Abstract
Considerable discussion has transpired regarding whether chronic fatigue syndrome is a distinct illness from Myalgic Encephalomyelitis. A prior study contrasted the Myalgic Encephalomyelitis International Consensus Criteria with the Fukuda and colleagues’ chronic fatigue syndrome criteria and found that the Myalgic Encephalomyelitis International Consensus Criteria identified a subset of patients with greater functional impairment and physical, mental, and cognitive problems than the larger group who met Fukuda and colleagues’ criteria. The current study analyzed two discrete data sets and found that the Myalgic Encephalomyelitis International Consensus Criteria identified more impaired individuals with more severe symptomatology.
The term Myalgic Encephalomyelitis (ME) was first used in an anonymous editorial in an issue of the Lancet (Anonymous Editorial, 1956). Using this term, Ramsay (1988) published a case definition for ME (Hyde et al., 1992). Subsequently, a case definition was developed utilizing the term Myalgic Encephalomyelitis/chronic fatigue syndrome (ME/CFS; Carruthers et al., 2003), known as the 2003 Canadian Clinical ME/CFS case definition. These criteria required the occurrence of seven specific ME/CFS symptoms. Several of the individuals who were involved in creating the ME/CFS criteria, along with other scientists and clinicians, recently published the Myalgic Encephalomyelitis International Consensus Criteria (ME-ICC; Carruthers et al., 2011). In addition to requiring the presence of eight symptoms from four domains, these criteria specify that the impact of the illness must result in a 50 percent or greater reduction in the patient’s premorbid activity level.
In contrast, most scientists have used the Fukuda et al. (1994) case definition in researching CFS. This case definition requires an individual to experience six or more months of chronic fatigue of a new or definite onset that is not substantially alleviated by rest, not the result of ongoing exertion, and results in substantial reductions in occupational, social, and personal activities (Fukuda et al., 1994: 956). The Fukuda et al. case definition employs a polythetic approach for assessing symptomatology. Thus, in contrast to the ME/CFS (Carruthers et al., 2003) and ME-ICC (Carruthers et al., 2011) case definitions, the Fukuda et al. criteria require any four symptoms out of a possible eight, so individuals who meet Fukuda et al. criteria may not have core CFS symptoms such as post-exertional malaise.
In a study of individuals who had been diagnosed using the Fukuda et al. (1994) CFS criteria, Brown et al. (2013) examined whether these participants also met the ME-ICC (Carruthers et al., 2011). Findings indicated that the ME-ICC identified individuals with more serious symptomatology and functional disability than those who met only the Fukuda et al. criteria. Unfortunately, there were two limitations in this initial effort to compare this CFS criteria and the ME-ICC. First, individuals recruited into the sample had to have been diagnosed with CFS, so this requirement may have led to a selection bias. Second, the instrument used to measure ME-ICC symptoms was created prior to the criteria’s publication, so that a number of symptoms could only be assessed indirectly. This study used a new instrument that better assessed ME-ICC symptoms and examined two groups of participants who were recruited using different case ascertainment methods to reduce selection bias. We hypothesized that the ME-ICC would identify a more impaired, symptomatic group than the Fukuda et al. criteria.
Method
Case definitions
CFS case definition
A case of CFS is defined by Fukuda et al. (1994) as the presence of the following criteria: (1) clinically evaluated, unexplained, persistent, or relapsing chronic fatigue that is of new or definite onset (has not been lifelong), is not the result of ongoing exertion, and is not substantially alleviated by rest and results in substantial reduction in previous levels of occupational, educational, social, or personal activities; and (2) the concurrent occurrence of four or more core symptoms, all of which must have persisted or recurred during 6 or more consecutive months of illness and must not have predated the fatigue (Fukuda et al., 1994: 956). Because frequency and severity criteria were not specified for the symptoms required in this case definition, participants needed to report frequency and severity scores of at least 1 for a symptom to be counted toward the four required symptoms. Using the Fukuda et al. criteria, 96.3 percent met criteria in the DePaul sample and 86.5 percent in the Newcastle sample. Table 1 provides a summary of the Fukuda et al. criteria.
Summary of case definition criteria: CFS criteria (Fukuda et al., 1994) and Myalgic Encephalomyelitis International Consensus Criteria (ME-ICC; Carruthers et al., 2011).
CFS: chronic fatigue syndrome.
ME-ICC case definition
The ME-ICC (Carruthers et al., 2011) state that symptom severity must result in a 50 percent or greater reduction of a patient’s premorbid activity level for a diagnosis. Additionally, symptoms from four major groupings are required. First, to meet criteria, a person must experience post-exertional neuroimmune exhaustion (PENE). Within the neurological impairment symptom grouping, a patient must have at least one symptom from three of the following four symptom categories: (1) neurocognitive impairments (e.g. difficulty processing information and short-term memory loss), (2) pain, (3) sleep disturbance, and (4) neurosensory, perceptual, and motor disturbances (e.g. inability to focus vision, sensitivity to light, and feeling unsteady on feet). The third category is immune, gastro-intestinal and genitourinary impairments, and individuals must have at least one symptom from three of the following five symptom categories: (1) flu-like symptoms, (2) susceptibility to viral infections with prolonged recovery periods (3) gastro-intestinal tract symptoms (e.g. nausea and abdominal pain), (4) genitourinary symptoms (e.g. urinary urgency), and (5) sensitivities to food, medications, odors, or chemicals. The final category is energy production/transportation impairments, and at least one symptom from one of the following four symptom categories must be present: (1) cardiovascular (e.g. orthostatic intolerance), (2) respiratory (e.g. labored breathing), (3) loss of thermostatic stability (e.g. subnormal body temperature), and (4) intolerance of extremes of temperature. Participants needed to report frequency and severity scores of at least 2 for a symptom to meet criteria. In the DePaul sample, 57.1 percent met the ME-ICC, and 58.3 percent of the Newcastle sample met these criteria. Table 1 provides a summary of the ME-ICC.
Research participants
The DePaul sample was a convenience sample of adults self-identifying as having ME, CFS, or ME/CFS that was collected between May 2010 and April 2012. The Newcastle sample was collected between June and September 2012 and consisted of patients referred to the Newcastle-upon-Tyne Royal Victoria Infirmary from primary care who fulfilled the Fukuda et al.’s (1994) CFS diagnostic criteria. Patients were given a complete medical work up. These two case ascertainment methods represent varied methods of patient recruitment that are currently used in studies of this illness.
DePaul sample
To be eligible for inclusion in the DePaul sample, an individual needed to be between the ages of 18 and 65 years, capable of reading and writing English, and have a self-reported current diagnosis of ME, CFS, or ME/CFS. Following approval by DePaul University’s Institutional Review Board, participants were recruited from a variety of sources: internet forums, support groups, individuals who had participated in the DePaul ME/CFS Research Team’s studies in the past and had indicated interest in future studies, and individuals who had emailed the team’s address with interest in future studies. Participants were given three options for completing the surveys: an electronic survey, a hard-copy survey, or a verbal survey over the telephone. Participants could complete these surveys at home or in person at the Center for Community Research at DePaul University. Participants were not given a timeline for survey completion due to the unpredictable nature of this illness that can result in unexpected, rapid declines in functioning. The first 100 individuals who completed the survey received a US$5.00 gift card to Amazon.com for participation.
Of the original 217 individuals who completed the study measures, 28 participants were excluded due to endorsing lifelong fatigue or exclusionary medical or psychological conditions that preclude a diagnosis of CFS based on the Fukuda et al. (1994) case definition. The ME-ICC (Carruthers et al., 2011) do not consider lifelong fatigue to be exclusionary, so only 21 participants were excluded when applying this case definition.
Demographically, the sample was 83.5 percent female and 16.5 percent male. Regarding self-reported race, 97.9 percent of the sample identified as Caucasian, 0.5 percent as Asian, and the remaining 1.6 percent identified as “Other.” In reporting work status, 55.3 percent of the sample stated that they were currently on disability, while 12.8 percent of the sample were working part- or full-time. With regard to educational level, 39.9 percent of the sample held a graduate or professional degree, 35.6 percent held a college degree, 17.6 percent had completed at least 1 year of college, and 6.9 percent had completed high school or an equivalent degree (e.g. General Educational Development (GED)). The mean age of the sample was 51.6 years (standard deviation (SD) = 11.2 years).
Newcastle sample
Participants were consecutive patients referred to the Newcastle-upon-Tyne Royal Victoria Infirmary from primary care who fulfilled the Fukuda et al. (1994) diagnostic criteria for CFS. These criteria exclude those with a number of significant psychiatric disorders and other confounding medical conditions such as cancer. Primary care physicians referred patients with a suspected CFS diagnosis for complete medical assessment at Newcastle-upon-Tyne Royal Victoria Infirmary clinic. At the infirmary, a comprehensive medical history and examination was performed by an experienced consultant physician. Those who met eligibility criteria completed a written informed consent process before being included in the sample. They completed the study measures by hard copy. The Newcastle sample consisted of 100 participants. One participant was excluded due to morbid obesity, and three additional participants were excluded due to lifelong fatigue when applying the Fukuda et al. (1994) criteria.
Demographically, the sample was 81.3 percent female and 18.7 percent male. Regarding self-reported race, 99.0 percent of the sample identified as Caucasian and 1.0 percent as multiracial. In reporting work status, 30.2 percent of the sample stated that they were currently on disability, while 36.1 percent of participants were working part- or full-time. With regard to education level, 18.8 percent held a graduate or professional degree, 28.1 percent held a college degree, 20.8 percent had completed at least 1 year of college, 13.5 percent had completed high school or an equivalent degree (e.g. GED), and 11.5 percent had not completed high school. The mean age of the sample was 46.0 (SD = 14.2).
Measures
The DePaul Symptom Questionnaire
All participants completed the DePaul Symptom Questionnaire (DSQ; Jason et al., 2010), a self-report measure of CFS, ME/CFS, and ME symptomatology, demographics, and medical, occupational, and social history. The DSQ contains items that tap the dimensions of the ME-ICC (Carruthers et al., 2011) and the Fukuda et al. (1994) CFS criteria. Participants were asked to rate each symptom’s frequency over the past 6 months on a 5-point Likert scale (0 = none of the time, 1 = a little of the time, 2 = about half the time, 3 = most of the time, and 4 = all of the time). Likewise, participants were asked to rate each symptom’s severity over the past 6 months on a 5-point Likert scale (0 = symptom not present, 1 = mild, 2 = moderate, 3 = severe, and 4 = very severe). The DSQ has evidenced good test–retest reliability among both patient and control groups (Jason et al., submitted). The development of the DSQ was based upon the CFS Questionnaire (Jason et al., 1997), which evidenced good inter-rater and test–retest reliability and was able to sensitively distinguish among individuals with CFS, Major Depressive Disorder, and healthy controls (Hawk et al., 2006). Like the DSQ, the CFS Questionnaire assesses for frequency and severity over the past 6 months, but the severity rating is on a scale from 0 to 100, whereas the DSQ uses a Likert scale. To facilitate comparison with the CFS Questionnaire, the DSQ frequency and severity scores were multiplied by 25 to create a 100-point scale. Each symptom’s 100-point frequency and severity scores were then averaged to obtain a composite score. The final difference between these two questionnaires is that the CFS Questionnaire was not developed to tap the ME-ICC requirements, while the DSQ was developed to assess these criteria. The DSQ is available through Research Electronic Data Capture’s (REDCap) (Harris et al., 2009) shared library (https://redcap.is.depaul.edu/surveys/?s=tRxytSPVVw).
Medical outcomes study 36-item Short-Form Health Survey or RAND Questionnaire
The 36-item Short-Form Health Survey (SF-36) is a 36-item self-report measure of health and its impact on one’s functioning (Ware and Sherbourne, 1992). Lower scores indicate worse health or more impaired functioning. Test construction studies of the SF-36 have demonstrated sufficient psychometric properties (McHorney et al., 1994), and the SF-36 has also been shown to be a valid measure of functional status in a CFS population (Buchwald et al., 1996).
Statistics
Because most participants who met the ME-ICC (Carruthers et al., 2011) also met the Fukuda et al. (1994) criteria, two independent groups were created for comparison purposes. Participants who met the ME-ICC (referred to as the ME-ICC group) were compared to participants who met the Fukuda et al. case definition but did not meet the ME-ICC case definition (referred to as the CFS group). Multivariate analyses of variance (MANOVAs) were used to analyze the DePaul sample. We were not able to use MANOVAs for the Newcastle sample due to the smaller sample size and violations of MANOVA assumptions, so individual analyses of variance (ANOVAs) (or adjusted F-tests, in cases of unequal variances) were conducted for each symptom. Note that, due to the number of comparisons, results that are significant at the p < .01 level can be interpreted with more confidence than those that are significant at the p < .05 level.
Results
Demographics
Table 2 presents demographic, psychiatric, and illness onset data for the CFS and ME-ICC groups. In the DePaul sample, there was a significant difference in age between the CFS group (M = 54.0, SD = 11.4) and the ME-ICC group (M = 49.8, SD = 10.9), t(183) = 2.57, p = .01. In addition, the two groups differed in their responses about what they believed to be the cause of their fatigue (p = .01, two-tailed Fisher’s exact test). There were no significant differences between the two groups in the Newcastle sample.
Demographics, psychiatric characteristics, and onset issues.
CFS: CFS Group, defined on page 5; ME: ME-ICC group, defined on page 5; SD: standard deviation.
p < .05.
Functional status
Table 3 presents data from the SF-36. In the DePaul sample, a MANOVA indicated that the ME-ICC group was significantly different from the CFS group (Wilks’ lambda = .84, F(8, 173) = 4.08, p < .001). Upon examination of the univariate tests, the ME-ICC condition showed significantly worse scores than the CFS group on the following five subscales: Physical Functioning (F(1, 180) = 6.87, p = .01), Role Physical (F(1, 180) = 5.67, p = .02), Bodily Pain (F(1, 180) = 19.71, p < .001), General Health (F(1, 180) = 7.78, p < .01), and Vitality (F(1, 180) = 4.30, p = .03). In the Newcastle sample, a Brown–Forsythe test of the General Health subscale indicated significantly worse scores in the ME-ICC group (F(1, 32.22) = 11.29, p < .01). For all remaining subscales, with the exception of Mental Health, scores of the ME-ICC group were directionally worse, but not significant.
SF-36 subscales (higher score indicates less impairment).
SF-36: 36-item Short-Form Health Survey; CFS: CFS Group, defined on page 5; ME: ME-ICC group, defined on page 5; SD: standard deviation.
p < .05; ** p < .01; *** p < .001.
When conducting the analysis above, the large amount of variance in Role Physical scores led to a significant Box’s M test, which tests the MANOVA assumption of homogeneity of covariance matrices. Therefore, the results of this MANOVA were confirmed through conducting a MANOVA on the remaining seven subscales (Wilks’ lambda = .85, F(7, 173) = 4.31, p < .001) and an adjusted F-test on the Role Physical subscale (F(1, 103.18) = 4.24, p = .04).
Symptoms
Table 4 lists the symptoms analyzed in the DSQ. To compare the CFS and ME-ICC groups in the DePaul sample, an ANOVA was conducted on the Fatigue symptom, and MANOVAs were conducted on the following categories of symptoms: Post-Exertional Malaise, Sleep, Pain, Autonomic, Neuroendocrine, and Immune. Significant differences were found for the Post-Exertional Malaise, Pain, Autonomic, Neuroendocrine, and Immune categories. Univariate tests revealed significant differences in 46 symptoms in the DePaul sample. In the Newcastle sample, ANOVAs showed significant differences between the CFS and ME-ICC groups’ scores for 33 symptoms. For all significant differences, the ME-ICC group reported worse symptom scores. Across both samples, most differences were significant at the p < .001 level.
Symptoms (higher score indicates more impairment).
CFS: CFS Group, defined on page 5; ME: ME-ICC group, defined on page 5; SD: standard deviation.
p < .05; **p < .01; ***p < .001.
Discussion
This study compared the ME-ICC (Carruthers et al., 2011) with the Fukuda et al. (1994) CFS criteria through analyzing two distinct samples. While the Fukuda et al. criteria are the most widely used, the Carruthers et al. (2011) criteria have received considerable attention due to the large number of ME and CFS experts who authored them. To our knowledge, only one other study to date has compared these two case definitions (Brown et al., 2013), but the study was limited by its case ascertainment method. The current study found that the ME-ICC case definition identified patients with more functional impairments and worse symptoms than the group of patients who met the Fukuda et al. criteria.
Using the Fukuda et al. (1994) CFS case definition, 96.3 percent met criteria in the DePaul sample and 86.5 percent in the Newcastle sample. However, when using the Carruthers et al. (2011) ME-ICC case definition, only 57.1 percent met criteria in the DePaul sample and 58.3 percent in the Newcastle sample. These consistent findings suggest that about 60 percent of patients meet the ME-ICC case definition, whereas the Fukuda et al. criteria identify a larger group of patients.
In Table 3, the ME-ICC group showed significantly worse scores in subscales measuring physical health, but no differences were found in subscales measuring mental health. Additionally, in Table 4, the ME-ICC group reported worse symptoms than the CFS group. These findings support the notion that the ME-ICC identify a more impaired sample, even across different patient recruitment methods.
The first US case definition by Holmes et al. (1988) required patients to report at least 8 of 11 minor symptoms. The requirement of eight or more minor symptoms raised concerns that this case definition could inadvertently select for individuals with psychiatric problems (Katon and Russo, 1992). A few years later, an international working group developed the revised case definition for CFS (Fukuda et al., 1994), which was followed by the creation of the ME/CFS (Carruthers et al., 2003) and ME-ICC (Carruthers et al., 2011) case definitions that included more specific symptom requirements. Maes et al. (2012) demonstrated the importance of requiring specific symptoms through dividing individuals with Fukuda-defined CFS into two groups: CFS with post-exertional malaise and CFS without post-exertional malaise. This study showed that individuals with post-exertional malaise had more severe symptoms and more immune abnormalities than those without it.
While post-exertional malaise may need to be a required symptom in case definitions, the Canadian ME/CFS criteria (Carruthers et al., 2003) required seven symptoms, rather than the four required by Fukuda et al. (1994), and the ME-ICC (Carruthers et al., 2011) required eight symptoms, similar in number to what was required by Holmes et al. (1988). The implications of requiring larger numbers of symptoms might need to be considered, particularly in terms of psychiatric comorbidity (Brown et al., 2013). While the present study did not find differential rates of psychiatric comorbidity between the CFS and ME-ICC groups, these findings were not based on a structured clinical interview.
The authors of the ME-ICC case definition recently published a primer (Carruthers et al., 2012) in which they provided guidelines for determining if symptoms meet thresholds for criteria. As an example, post-exertional malaise is referred to as PENE. In the self-report questionnaire included in the primer, PENE is characterized by (a) “Marked, rapid physical or cognitive fatigability in response to exertion”; (b) “Symptoms that worsen with exertion”; (c) “Post-exertional exhaustion”; (d) “Exhaustion is not relieved by rest”; and (e) “Substantial reduction in pre-illness activity level due to low threshold of physical and mental fatigability” (Carruthers et al., 2012: 10). This imprecise level of specification leads to a number of issues in operationalizing the criteria. First, it is unclear whether all five characteristics must be present for PENE to exist. Furthermore, the precise definition of these characteristics is still ambiguous. For example, the description of the onset and duration of PENE is vague, as it does not specify the length of time that individuals must experience this symptom in order to meet criteria.
In addition, the ME-ICC primer (Carruthers et al., 2012) designated severity levels for the assessment of activity reduction; however, these levels deviated from the original case definition. Instead of the three levels of severity indicated in the ME-ICC (Carruthers et al., 2011), the primer includes four levels (mild, moderate, severe, and very severe): the mild level signifies that a person “meets criteria” and is experiencing “significant” reductions in activity, the moderate level signifies that a person has experienced approximately a 50 percent reduction in pre-illness activity level, the severe level signifies individuals who are unable to function outside of the home, and the very severe level signifies individuals who are confined to their beds and who have difficulty caring for their own basic needs. It is unclear why the ME primer (Carruthers et al., 2012) implemented four severity levels of activity reduction, while only three were specified in the ME-ICC (Carruthers et al., 2011). More importantly, the mild level equated to an approximate 50 percent reduction in activity levels in the Carruthers et al. (2011) criteria, but the moderate level equated to a 50 percent reduction in the Carruthers et al. (2012) criteria. Furthermore, the language used in both the ME-ICC (Carruthers et al., 2011) and the ME primer (Carruthers et al., 2012) lacked specific definitions and assessment tools for consistently and accurately assessing substantial activity reductions and symptom severity in individuals with the illness. For instance, it is unclear how to determine whether someone is experiencing a “significant” reduction in activity versus a 50 percent reduction in activity. Without clearly defined criteria and adequate assessment tools, determining whether an individual meets these criteria is left to clinical discretion, which can differ greatly across clinicians. Thus, scientists and clinicians might encounter reliability problems when utilizing this new case definition.
Sources of variance can be divided into the following five categories: subject variance, occasion variance, information variance, observation variance, and criterion variance (Jason and Choi, 2008). Criterion variance accounts for the largest source of diagnostic unreliability, and is most likely to occur when operationally explicit criteria do not exist for diagnostic categories. In other words, inclusion and exclusion criteria must be consistent across measures to adequately compare fatigue states across patients. When diagnostic categories lack reliability, the validity (i.e. usefulness) of a diagnostic category is inherently limited. In other words, the extent to which a diagnostic category is unreliable places on its potential validity for any type of clinical, research, or administrative use.
Diagnostic criteria should specify which diagnostic instrument to use, which individuals to interview, and how to determine the presence and severity of symptoms. It is also necessary to specify the number and type of symptoms that must be present in order to make a particular diagnosis. Definitions of fatigue should also include specific guidelines pertaining to the importance of symptom severity in the diagnostic procedure. For example, if a patient endorses a symptom such as post-exertional malaise, standardized questions should identify the duration, frequency, and severity of the symptom, including its onset, pattern, intensity, and other associated factors.
Based on these analyses, the ME-ICC (Carruthers et al., 2011) appear to select a more functionally impaired and symptomatic group of individuals when compared to those who met only the Fukuda et al. (1994) criteria. Given the high level of interest among clinicians and scientists regarding the ME-ICC, more research should be conducted to investigate how these criteria, as well as the specific instruments developed to assess these criteria, potentially select different patient cohorts than the Fukuda et al. criteria. Additional studies are needed to determine if biological and psychiatric differences exist between those who meet these two case definitions. Additionally, researchers should continue to operationalize current criteria to reduce criterion variance and use more sophisticated analytic techniques to identify the critical dimensions of these illnesses (Jason et al., 2012).
Footnotes
Funding
Funding was provided by NIAID (grant numbers AI 49720 and AI 055735). We appreciate the ME Research UK organization, which provided a grant to collect the Newcastle sample.