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

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

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3Current Case Definitions and Diagnostic Criteria, Terminology, and Symptom Constructs and Clusters

A central element of the committee's charge was to “consider the various existing definitions [for ME/CFS] and recommend clinical diagnostic criteria for the disorder to address the needs of health providers, patients and their caregivers.” At least 20 sets of case definitions or diagnostic criteria currently exist for ME/CFS (Brurberg et al., 2014), yet as noted in Chapter 1, many ME/CFS patients struggle for years before being diagnosed. In one survey, more than 70 percent of ME/CFS patients reported seeing four or more doctors before receiving a diagnosis (CFIDS Association of America, 2014). During the committee's first meeting, Dr. Nancy Lee spoke on behalf of the study sponsors, acknowledging “the considerable need for faster and more accurate diagnoses for patients” and expressing her hope that this committee would “provide guidance to the broader medical community on how to identify and diagnose ME/CFS in the clinical setting.”1 To set the stage for the chapters of this report that offer this guidance, this chapter provides some background information on case definitions and diagnostic criteria for ME/CFS, a brief review of some of the existing case definitions and diagnostic criteria, a discussion of the terminology used to refer to this illness, and a review of the literature on symptom constructs and clusters.


Clinicians use diagnoses to manage illness, provide appropriate treatment, and predict prognosis. Diagnostic criteria provide guidance to clinicians on the specific signs, symptoms, or test results that indicate the presence of an illness, and classifying patients into diagnostic categories facilitates communication among clinicians and researchers (Coggon et al., 2005; Jason et al., 2006). Case definitions are a specific type of diagnostic criteria used to define an illness and are generally used for disease surveillance or investigations of infectious disease outbreaks (CDC, 2013). They are used to identify patients with a specific illness and are essential for disease-related research (Christley et al., 2011). Case definitions work well for illnesses for which the underlying pathology is understood and can be observed; establishing the presence of disease-specific pathology through examination or testing provides a gold standard for diagnosis of a particular disease, and potential case definitions can be compared against this standard. Case definitions often are assessed in terms of sensitivity, or the ability to identify patients with an illness correctly, and specificity, or the ability to exclude patients that do not have the illness. The appropriate balance of sensitivity and specificity varies depending on the purpose of a case definition (Coggon et al., 2005).

When the underlying pathology of an illness is unknown, as with ME/CFS, there is no gold standard against which to assess the sensitivity or specificity of a case definition. In these circumstances, diagnostic criteria may be more useful for “classifying people for the ultimate purpose of preventing or managing illness.” Then, the accuracy or precision of diagnostic criteria and case definitions may be assessed in terms of how well they “distinguish groups of people whose illnesses share the same causes or determinants of outcome (including response to treatment)” (Coggon et al., 2005, p. 950). There are many examples of diagnostic criteria for illnesses without a clearly observable pathology, such as the Jones criteria for acute rheumatic fever. No symptom, sign, or test can be used to diagnose acute rheumatic fever; the Jones criteria divide clinical and laboratory findings into major and minor manifestations. A diagnosis of acute rheumatic fever is indicated if a patient has evidence of a preceding group A streptococcal infection and either two major and one minor manifestations or one major and two minor manifestations (Dajani et al., 1992). Another example is the Diagnostic and Statistical Manual of Mental Disorders (DSM), which provides diagnostic criteria for mental disorders (such as autism and posttraumatic stress disorder) that are “concise, explicit, and intended to facilitate an objective assessment of symptom presentations in a variety of clinical settings” (APA, 2013, p. xli).

Existing Diagnostic Criteria for ME, CFS, and ME/CFS

Because the pathology of ME/CFS remains unknown and there is no diagnostic test for the disorder, most of the existing diagnostic criteria for ME/CFS were developed through the consensus of experts. This approach is not unusual for an illness without a gold standard for diagnosis; consensus-based diagnostic criteria have been developed, for example, for the functional gastrointestinal disorders and gastro-esophageal reflux disease (Drossman, 2006; Jason et al., 1999; Vakil et al., 2006). However, consensus reached by one group of experts is unlikely to represent all of the various perspectives within a field (Coggon et al., 2005; Morris and Maes, 2013; van der Meer and Lloyd, 2012). Further, diagnostic criteria developed by consensus of a group are likely to reflect the biases of the individuals within that group (Morris and Maes, 2013; van der Meer and Lloyd, 2012). This committee acknowledges that it faced the same limitations in fulfilling its charge to develop diagnostic criteria for ME/CFS using a consensus-based methodology; further discussion of this issue can be found in Chapter 7.

For this study, the committee was specifically asked to review the 2003 Canadian clinical case definition for ME/CFS (often called the Canadian Consensus Criteria [CCC]), the 2007 Clinical Guidelines for CFS/ME of the British National Institute for Health and Clinical Excellence (NICE), the 2010 revised Canadian Consensus Criteria for ME/CFS (Revised CCC), and the 2011 International Consensus Criteria for ME (ME-ICC). The committee also reviewed the case definition for CFS developed by Fukuda and colleagues (1994) (the Fukuda definition) because it has been used extensively to define research populations and is commonly used in clinical practice, as well as the case definitions developed for use in the pediatric population (Carruthers et al., 2003, 2011; Jason et al., 2006; Royal College, 2004). With the exception of the pediatric case definitions, which are discussed later in the chapter, the essential elements of these case definitions and diagnostic criteria, extracted from their original papers, are summarized in Table 3-1.

TABLE 3-1. Elements of Selected Case Definitions and Diagnostic Criteria for ME/CFS.


Elements of Selected Case Definitions and Diagnostic Criteria for ME/CFS.

Fukuda Case Definition for CFS (1994)

In 1994, Fukuda and colleagues published a case definition for CFS and idiopathic chronic fatigue that was intended to guide research in adult populations (CDC, 2012). The Fukuda definition defines chronic fatigue as “self-reported persistent or relapsing fatigue lasting 6 or more consecutive months” and requires a clinical evaluation to identify or rule out medical or psychological conditions that could explain the chronic fatigue's presence. A diagnosis of CFS requires the absence of exclusionary conditions, severe chronic fatigue, and at least four of eight minor symptoms.

The Fukuda definition does not require what some consider core symptoms of ME/CFS, such as post-exertional malaise (PEM) and neurocognitive symptoms. The definition has been criticized for being overly inclusive, particularly of patients whose symptoms may be caused by a psychiatric disorder. Because many of the minor symptoms overlap with the symptoms of major depression, patients with major depression may be misclassified by the Fukuda definition (Jason et al., 1999, 2010). Some criteria for fatigue severity and minor symptoms are listed in Table 3-1, but many have argued that the Fukuda definition fails to sufficiently operationalize the major and minor symptoms, leading to variations in the way these symptoms are interpreted (Jason et al., 1999; Reeves et al., 2003). Further, a major limitation of the Fukuda definition is that its criteria are polythetic, which inevitably leads to great heterogeneity among the group of patients diagnosed according to these criteria. For instance, two patients could have very little symptom overlap yet both be diagnosed with CFS.

The Fukuda definition indicates that patients who fail to meet its criteria for fatigue severity and at least four minor symptoms should be diagnosed with idiopathic chronic fatigue. The research guidelines recommend subgrouping cases of CFS or idiopathic chronic fatigue by the presence or absence of comorbid conditions, level of fatigue, duration of fatigue, and level of physical function (Fukuda et al., 1994). Despite the challenges noted above, the Fukuda case definition is the most widely used definition in ME/CFS research, and it is also used for clinical evaluation of patients (Brurberg et al., 2014; CDC, 2012).

Canadian Consensus Criteria for ME/CFS (2003)

Carruthers and colleagues (2003) published the CCC as a clinical working case definition to assist physicians and other clinicians in making a diagnosis of ME/CFS. Because fatigue can be present in many other illnesses, the CCC requires for a diagnosis of ME/CFS the presence of four cardinal symptoms—fatigue, PEM, sleep dysfunction, and pain—as well as minor symptoms grouped by region of pathogenesis (see Table 3-1). Thus, for a diagnosis of ME/CFS, the CCC requires that symptoms be present from the following six symptom categories for 6 months or longer:

  • fatigue, including substantial reduction in activity level;
  • PEM and/or post-exertional fatigue;
  • sleep dysfunction;
  • pain;
  • neurologic/cognitive manifestations; and
  • autonomic, neuroendocrine, or immune manifestations.

The authors intentionally included more symptoms than had been specified in previous diagnostic criteria to help clinicians identify patients with unique combinations of symptoms, and a symptom merely must be present to count toward a diagnosis.

NICE Clinical Guidelines for CFS/ME (2007)

In 2007, NICE published clinical guidelines for the diagnosis and management of ME/CFS, referred to as CFS/ME (NICE, 2007). The NICE criteria for diagnosis require the presence of fatigue and at least one other symptom, and these symptoms must have persisted for at least 4 months (see Table 3-1 for more information). Although the NICE criteria require fewer total symptoms relative to other diagnostic criteria for ME/CFS, the guidelines note that PEM or post-exertional fatigue, cognitive difficulties, sleep disturbance, and chronic pain are key features of the illness and that a diagnosis of ME/CFS should be reconsidered if none of these symptoms are present. As with other criteria, the NICE guidelines recommend that alternative diagnoses be ruled out before a diagnosis of ME/CFS is given. These guidelines also provide a list of “red flags” and potential comorbidities that should be investigated.

Revised Canadian Clinical Case Definition for ME/CFS (2010)

In 2010, Jason and colleagues revised the CCC and provided explicit rules for applying this case definition, including a questionnaire for assessing symptoms. The Revised CCC was intended to better operationalize the CCC. The authors provided operational definitions for several key symptoms to improve diagnostic reliability and use of the CCC in research studies (Jason et al., 2010, 2013b). For a diagnosis of ME/CFS, the Revised CCC requires the presence of symptoms from the same six categories (with some wording differences) as those of the original CCC (Jason et al., 2010).

The Revised CCC recommends the use of a structured questionnaire (the DePaul Symptom Questionnaire) (DePaul Research Team, 2010) to gather standardized information on symptoms as well as the use of the scales of the Short Form 36-Item Questionnaire (SF-36) of the Medical Outcomes Study to assess whether a patient has a substantial reduction in functioning (McHorney et al., 1993). A symptom must be present with moderate severity about half of the time to meet criteria for a symptom category, and a patient must score below a certain maximum score on at least two of the three scales of the SF-36 to meet criteria for a substantial reduction in functioning.

International Consensus Criteria for ME (2011)

Carruthers and colleagues (2011) published the ME-ICC for both clinical and research use. The authors started with the CCC and made extensive changes. Referring to “recent research and clinical experience that strongly point to widespread inflammation and multi-systemic neuropathology,” the authors chose to use the term “ME” instead of “CFS” or “ME/CFS” (Carruthers et al., 2011, p. 327). This decision has been challenged by other researchers in the field who oppose the use of the term, asserting that there is no convincing evidence of inflammation in ME/CFS (van der Meer and Lloyd, 2012).

The ME-ICC no longer requires a 6-month waiting period before a diagnosis is made and includes operational notes for each of the symptom criteria. To be diagnosed, a patient must experience post-exertional neuroimmune exhaustion—the authors' term for PEM—as well as symptoms from three symptom categories:

  • neurological impairments (which encompass neurocognitive impairments; pain; sleep disturbance; and neurosensory, perceptual, and motor disturbances);
  • immune, gastrointestinal, and genitourinary impairments; and
  • energy production/transportation impairments.

To receive a diagnosis of ME, a patient must have symptoms that result in a substantial reduction in activity compared with premorbid activity levels. A 50 percent reduction in pre-illness activity level is considered only a “mild” reduction. The ME-ICC does not provide guidelines on the severity or frequency of symptoms that must be present for a diagnosis (Jason et al., 2013b). It does not suggest the use of a standardized questionnaire for clinical diagnosis but recommends that all patients in research studies complete the International Symptom Scale to increase the reliability of data collection.

Comparison of Existing Diagnostic Criteria

The diagnostic criteria described above have similarities and differences. The Revised CCC and the ME-ICC share the most similarities with the CCC, but that is to be expected given that both used the CCC as a starting point. All of the criteria require that other explanations for a patient's symptoms be ruled out before a diagnosis of ME/CFS can be made, although the list of exclusionary conditions differs across the criteria. While all of the criteria make clear that they are describing and defining the same illness, some vary in the terminology used to refer to the illness or to specific symptoms. The following subsections compare some of the major components of the various diagnostic criteria and summarize the literature comparing the groups of patients identified by these criteria.

Required and Additional Symptoms

The existing diagnostic criteria focus on similar sets of symptoms, but they differ markedly in the number of symptoms required and how those symptoms are defined. The Fukuda definition and the NICE guidelines are perhaps the most straightforward. Both require persistent fatigue of new or definite onset; the NICE criteria require 1 additional symptom from a list of 10 minor symptoms, and the Fukuda definition requires 4 additional symptoms from a list of 8 minor symptoms. The CCC, Revised CCC, and ME-ICC require PEM (referred to in the ME-ICC as post-exertional neuroimmune exhaustion), while PEM is one of the minor symptoms in the Fukuda definition and listed as a feature of the fatigue required in the NICE guidelines. In addition to fatigue and PEM, pain and sleep disturbance are required symptoms for a diagnosis using the CCC and Revised CCC.

The CCC, Revised CCC, and ME-ICC divide additional symptoms into symptom categories. The CCC and Revised CCC require at least two neurological/cognitive manifestations and some combination of autonomic, neuroendocrine, and immune manifestations. The ME-ICC lists many of the same additional symptoms but categorizes them differently (see Table 3-1).

It is important to note that when diagnostic criteria require any symptom on a list to classify a patient as having a disease, they risk including groups of patients that do not suffer from the same disease. For instance, the CCC provides a list of several neurological impairments. If one of these symptoms is present, the patient is considered to have fulfilled the neurological impairment requirement. For example, reduced working memory and ataxia would both indicate neurocognitive impairment, but patients presenting with memory impairment might suffer from a different entity than patients with ataxia.

Comparison of Groups Selected by Various Diagnostic Criteria

Many patients with ME/CFS meet more than one set of diagnostic criteria given the overlap of symptoms among criteria. Several studies have compared the groups of patients selected using different ME/CFS criteria and found that the various criteria select groups of patients with differences in symptomatology and impairment (Jason et al., 2013b). Most of these studies have compared patients fulfilling the Fukuda definition with patients fulfilling another of the sets of ME/CFS criteria described above.

In general, the Fukuda definition identifies a larger, more heterogeneous group of patients compared with the other criteria (Jason et al., 2012a). The symptoms in the Fukuda definition can be present in other illnesses, and if exclusionary conditions are unknown or unaccounted for, patients with lupus or multiple sclerosis may be incorrectly diagnosed (Jason et al., 1997; King, 2003). Most patients that fulfill the CCC will also fulfill the Fukuda definition; not all patients fulfilling the Fukuda definition will also fulfill the CCC (Nacul et al., 2011; Pheby et al., 2011). Patients fulfilling the CCC have a higher prevalence and severity of symptoms than those fulfilling the Fukuda definition (Nacul et al., 2011). The CCC also has been shown to select patients with more functional impairment, fatigue, weakness, and neuropsychiatric and neurological symptoms relative to the Fukuda definition (Jason et al., 2004b; Morris and Maes, 2013; Watson et al., 2014). In addition, patients diagnosed with the CCC were found to have less psychiatric comorbidity than those diagnosed with the Fukuda definition (Jason et al., 2004b).

The CCC requires only the presence of a symptom to count toward a diagnosis, whereas the Revised CCC specifies that minimum levels of frequency and severity be present for a symptom to count toward a diagnosis. Fewer patients meet the criteria for ME/CFS under the Revised CCC than do so under the CCC or the Fukuda definition (Jason et al., 2012a). Up to 75 percent of patients fulfilling the Fukuda definition will also fulfill the CCC, suggesting that the CCC selects a subset of these patients (Jason et al., 2013a; Nacul et al., 2011). Patients fulfilling the Revised CCC have more severe functional impairment and physical and cognitive symptoms relative to those fulfilling the Fukuda definition. In contrast to the CCC, and perhaps as a result of requiring higher frequency and greater severity of symptoms, the Revised CCC identifies patients with significantly more psychiatric comorbidity compared with the Fukuda definition (Jason et al., 2012a).

The ME-ICC has been shown to select for a subset of patients that also meet the Fukuda definition. Patients that fulfill the ME-ICC have more severe functional impairment and more physical, mental, and cognitive problems than those that fulfill the Fukuda definition. There has been conflicting evidence on rates of psychiatric comorbidity in those fulfilling the ME-ICC compared with the Fukuda definition, which may be attributable to the different measures used in different studies (Brown et al., 2013b; Jason et al., 2014).

Challenges Created by Multiple Sets of Criteria

The way a definition is operationalized can dramatically affect the specificity of diagnostic criteria. Jason and colleagues (2013b) examined different thresholds for ME/CFS symptoms and found that merely requiring a symptom to be present without specifying a minimum level of frequency or severity resulted in more frequent misdiagnosis of healthy controls as having ME/CFS. Without a minimum threshold for assessing symptoms, 33.7 percent of healthy controls fulfilled the Fukuda definition, 20.7 percent fulfilled the CCC, and 14.6 percent fulfilled the ME-ICC. After applying minimum thresholds for frequency and severity (symptoms must be present at least half of the time with at least moderate severity), only 4.7 percent of healthy controls fulfilled the Fukuda definition, while 3.7 percent fulfilled both the CCC and ME-ICC. The operational ambiguity has important consequences for research in ME/CFS, as different studies operationalize the criteria in different ways, limiting comparisons across studies. Having different case definitions also has resulted in diagnostic unreliability and confusion for clinicians, patients, and their families.

In April 2014, the U.S. Social Security Administration—the government agency responsible for administering disability benefits—revised its guidelines for evaluating disability claims involving ME/CFS. The new ruling replaced previous guidelines, which were based on the Fukuda definition of CFS. The updated guidelines are based on adaptations of the Fukuda definition and some elements of the CCC and ME-ICC (Social Security Ruling, 2014). Although disability is a legal decision and not a medical diagnosis, the U.S. Social Security Administration's incorporation of more recent diagnostic criteria indicates the usefulness of these criteria for identifying ME/CFS. More information on disability related to ME/CFS can be found in Appendix C.

Validation of Diagnostic Criteria for ME/CFS

In a recent systematic review, Brurberg and colleagues (2014) identified 38 studies on comparison and evaluation of the existing diagnostic criteria for ME/CFS, which they considered “validation” studies. Their search strategy identified studies that either (1) independently applied multiple case definitions to the same population; or (2) sequentially applied multiple case definitions (with assumed increasing specificity) to the same population; or (3) indirectly compared prevalence estimates from multiple case definitions applied to different populations. All clinical and basic science studies were excluded. Most of these studies examined the Fukuda definition; there were a few validation studies for the CCC and ME-ICC and none for the NICE guidelines. Most of the studies had serious limitations, and there were no rigorous assessments of the reproducibility or feasibility of case definitions.

Pediatric Definitions

Although most of the diagnostic criteria described above were developed for adults, they have been used to diagnose children and adolescents in both clinical and research settings. ME/CFS usually is equally represented in younger male and female children, yet it occurs more frequently in female than in male adolescents (Royal College, 2004). Two case definitions have been developed specifically for children (one proposed by Jason and colleagues and one developed by the Royal College of Paediatrics), but the CCC, NICE guidelines, and ME-ICC include guidelines for diagnosing ME/CFS in children (Carruthers et al., 2003, 2011; Jason et al., 2006; NICE, 2007; Royal College, 2004). The concerns and limitations described above for the case definitions and diagnostic criteria for adults apply also to criteria used to diagnose children and adolescents.

Canadian Consensus Criteria for ME/CFS (2003)

Although there are no separate criteria for children in the CCC, these criteria note that children with ME/CFS usually have numerous symptoms, and “their hierarchy of symptom severity may vary from day to day” (Carruthers et al., 2003, p. 21). Children fulfilling the CCC may be diagnosed after the illness persists for 3 months (rather than the 6 months required for adults) (Carruthers et al., 2003).

Royal College of Paediatrics and Child Health Evidence-Based Guideline for the Management of CFS/ME in Children and Young People (2004) and NICE Guidelines (2007)

The Royal College of Paediatrics and Child Health proposed pediatric criteria for ME/CFS in 2004. The authors considered whether the shorter duration of 3 months for diagnosis rather than 6 months is appropriate in children. They concluded that, in the absence of compelling epidemiological data, the diagnosis of ME/CFS requires 6 months. They nonetheless suggest that pediatricians should be “prepared to make a positive diagnosis of CFS/ME when a child or young person has characteristic symptoms supported by normal results and when the symptoms are causing significant functional impairment. This diagnosis does not depend on a specific time frame, and a positive diagnosis of CFS/ME is not a prerequisite for the initiation of an appropriate management plan” (Royal College, 2004, p. 27). Nevertheless, the NICE guidelines, published in 2007, recommended a duration of symptoms of 3 months for children and young people (NICE, 2007).

International Association for CFS/ME Pediatric Case Definition (2006)

The International Association for CFS/ME's (IACFS/ME's) pediatric case definition, developed by Jason and colleagues (2006), incorporates elements of the Fukuda definition and the CCC and was intended to facilitate clinical and research diagnoses of ME/CFS in children and adolescents. Like the CCC, the pediatric definition requires 3 months of clinically evaluated, unexplained, persistent or relapsing chronic fatigue as well as cardinal symptoms of ME/CFS: PEM, unrefreshing sleep, pain, and neurocognitive manifestations. To fulfill the pediatric definition, a patient must also have some combination of autonomic, neuroendocrine, or immune manifestations. As noted in the CCC, the pediatric definition highlights “the individuality of symptom patterns and unpredictability of symptom severity among youngsters with ME/CFS” (Jason et al., 2006, p. 5). The pediatric definition also was intended to represent the importance of particular symptoms, including dizziness, decreased endurance with symptoms, pain, and flu-like symptoms.

The onset of ME/CFS symptoms in pediatric populations can be abrupt or insidious. This definition recommends that patients who have experienced symptoms for 1 to 2 months should be classified as “CFS-like.” A small number of patients may present with no pain or sleep dysfunction or have only two to four of the cardinal ME/CFS symptoms described above. These individuals may be given a diagnosis of atypical pediatric ME/CFS (Jason et al., 2006). Subsequently, Jason and colleagues (2009) further subdivided these criteria into severe and moderate. As with the diagnostic criteria for adults, the pediatric definition includes a list of medical and psychiatric conditions that may also cause chronic fatigue and should be considered exclusionary.

International Consensus Criteria for Pediatric ME (2011)

The ME-ICC, as discussed above, was developed for both clinical and research use and includes considerations for diagnosing children and adolescents. The ME-ICC also emphasizes the fluctuation of symptoms and symptom severity in pediatric ME/CFS as well as the gradual onset of symptoms. In addition to PEM, the most prominent pediatric symptoms include headaches, neurocognitive impairments, and sleep disturbances. The ME-ICC also notes that pain in pediatric ME/CFS “may seem erratic and migrate quickly” and that “joint hypermobility is common” (Carruthers et al., 2011, p. 330).

Comparison of Pediatric Diagnostic Criteria

Differences among the diagnostic criteria for pediatric ME/CFS are similar to those among the adult criteria, but some aspects are consistent in most of the pediatric criteria. All the pediatric criteria except the Royal College of Paediatrics guideline recognize the more gradual or insidious onset of symptoms relative to adults, require that symptoms persist for a shorter period of time before diagnosis than in adults, and highlight the variability of symptoms and symptom severity in individual pediatric patients. They all note that ME/CFS symptoms often make it more difficult to do schoolwork, so children and adolescents with ME/CFS may be misclassified as having “school phobia.”2 All include information to help clinicians differentiate ME/CFS from school phobia (Carruthers et al., 2003, 2011; Jason et al., 2006). Although children with school phobia and ME/CFS may have similar complaints, symptoms of the former condition usually disappear when a child is allowed to stay home or on weekends or holidays (Jason et al., 2006). Moreover, children with school phobia continue to enjoy their hobbies and leisure activities, while children with ME/CFS are likely to abandon them to keep up in school and spend their out-of-school hours resting (Carruthers et al., 2011; Jason et al., 2006). School phobia is listed as a comorbidity in the IACFS/ME pediatric case definition, and “primary” school phobia is considered an exclusionary condition in the ME-ICC. Both of these criteria note that it is important to determine the timeline of symptoms, as school phobia may develop as a consequence of ME/CFS in situations where academic performance becomes difficult or bullying due to ME/CFS symptoms occurs (Carruthers et al., 2011; Jason et al., 2006). Jason and colleagues (2006) note that a comprehensive evaluation should be able to distinguish between the two conditions.

The use of different diagnostic criteria and case definitions has posed the same challenges for research into pediatric ME/CFS as it has for research with adults. The IACFS/ME pediatric case definition was developed years after similar criteria existed for adults, so it is not surprising that much of the research on pediatric populations has used the Fukuda definition (Jason et al., 2006). The use of different definitions to define research populations impedes the ability to compare results across studies.

Research Subgroups

The Fukuda definition identifies essential and optional variables for subgrouping patients in formal studies (research subgroups), yet many researchers have not examined subgroups of patients according to these guidelines. There are numerous ways to stratify patients with ME/CFS (see Box 3-1). Evidence specific to certain subgroups of ME/CFS is discussed in Chapters 4, 5, and 6.

Box Icon

BOX 3-1

ME/CFS Research Subgroups. Fulfillment of different case definitions or diagnostic criteria Illness onset: sudden or gradual


In response to its directive to “recommend whether new terminology for ME/CFS should be adopted,” the committee considered the variety of names that have been proposed for ME/CFS. Over the years, many patients and advocates have suggested a variety of other names they find more appropriate (Dimmock and Lazell-Fairman, 2014; Jason et al., 2001, 2004a). The committee asked members of the public to suggest a new name for the illness, and these suggestions can be found in Box 3-2. The most common suggestions were “myalgic encephalomyelitis,” “myalgic encephalomyelitis/chronic fatigue syndrome” (ME/CFS), and “chronic fatigue and immune dysfunction syndrome” (CFIDS). The most commonly used names include “chronic fatigue syndrome” and “myalgic encephalomyelitis,” either of which may be used alone or in combination with others. Other names include “benign myalgic encephalomyelitis,” “post-viral fatigue syndrome,” and “epidemic neuromyasthenia.”

Box Icon

BOX 3-2

Suggestions for a New Name Received from Members of the Public. Myalgic encephalomyelitis Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)

As discussed in Chapter 2, many patients and researchers are critical of the term “chronic fatigue syndrome,” which is the name most commonly ascribed to this disease in the United States (but not in other parts of the world). Patients in particular find this term stigmatizing and trivializing, and there is evidence to support these perspectives. The way an illness is labeled affects the illness experience (Wojcik et al., 2011). Labels convey meanings that affect patients' perception of their illness as well as the reactions of others, including medical personnel, family members, and colleagues (Jason and Richman, 2008; Jason et al., 2002b; Wojcik et al., 2011). As noted in Chapter 2, patients have reported that many clinicians are dismissive, making such comments as “I am fatigued all the time, too.” Perceptions of a patient by others are important because they have been shown to affect the course of a disorder and may be associated with different outcomes (Wojcik et al., 2011).

In addition to the personal experiences presented in Chapter 2, several investigators have examined the attitudes and beliefs elicited by different diagnostic labels for ME/CFS. Among medical students, the term “myalgic encephalomyelitis” was more likely to be classified as a disease than the term “chronic fatigue syndrome” (Erueti et al., 2012). Among medical trainees and college students, the term “myalgic encephalomyelitis” was “more likely to prompt beliefs in a physiological cause for the illness” than the term “chronic fatigue syndrome” (Jason et al., 2002b, 2004a, p. 223).

Conclusion: The committee agrees that the term “chronic fatigue syndrome” often results in stigmatization and trivialization and should no longer be used as the name of this illness.

In considering which name would be most appropriate, the committee turned first to ME—“myalgic encephalomyelitis” or “encephalopathy.” Historically, however, the diagnostic criteria for ME have required the presence of specific or different symptoms from those required by the diagnostic criteria for CFS; thus, a diagnosis of CFS is not equivalent to a diagnosis of ME. This term also fails to convey the full spectrum of this disorder. While the term “encephalopathy” suggests the presence of global brain dysfunction, a symptom supported by research, the term “encephalomyelitis” suggests brain inflammation, for which there is much less evidence at present. Similarly, the term “myalgia” refers to a symptom that is neither a distinguishing aspect of this illness nor a severe symptom in many patients with ME/CFS. The committee noted that many of the other proposed names focus on particular organ systems, while others suggest particular etiologies for this disorder, such as immune or infectious, which are not yet proven. The committee's recommendations for new terminology for ME/CFS are presented in Chapter 7.


Committee members read and reviewed selected articles with the following questions in mind: Is there a set of core symptom constructs that defines ME/CFS and distinguishes it from other disorders? Are there particular clusters or characteristics of symptoms that reliably identify subgroups of individuals with ME/CFS? (For more information on the methodology of the literature review, see Chapter 1.)

Many of the limitations of the evidence base on ME/CFS described elsewhere in this report apply to this literature (see Chapter 4). For example, studies used different measures to assess various symptoms. Some instruments measured the presence or absence of a symptom in a dichotomous manner; others categorized symptoms according to frequency or severity or both. Some studies evaluated a narrow or limited set of symptoms and failed to assess potentially relevant symptoms, such as PEM or flu-like complaints. The study investigators used a variety of analytic methods, including factor analysis, principal component analysis, cluster analysis, and classification and regression tree (CART). They rarely specified either the rationale for or the limitations of the method they chose. Small studies with few individuals sharing particular constellations of symptoms sometimes limited the ability to tease out distinct clusters or subgroups of ME/CFS patients.


Key Symptom Constructs Identified by Factor Analyses

Several investigators used factor analysis to explore the relations or components of symptom constructs or to reduce large sets of symptom data to a few structural components. As these particular factor analyses did not differentiate among groups of people with and without illness, their findings cannot be used to create a discriminating case definition. In the absence of standard protocol, investigators assigned somewhat different names to groups of symptoms (e.g., “cognitive problems,” “cognitive difficulties”) and identified different numbers of factors (e.g., four to six) as important (Arroll and Senior, 2009; Jason et al., 2002). They used different statistical approaches and made different decisions about how factors were “extracted” and “rotated.”3 Some used low threshold factor loading values, which resulted in retaining symptoms that contributed relatively little information. Only one study involved both an exploratory and a confirmatory analysis (Nisenbaum et al., 2004).

Most authors identify fatigue-type factors as an integral symptom construct of ME/CFS (Arroll and Senior, 2009; Jason and Taylor, 2002; Nisenbaum et al., 1998, 2004; Ray et al., 1992). In two studies, fatigue is considered part of a multidimensional construct encompassing fatigue, mood, and cognition (Nisenbaum et al., 1998, 2004), while in two other studies, fatigue is considered part of a bidimensional construct related to either rest or PEM (Arroll and Senior, 2009; Jason and Taylor, 2002). Several studies identify a “neurocognitive difficulty” factor that includes such symptoms as slowness of thought; mental fog; and problems with concentrating, memory, or understanding (Arroll and Senior, 2009; Hickie et al., 2009; Jason and Taylor, 2002; Ray et al., 1992). Some identify a “musculoskeletal” factor that includes such symptoms as muscle or joint aches and pains and weakness (Brimacombe et al., 2002; Hickie et al., 2009; Nisenbaum et al., 2004; Tseng and Natelson, 2004); a “viral flu-like” factor that includes such complaints as fever, sore throat, and tender lymph nodes (Brimacombe et al., 2002; Nisenbaum et al., 1998, 2004; Tseng and Natelson, 2004); an emotional distress or mood or anxiety disturbance factor (Arroll and Senior, 2009; Fostel et al., 2006; Hickie et al., 2009; Ray et al., 1992); a somatic factor that includes such gastrointestinal complaints as stomach pain or diarrhea (Arroll and Senior, 2009; Nisenbaum et al., 2004; Ray et al., 1992); and a sleep difficulties factor (Fostel et al., 2006; Hickie et al., 2009).

Symptom Constructs and Clusters That Distinguish ME/CFS Patients

Few studies examined whether particular symptom clusters or characteristics of symptom constructs (e.g., severity, frequency) differentiated individuals with ME/CFS from healthy individuals or individuals with fatigue due to conditions other than ME/CFS. One study involving 236 participants who had been diagnosed by physicians using either the Fukuda definition or the CCC and 86 healthy controls examined the frequency and severity of 54 symptoms reported on the DePaul Symptom Questionnaire (Jason et al., 2013b). Three symptom constructs (PEM, memory and concentration problems, unrefreshing sleep) were more prevalent among ME/CFS patients compared with other constructs (e.g., headaches, joint pain, muscle aches, sore throat, lymph node problems). Using a CART algorithm, the investigators found that three symptoms (fatigue or extreme tiredness, inability to focus on more than one item at a time, experiencing a dead or heavy feeling after starting to exercise) accurately classified 95.4 percent of the study participants as patients or healthy controls when a minimum frequency and severity score of 2 (symptom must be of at least moderate intensity and be present at least half of the time) was used for the symptoms.

A community-based study of 780 adults in Chicago who reported chronic fatigue symptoms subdivided the sample into individuals with (1) ME/CFS who had four or more symptoms of the Fukuda definition, (2) idiopathic chronic fatigue, or (3) fatigue explained by medical or psychiatric conditions (Jason et al., 2002a). Symptoms were assessed with the CFS Screening Questionnaire administered via telephone, and diagnoses were not verified by physician evaluation. Four factors—“lack of energy,” “physical exertion,” “cognitive functioning,” and “fatigue and rest”—most accurately defined fatigue-related symptomatology in individuals with severe fatigue lasting 6 months or longer. The group with ME/CFS meeting the Fukuda definition consistently had more severe symptomatology for all four dimensions of fatigue compared with those in the idiopathic fatigue group. Another analysis of data from this study, limited to 166 individuals who were medically evaluated, identified three clusters of participants (Jason and Taylor, 2002). The cluster that contained the highest proportion of participants with ME/CFS was characterized by high post-exertional fatigue and fatigue not alleviated by rest.

A study conducted in Germany compared the presence or absence of 26 “unspecific” symptoms in outpatients with severe fatigue who had ME/CFS (n = 91), systemic lupus erythematosus (n = 41), or fibromyalgia (n = 58) (Linder et al., 2002). ME/CFS patients met the Fukuda definition for ME/CFS or for idiopathic chronic fatigue. Neither PEM nor postexertional precipitation/exacerbation of symptoms was examined. Four analytic methods, including regression tree analysis and artificial neural network analysis, were used to generate classification criteria that would differentiate the patients with ME/CFS from those with lupus and fibromyalgia. Although the various analytic methods resulted in different optimum sets of classification criteria, symptoms that appeared to best differentiate ME/CFS patients from the other patients were “acute onset of fatigue” and “sore throat.”

Hickie and colleagues (2009) analyzed heterogeneous data collected from 33 different studies in 21 countries. They found that patients diagnosed with ME/CFS, compared with people with chronic fatigue but no ME/CFS diagnosis, more commonly reported “musculoskeletal pain/fatigue” symptom factors (e.g., “pain in arms or legs”) and “neurocognitive difficulties” (e.g., “poor concentration”) and less commonly reported “sleep disturbance/fatigue” symptom factors (e.g., “waking up tired”). A study involving patients recruited both from tertiary clinics and through advertisements concluded that a broad diversity of ancillary symptoms distinguishes ME/CFS from other fatiguing syndromes and that exertional exhaustion helps separate ME/CFS and ME/CFS-like patients from healthy controls (Baraniuk et al., 2013).

Using data from a population-based telephone survey in San Francisco, Nisenbaum and colleagues (1998) attempted to identify the correlations between severe fatigue not explained by medical or psychiatric conditions and lasting either less than 6 months or 6 months or longer and 30 symptoms perceived to be “significant health problems” during the previous 4 weeks. A random sample of 1,078 adults with no fatigue and a total of 1,510 adults with unexplained severe fatigue were interviewed. Through common factor analysis, the authors identified three correlated factors (“fatigue-mood-cognition” symptoms, “flu-type” symptoms, and “visual impairment”) that explained the correlations between fatigue lasting 6 months or longer and 14 interrelated symptoms. The authors could identify no factors that explained the correlations between fatigue lasting less than 6 months and other symptoms. They concluded that “these results provide empirical support for the interrelations among unexplained fatigue of ≥ 6 months' duration and symptoms included in the CFS case definition.” They interpreted the study findings as suggesting that as unexplained fatigue continues (with 6 months being a possible threshold), other “natural” accompanying symptoms that may help define the presence of ME/CFS are likely to arise.

A second study by Nisenbaum and colleagues (2004) examined the presence or absence of 21 symptoms in 1,391 chronically fatigued patients, including 43 patients with diagnosed ME/CFS. Factor scores for three symptom areas (musculoskeletal, infection, and cognition-mood-sleep) were created, and cluster analysis was used to generate three groups of patients. Cluster 1 (n = 232) represented the healthiest patients and included very few patients with ME/CFS, while cluster 3 (n = 455) included most of the ME/CFS patients and patients who were most chronically unwell. Agreement between clusters and fatigue subgroups was poor. The authors concluded that ME/CFS may represent the severe end of a spectrum of “chronic unwellness syndrome” but that chronic unwellness per se is not sufficient to distinguish patients with ME/CFS from those with other fatigue states.

Symptom Constructs and Clusters That Identify Subgroups

A small study involving 114 participants meeting the Fukuda definition for ME/CFS who were recruited to participate in a trial used cluster analysis to identify three subgroups of patients: symptomatic and highly overextended individuals (n = 20), less symptomatic and moderately overextended individuals (n = 34), and symptomatic and mildly overextended individuals (n = 37) (Brown et al., 2013a). Overextension was measured by an “energy envelope quotient” calculated from self-rated measures of energy capacity and energy expended. The cluster of individuals who were symptomatic and mildly overextended had more pain than individuals in the other clusters. Another study involving the same patients found that patient fatigue patterns reported during a single day could be subtyped into the following three categories based on fatigue intensity and variability: group 1 had high fatigue intensity and low variability; group 2 “had moderate fatigue intensity and high variability, with fatigue intensity decreasing over time”; and group 3 “had moderate fatigue intensity and high variability, with fatigue intensity increasing over time” (Jason et al., 2012a, p. 4).

A study of 246 patients recruited from support groups who self-reported that they had been diagnosed with ME/CFS according to the Fukuda definition used cluster analysis to identify low, medium, and high symptomatology subgroups (Arroll and Senior, 2009). Individuals in the high symptomatology subgroup had high scores in all five factor domains (fibromyalgia syndrome [FMS]-like, depression/anxiety, fatigue/PEM, cognitive/neurological, irritable bowel syndrome [IBS]-like). Individuals in the low symptomatology subgroup had average scores in the depression/anxiety domain and low scores in all other domains.

Two studies explored gender differences in the expression of symptoms. One of these studies examined 121 patients meeting the Fukuda definition and found no gender differences in severity of fatigue or functional status; however, women were more likely than men to have flu-like symptoms and less likely to have comorbid depression (Tseng and Natelson, 2004). The second, larger study of 780 adults reporting chronic fatigue found that women experienced more difficulty with memory, concentration, and information processing than men (Jason et al., 2002a). This study also found that middle-aged and older individuals with chronic fatigue reported more difficulties with energy, tiredness, weakness, and fatigue and greater fatigue symptomatology following exertion relative to individuals younger than 40. Finally, individuals of low socioeconomic status reported more severe fatigue related to exertion compared with those of higher socioeconomic status.

One study examined differences in disease presentation in older and younger Fukuda-diagnosed ME/CFS patients (Lewis et al., 2013). The study matched 25 older patients (> 50) to 25 younger patients (16-29) on gender and length of history and found very different disease phenotypes between the two groups. Specifically, the older patients demonstrated greater fatigue, a higher rate of depression, greater autonomic dysfunction, lower baroflexic sensitivity, and more prolonged left ventricular ejection time. The findings of this study suggest a greater disease impact in older patients.


These studies provide insufficient evidence to conclude that a specific cluster of symptoms universally defines ME/CFS or that the presence of a particular cluster of symptoms reliably distinguishes among ME/CFS subgroups or distinguishes ME/CFS from other disorders. Individual symptom constructs that may help distinguish adults with ME/CFS from those with other conditions include intense fatigue or tiredness that is worsened by exertion and not alleviated by rest, neurocognitive difficulties characterized by slowness of thought or mental fog, and unrefreshing sleep. Severity scores for such constructs as fatigue appear to be higher in individuals with ME/CFS than in those without ME/CFS. Accordingly, it is important to consider symptom thresholds that take severity into account when operationalizing any diagnostic criteria for ME/CFS.


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Japanese investigators have frequently used the term “school phobia” to refer to pediatric ME/CFS (Miike et al., 2004).


Factor extraction and rotation are essential steps in exploratory factor analysis. Extraction is performed to produce factor loadings with the hope of large loading on one factor and small loadings on other factors—this is known as “simple structure.” There are several approaches to extraction, and principal axis factoring and maximum likelihood are considered the most appropriate methods for small sample sizes. Rotation then maximizes high loadings and minimizes low loadings to achieve the simplest structure. The two basic approaches to rotation are “orthogonal” and “oblique,” with various algorithms to employ with each method. The former assumes no correlation between factors, and the latter assumes correlation (Kim and Mueller, 1978).

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