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Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)


Acknowledgements

This chapter includes information included by Drs. Gary S. Marshall and Bryan D. Carter in previous editions of the book. It also relies heavily on the collaborative efforts of members of the international writing group for the Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Primer, Drs. Rosemary A. Underhill, Kenneth J. Friedman, Alan Gurwitt, Marvin S. Medow, Malcolm S. Schwartz, Nigel Speight, Julian M. Stewart, Rosamund Vallings, and Katherine S. Rowe, with contributions from Drs. Faith Newton and Evan Spivack.

Similar to its adult counterpart, the pediatric form of what is now termed myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex, chronic, multisystem disorder. The US National Institutes of Health and the Centers for Disease Control and Prevention currently refer to the illness as ME/CFS, as we will in this chapter, acknowledging that while evidence of classical encephalomyelitis is lacking, there is growing evidence of disturbed central and autonomic nervous system function.

By definition, ME/CFS is associated with a substantial impairment in the activities previously tolerated by affected individuals. Symptoms can begin abruptly in temporal association with a number of infectious illnesses, including Epstein-Barr virus infection, or onset can be gradual and insidious. There is no gold standard diagnostic laboratory test for ME/CFS. Clinicians make the diagnosis by adhering to one or more of the existing clinical case definitions. ME/CFS can be readily recognized clinically by its characteristic profound fatigue, worsening of symptoms if the individual exceeds his or her usual levels of physical or cognitive activity (termed post-exertional malaise [PEM]), unrefreshing sleep, orthostatic intolerance, and cognitive dysfunction. The exclusion of other causes of symptoms through history, clinical evaluation, and the judicious use of laboratory testing—along with confirmation of the physical examination abnormalities that can be present in ME/CFS—help confirm the diagnosis. No uniform cause has been identified, nor is there a single pharmacologic agent that is consistently effective for the entire symptom complex. Importantly, however, symptomatic therapy can improve overall function, as can the recognition and management of several treatable co-morbid conditions.

Case Definition

Illnesses that closely resemble ME/CFS have appeared sporadically or in cluster outbreaks in several countries during the last century. ME was the name given by Ramsey to describe an outbreak at the Royal Free Hospital in London in 1955. The designation CFS emerged from an outbreak investigation in Incline Village, Nevada, in the 1980s, from which the 1988 Holmes case definition was generated.

The Holmes case definition was modified in 1994 by an international consensus panel, with the resulting diagnostic guidelines often referred to as the Fukuda criteria. Used extensively in research studies over the past 25 years, these criteria required the presence of self-reported persistent or relapsing fatigue lasting 6 or more consecutive months, which is of new or definite onset (not lifelong), not the result of ongoing exertion, and not substantially alleviated by rest, resulting in a substantial reduction in previous levels of occupational, educational, social, or personal activities. Four of eight symptom criteria were required. The fatigue criterion has been reproduced with minimal change in subsequent case definitions by other groups. Several limitations of the Fukuda criteria have become apparent, such as the lack of a hierarchy of symptoms, no insistence on core symptoms that would help differentiate ME/CFS from other common causes of chronic fatigue, and no requirement to specify the frequency and severity of symptoms, an omission that could allow individuals with a low intensity of symptoms to qualify for the diagnosis. , ,

Two key findings received greater emphasis after the 1994 publication of the Fukuda criteria. One was the recognition that post-exertional malaise was helpful in distinguishing ME/CFS from other fatiguing conditions, including depression (in which, by contrast, exercise tends to lead to improved well-being). The other was the observation that orthostatic stress could provoke increased ME/CFS symptoms, including fatigue, PEM, and cognitive symptoms. A new case definition in 2003 (often referred to as the Canadian Consensus Committee Criteria ) and the International Consensus Criteria for ME in 2011 placed more emphasis on PEM in the case definition, but neither required orthostatic intolerance to be present, and both were relatively cumbersome to apply in clinical practice.

In 2015, after reviewing over 9000 papers on the illness, a committee of the US Institute of Medicine (IOM) published a simplified case definition that emphasized the core symptoms of the disorder ( Box 200.1 ). Although the case definition requires the presence of symptoms for at least 6 months, symptomatic therapy need not be deferred until after 6 months have elapsed.

BOX 200.1
Institute of Medicine Criteria for ME/CFS a

a The diagnosis assumes that, after careful investigation, no other disorder is identified that could explain the patient’s symptoms.

Modified from reference 1.

  • The diagnosis requires the presence of all of the following three symptoms:

  • A substantial reduction or impairment in the ability to engage in pre-illness levels of occupational, educational, social, or personal activities that persists for more than 6 months and is accompanied by fatigue, which is often profound, is of new or definite onset (not lifelong), is not the result of ongoing exertion, and is not substantially alleviated by rest

  • Post-exertional malaise b

    b The diagnosis of ME/CFS should be questioned if patients do not have these symptoms at least half the time with at least moderate intensity.

  • Unrefreshing sleep b

  • Plus presence of at least 1 of the 2 following manifestations:

  • Cognitive impairment b

  • Orthostatic intolerance

Epidemiology

Annual incidence estimates for pediatric ME/CFS vary from 12/100,000 in the Netherlands based on physician report to 43/100,000 in Norway. , The latter estimates were derived from the entire population database of Norwegians 5 years of age and older after linking to clinic and hospital diagnoses using the ICD-10 code of G93.3 (myalgic encephalomyelitis). Age-specific incidence rates were 8.1/100,000 for those 5–9 years, 43.7/100,000 for those 10–14 years, and 43.1/100,000 for those 15–19 years. That study identified two distinct peaks of incidence at ages 10–19 and 30–39 years.

Prevalence estimates for ME/CFS vary considerably depending on the case definition used, whether a physician examination was performed (as is required by all case definitions), and the methodology of case ascertainment (clinic-based or provider-based report versus population-based surveys). Table 200.1 shows prevalence estimates from the small number of published pediatric studies. , Wide variability in the available estimates and their 95% confidence intervals makes it difficult to know true disease prevalence. Other challenges to obtaining accurate prevalence data include the absence of a confirmatory diagnostic test, differing clinician attitudes about the diagnosis in adolescents, differing intensity of ascertainment for the core symptoms and exclusionary conditions, and differing techniques for operationalizing the diagnostic criteria.

TABLE 200.1
Prevalence of Pediatric ME/CFS
Country Year Case Definition Methodology Age in Years Prevalence per 100,000 Comment
Australia 1990 Unexplained fatigue
+ cognitive impair-ment for 6 months		 Physician referral ≤9
10–19		 5.5
48		 All those under 10 were males. For 10–19 year olds, 95% CI for the prevalence estimate: 22–91.
USA 1994 Fukuda Population based 2–11
12–17		 0
116		 Prevalence refers to CFS-like, not confirmed CFS cases after physician evaluation
USA 2004 Fukuda Population survey 12–17 338 Prevalence refers to CFS-like. No CFS cases identified. Only 35% of those with CFS-like symptoms were examined by a physician. M:F ratio 1:1.
UK 2007 Fukuda Population based 11–15 50 Only 1 individual with CFS identified. 95% CI for the prevalence estimate: 10–900.
Netherlands 2011 Fukuda National survey of physicians 10–18 111 Only 48% of physicians responded.
No independent confirmation of the diagnosis
Half of GPs did not consider CFS to be a distinct diagnosis.
USA 2020 Fukuda, IOM, and pediatric Population based 5–8
9–11
12–14
15–17		 140
453
816
1249		 Overall prevalence for 5–17 years: 750/100,000;
17% Black, 26% Hispanic, 55% White.
Symptoms: 91% with fatigue, 83% with PEM; only 38% with dizziness.

The true proportion who meet criteria for pediatric ME/CFS also could be underestimated if clinicians diagnose children as having deconditioning (see Chapter 15 ), postural tachycardia syndrome (POTS), or other forms of orthostatic intolerance without exploring whether they also satisfy criteria for ME/CFS. Pediatric orthostatic dysregulation affects up to 15% of the adolescent population, with many individuals with POTS reporting symptoms that overlap with ME/CFS, including fatigue, cognitive dysfunction, and PEM.

Several unexplained differences exist between population-based and clinical samples. Population-based samples identify the illness as affecting all races and socioeconomic groups. Some US population-based studies identify ME/CFS as more common in those of Black race and Latino background, with differences from specialty clinic populations attributed to the absence of universal health insurance and other socioeconomic factors. In countries such as Australia in which there are no financial barriers to medical care, tertiary care specialist clinics report a disproportionate number of Whites with ME/CFS (typically 90% or more of the study population) compared with Whites representing 25% of the regions’ general populations.

Despite the methodologic difficulties in identifying accurate prevalence, several epidemiologic features are clear. Although ME/CFS has been reported in children as young as 2 years, it more commonly begins during adolescence. In adolescence, females are more likely to develop CFS than males, in a ratio of 2-3:1. , , Although family members often are affected, there is no evidence of person-to-person transmission of ME/CFS. Instead, a genetic predisposition is likely, as there is a higher rate of ME/CFS in monozygous than dizygous twins. It is not uncommon for more than one member of a family to be affected. A Utah study using a large genealogic database identified significantly elevated relative risks of ME/CFS in first- (2.7), second- (2.3), and third- (1.9) degree relatives.

ME/CFS patients can meet diagnostic criteria for heritable disorders of connective tissue, most notably Ehlers-Danlos syndrome (EDS). Furthermore, the odds ratio for having joint hypermobility is 3-fold higher among ME/CFS patients, with 60% of ME/CFS patients and 24% of age and sex matched controls having joint hypermobility. Conversely, fatigue, orthostatic intolerance, and pain are prevalent in patients with EDS, emphasizing the overlapping phenotypes.

Pathogenesis

ME/CFS is a heterogeneous disorder. This section highlights only some of the more consistent observations that have emerged in the last 25 years.

Infection

A prospective study in a rural region of Australia followed a cohort of patients after a variety of acute infections due to Epstein–Barr virus, Coxiella burnetii , and Ross River virus. Eleven percent of the cohort met the study definition of ME/CFS at 6 months after the infections, characterized by disabling fatigue, musculoskeletal pain, neurocognitive difficulties, and mood disturbance. The main risk factor for ME/CFS at 6 months was the severity of the initial infection, not age or psychological factors. Similarly, a large prospective cohort of US adolescents identified ME/CFS in 13% 6 months after acute infectious mononucleosis. By 12 months, 7% still met ME/CFS criteria, with 4% still meeting criteria 24 months after the acute illness. Females were significantly more likely to meet criteria for ME/CFS at all time points. The severity of the acute infection also was a risk factor for persistent symptoms in this and in other studies of adolescents following mononucleosis. In contrast, ME/CFS following severe acute respiratory syndrome (SARS-CoV-2), is independent of the severity of the initial infection, and can affect patients who have had mild respiratory impairment. ,

Although ME/CFS can be preceded by infection with a variety of bacterial and viral pathogens—including EBV, parvovirus B19, Giardia lamblia , and severe acute respiratory syndrome (SARS-CoV-1 , and CoV-2 ), evidence that ME/CFS is due to persistent active infection is lacking. A large cross-sectional study of Norwegian adolescents found no differences between those with ME/CFS and healthy controls in serologic findings for Borrelia burgdorferi , EBV, CMV, and parvovirus B19. Polymerase chain reaction (PCR) testing was negative in both cases and controls for B. burgdorferi , CMV, adenovirus, and enterovirus. For other organisms, including HHV-6, the PCR results did not differentiate between cases and controls. In adults, deficient EBV-specific B- and T-lymphocyte memory responses in those with ME/CFS suggest an impaired ability to control the early steps of EBV reactivation, but those with ME/CFS do not have true chronic active EBV infection or end-organ involvement.

Despite some initial enthusiasm generated in case series, antiviral therapies, including acyclovir and valganciclovir, have not proven beneficial in randomized controlled trials in adults. , , One small pediatric study suggested a potential benefit with isoprinosine, but this work has yet to be replicated. The evidence for chronic infections in general and specifically viral infections as possible contributors to symptoms continues to be reviewed. ,

Experimentally, partial reactivation of HHV-6 in response to cellular stress in vitro is associated with secretion of a factor that induces mitochondrial fragmentation and associated reductions in ATP production as well as a powerful protective effect against infection by influenza-A and HSV-1. This factor in the supernatant of cells with reactivated HHV-6 could be transferred to virus-naïve cells, with replication of metabolic and antiviral changes. Serum from ME/CFS patients also induced similar changes in mitochondrial morphology, as well as antiviral activity in healthy cultured cells, but serum from healthy controls did not.

Immune Dysfunction

ME/CFS has no clear features consistent with a classical immunodeficiency disorder. Reported immunologic abnormalities in ME/CFS have been inconsistent and have not identified a distinct profile. , NK cell cytotoxicity has been one of the more studied phenomena but is not found in all studies. Other work has investigated cytokine abnormalities , and autoimmune phenomena. Some have argued that, because of the biological nature of cytokines as local communication factors and the multitude of methodologic problems in their measurement, a peripheral blood cytokine signature in ME/CFS is unlikely to be found, although a difference in cytokines in cerebrospinal fluid has been reported. Autoimmune origins of disease pathogenesis were supported by a small trial suggesting improvement in function after B-lymphocyte depletion using rituximab, but these findings were not replicated in a larger phase III clinical trial.

Pediatric studies of immune impairment have enrolled smaller numbers and should be interpreted with caution. One pediatric ME/CFS study found no differences in NK cell numbers or function. Differences have been identified between ME/CFS patients and controls in both proliferative and inhibitory responses of T lymphocytes to phytohemagglutinin, dexamethasone, and the β-2 adrenergic agonist terbutaline. Adolescents with ME/CFS had an increased proportion of lymphocytes and neutrophils undergoing apoptosis in one study. Plasma levels of individual cytokines and cytokine network measures did not differ from those of controls in a large study of adolescents with ME/CFS.

A randomized trial of 3 monthly doses of 1 gram/kg of immune globulin intravenous (IGIV) in 71 adolescents with ME/CFS showed a significant improvement in overall function at 6 months in treated subjects. In this trial, 52% of participants had cutaneous anergy. Despite these results (published in 1997), no pediatric IGIV trial has been attempted to replicate this work. Adult studies of IGIV have shown mixed results.

Minor autoimmune phenomena such as low-level antinuclear antibody titers sometimes are present. In one large Australian study, 21% of the pediatric ME/CFS participants had ANA titers of 1:160 or higher, but without evidence of elevations in ESR, anti-double-stranded DNA, or other laboratory abnormalities consistent with a rheumatologic disorder.

Allergies and food sensitivities have been reported to be more common in adults with ME/CFS compared with both population estimates and healthy controls. In one outbreak in a farming community, allergy and asthma were significant risk factors for pediatric ME/CFS. One study identified a delayed, non-IgE-mediated hypersensitivity or intolerance to milk protein—reflected by a triad of symptoms including epigastric pain, gastroesophageal reflux, and early satiety—in 31% of a cohort with adolescent ME/CFS. Similar symptoms can be seen with delayed hypersensitivity to other food proteins (soy, wheat, and egg, or with non-celiac gluten sensitivity), but these are less common.

Mast cell activation syndrome (MCAS), first defined a decade ago, is associated with a wide range of systemic symptoms that overlap substantially with ME/CFS, including fatigue, orthostatic intolerance, pain, and cognitive dysfunction. , Patients with MCAS often report intolerance of multiple medications and foods, along with cutaneous signs like facial flushing, rashes, and urticaria. Mast cell activation can be triggered by a variety of infectious agents, cytokines, allergens, vibration, and barometric pressure changes. A subset of persons with POTS have MCAS, and MCAS has been associated with joint hypermobility and EDS. Two opposing consensus criteria for the diagnosis of MCAS have been proposed. , One hypothesis proposes that stimulation of hypothalamic mast cells by various triggers can activate microglia, in turn leading to inflammation in the brain and to other disturbances of homeostasis.

In adults with ME/CFS or orthostatic intolerance, several studies have identified autoantibodies against adrenergic and muscarinic acetylcholine receptors. One group has speculated that impaired function of β-2 adrenergic autoantibodies could result in diminished control of the pro-inflammatory response of monocytes, diminished control of T-lymphocyte proliferation during infection, and excessive vasodilation, thereby linking immune, infectious and autonomic abnormalities. , A small pilot study of immunoadsorption to remove β-2 antibodies was associated with improved ME/CFS symptoms in 7 of 10 patients, with 3 experiencing a moderate to marked improvement for at least 6 months.

Orthostatic Intolerance

Chronic fatigue and exercise intolerance are prominent in a variety of overlapping syndromes of circulatory dysfunction. In 1995, a report described 7 nonsyncopal adolescents with chronic fatigue or ME/CFS who developed tachycardia and neurally mediated hypotension along with worse fatigue during head-upright tilt to 70 degrees. Of the 7, 4 improved when treated with medications typically used in the management of syncope. This was followed by a study of adolescents and adults with ME/CFS in whom orthostatic symptoms were common in daily life, fatigue was worse with prolonged standing and warm environments, and head-up tilt to 70 degrees provoked worse fatigue, lightheadedness, warmth, and nausea. Of 23 participants, 16 patients but no controls developed neurally mediated (vasovagal) hypotension in the first 45 minutes of upright tilt, characterized by a sustained 25 mm Hg drop in systolic blood pressure. With open treatment of the hypotension using increased sodium and fluid intake, as well as fludrocortisone, atenolol, midodrine, and other drugs, most patients reported improved symptoms and scores on a unidimensional wellness scale from 3.6 out of a possible 10 at the start of treatment to 6.9 on therapy.

In all subsequent pediatric studies involving the assessment of the response to upright posture, those with ME/CFS have had higher rates of orthostatic intolerance than healthy controls, reaching over 90% in several studies. , The most common abnormalities over time have been POTS and neurally mediated hypotension ( Fig. 200.1 ). Acrocyanosis of the dependent limbs is a common physical finding ( Fig. 200.2 ). Abnormalities in sympathetic tone, catecholamine levels, thermoregulation, and reductions in cerebral oxygenation upon standing have been reported in pediatric ME/CFS. , ,

FIGURE 200.1, Common forms of orthostatic intolerance in pediatric ME/CFS. (A) Postural tachycardia syndrome (POTS) requires a 40 beat per minute (bpm) increase in heart rate (HR) in adolescents 12–19 years (or 30 bpm in those >19) in first 10 minutes of standing or head-up-tilt testing, along with chronic orthostatic symptoms, without OH in first 3 minutes. Note the 51 bpm HR change and the provocation of typical orthostatic symptoms. (B) Neurally mediated hypotension (NMH) requires a 25 mm Hg decrease in systolic blood pressure, with orthostatic symptoms, and with bradycardia usually appearing as blood pressure falls. Note the symptoms immediately on head-up tilt, followed abruptly by hypotension and syncope with brief tonic-clonic movements at the time of loss of consciousness. NMH usually takes longer than 5 minutes to develop. POTS and NMH are not mutually exclusive diagnoses.

FIGURE 200.2, Acrocyanosis. Both panels show the purple discoloration of the dependent limbs. The right panel shows the absence of capillary refill >5 seconds after the examiner’s fingers have compressed the skin.

Extracranial Doppler imaging of both internal carotid and both vertebral arteries during head-up tilt is a new method for measuring total cerebral blood flow. In a large study using this technique in 429 adults with ME/CFS and 44 controls, the controls experienced a 7% reduction in total cerebral blood flow after a maximum of 30 minutes upright. In contrast, cerebral blood flow fell by 26% in those with ME/CFS overall, 28% in the 62 with delayed orthostatic hypotension, 29% in the 120 with POTS, and 24% in the 247 who would otherwise have been regarded as normal during tilting. In all, 90% of adults with ME/CFS experienced a significant reduction in cerebral blood flow when upright. The degree of cerebral blood flow reduction correlated with the number of orthostatic symptoms. It remains unclear why orthostatic intolerance is so prevalent in ME/CFS, although it can appear after apparent acute infectious illnesses, in association with MCAS, and it may have an autoimmune etiology in a subset, a finding that would be consistent with the predominance of females with ME/CFS. Orthostatic intolerance has been reported following SARS-CoV-1 and -2. , It is associated with MCAS, and it may have an autoimmune etiology in a subset, two findings that would be consistent with the predominance of females with ME/CFS.

Exercise Abnormalities

Several adult studies have confirmed abnormal physiologic responses to exercise in ME/CFS. Although the majority of ME/CFS patients have reduced oxygen capacity during a cardiopulmonary exercise test (CPET), a greater difference can be noted when CPET studies are conducted on consecutive days. In contrast to healthy individuals, who usually experience an unchanged or slightly improved exercise performance on day 2, ME/CFS patients have significantly lower maximal oxygen uptake and workload measurements on day 2, even if their effort was normal. Disease severity negatively influences exercise capacity, with the worst deterioration in exercise performance noted in those judged to have severe ME/CFS. Few pediatric ME/CFS exercise studies have been performed, and none has included consecutive-day tests.

Self-reported post-exertional increases in fatigue and other symptoms are accompanied by objective changes in gene expression. In response to a 25-minute submaximal exercise test, adults with ME/CFS but not controls develop a marked increase in physical and mental fatigue as well as pain, peaking at 24 hours but persisting for at least 48 hours. The increase in symptoms correlated with the timing of elevations in the expression of several metabolite-detecting, adrenergic, and immune genes on peripheral blood mononuclear cells. The patterns of gene expression in the adults with ME/CFS were distinct from those of individuals with other fatiguing illnesses, including multiple sclerosis.

Another study that incorporated functional magnetic resonance imaging (MRI) and neuropsychological testing after exercise also showed a significant increase in symptoms for patients compared with healthy controls, accompanied by pre- to post-exercise improvements in cognitive performance for healthy controls and worsening for ME/CFS patients. Functional MRI imaging confirmed increased brain activity from pre- to post-exercise in several regions for those with ME/CFS compared with controls.

Neuroendocrine and Metabolic Function

Fatigue and orthostatic intolerance are prominent features in Addison disease and other forms of adrenal insufficiency. Early studies in adults with ME/CFS identified low levels of cortisol in serum and in 24-hour urine specimens. Randomized clinical trials of low-dose cortisol, however, were associated with only a minimal improvement in symptoms and function, and, importantly, these improvements were accompanied by the emergence of potentially life-threatening adrenal insufficiency after 12 weeks. Hydrocortisone is not recommended for chronic treatment of ME/CFS. Some pediatric studies have shown significantly lower cortisol response to synthetic ACTH injection in ME/CFS patients compared with controls, although the mean cortisol levels remained within the normal range.

Despite a longstanding interest in bioenergetic defects and mitochondrial dysfunction as potential contributors to the pathophysiology of ME/CFS symptoms, no evidence of a primary defect in mitochondrial metabolism has been identified. Pediatric ME/CFS patients do not share the biochemical abnormalities of inborn errors of mitochondrial metabolism that present in early childhood, such as elevations in lactate and pyruvate, or evidence of strokes, but late-onset mitochondrial disease with myopathy or cardiomyopathy can present with exercise intolerance, and has some overlaps with ME/CFS. Subtle mitochondrial and metabolic dysfunction is an active area of research interest, with some work suggesting a hypo-metabolic state as a conserved response to perceived danger either in the organism as a whole or in immune cells.

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