blood cells (43), and abnormal T-cell inhibitory or proliferative responses to stimuli (44). Although one small study showed elevations or reductions in some cytokine populations (45), a larger investigation found no evidence of cytokine abnormalities (46). Very little research has been devoted as to whether allergies, food intolerance, or mast cell activation play a contributing role in the pathophysiology of ME/CFS symptoms.

A small randomized trial in adults demonstrated improvement in ME/CFS symptoms after rituximab-mediated B-cell depletion (47), but there have been no pediatric studies.

Circulatory Abnormalities

Lightheadedness is very common in pediatric ME/CFS, and prolonged upright posture can aggravate other symptoms, including fatigue, headache, nausea, and cognitive dysfunction (48–50). Controlled studies have shown a higher prevalence of postural tachycardia syndrome (POTS) and neurally mediated hypotension (NMH) in pediatric patients with ME/CFS (49, 51–55). More work is needed to define the causes of NMH and POTS. Both can follow infectious illnesses, and themselves can be secondary to autoimmune phenomena. Other circulatory abnormalities in pediatric ME/CFS include a delayed recovery of cerebral oxygenation after a brief period of standing compared to healthy controls (54), and the demonstration that cognitive problems are exacerbated by orthostatic stress (50, 56).

Low blood volume has also been found in some adult patients with ME/CFS (57–60). The initiation of treatments directed at OI can sometimes relieve ME/CFS symptoms in pediatric as well as adult patients (see Orthostatic Intolerance).

Neuroendocrine Abnormalities

The similarity in symptoms between ME/CFS and adrenal insufficiency has prompted investigation into abnormal hypothalamic-pituitary-adrenal axis function in both adults and adolescents. Several (albeit not all) pediatric ME/CFS studies have identified statistically lower cortisol levels and urine cortisol:creatinine values in ME/CFS patients compared to healthy controls (34, 44, 61–63). However, the cortisol values in those with ME/CFS are still within the normal range, raising questions regarding the clinical relevance of these findings. Treating ME/CFS with supplemental cortisol brings only modest clinical benefits, and in adult studies is associated with the development of potentially life-threatening adrenal insufficiency (64).

Brain Imaging Abnormalities

The high prevalence of cognitive dysfunction has focused attention on the hypothesis that abnormalities in the central nervous system are important in the pathophysiology of ME/CFS. Using several brain imaging techniques, some small studies in adults have shown a variety of differences between ME/CFS patients and controls including increased activation of microglia or astrocytes (65), volume loss in white and gray matter (66, 67), reductions in absolute cerebral blood flow (68), and increased ventricular lactate (69, 70). Both pediatric and adult studies have shown that patients activate a wider distribution of neural resources to perform a specific cognitive task (71–73). Improving brain blood flow improves cognitive performance in those with ME/CFS (74).

Metabolic Abnormalities

Profound exhaustion and post-exertional worsening of symptoms are hallmarks of ME/CFS. Adult studies have shown impaired oxygen consumption during exercise and activation of anaerobic metabolic pathways in the early stages of exercise (75, 76). When exercise testing is conducted on two consecutive days, there is a decline in exercise performance and an abnormal recovery response (decline in VO2 max) on the second day (77, 78). In single day pediatric exercise studies, those with CFS exercised less efficiently than controls who had recovered from mononucleosis, but significant differences in peak work capacity were not found (79).

These findings in adults, together with increased ventricular lactate have led to the hypothesis that ME/CFS symptoms might be due to a problem in mitochondrial bioenergetics and ATP production (80, 81). Thus far, the exact role of mitochondrial dysfunction in ME/CFS has not been clearly established.

Gene Studies

Studies in adult patients with ME/CFS have shown alterations in the expression of genes controlling immune modulation, oxidative stress and apoptosis. Several subtypes were reported, and the presence of some of these subtypes, correlated with symptom severity (82, 83). Moderate exercise increased the expression of sensory, adrenergic and immune genes in patients with ME/CFS, but not in controls (83). Epigenetic differences between those with ME/CFS and healthy controls have recently been described (84).

The prevailing theories related to pathophysiological mechanisms are not necessarily mutually exclusive. Circulatory dysfunction, for example, can be caused by infections and immune mechanisms, and in turn can have effects on inflammation, oxygen delivery to cells, and microglial activation. A more complete discussion of the potential pathophysiological mechanisms of ME/CFS symptoms is beyond the scope of this primer.

Adolescent Development

Puberty is defined as the time when a young person’s body, feelings, and relationships change from those of a child into those of an adult. Changes occurring in the young person’s body include a growth spurt, enlargement of the genitalia, development of androgen hair, and the onset of sexual functions including ejaculation or menses. Striking emotional and psychological changes occur. Puberty is a time of significant development of self-awareness, abstract thinking, increased sensitivity, and mood changes.

Myalgic encephalomyelitis/chronic fatigue syndrome preceding puberty can impact the development of both the physical, pubertal changes, and the young person’s emotional state and self-image. There can be delay or acceleration of pubertal changes or alteration of physiological processes including hypo-function or, less commonly, hyper-function of the neuroendocrine system. The development of ME/CFS following puberty can be associated with a delay in normal, psychological development fostered by social isolation. Cessation of menstruation can also occur and this can be of great concern to the patient.

Puberty, with its physiological changes, can also significantly exacerbate pre-existing ME/CFS symptoms. The risk of developing ME/CFS increases after puberty especially in females compared to males. The post-pubertal F:M sex ratio is 3–4:1.

Clinical Diagnosis

The diagnosis of ME/CFS is based on a careful clinical history, recognition of the pattern of symptoms, and the exclusion of other illnesses that might explain the symptom complex. Currently, there is no valid, reliable laboratory test that confirms the diagnosis. Moreover, although the physical examination is not entirely normal, there are no specific diagnostic clinical signs and frequently the patient does not look ill. The diagnosis is often overlooked or delayed and is sometimes made retrospectively when the child is older.

Several varied clinical criteria are currently used to diagnose ME/CFS in children and adolescents. None have been clinically validated in formal studies. The 1994 Fukuda case definition (1), see Appendix A, is often used, but was designed for research purposes in adults and can exclude some young patients with ME/CFS and include others, who are later found to have another illness (27). The 2003 Canadian clinical case definition (CCC) (24) is widely used in adults, because it emphasizes the core symptoms of the illness. A pediatric case definition based on the CCC was published in 2006 (27). The latter is somewhat complex for use in clinical practice. The following diagnostic criteria are offered by our experienced clinicians and are based on their collective experience and insight. The criteria provide useful diagnostic sensitivity within a heterogeneous pediatric ME/CFS patient population. A symptom severity scoring system is included to increase the specificity of the diagnostic criteria.

Myalgic encephalomyelitis/chronic fatigue syndrome is characterized by numerous symptoms in multiple body systems, but its diagnosis requires only the presence of a group of specific, core symptoms.

• The cardinal feature of ME/CFS is malaise and the exacerbation of symptoms after a variety of forms of effort (most commonly physical or cognitive activity or orthostatic stress). Post-exertional symptoms can persist for hours, days, or weeks and are not relieved by rest. This symptom is uncommon in other illnesses.

• Other core symptoms are impaired physical and/or cognitive function, fatigue, sleep disturbance, cognitive symptoms, and pain.

• Some or all symptoms are present every day (symptoms often fluctuate significantly in intensity during the day or from day-to-day).

• Symptoms are mostly moderate to severe.

• Symptoms have persisted or recurred for at least 6 months (a provisional diagnosis and appropriate management can be instituted before 6 months).

• Other fatiguing illnesses must be excluded by history, physical examination, and medical testing.

The diagnostic criteria are set out as a Clinical Diagnostic Worksheet which can be used in clinical practice. The worksheet can also be completed at follow-up visits to confirm the diagnosis, or track progress. Additional symptoms can be present in multiple organ systems. Those that are commoner in young patients include (a) orthostatic intolerance (OI): prolonged upright posture can induce symptoms such as lightheadedness, increased fatigue, cognitive worsening, headaches, and/or nausea. Postural tachycardia syndrome (POTS) or NMH is often present, (b) hypersensitivities to light, noise, touch, odors. and/or medications, (c) thermo-regulatory imbalance including low body temperature, intolerance to heat and cold, and cold hands and feet, (d) gastrointestinal symptoms such as abdominal pain, nausea, and anorexia, (e) worsening of fatigue in the days before and during the onset of menses can occur in young women, and (f) other co-morbid conditions can be present and are discussed in detail in Section “Comorbid Medical Conditions.”

Pediatric ME/CFS: Clinical Diagnostic Worksheet:

Patient Name _____________________________________________________ Patient ID ________________________ Date __________

Criteria for the diagnosis of ME/CFS in children and adolescents:

• Impaired function, post-exertional symptoms, fatigue, sleep disturbance, neurocognitive problems, and pain.

• Some or all symptoms are present every day (symptoms often fluctuate significantly in intensity during the day or from day-to-day).

• The symptoms are mostly moderate to severe.

• Symptoms have persisted or recurred for at least 6 months (a provisional diagnosis and appropriate management can be instituted before 6 months).

• Other fatiguing illnesses have been excluded by history, physical examination, and medical testing

Have the following symptoms persisted or recurred during the past 6 months? Present Symptom severity in the past month: absent (0), mild (1), moderate (2), and severe (3) 1. Impaired function: there is loss of mental and/or physical stamina and a substantial reduction in ability to take part in personal, educational, and/or social activities Yes [ ] No [ ] 2. Post-exertional symptoms: normal activity or mild/moderate exertion is followed by worsening of malaise, fatigue, and other symptoms. Recovery takes more than 24 h Yes [ ] No [ ] 3. Fatigue: the fatigue is not the result of ongoing exertion, is not relieved by rest, and is medically unexplained. Fatigue can worsen with prolonged upright posture Yes [ ] No [ ] 4. Sleep problems: sleep is unrefreshing with disturbed quantity or rhythm that can include daytime hypersomnia, nighttime insomnia, and day/night reversal Yes [ ] No [ ] 5. Cognitive problems: any of the following: difficulty in concentration or focusing, difficulty understanding information and/or expressing thoughts, difficulty finding words or numbers, impaired short-term memory, absent mindedness, slowness of thought. Cognitive problems can be provoked by, or worsen with prolonged upright posture and/or physical or mental activity. Some young patients may not recognize these problems, but they might be noticed by a parent or teacher. Yes [ ] No [ ] 6. Pain: can be widespread or localized, commonly seen are: chronic daily headaches, myalgias, abdominal pain, joint pains, sore throats, and painful lymph nodes. Pain can be worsened by prolonged upright posture. Rarely is pain absent Yes [ ] No [ ] Total symptom severity score:

Other symptoms present in many, but not all, pediatric patients with ME/CFS:

Orthostatic intolerance: prolonged upright posture can induce symptoms that can include lightheadedness, increased fatigue, cognitive worsening, headaches, and/or nausea. Postural tachycardia syndrome (POTS) or neurally mediated hypotension (NMH) are often present.

Hypersensitivities: to light, noise, touch, odors, and medications.

Thermo-regulatory imbalance: low body temperature, intolerance to heat and cold, and/or cold hands and feet.

Gastrointestinal symptoms: abdominal pain, nausea and/or anorexia.

To diagnose ME/CFS:

• Symptom criteria 1, 2, and 3 are present together with at least two of criteria 4, 5, and 6: Yes [ ] No [ ]

• Symptoms are present for 6 months and some or all symptoms are present daily: Yes [ ] No [ ]

• No other diagnosis found from the history, physical examination, and medical testing: Yes [ ] No [ ]

• Symptom severity score: 0–4 ME/CFS unlikely; 5–12 mild/moderate ME/CFS; 13–18 moderate/severe ME/CFS

_______ Patient meets criteria for ME/CFS.

_______ Full criteria not met. Patient should be monitored and symptoms should be managed.

The pattern of ME/CFS symptoms is distinctive and the diagnosis can easily be made in most cases, but there can be some diagnostic challenges. Younger children, especially those under 10 years of age, might not report symptoms accurately. They might not remember having experienced full health and might assume tiredness is normal. The first sign of the illness might be the child’s marked limitation of physical and/or mental activity, noticed by a parent or a teacher. Young patients with ME/CFS might not necessarily recognize that they have symptoms such as cognitive problems or malaise until their health has improved. Some patients might not consider themselves as having post-exertional symptoms because they have learned to pace their activities. Symptoms of ME/CFS wax and wane over time. Some patients might report that one particular symptom was present previously, but has improved by the clinic visit. Symptoms that persist are more easily recalled.

Patient History

It is critical to allocate enough time for a careful, comprehensive history to be taken from the patient and the parents. The history is not only vital to diagnosis, but also taking the history in a thorough and empathetic manner engenders the trust of the patient and family, shows that the clinician takes the patient’s illness seriously, and is an important prelude to management. Teenagers usually need an opportunity for discussion without a parent present. The initial evaluation might require more than one office visit because the history is sometimes lengthy and the patient might lack sufficient stamina. Some patients might need to lie down during office visits. For other seriously ill patients, an office visit might be impossible, and they require home visits.

The clinician might find it helpful to first ask the patient to list current symptoms in order of severity, to get a sense of the areas that will need to be explored. It is important to ask the patient and the parents what are their major concerns. This can be an opportunity to correct misinterpretations, e.g., “I think I might have cancer.” Then the history requires attention to the full range of defining symptoms of ME/CFS, recording both frequency and severity.

Information about diet, sleep patterns, depressed mood, anxiety, school performance, relationships with family and friends, drug use, and family and developmental history needs to be obtained. The family history might reveal other family members with ME/CFS symptoms and there is also a higher prevalence of disorders such as fibromyalgia, joint hypermobility, temporomandibular joint dysfunction, anxiety, syncope, and irritable bowel disease.

To assess function, ask about what happens when the young person tries to do activities that she/he previously tolerated, and about activities the individual must now limit or avoid. This can indicate very significant life changes and losses experienced by the patient.

Frequent monitoring of the patient once every 1–3 months, depending on the level of illness severity is important. Young patients who are ill appreciate continuing care. Functional improvement can be judged by determining how much activity generates post-exertional worsening of symptoms. Progress should be measured over time, rather than at a single clinic visit. In patients who are improving, fatigue is often the last symptom to resolve, since young patients often prefer to increase their activities and tolerate the resulting fatigue. The practitioner must be alert for the emergence of new symptoms. They might not be related to ME/CFS, but due to another illness.

Physical Examination

A thorough physical examination, including a neurological exam is important to exclude other causes of fatigue. Physical signs in ME/CFS are subtle and none are diagnostic. Many patients do not look ill, but noticeable facial pallor is sometimes apparent and often precedes the onset of extreme tiredness in the patient. The pallor can be associated with sub-orbital dark shadows. The pharynx can show non-exudative pharyngitis and cervical and axillary lymph nodes might be palpable and tender. Muscle tenderness is a feature of co-morbid juvenile fibromyalgia. Fibromyalgia is less common in children with ME/CFS than in adults. The hands and feet can be unusually cold and dependent rubor of the legs is often present when standing or sitting. The physical exam should include an assessment for common co-morbid conditions such as OI [heart rate (HR) and blood pressure (BP) sitting and standing], joint hypermobility, and postural dysfunctions (see Comorbid Medical Conditions).

At illness onset, pyrexia can be present and this can persist for some weeks. If fever is present several months into the illness, other causes of fever should be sought. In established cases, slightly subnormal temperature, 96.8–98.0°F (36.0–36.7°C), is common. Some children with ME/CFS have higher resting HRs than expected and occasional patients have resting hypotension. More commonly, HR and BP abnormalities emerge in response to upright posture. The diagnosis and management of orthostatic problems is discussed in the section “Comorbid Medical Conditions.”

Laboratory Testing

Basic laboratory studies (Table 1) should be performed to identify other causes of fatigue and any organ system dysfunction. Most routine laboratory tests are within the normal range, and do not correlate with overall function, even in the presence of substantial debilitation. Measures of iron stores, vitamin B12 level, and screening for celiac disease are recommended because of their subtle or absent manifestations on physical examination.

TABLE 1

Table 1. Investigation of ME/CFS: routine laboratory testing.

Additional testing (Table 2) is based on history, examination and laboratory findings. For example, a search for infections such as Lyme disease depends on the symptoms and on whether the young patient resides in, or has traveled to, endemic areas. Serology for some infectious illnesses can be weakly positive. Although standard serology for EBV and CMV can help with categorizing whether the illness might have been initiated by these organisms, these test results usually do not change management. MRIs of the brain and spine are not routinely indicated, but clearly are important if there are abnormal neurological signs.

TABLE 2

Table 2. Investigation of ME/CFS: tests to be considered when indicated.

Differential Diagnosis, Exclusionary Medical Conditions

Myalgic encephalomyelitis/chronic fatigue syndrome should not be diagnosed if the patient has an identifiable medical or primary psychiatric condition that could plausibly account for the presenting symptoms. If ME/CFS symptoms persist after adequate treatment of other confounding illnesses, a diagnosis of ME/CFS can be considered.

Fatigue is an early symptom in many medical conditions and can be present before the appearance of the diagnostic features of the underlying illness. Careful follow-up over time is needed in order to identify illnesses that might mimic ME/CFS in their early stages. The presence of post-exertional malaise and exacerbation of symptoms after increased cognitive or physical effort increases the likelihood that ME/CFS is the correct diagnosis. The more common conditions in the differential diagnosis are shown in Table 3. For a more comprehensive list of the less common disorders in the differential diagnosis, see Appendix B. If there is diagnostic uncertainty and referral is necessary, it should be preferably to a specialist familiar with ME/CFS.

TABLE 3

Table 3. Common conditions in the differential diagnosis of ME/CFS.

Co-Existing Medical Conditions

A number of non-exclusionary conditions can co-exist with ME/CFS (Table 4). If present, co-existing conditions should be evaluated independently and treated appropriately. Some co-existing medical conditions that are seen significantly often in young patients with ME/CFS and significantly reduce the patient’s functional capacity are discussed in more detail in the section “Comorbid Medical Conditions.”

TABLE 4

Table 4. Non-exclusionary overlapping conditions.

Cognitive Impairment

Cognitive deficits (sometimes called “brain fog”) are some of the most functionally disabling symptoms of ME/CFS. They are of great concern to children and adolescents because they impact their ability to learn and attend school (see The School System). Cognitive impairments are similar in both adult and young patients with ME/CFS. Slow mental processing speed, impaired working memory, poor learning of new information, difficulty with word retrieval, increased distractibility, decreased concentration and attention span, and inability to multitask may be found (85–87).

The severity of cognitive problems fluctuates together with disease activity both during the day and from day-to-day. Cognitive deficits can be related to abnormal neurological pathophysiology and reduced cerebral blood flow (see Etiology and Pathophysiology).

Any form of mental activity can be followed by diminished cognitive functioning as well as other post-exertional symptoms in a manner similar to the exacerbation following physical exertion. Cognitive symptoms can also be aggravated by a multitude of other factors including: pain (especially headaches), poor sleep, prolonged upright posture, a noisy classroom, eye fatigue from staring at a computer screen for too long, carrying heavy books around school, and social interactions. Young patients might be motivated to keep up with their peers and push themselves mentally, physically, and socially beyond their comfort zone, and suffer cognitive consequences. Cognitive problems can also be exacerbated by the stress of living with a chronic (often undiagnosed) illness (see Psychological Reactions Secondary to ME/CFS: Distinction from Depression and Anxiety Disorders).

Psychological Reactions Secondary to ME/CFS: Distinction from Depression and Anxiety Disorders

Studies focusing on psychological problems in pediatric ME/CFS patients are limited. In this section, available studies have been supplemented by the insights of our experienced clinicians. It is important to distinguish: (a) normal emotional reactions to ME/CFS from (b) clinically significant psychiatric symptoms such as depression or anxiety secondary to ME/CFS and from (c) a primary psychiatric illness such as Major Depressive Disorder (MDD) or an anxiety disorder without co-existing ME/CFS.

Emotional Responses to a Chronic Illness

Emotional responses to the difficulties of ME/CFS are common. These responses are similar to the responses of young patients with other chronic illnesses. Grief and anger can arise over illness-related losses, from negative responses to the illness from family members, friends and school staff, and from the pervasive stigmatization of this particular illness. Apprehension commonly follows the onset of an illness, which can be undiagnosed and about which there is generally ignorance. There can be frustration with the inability to do things that were easily done beforehand. Outbursts of weeping can stem from excessive tiredness and/or feeling overwhelmed. Emotional distress can also occur because of disbelief by others regarding the reality of the illness, or by the prescription of inappropriate remedies by health-care providers.

Some young patients despair of medical care and plead to decline hospital admission, due to previously experiencing the hostile and disbelieving attitudes of some health care providers and/or the exacerbation of their illness by increased hospital-related activity and the noisy environment. These emotional responses to the illness do not ordinarily rise to the level of a psychiatric disorder, but occasionally, psychiatric symptoms are more severe, and a clinically diagnosable, psychiatric disorder can co-exist with ME/CFS.

Identifying Clinically Significant Depression and Anxiety Co-Existing with ME/CFS

The most common secondary psychiatric symptoms are depression and anxiety. These symptoms can be present together in the young patient. Clinically significant depression and anxiety can be uncovered by clinical evaluation and the use of standardized questionnaires. Occasionally depression or anxiety predate the onset of the illness, but distinctive, abnormal, pre-illness personality characteristics have not been identified in young ME/CFS patients.

Identifying psychological disorders in younger children can be difficult. They might not manifest depressed mood, as they might not be developmentally able to sense, and verbalize their moods. Rather, they might show behavioral symptoms such as irritability, low frustration tolerance, tantrums, somatic complaints, and/or withdrawal.

Many young patients with ME/CFS are miserable and discouraged (fed up) by being ill, but are not necessarily depressed. There is a higher incidence of clinical depression when the young patient has encountered disbelief in the reality of her/his illness.

In otherwise healthy young people, approximately 2% of children and 4–8% of adolescents have a diagnosable, major depressive disorder (MDD). Less severe episodes of depression can be seen in another 5–10% of children and adolescents. In adolescents, twice as many females as males meet criteria for depression. In one large study of ~400 patients with ME/CFS, 25% had clinical depression using the Beck scale, while the baseline level of depression in the adolescent population was 20% (88).

Raised apprehension levels are a common response to illness. Anxiety secondary to ME/CFS can arise with the illness onset and persist because the illness affects all aspects of the young person’s life. Clinical observation suggests that the incidence of panic attacks might be higher in young patients with ME/CFS than in a normal population of teenagers. Clinical observation has also shown a higher degree of anxiety in patients with co-morbid OI and joint hypermobility. It is postulated that the anxiety might be associated with raised levels of catecholamines and reduced brain blood flow in these conditions.

Differentiating ME/CFS from Primary Depressive and Anxiety Disorders without Co-Existing ME/CFS

This can be challenging. Symptoms common to both ME/CFS and psychiatric illness include fatigue, change in activity levels, reluctance to engage in social activities, difficulty sleeping, poor memory and concentration, appetite/weight changes and absence from school.

Some features distinguishing ME/CFS from primary psychiatric illnesses are shown in Table 5. In patients with ME/CFS, long-lasting post-exertional exacerbation of fatigue and other symptoms can follow mild exertion or even normal activity, whereas patients with major depression or anxiety often feel better after increased activity, exercise, or mental effort. OI, hypersensitivities to light, noise and medications and/or low body temperature, and intolerance to heat and cold are typical of ME/CFS, but not typical of psychiatric illnesses. Young women with ME/CFS often experience greater premenstrual mood lability.

TABLE 5

Table 5. Symptom comparison between depression/anxiety disorders and ME/CFS in children and adolescents.

Most teenagers with ME/CFS are highly motivated to recover and return to their previous lives. They generally have a strong desire to be more active, but cannot tolerate the necessary exertion. In contrast, patients with major depression do not have the desire to be more active but could be.

Adolescents with MDD show depressed mood, a sense of worthlessness or guilt, low self-esteem, loss of interest in socializing and in previously enjoyable circumstances (anhedonia), and a lack of interest in the future. Although these are typical symptoms of MDD, some young people with ME/CFS (but without co-morbid depressive illness) might also feel guilty because their illness has disrupted their family, and a parent might have had to give up work to care for them. They might also be reluctant to make plans to socialize, because they know from past experience that they might find themselves at the time of the event to be too ill to participate, have to cancel, and let down their friends. Anhedonia has not been reported in ME/CFS unless MDD was also present. Young people with ME/CFS often take much pleasure in previous activities, even if the activities exceed their energy reserves and cause subsequent symptom exacerbation.

In young people with MDD suicidal thoughts and suicide attempts can occur, more so in adolescents than in younger children. If suicidal thoughts are present a suicide evaluation should be done and referral to a child psychiatrist is often helpful. Suicidal thoughts are only seen in ME/CFS when MDD is also present.

Myalgic encephalomyelitis/chronic fatigue syndrome has a significant impact on a young patient’s parents and siblings. This impact of the illness on family members can have a secondary effect on the patient (see Impact of ME/CFS on the Family). Psychiatric symptoms persisting during the recovery phase of ME/CFS can make it difficult to determine whether the patient’s limitations are due to ME/CFS, or due to associated psychiatric illness.

Psychiatric Illnesses That May be Misdiagnosed in Young Patients with ME/CFS

Lack of familiarity with the clinical diagnostic features of ME/CFS and skepticism about its existence has often resulted in a misdiagnosis with one of the following conditions:

• Factitious disorder by proxy (Munchausen syndrome by proxy, fabricated or induced illness) (FDP/MSBP).

• School refusal (school phobia).

• Pervasive refusal syndrome (PRS).

• Somatoform disorder.

Factitious Disorder by Proxy (Munchausen’s Syndrome by Proxy, Fabricated or Induced Illness)

In cases of FDP/MSBP, the perpetrator, usually the mother, induces illness in the victim who is often her very young child. [The average age of patients with FDP/MSBP is 4 years old and 50% of patients are <2 years old (89)] Such cases are extremely rare. Most pediatricians only see 1–2 cases in their whole professional careers. FDP/MSBP can be difficult to diagnose but it is a diagnosis that needs to be made as it is a form of child abuse and can result in death of the child.

FDP/MSBP is sometimes falsely diagnosed in young persons with ME/CFS. A report in the press showed that of 143 young persons diagnosed with ME/CFS, but alleged to be victims of FDP/MSBP, (who were assisted by a charity), none were found to be cases of FDP/MSBP (90).

Thus, the treating physician might need to firmly establish the diagnosis of ME/CFS and show how ME/CFS differs from MSBP/FDP. Some distinguishing features are shown in Table 6 (89).

TABLE 6

Table 6. Comparison between ME/CFS and factitious disorder/Munchausen’s syndrome by proxy/fabricated or induced illness.

During history taking, the parents sometimes refuse permission for the clinician to speak to the young person without a parent being present. The young patient and parents might have had previous unhappy or unhelpful experiences with other professionals. Similarly, a young person with ME/CFS may turn to her/his parents when being questioned. This is a natural response in an ill child who has cognitive dysfunction. These behaviors by themselves do not support a diagnosis of FDP/MSBP. Suspicion of FDP/MSBP can result in referral to child protection services (CPS). Young persons with ME/CFS placed in CPS do not fare well. When separated from their parents and sent to live with foster parents or admitted to psychiatric institutions, their ME/CFS symptoms have often worsened.

School Refusal (School Phobia)

School refusal has an estimated prevalence of 1–5% and is more common than ME/CFS. It occurs predominately in children less than 12 years of age (91). Children with school refusal fail to attend school because attendance causes emotional distress and anxiety. At the prospect of going to school, the young person exhibits behavioral symptoms, including temper tantrums, crying, angry outbursts, threats to hurt her/himself, and/or a variety of somatic complaints, such as nausea, dizziness, pains, diarrhea, or trembling.

In contrast, young people with ME/CFS usually want to attend school but are prevented from doing so by physical limitations. Other distinguishing features of ME/CFS are post-exertional malaise with exacerbation of other symptoms and OI. Symptoms of school refusal improve once the child is allowed to stay at home and resolve during weekends and school vacations. By contrast, in the young patient with ME/CFS, symptoms persist during weekends and school vacations, but can improve slightly due to decreased activity. During convalescence from severe ME/CFS, the young patient might find it difficult to return to school, having been absent for a variable period of time, having lost contact with many of her/his friends and because of concern those symptoms might worsen. Such hesitancy should not be misdiagnosed as “school refusal.” It should be managed with understanding by the parents, the physician and school personnel.

Pervasive Refusal Syndrome

This condition describes a young patient who has despaired of any help from medical care and has lost all hope, as if wanting to die and, therefore, rejects medical care. It is extremely rare. Individual case reports are still being published. The young person refuses food and fluids, and might pull out IV cannulas and nasogastric tubes. It has occurred in young patients with neoplastic disease sickened by too many interventions and it has been described subsequent to sexual abuse. PRS is sometimes wrongly diagnosed in very severe cases of ME/CFS, when the young patient is physically incapable of sitting up or even swallowing. In contrast to PRS, the young person with severe ME/CFS usually wants to get better and co-operates with medical help such as tube feeding. Management of the two conditions consists of the avoidance of stress, medical help with nutrition, assistance with living confined to bed, and an empathetic form of management to which the young person gives consent. A mistaken diagnosis of PRS in a patient with very severe ME/CFS can result in transfer of care to a psychiatrist whose management might include detrimental regimes, such as forced exercise and separation from family.

Somatoform Disorders

Somatoform disorders are psychiatric disorders that cause bodily symptoms that cannot be traced back to a physical cause. Prior to diagnosing a somatoform disorder, it is necessary to rule out medical conditions with overlapping symptoms, (such as ME/CFS). Symptoms such as pain occur in both ME/CFS and somatoform disorders, but post-exertional exacerbation of symptoms and orthostatic hypotension are found in ME/CFS, but not in somatoform disorders. Serious deterioration can occur in young patients with ME/CFS who are misdiagnosed as having somatoform disorder and given psychiatric treatment that includes rigidly enforced exercise.

Other Psychiatric Conditions

Some additional psychiatric conditions might need to be differentiated from ME/CFS. ME/CFS symptoms such as poor concentration and loss of short-term memory, noticed in the patient’s classroom, can sometimes lead to an erroneous diagnosis of attention deficit disorder without hyperactivity. If the young patient is unable to eat properly due to nausea and gastrointestinal symptoms, ME/CFS must be distinguished from an eating disorder. ME/CFS may also need to be distinguished from substance abuse.

Management/Treatment

Myalgic encephalomyelitis/chronic fatigue syndrome impacts a young person’s entire life. Coping with debilitating medical symptoms, changed relationships within the family, absence from school, and loss of socializing with peers can all result from the illness. These losses can trigger confusion and crisis. Often the patient might not have been diagnosed and might not have received appropriate help from previous health practitioners, since the young person may not look ill and may have a normal physical examination as well as normal routine laboratory tests.

Given the paucity of peer-reviewed literature on the management of ME/CFS in this age group, this chapter is a compendium of the experience of several clinicians, each of whom has treated children and adolescents with ME/CFS for over 20 years. The chapter provides recommendations primarily for ambulatory patients who are able to attend office visits even if using a wheelchair. Special consideration is given in the section “Severely Affected and Very Severely Affected Young Patients” for young people who are housebound or bedridden.

Approach to Management

Currently, there is no treatment protocol or intervention which will cure ME/CFS. The role of the physician is, therefore, first, to do no harm, second, to try to improve daily function, expand activity, and ameliorate specific symptoms, and third to support the patient and the family. School personnel often need to be educated about ME/CFS and made aware that ME/CFS is a physical/organic illness, not a psychological disorder. We caution against reliance on internet-based information because much of it is anecdotal, uncorroborated, and may be designed to sell unproven products or services.

Due to variation in symptoms and co-morbid conditions, no single approach works for all patients. Management requires careful attention by the patient, the family and the practitioner to factors that provoke symptoms and a willingness to try several approaches before improvement is achieved.

Most young people can achieve functional improvement. But even in the absence of improvement, the practitioner can help affected young people simply by continuing to evaluate them, providing encouragement, and discussing any new treatments that emerge. A survey of adolescents with ME/CFS found that doctors were considered to be most helpful when they validated the illness, acknowledged its effects, provided ongoing support, and monitored progress (23).

Management is based on: early diagnosis, educating the patient, the family and school personnel about the illness, determining the dominant causes of post-exertional symptoms, treating symptoms with non-pharmacological and pharmacological interventions, providing guidance on activity, diet, maintaining social contacts and educational opportunities, and monitoring progress.

Establishing the diagnosis of ME/CFS and acknowledging that the patient has a recognized illness can produce much relief. In explaining the illness, it is important to reassure the patient that the illness is real despite often normal blood-test findings and the potential for functional improvement should be emphasized. A firm diagnosis can relieve fears of other illnesses such as malignant disease, relieve fears of imminent mortality, validate the presence of symptoms, facilitate the development of a therapeutic partnership with the patient and family, enable the establishment of a management plan, and help organizations such as the young person’s school to provide appropriate education.

Misinformation or absence of information about ME/CFS is common. Educating the patient, the parents, the wider family and school personnel about the illness is important, e.g. providing handouts (Appendices C–E). Sometimes, school personnel and child protection services might need to be persuaded that their misapprehension that the young patient has factitious disorder by proxy (Munchausen’s syndrome by proxy) or pervasive refusal syndrome is wrong and that these mis-diagnoses can seriously harm the young patient.

Clinical management can be improved by the following suggestions:

• Obtain a written list of the patient’s most troublesome symptoms.

• Agree with the patient and family to focus on a limited number of symptoms.

• Recommend that a family member write down or record medical advice.

In reviewing the patient’s most troublesome symptoms, special attention should be paid to those factors which exacerbate symptoms, e.g., upright posture. Then a decision can be made about which symptoms should be addressed first.

Management focuses on non-pharmacological and pharmacological interventions. Medication can be most helpful in the relief of some individual symptoms. Since many pediatric patients with ME/CFS respond to much lower than standard doses of medication (1/2 or 1/4 of the usual dose), the dosage should start low and be increased slowly. In general any change in medication should be made one medication at a time, so that any favorable or unfavorable effects can be attributed to one medication.

Guidance needs to be given on an activity plan that helps the young person to function. Adolescent patients are encouraged to propose a personal, optimal balance of social, physical, and academic activities (and include something pleasurable outside of the home). Very little else is under their control. At each visit, the activity plan can be adjusted, in relation to symptom severity or improvement. Advice on schooling depends on the severity of the illness (see “The School System”).

Successful symptom management requires a regular review of symptoms and symptom severity. Visits every 1–3 months or so, depending on level of severity can be helpful. In patients who are improving, fatigue can be one of the last symptoms to subside. Young people often expand their activity level as they start to improve, preferring to tolerate some symptoms rather than remain on restricted activities so as to experience less fatigue. Thus, measuring improvement by asking solely about fatigue can underestimate progress. Functional improvement can be judged by determining how much activity it takes to provoke post-exertional worsening of symptoms. It can be helpful to use questionnaires/forms which measure activity, cognitive function, and mood to quantify the severity of the illness, and document progress. Brief questionnaires used in some pediatric ME/CFS studies include the Functional Disability Inventory (92), PedsQL (93), and Wood Mental Fatigue Inventory (94). Progress should be measured over months or years, rather than at a single clinic visit.

The young patient should be encouraged to report any changes or additional symptoms as symptoms of ME/CFS wax and wane. The physician might need to determine whether new or changing symptoms represent an altered ME/CFS symptomology, the onset of common co-morbid conditions, or whether new symptoms are suggestive of an alternative diagnosis. Changes to medications and/or their dosages might be required. Reassurance that medical advice from the treating physician will continue to be available can help the patient and family cope with the disease. Telephone or Skype contact can serve the same purpose for those who are more severely affected and unable to travel, or those who are geographically remote.

The Acute Stage of ME/CFS

In the early, acute, febrile stage of ME/CFS, the diagnosis can be uncertain and other causes of fever need to be considered. Adequate rest and activity management are the mainstays of treatment. Premature resumption of activity or attempts to return to school can result in a relapse or increased severity of symptoms.

Sleep Problems

Patients with ME/CFS experience unrefreshing sleep. Disturbed sleep patterns include difficulty falling or staying asleep, frequent awakenings, vivid dreams, day/night reversal, and hypersomnia. For many young patients, naps are important to get through the day, but marked daytime sleepiness can result from conditions such as sleep apnea. Sleepiness can be measured using the Epworth sleepiness scale (95).

Hypersomnia (sleeping for up to 20 h a day) can occur in the early stages of the illness and can persist for weeks and occasionally months. Young people who sleep for more than 12 h at a time can develop dehydration. During wakeful periods, the young patient’s parents/caregivers need to ensure adequate hydration and nourishment. When oral hydration and nourishment are inadequate, tube feeding is necessary. If hypersomnia persists for months, the young person should be evaluated by a sleep specialist, preferably one who is familiar with ME/CFS.

Conventional sleep hygiene measures for insomnia in otherwise healthy people can be ineffective in young people with ME/CFS, but the following measures can be helpful:

• Balance daytime activity with rest (pacing of activity), to avoid post-exertional symptom exacerbation, which can interfere with sleep (see Fatigue, Post-Exertional Symptoms, Exercise Intolerance).

• Eliminate caffeine-containing beverages in the late afternoon and evening.

• Avoid television, computers, and electronic devices before and after bedtime, (light from electronic devices can aggravate insomnia and fatigue).

• A carbohydrate snack at bedtime might be helpful (96).

If insomnia or sleep reversal is profound, sleep medications, can be started at a low-dose. The risk of adverse effects needs to be balanced with the gains from a better night’s sleep and sleeping the same hours as other family members. The medications chosen should be safe for long-term use and should be taken early enough to be effective at bed time. Non-pharmacological remedies can include herbal teas, such as Chamomile. Commonly used medications are listed in Table 7. For more severe problems, Zolpidem and trazodone can be used with caution. Controlling pain (see Pain) will often help sleep.

TABLE 7

Table 7. Medications for sleep.

Pain

Pain in ME/CFS can be widespread or localized. Sometimes pain is so severe that the patient is unable to tolerate even a gentle touch. Common types of pain include: headache, abdominal pain, myalgia, joint pain, sore throat, lymph nodes, eye pain and occasionally pelvic pain or dysuria (97, 98). It is important to treat localized pain such as headache, because pain can amplify other symptoms.

Chronic, daily headaches, which can fluctuate in severity from week-to-week, are common. If they are episodic, a diagnosis of migraine should be considered. Possible triggers include inadequate sleep, stress, skipped meals, specific foods and supplements (including, but not limited to chocolates, nuts, and aspartame). Initial intervention focuses on avoiding the common triggers. Migraine-prevention drugs are worth a trial for both episodic and non-episodic chronic, daily headaches. Commonly used medications are shown in Table 8. Beta blockers can help headaches that are associated with OI (see Orthostatic Intolerance).

TABLE 8

Table 8. Medications for headaches.

Myalgia and pain from co-morbid fibromyalgia can be found in from 10 to 30% of pediatric patients with ME/CFS and is less common than in adults (98). Abdominal pain and Nausea are common (98, 99). Abdominal hyperalgesia may also occur. Gastrointestinal motility disorders can be present, especially in patients with OI.

Helpful, non-pharmacological remediation for pain includes: pacing of activity to avoid flare-ups (see Fatigue, Post-Exertional Symptoms, Exercise Intolerance), hot or cold packs for treatment of tender points, warm baths, muscle liniments, physical therapy, transcutaneous electrical nerve stimulation, acupuncture, massage, yoga or Tai Chi, biofeedback, and mindfulness-based stress reduction techniques. These interventions might not be effective in some patients and might be poorly tolerated in others.

For persistent pain, medications might be needed. Over-the-counter medications such as aspirin, acetaminophen, paracetamol and NSAIDS are rarely effective for ME/CFS pain, but NSAIDS can ameliorate dysmenorrhea. Topical treatment for pain includes lidocaine patches. Some commonly used prescription pain medications and their dosages for adolescents are listed in Table 9. We recommend beginning at a low-dose and increasing very cautiously. If pain is generalized, the higher dosages might be needed. Multiple trials of medication might be necessary to achieve adequate relief.

TABLE 9

Table 9. Medications for generalized pain.

Young people with severe pain sometimes need strong analgesics. Opiates are occasionally necessary. Their use requires full documentation. For young people with complex pain syndromes, referral to a pain clinic (preferably one that is familiar with ME/CFS) might be helpful. We have received anecdotal information from some young patients that their chronic pain was improved by the use of cannabis or synthetic cannabinoids. There have been no clinical trials of this medication.

Fatigue, Post-Exertional Symptoms, Exercise Intolerance

Myalgic encephalomyelitis/chronic fatigue syndrome is characterized by the body’s inability to produce adequate energy for the normal range of human activity. Patients with ME/CFS experience persisting, overwhelming, physical and cognitive exhaustion that is not relieved by rest or sleep. There is a loss of physical and mental stamina. Sometimes there is a feeling of being tired and wired (overstimulated). Fatigue in ME/CFS is pathological. It is qualitatively and quantitatively different from the normal fatigue experienced by healthy people following exertion which is relieved by a good night’s sleep.

Following even minor physical, cognitive or orthostatic activity, the fatigue and other ME/CFS symptoms are worsened. This worsening of symptoms can occur any time from immediately following activity, to up to 48 hours following activity and it can last for days or weeks or months. This phenomenon is the cardinal feature of ME/CFS.

Although the overall mechanism for triggering post-exertional symptoms is currently unknown, fatigue, post-exertional symptoms and exercise intolerance in ME/CFS might be related to defective energy metabolism. Aerobic metabolism has been shown to be impaired in adult patients with ME/CFS (100). This impairment leads to an increased reliance on anaerobic metabolism which is much less efficient at producing energy.

Activity and Exercise

Activities of daily living, education and social contact related activities can comprise a tolerable amount of energy expenditure for some patients, but these activities can comprise an excessive amount of activity for others. Adding an exercise program to the schedule of a young person who can barely manage to cope with limited educational activities can be counterproductive. Exercise has been promoted as therapeutic in patients with ME/CFS, but many patients drop out of exercise studies because exercise clearly made them worse (101). Some individuals with ME/CFS mistakenly over-exercise in an attempt to reduce fatigue and then incur post-exertional relapse. No studies have shown that exercise can produce a cure for ME/CFS.

Occasionally an excess of caution in young patients and/or their care givers can result in too much rest. Prolonged periods of complete bed rest should be avoided except in the most severely affected patients. Studies in adults have shown that 2 weeks of complete bed rest can be followed by a substantial reduction in plasma volume, and by OI (102). Striking the right balance between rest and activity while avoiding post-exertional symptoms requires trial and error.

However, for some patients with less severe ME/CFS, or during a remission, a suitable exercise program can improve function and provide some enjoyment. Any exercise program should not take priority over activities of daily living, education and socialization. Special care also needs to be taken to ensure that exercise is not advanced too rapidly or too soon, as by definition, excessive exercise can exacerbate ME/CFS symptoms.

Pacing of Activities and the Energy Envelope

Young people with ME/CFS often do better when they (and their parents) learn to adapt their lifestyles to live within their capabilities, and pace or spread out their activities so that they can avoid a boom and bust cycle of over-activity on a given day followed by a “crash” the following day. Remaining as active as possible while avoiding post-exertional flare-ups delineates an optimal zone of activity termed the “energy envelope.” It has been shown in adults that fatigue severity declines when patients stay within their energy envelope (103).

Activities can be planned by the young patient over a weekly period. She/he should be encouraged to balance intellectual, social and physical activities, and to make a commitment to undertake segments of each component regularly. This allows the patient and family members to regain some control over their lives. It must be remembered that activity levels fluctuate from day-to-day and patients sometimes experience set-backs in their available energy reserves. Family members need to recognize that set-backs can occur and any activity plan needs to be flexible.

Recommendations for Improving Activity Levels

Guidelines for exercise in healthy, but sedentary young people are inappropriate for patients with ME/CFS, because strict adherence to these guidelines can cause post-exertional relapse. For some young patients, it might be necessary to first treat their OI and improve their ability to remain upright before any exercise can be adequately tolerated. Consultation with a physical therapist or rehabilitation specialist knowledgeable about ME/CFS is often helpful.

For the Most Impaired Young People

Advice for those who are homebound or confined to bed can be found in Section “Severely Affected and Very Severely Affected Young Patients.”

For the Moderately Impaired

Exercise while lying down should be advised when exercise while sitting or standing is poorly tolerated. Manual forms of physical therapy to improve mobility can be a bridge to tolerating exercise without prolonged exacerbations, especially for those with impaired range of motion on examination (104). Exercise should begin with as little as 1–2 min of gentle stretching followed by rest. When recovery has occurred another 1–2 min can be attempted. When stretching exercises do not trigger post-exertional symptoms, intervals of recumbent exercise can be added such as leg lifts while supine, or the use of a recumbent stationary bicycle. The individual can be encouraged to increase the duration of activity very gradually, provided that the prior period of activity has not aggravated symptoms, until a reasonable exercise volume has been achieved. Rest between activities is needed, and young people are advised to avoid the “push-crash” cycle of excessive activity on a good day followed by prolonged post-exertional collapse. Exercise in a swimming pool is sometimes better tolerated, provided the water is not too warm, as there is an external counter-pressure from the water that can improve circulatory function.

Mildly Impaired Patients

Leisurely walking with an initial duration of 5–15 min followed by a rest is suggested. The duration or pace of the walking can be increased gradually provided post-exertional symptoms do not occur.

Higher Functioning Patients

An exercise program might involve joining some organized sporting activities at school, but with modified participation. The effect of exercise on ME/CFS should be discussed with the student, her/his parents and the school personnel. Everyone should be reminded that when the patient feels that she/he has done enough, she/he must stop and rest and never force her/himself to achieve more. Fluctuations in illness severity are also common and patients might find that they need to reduce their activities for a period of time.

Medications for Fatigue

Trials of medications for fatigue have not been conducted in children and adolescents with ME/CFS. A limited number of controlled trials have been conducted in adults. Dexamphetamine, 5–10 mg twice daily for 4 weeks was tested in 20 adults with ME/CFS. The dexamphetamine group had a significant improvement in Fatigue Severity Scale scores at the end of the trial (105). Methylphenidate 10 mg twice daily for 4 weeks was tested in 60 adults with ME/CFS. Compared to placebo, it reduced the severity of fatigue and concentration problems (106). Lisdexamphetamine was helpful for executive function, fatigue and pain in adults with CFS in a small randomized trial (107). Modafinil has been shown to be effective for fatigue in adults with multiple sclerosis. When tested in 14 adults with ME/CFS the treatment effect was uncertain, but these data need to be viewed with caution due to the small number of patients tested (108).

Low vitamin B12 levels can be associated with fatigue, cognitive problems, balance difficulties, and hypotension. This has led some clinicians to administer vitamin B12 injections to adults with ME/CFS in an attempt to improve symptoms and function. The typical dose used is 1,000 μg IM weekly for 4 weeks to assess the response and estimate the duration of effect (typically 3–7 days). A patient survey of treatment rated results as good by some patients (109). There have however been no randomized placebo controlled trials of vitamin B12 for ME/CFS in young people.

Many patients self-medicate with caffeine in coffee and popular energy drinks. While this can be useful, patients should be cautioned against consuming excessive amounts of caffeine as this can cause tachycardia and agitation.

Medications for fatigue might need to be reserved for potentially exhausting occasions such as school exams. If effective, the young person should try to avoid exceeding their individual energy envelope.

Cognitive Impairment

Cognitive difficulties are an integral part of ME/CFS and they have a significant impact on schooling. Advice on educational accommodations is given in Section “The School System.” The young patient needs to recognize issues that aggravate cognitive difficulties and when possible, avoid them. Aggravating factors include mental and physical activity; distraction by noise or bright lights; and prolonged standing.

Cognitive problems can be improved by:

• Pacing of activities: the young person should be mentally active for short periods of time, followed by adequate periods of rest; she/he should learn to recognize when she/he is tired.

• Performing mental work lying down can sometimes be better than sitting up.

• The effective treatment of insomnia, pain, depression, and/or anxiety.

• Snacks and frequent drinks.

• Self-medicating with caffeine-containing drinks.

• The use of prescribed stimulants such as low-dose methylphenidate can benefit some patients; the patient should be warned that there is a risk that a sense of well-being can lead to over-activity.

• Learning to cope with the stress of having a chronic illness (see Support and Coping Skills).

Immune System Support

A limited number of trials of intravenous immunoglobulin (IVIG) have been undertaken in adults, with mixed results. In adolescent patients a double blind placebo controlled randomized trial of IVIG 1 g/kg monthly (max dose 60 g) for 3 months was found to have moderate effectiveness for overall function (a combination of school attendance, school work, social activities, and physical activities). Patients also reported general improvements in all ME/CFS symptoms, many reporting feeling completely well by the 6-month follow-up. The placebo group also improved but more gradually, matching the functioning of the intervention group after 5–7 years of follow-up. The trial showed that the benefit from IVIG was in reducing the duration of illness (42). However, IVIG is relatively expensive, is not always available due to health insurance restrictions and other limitations and it can be associated with serious adverse effects, e.g., aseptic meningitis after infusion, and anaphylaxis in those with IgA deficiency (110).

Depression and Anxiety

Mild or moderate secondary psychiatric problems often can be managed by the primary care physician, provided the physician feels comfortable with informal counseling. Giving support and encouragement to the patient can be adequate treatment. Various forms of support and psychotherapy helpful for learning to cope with the illness are given in Section “Support and Coping Skills.” When referral to a child psychiatrist or psychologist is needed, it is likely to be more successful if she/he is familiar with ME/CFS.

The treatment of other symptoms of ME/CFS such as pain or insomnia can also help to relieve emotional distress. If antidepressant medications are indicated, it should be noted that young patients with ME/CFS often respond to a smaller than expected dosages of these medications and careful follow-up is important.

Support and Coping Skills

The young person with ME/CFS needs to learn to adapt to the reality of the illness, and integrate it into a meaningful life despite sometimes severe physical limitations. Above all, the young patient needs to develop a sense of achievement in her/his life, however, small.

All aspects of the young person’s life might need to be addressed. She/he might need to deal not only with physical and cognitive limitations, but also with misunderstanding of the illness, fear, grief, anger, guilt and isolation. Sometimes having ME/CFS can result in abnormal illness behavior, such as denial of the reality of the illness.

A patient’s needs early in the illness might differ from her/his needs in later years, as health improvement is being achieved. Young patients should be encouraged to verbalize their fears and needs. Only the young person her/himself knows how she/he really feels. For instance, many young people fear getting behind their peers academically, never being able to catch up, and consequently losing friends. There should be opportunity to talk things through with a trusted professional who understands the illness. Although the parents can be present, the discussion should be primarily with the patient, so that she/he is also involved in decision making and feels part of the team approach. Teenagers usually need an opportunity for discussion without a parent present.

Our experience suggests that the following elements of basic supportive therapy can be helpful:

• Exploring what the patient and her/his parents already know about the illness.

• Teaching the patient and her/his family about ME/CFS and correcting any misinformed notions about cause, course of the illness and forms of management.

• Making it clear that ME/CFS is a medical/biological illness, but that often there can be understandable, secondary, emotional reactions.

• Clarifying and discussing the patient’s and family’s particular anxieties and mood changes.

• Discussing strategies such as pacing of activities (see Fatigue, Post-Exertional Symptoms, Exercise Intolerance) that enable the patient to live within the limitations of the illness.

• Ensuring the medical management of symptoms.

• Making clear that you (as the treating physician and/or therapist) will be available as new questions arise and setting up follow-up appointments.

These steps can be carried out by the primary care physician if she/he is comfortable doing so. If not, or if the patient’s situation is complex or severe, a social worker, psychologist, or child psychiatrist, preferably one who is knowledgeable about ME/CFS, can be consulted.

Coping Skills Training

Young patients with ME/CFS benefit from practical suggestions for coping with chronic illness. For example, it can be helpful to provide strategies for demystifying the illness and explaining it to other people: ME/CFS is like having mononucleosis (glandular fever) and then not recovering from it.

We recommend:

• A private space at home, so that the young patient’s rest will be undisturbed and she/he is able to work without being distracted.

• Developing a daily routine, especially for patients who are housebound.

• Attempting to achieve a normal day/night cycle, to help the patient fit in with the family’s daily schedule and make school possible.

• Encouraging participation in education, however minimal, but without undue pressure (see The School System).

• Providing time for meeting with friends and for family treats.

• Incorporating rewards for achievements.

• Joining a local patient support group (if available, and if it has competent leadership).

• The use (when appropriate) of stress reduction techniques such as music, visualization, self-hypnosis and/or mindfulness-based cognitive therapy (111).

Cognitive Behavioral Therapy (CBT)

The benefit of CBT as a psychotherapeutic intervention for ME/CFS is currently ambiguous. CBT has been shown to be helpful for some pediatric ME/CFS patients (112–115). However, in adults, the effect size of CBT is rather modest and the effects are not always sustained (116). CBT can produce adverse effects (101). The assertion that CBT can “reverse” or cure the illness is not supported by follow-up studies (117) and immunological changes found in the illness have been shown not to be reversed by CBT (118).

The hypothesis underlying the rationale for the use of CBT in ME/CFS patients proposes that the patient’s poor health is perpetuated by avoidance of activity and by maladaptive fears, such as anxiety about symptoms that emerge after activity (119). CBT aims to improve coping with the illness by changing these “maladaptive cognitive responses” and encouraging graded exercise as well as incremental increases in other activities. The notion that the illness is perpetuated solely by dysfunctional attitudes and beliefs is speculative, lacks empirical support and is not consistent with our current understanding of the pathophysiology of ME/CFS (see Etiology and Pathophysiology). This hypothesis has led to patients being blamed for failure to recover, because, in the view of the therapist, they have not changed their so called “maladaptive cognitive responses.” Furthermore, CBT that includes rigidly enforced graded exercise frequently leads to severe relapse in patients with ME/CFS.

Nevertheless, some of the elements of CBT are part of a common sense management of many medical problems, provided they are introduced in a pragmatic and flexible manner to help individuals cope with chronic illness (113–115, 120, 121). These elements include recommendations already given in this section. It is most important for a patient with ME/CFS that any attempt to increase her/his activity level or to exercise be flexible, rather than rigid, permitting the patient to avoid exceeding her/his energy limit. The patient should also be advised that CBT does not cure the illness, but it can help in learning to live within its limitations. CBT is not always available and it can be costly. It is likely to be more successful if the therapist is knowledgeable about ME/CFS.

Dietary Management

This section discusses nutrition in patients who are able to take adequate nourishment by mouth. Patients unable to maintain adequate nourishment by mouth are discussed in the section on the severely affected (see Severely Affected and Very Severely Affected Young Patients).

Many young people with ME/CFS experience a variety of gastrointestinal symptoms that can interfere with nutrition. Common complaints are: lack of appetite, especially in the morning, nausea, abdominal pain that might or might not be associated with eating, heartburn, feeling “full” even after a small meal, abdominal bloating, and discomfort that can be associated with particular foods, e.g., dairy or wheat. Co-morbid gastrointestinal conditions are present in some young patients. These are discussed in the section “Gastrointestinal Issues.”

Reduced food intake can stem from food fads. The young person might be a fussy eater, might claim to be “allergic” to almost all foods, or might be fearful that certain foods make the illness worse. Some young people with ME/CFS have a very disordered body clock—up all night, asleep all day—making mealtimes very awkward. As a result of these problems, some young people with ME/CFS develop weight loss. Alternatively, others become obese due to lack of exercise or increased “snacking” for an energy boost, from boredom, or occasionally due to increased appetite from medications. If there is no logical explanation, weight changes should be investigated.

Parental concern and pressure to eat more can contribute to stress in the family. The goal is for the young person to get a balanced nutritional diet, including food they enjoy, with plenty of variety. Educating the patient about how the body needs fuel to function and provide energy can be helpful.

We recommend

• Regular, small meals, little and often, and between meal snacks.

• Plentiful salt for those with co-morbid OI.

• Avoid too much fluid with meals if experiencing bloating.

• A carbohydrate snack at bedtime or if wakeful during the night can encourage sleep.

Extra foods that can be incorporated in the diet in some circumstances include: yogurt, if the illness began with or is complicated by gastrointestinal infection, ginger drinks for nausea, peppermint for indigestion, or garlic to help overcome/prevent infection. Evidence for these being helpful is anecdotal. Snacks should be readily available and nutritious, but include some treats. In school, permission might be needed to have snacks and drinks readily available, particularly during long exams.

Fluid intake should be liberal:

• Drinks should be readily available, water is ideal, do not “over-drink.”

• Electrolyte drinks can be helpful, avoid those containing fermentable oligo-, di-, mono-saccharides and polyols (FODMAPs) (see “Supplements”).

• Avoid alcohol and too much caffeine (coffee, cola, energy drinks).

Supplements

If the diet is good, supplements should not be needed, although sometimes they can be beneficial. Occasionally, an excess of supplements can cause problems e.g., too much vitamin C can lead to diarrhea. The following supplements may sometimes be useful:

• Vitamin D if patient lacks sunlight, due to light sensitivity or if seldom outside. Low vitamin D levels can be associated with headaches and pain and these symptoms improve with raising vitamin D blood levels.

• Magnesium at bedtime can help with pain and cramps (take with apple juice or apple to aid absorption), it also helps relieve constipation.

• Vitamin B12 injections can help with low energy/brain fog, or vitamin B12 can be taken as sub-lingual tablets.

• Probiotics can help irritable bowel symptoms, or if taking antibiotics.

• Iron tablets for iron deficiency with/without anemia (the cause of anemia should be determined), take with citrus juice to aid absorption.

Recent attention has focused on dietary FODMAPs. These are short chain carbohydrates (oligosaccharides, disaccharides, monosaccharides and related alcohols) that are commonly found in the modern western diet and are poorly absorbed in the small intestine. They include short chain polymers of fructose (fructans), galactose (galactans), disaccharides (lactose), monosaccharides (fructose), and sugar alcohols (polyols) such as sorbitol, mannitol, xylitol and maltitol. There is evidence that restriction of FODMAPs can have a beneficial effect for those with irritable bowel syndrome and other functional gastrointestinal disorders. It might, therefore, be useful to restrict the dietary intake of these types of carbohydrates for ME/CFS patients with co-morbid gastrointestinal symptoms.

Alternative and Complementary Medicine

Many alternative and complementary therapies have been promoted for ME/CFS. It is difficult to determine whether these therapies actually work, because the symptoms of ME/CFS vary so much from day-to-day. Anecdotal evidence suggests that acupuncture, massage, pilates, and yoga can help pain in some adults, but no published studies have assessed their benefit in young people.

The clinician should identify the use of herbal/natural remedies or supplements. The contents of complementary medicines are not regulated for dose or composition. Caution must be exercised regarding side effects because if used with prescribed medications, there can be interactions.

Unfortunately, in the hope of a cure, parents of young patients with ME/CFS often ask the young patient to try costly, non-established and speculative treatments but find little or no clinical improvement. Feedback from young people with ME/CFS indicated that 80% had tried up to 30 different alternative therapies. Only massage for pain relief and “good dietary advice” achieved “some benefit” in up to 30% of patients. A common comment from the patients was that they “were glad when their parents stopped shopping around for a cure.” (23). A review of alternative medicine studies in adults with ME/CFS revealed generally poor methodologies and limited evidence of any benefit (122, 123).

Co-morbid Conditions

Co-morbid conditions are seen frequently in young patients with ME/CFS and are major contributors to illness severity. Their successful management can result in substantial lessening of the burden of illness. A list of co-morbid conditions is given in Table 4. This section will discuss those co-morbid conditions that can have a significant impact on the illness, including orthostatic intolerance, joint laxity, gynecological problems, gastrointestinal problems, allergies, intolerances and neuroanatomic abnormalities.

Orthostatic Intolerance (OI)

The term OI refers to a group of conditions in which symptoms worsen with quiet upright posture and are improved but not always abolished by lying down. Typical symptoms are those of cerebral hypo-perfusion or sympathetic activation. Studies report higher rates of OI in pediatric patients with ME/CFS than in healthy children and higher rates than in adult patients with ME/CFS. An estimated 60–95% of young patients with ME/CFS have orthostatic symptoms (49). OI is more common in girls after puberty (sex ratio 3:1). OI can follow an infectious illness or an immunization.

Because there are more patients needing help with the management of OI than specialists trained to meet their needs, we have included the salient points of diagnosis and management of OI in this section. There is more detailed information on the pathophysiology and testing for OI in Appendix G.

Symptoms of OI in young patients can precede the onset of ME/CFS or they can arise a period of time after the onset of ME/CFS. Some young patients with symptoms of OI do not develop symptoms of ME/CFS, while in others, the concurrent diagnosis of ME/CFS has been missed, because symptoms such as post-exertional worsening have not been asked about.

Orthostatic symptoms include any of the following: increased fatigue, lightheadedness, white-outs or black-outs of the visual field, visual dimming, mental fog, headaches, nasuea, pain, or shortness of breath. Upright posture consistently aggravates ME/CFS symptoms and patients report worsening fatigue and other symptoms while standing in line, in hot environments like a shower, or in the summer heat. Many patients adopt postural counter-maneuvers—such as sitting with knees to chest, doing homework in a reclined position, crossing the legs when standing, fidgeting in line—but are not aware of why they have done so. Some adolescents might not report lightheadedness, so asking about symptoms that emerge during prolonged upright posture can be revealing.

Characteristic physical appearances include facial pallor and a reddish-purple discoloration of the dependent limbs (acrocyanosis) when sitting or standing for more than a few minutes. Symptoms of OI can occur without prominent changes in heart rate and blood pressure, but are often associated with objective circulatory disorders. Postural tachycardia syndrome (POTS) is the most common, neurally mediated hypotension (NMH) is less common, and orthostatic hypotension (OH) is uncommon in pediatric patients. The detection of POTS, NMH, and OH require a prolonged period of orthostatic stress and they can be missed with brief duration 1–2 min orthostatic vital sign measurements. We recommend a 10 min standing test in all young people with ME/CFS to ascertain whether orthostatic symptoms occur and determine whether POTS and/or OH are present (Table 10). Patients with NMH are generally symptomatic soon after standing, but longer duration tilt table testing is required to elicit the hypotension. Tilt table testing requires referral to a specialist center and is costly.

TABLE 10

Table 10. Orthostatic testing.

POTS: In adolescents, this diagnosis requires the reproduction of orthostatic symptoms together with a 40 bpm change in HR, from supine to 10 min upright, or a HR of ≥120 (124). Some individuals who have POTS early in upright posture go on to develop NMH if the orthostatic challenge is prolonged beyond 10 min.

Neurally mediated hypotension requires the production of orthostatic symptoms with a 25 mm Hg drop in systolic BP, usually without an increase in HR, and can be associated with junctional rhythm (recognized by a loss of P waves on the EKG) at the time of pre-syncope or syncope. The terms vasovagal syncope, neurocardiogenic syncope and NMH are synonymous. Syncope need not be present to make the diagnosis of NMH, as many affected individuals with lightheadedness and other symptoms sit or lie down before fainting.

Orthostatic hypotension is defined by a BP reduction of at least 20 mm Hg systolic or 10 mm Hg diastolic within the first 3 min of upright posture (124). This problem is rarely seen in pediatric patients except at times of hypovolemia, such as febrile illness, acute dehydration, hemorrhage, adrenal insufficiency, or excessive histamine release.

Management/Treatment

The lack of treatment studies in young people with OI and the lack of specialists with experience in OI contribute to difficulties in managing this condition. Some young patients have characteristic symptoms of OI, but at the time of testing have a standing HR rise or BP fall which is insufficient to diagnose POTS, NMH, or OH. They might still benefit from treatment.

The first step in management is non-pharmacological and emphasizes four main points: (a) avoid conditions that increase pooling of blood, (b) improve venous return to the heart, (c) avoid depletion of salt and water and other causes of low blood volume, and (d) avoid increasing catecholamines beyond their baseline levels (whi