What is in a name? Comparing diagnostic criteria for chronic fatigue syndrome with or without fibromyalgia

What is in a name? Comparing diagnostic criteria for chronic fatigue syndrome with or without fibromyalgia Mira Meeus, Kelly Ickmans, Filip Struyf, Daphne Kos, Luc Lambrecht, Barbara Willekens, Patrick Cras & Jo Nijs Clinical Rheumatology Journal of the International League of Associations for Rheumatology ISSN 0770-3198 Clin Rheumatol DOI 10.1007/s10067-014-2793-x 1 23 Your article is protected by copyright and all rights are held exclusively by International League of Associations for Rheumatology (ILAR). This e-offprint is for personal use only and shall not be self-archived in electronic repositories. If you wish to self-archive your article, please use the accepted manuscript version for posting on your own website. You may further deposit the accepted manuscript version in any repository, provided it is only made publicly available 12 months after official publication or later and provided acknowledgement is given to the original source of publication and a link is inserted to the published article on Springer's website. The link must be accompanied by the following text: "The final publication is available at link.springer.com”. 1 23 Author's personal copy Clin Rheumatol DOI 10.1007/s10067-014-2793-x ORIGINAL ARTICLE What is in a name? Comparing diagnostic criteria for chronic fatigue syndrome with or without fibromyalgia Mira Meeus & Kelly Ickmans & Filip Struyf & Daphne Kos & Luc Lambrecht & Barbara Willekens & Patrick Cras & Jo Nijs Received: 26 February 2014 / Revised: 11 September 2014 / Accepted: 29 September 2014 # International League of Associations for Rheumatology (ILAR) 2014 Abstract The current study had two objectives. (1) to compare objective and self-report measures in patients with chronic fatigue syndrome (CFS) according to the 1994 Center for Disease Control (CDC) criteria, patients with multiple sclerosis (MS), and healthy controls, and (2) to contrast CFS patients who only fulfill CDC criteria to those who also fulfill the criteria for myalgic encephalomyelitis (ME), the 2003 Canadian criteria for ME/CFS, or the comorbid diagnosis of fibromyalgia (FM). One hundred six participants (48 CFS patients diagnosed following the 1994 CDC criteria, 19 MS patients, and 39 healthy controls) completed questionnaires assessing symptom severity, quality of life, daily functioning, and psychological factors. Objective measures consisted of activity monitoring, evaluation of maximal voluntary contraction and muscle recovery, and cognitive performance. CFS patients were screened whether they also fulfilled ME criteria, the Canadian criteria, and the diagnosis of FM. CFS patients scored higher on symptom severity, lower on quality of life, and higher on depression and kinesiophobia and worse on MVC, muscle recovery, and cognitive performance compared to the MS patients and the healthy subjects. Daily activity levels were also lower compared to healthy subjects. Only one difference was found between those fulfilling the ME criteria and those who did not regarding the degree of kinesiophobia (lower in ME), while comorbidity for FM significantly increased the symptom burden. CFS patients report more severe symptoms and are more disabled compared to MS patients and healthy controls. Based on the present study, fulfillment of the ME or Canadian criteria did not seem to give a clinically different picture, whereas a diagnosis of comorbid FM selected symptomatically worse and more disabled patients. Electronic supplementary material The online version of this article (doi:10.1007/s10067-014-2793-x) contains supplementary material, which is available to authorized users. M. Meeus Department of Rehabilitation Sciences and Physiotherapy, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium D. Kos Division of Occupational Therapy, Artesis Plantijn University College Antwerp, Antwerp, Belgium M. Meeus : K. Ickmans : F. Struyf : J. Nijs Department of Rehabilitation Sciences and Physiotherapy, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium D. Kos Rehabilitation Sciences, KU Leuven, Leuven, Belgium M. Meeus : K. Ickmans : F. Struyf : D. Kos : J. Nijs Pain in Motion International Research Group http://www.paininmotion.be K. Ickmans : J. Nijs Departments of Human Physiology and & Rehabilitation Sciences, Faculty of Physical Education & Physiotherapy, Vrije Universiteit Brussel, Brussel, Belgium K. Ickmans : J. Nijs Department of Physiotherapy and Rehabilitation, University Hospital Brussels, Brussel, Belgium L. Lambrecht Private practice for internal medicine, Ghent, Belgium B. Willekens : P. Cras Department of Neurology, Faculty of Medicine, University and University Hospital Antwerp, Antwerp, Belgium M. Meeus (*) Rehabilitation Sciences and Physiotherapy, Ghent University, Campus Heymans (UZ) 3 B3, De Pintelaan 185, Ghent, Belgium e-mail: mira.meeus@ugent.be URL: http://www.paininmotion.be Author's personal copy Clin Rheumatol Keywords Chronic fatigue syndrome . Diagnosis . Fibromyalgia . Multiple sclerosis . Psychomotor performance . Symptom assessment Introduction Chronic fatigue syndrome (CFS) is a debilitating and complex disorder, mainly characterized by extreme fatigue together with several other side criteria [1]. The pooled prevalence for self-reporting assessment of CFS is 3.28 % (95 % confidence interval (CI) 2.24–4.33) and 0.76 % (95 % CI 0.23– 1.29) for clinical assessment, based on the meta-analysis of Johnston et al. [2] with over 75 % female patients [3]. But, little is known about its etiology, making prevention and treatment challenging. Moreover, the diagnosis is not straightforward, and multiple attempts have been made to provide diagnostic guidelines. The original criteria for the diagnosis of CFS were developed for the US Center for Disease Control (CDC) in 1988 [4] and were revised in 1994 [1]. To date, the 1994 CDC criteria are identified as the most widely applied criteria among prevalence studies. This case definition was the most widely accepted definition available at the time of these studies and is also still the current criteria used by the CDC [2, 5]. To fulfill these criteria, patients have to present with a prolonged debilitating fatigue, and at least four out of eight frequently reported minor criteria including headaches, recurrent sore throats, fever, muscle and joint pain, and neurocognitive complaints. Both the fatigue and the minor criteria have to be present for at least 6 months, while the fatigue should be of a new or definite onset, not substantially alleviated by rest and capable of significantly reducing the patient’s activity level. Crucially, other possible causes of a patient’s symptoms should be excluded, often by testing, before this diagnosis is given [1]. However, there have been suggestions that the criteria are vaguely worded and lack guidelines to assist health care professionals in their interpretation and that, overall, the CDC 1994 definition lacks specificity [6, 7] . In 2001, an expert medical consensus panel, established by the Expert Subcommittee of Health Canada, held a 3-day consensus workshop to review the clinical and research aspects of CFS. This workshop generated a new clinical working case definition, including a diagnostic protocol [8], for the illness, which was also renamed myalgic encephalomyelitis/ chronic fatigue syndrome (ME/CFS) to reflect the inclusion of patients, particularly those from the UK, with the pre-1994 diagnosis of myalgic encephalomyelitis (ME). These criteria for ME/CFS specified that post-exertional malaise must occur with a loss of physical or mental stamina, or rapid muscle or cognitive fatigability, with recovery usually taking 24 h or longer to occur, and they also required the presence of neurocognitive dysfunction. To meet the criteria, a person must also experience at least one symptom indicating sleep dysfunction, at least one symptom indicating significant bodily pain, and at least one symptom from two of the following categories: autonomic manifestations, neuroendocrine manifestations, and immune manifestations [8, 9]. To date, these “2003 Canadian criteria” for the diagnosis of ME/CFS have received little attention by clinicians and researchers across the world, and few studies using this definition have been published in the scientific literature [5]. Similarly, very few clinical studies using older criteria for the diagnosis of myalgic encephalomyelitis (ME) alone have been published, despite the fact that a number of definitions exist in (reviewed in [10]). The most widely known were put forward by Ramsay and colleagues [11, 12] and these were incorporated into later versions. In essence, the cardinal features of ME under these rubrics include a sudden onset of symptoms; physical or mental fatigue or muscle weakness after minimal exertion, persisting long after exertion ends; one or more symptoms indicating the involvement of the central nervous system, including concentration and memory difficulties; and marked fluctuation of symptoms. Patients with these clusters of symptoms have, since the publication of the revised CDC criteria for CFS in 1994, tended to be diagnosed with CFS by medical and health care professionals. Nevertheless, controversy regarding the diagnosis of CFS continues to exist in the scientific community, as well as among patient-based groups and organizations, and there have been attempts to compare and contrast the various criteria for diagnosing CFS patients. One study compared the 2003 Canadian criteria with the 1994 CDC criteria and found the Canadian criteria to select cases with less psychiatric comorbidity, and more functional impairment, fatigue, neuropsychiatric, and neurological symptoms [13]. Another study compared ME criteria with the 1994 CDC criteria for CFS and concluded that individuals meeting ME criteria were more symptomatic in the neurological and neuropsychiatric domains [14]. However, methodological issues preclude generalizing the findings from either studies: The sample sizes were low and the results rely on self-reported measures rather than objective study findings. A recent study by Jason et al. accounted for some of these shortcomings by studying 113 patients and using a cognitive test and heart rate assessment [15]. Based on the preliminary evidence, the results suggest that important differences might exist between the ME, 2003 Canadian criteria, and 1994 CDC criteria and that further investigations are warranted, particularly investigations employing objective measures. Indeed, it has been shown repeatedly that CFS patients perform less habitual physical activity [16] and have delayed muscle recovery following exercise [17], reduced psychomotor speed, and impaired cognitive performance [18]. But, it is not clear whether these symptoms and dysfunctions are present in all CFS patients irrespective of criteria or, indeed, Author's personal copy Clin Rheumatol whether they are not also shared with a disease control group like MS patients. In addition, CFS is known to have a considerable overlap with fibromyalgia (FM), a chronic pain syndrome that has been defined by widespread pain for more than 3 months and the presence of additional symptoms like disturbed sleep, emotional distress, and pronounced fatigue [19, 20]. These two conditions are highly comorbid: Up to 70 % of CFS patients fulfill the American College of Rheumatology (ACR) criteria for the diagnosis of FM [21–23], but nevertheless, it seems that those with comorbid FM have more pain, disability, depressive symptoms, and worse exercise response [23–25], but seem to have less cognitive problems [25]. It is important therefore to examine the possible role of comorbid FM on the symptoms experienced by CFS patients Accordingly, the aims of this investigation are twofold: (1) to compare CFS patients fulfilling the 1994 CDC criteria with disease control group of MS patients and to a healthy control group and (2) to contrast those only fulfilling the 1994 CDC criteria with patients also fulfilling the ME criteria or the 2003 Canadian criteria, and those with comorbid FM, as regards to specific CFS characteristics, including physical function, amount of physical activity, muscle recovery following fatiguing exercise, psychomotor speed, cognitive performance, and symptoms of autonomic dysfunction. Methods Study participants Participants, being CFS patients meeting the 1994 CDC criteria for CFS, MS patients, and sedentary healthy control subjects, attended the university for 2 testing days (day 1 and day 8). A consecutive sample of patients with CFS were recruited via a physician specialized in internal medicine and CFS. The physician has extensive experience (over 20 years) with the diagnosis and treatment of patients with CFS, including differential diagnosis . Initial diagnosis was performed according to the 1994 CDC criteria for CFS [1], implying that all patients entering the study had undergone an extensive medical evaluation to exclude alternative explanations for their symptoms. The extensive medical evaluation included a large number of specialized examinations like routine and specialized blood tests (including but not limited to a complete blood cell count, determination of the erythrocyte sedimentation rate, a serum electrolyte panel, measures of renal, hepatic, and thyroid function, and rheumatological and virological screens), maximal exercise capacity testing, neurological examination, and gynecological, endocrinological, cardiac, gastro-intestinal, and psychiatric examination. Patients fulfilling the McDonald diagnostic criteria for MS [26, 27] were recruited through the neurology department of the University Hospital of Antwerp. All patients were recruited via a neurologist specialized in MS, with extensive experience in the diagnosis and treatment of patients with MS. Diagnosis of MS is based on the objective demonstration of dissemination of lesions in time and space, including magnetic resonance imaging and other paraclinical methods. The patients had to have an Expanded Disability Status Scale (EDSS) score of <6 and had to be relapse free in the last 3 months. The healthy inactive control group was recruited through advertisements in internet newsletters, university staff, personal contacts of the researchers, and by asking the patients to bring along a healthy friend or family member to participate in the study. Inactive is defined as having a sedentary job and performing <3 h of moderate physical activity/week. Moderate physical activity is defined as activity demanding at least the threefold of the energy spent passively [28]. All study participants had to be aged between 18 and 65 years. In order to preclude confounding factors, participants were excluded if they were pregnant or had been pregnant in the previous 12 months. They were asked to stop anti-depressive, anti-epileptic, and opioid pain medication 2 weeks prior to study participation, not to undertake physical exertion, and to refrain from consuming caffeine, alcohol, or nicotine on the day of the experiment. This enabled to minimize the role of confounding factors [25, 29]. The study was approved by the Ethics Committees of the University Hospital Brussels/Vrije Universiteit Brussel and the University Hospital Antwerp. Diagnostic screening During their first visit, subjects were asked to sign the informed consent form. Afterward, they underwent a battery of non-invasive tests to make a thorough assessment of the most prominent features of the illness CFS based on self-report measures and objective outcome measures. On testing day 1, patients with clinically diagnosed CFS were examined to determine whether they also fulfilled the ME criteria [12], 2003 Canadian criteria [8], and the 2010 American College of Rheumatology (ACR) criteria for the diagnosis of fibromyalgia [20] by completing questionnaires. To screen for comorbid FM, the symptom severity scale and the widespread pain index were calculated according to the current FM diagnostic guidelines [30]. Furthermore, it was ascertained that complaints were present for more than 3 months. The presence of comorbidities was already excluded during the extensive screening as part of the initial diagnosis of 1994 CDC CFS performed by the physician for study inclusion (see above). To meet the criteria for ME [12], as used by Jason et al. [14], patients had to confirm the presence of four cardinal features: (1) physical or mental fatigue or muscle weakness Author's personal copy Clin Rheumatol after minimal exertion which may persist long after exertion ends, (2) impairment of memory and concentration, (3) the marked fluctuation of symptoms, (4) and complaints present for at least 6 months [12]. Screening the 2003 Canadian criteria [8] consisted of evaluating the presence of seven core characteristics, including (1) pathological “fatigue” combining exhaustion, weakness, heaviness, general malaise, lightheadedness, and sleepiness that can be overwhelmingly debilitating; (2) post-exertional malaise; (3) impairment of memory and concentration; (4) unrefreshing sleep; (5) arthralgia and/or myalgia; and (6) several autonomic, neuroendocrine, and immune manifestations; (7) present for at least 6 months [8]. Outcome measures Self-report measures Subjects were then subjected to the measurement of fatigue severity, symptom severity, cognitions, and quality of life, which were evaluated with questionnaires in random order. Quality of life The Medical Outcomes Short Form 36 Health Status Survey (SF-36) was used to assess functional status and well-being or quality of life [31]. The SF-36 has been documented to have reliability and validity in a wide variety of patient populations [31], and it is the most frequently used measure in CFS research [32]. Fatigue severity The Checklist Individual Strength or CIS subjective fatigue experience, concentration difficulties, motivation, and physical activity was evaluated [33]. Higher scores on the CIS correspond to severe fatigue, many concentration difficulties, problems with motivation, and a low level of physical activity. Its psychometric properties are well established [33, 34]. Symptom severity In order to assess the severity of the symptoms, the CFS Symptom List, including visual analog scales (100 mm) for the 19 most frequent symptoms, was used. The CFS Symptom List is a self-reported measure for assessing symptom severity in CFS patients. Psychometric work supporting the use of the CFS Symptom List has been published [35]. Psychological factors Irrational fear of movement, or kinesiophobia, acceptance, and depression were assessed through self-reported measures. The Tampa Scale Kinesiophobia version CFS [36] is a modification of the Tampa Scale for Kinesiophobia, a self-assessment tool for the measurement of pain-related fear of movement [37]. Evidence supportive of the psychometric properties of the Tampa Scale Kinesiophobia version CFS has been provided [35, 36]. Acceptance refers to halting the dominant search for a definite solution of physical complaints and to a reorientation of attention toward positive everyday activities and other aspects of life [38]. Acceptance was assessed using the Illness Cognition Questionnaire, a valid measure frequently used for research purposes in MS and CFS [39, 40]. Hypervigilance for pain was evaluated with the Pain Vigilance and Awareness Questionnaire (PVAQ), constructed to investigate attention to pain in persons with chronic pain, a 16item measure of attention to pain that assesses awareness, consciousness, vigilance, and observation of pain. Roelofs et al. [41] provided support that the PVAQ is a reliable and valid measure of pain vigilance in FM patients. Finally, the Beck Depression Inventory-Primary Care (BDI-PC) was used for the assessment of depressive symptoms. The BD-PC appears to be a reliable and valid tool for the assessment of depressive symptoms in chronic patients [42]. Objective outcome measures Afterward, participants completed performance-based cognitive testing on a laptop computer. Cognitive performance (neurocognitive testing) Cognitive performance was assessed using a battery of three consecutive computer tasks: the psychomotor vigilance task (PVT), the operation span task (OSPAN), and the Stroop task. The tasks are chosen based on the outcome of a systematic literature review addressing neurocognitive performance of patients with CFS [18]. Each of the three tests have been used and described in detail in two of our previous studies in female CFS patients [43, 44]. Finally, on testing day 1, real-time assessment of physical activity was initiated, by attaching an accelerometer at the non-dominant wrist, which was worn until day 8 (testing day 2). Assessment of physical behavior and amount of physical activity The Actical (Mini Mitter, Bend, Ore, USA) accelerometer was attached for real-time monitoring of physical behavior. The Actical accelerometer has an omnidirectional sensor and is capable of measuring movement in one plane. Accelerometers are the gold standard for measuring physical behavior during daily activities. The Actical accelerometer has been used in scientific research and has shown to be valid for the real-time assessment of physical behavior [45]. For the present study, the monitors were initialized to save data in 1min intervals (epochs). Outcome measures of relevance are the average activity counts and the time spent sedentary, or spent on light, moderate, or vigorous activity. Author's personal copy Clin Rheumatol On testing day 2, maximal voluntary muscle contraction of the upper limb and muscle recovery following fatiguing exercise were evaluated. Muscle recovery following fatiguing exercise This was assessed along the lines of the fatiguing exercise testing protocol for local muscle groups described in the hallmark paper by Paul and colleagues [17]. Recovery from fatiguing exercise was measured using a hydraulic hand dynamometer (Saehan Corporation, Masan, Japan) which is supplied with an adjustable handle and an analogous reproduction of the delivered power in kilogram-force (kgf). Participants were asked to sit on a chair while holding the dynamometer in their nondominant hand with the elbow flexed at 90° and the forearm in neutral position. The screen was turned away from the participants so they could not see the amount of generated force. First, participants were instructed to grip the instrument as hard as possible (isometric maximum voluntary contraction (MVC)) in three consecutive attempts. They were verbally encouraged in a standardized way during each contraction to ensure that maximum contractions were obtained. The highest peak force of three attempts was stored for subsequent analysis (baseline MVC). Next, every participant performed a fatiguing exercise test consisting of 18 maximum contractions using a 50 % duty cycle (5-s contraction, 5-s rest). After the fatiguing exercise test (recovery phase), participants were instructed to make single 5-s isometric MVCs at time intervals of 0, 5, 10, 15, 20, 30, and 45 min post-exercise. These values were converted into percentages of baseline MVC with the latter being taken as 100 %. For statistical analyses, the recovery data were split into three sections. MVC0 equals the MVC at time interval of 0 min post-exercise, MVCRecovery equals the mean of the MVCs at time interval of 5 to 30 min post-exercise, and MVC45 equals the MVC at time interval of 45 min post-exercise. All assessments were performed by an examiner who was blinded for group allocation and outcome of the diagnostic evaluation. Additionally, patients were not informed about which diagnostic labels they fulfilled. between those fulfilling the FM criteria and those who did not, and idem for the ME criteria and the Canadian criteria. This means that within the CFS group, three pairs of groups were compared for every outcome measure. Significance levels was set at .05, but because of the multiple comparisons, Bonferroni corrections was applied, resulting in α=.017. Results Participants One hundred six study participants (n=48 CFS patients, 19 MS patients, and 39 healthy controls) were enrolled. As shown in Table 1, 30/48 (62.5 %) of the CFS patients also fulfilled the current diagnostic guidelines for FM. In addition, 38/48 (79.2 %) of the CFS patients also fulfilled ME criteria, 24/48 (50 %) also fulfilled 2003 Canadian criteria, and 20/48 (41.7 %) fulfilled all three CFS, ME, and Canadian criteria. Demographic characteristics are presented in Table 2. All groups were comparable for age (p=.183). Illness duration was not significantly different between the MS patients and the CFS patients (p=.083), nor between the different CFS groups. Self-reports The comparison of the self-report measures between CFS patients, MS patients, and healthy controls is all presented in Table 3. Also, in Table 3, the differences between CFS patients with comorbid FM or without comorbid FM are presented. Contrasting the diagnostic criteria for CFS resulted in only one significant difference; therefore, this difference is discussed here in the “Results” section, and for all Table 1 Distribution of 1994 CDC CFS patients according to criteria CDC ME 2003 Canadian FM Total count X X X X 2 9 5 2 4 9 2 15 Statistical analysis All data were analyzed using the Statistical Package for Social Sciences 21.0© for Windows (SPSS Inc. Headquarters, Chicago, Illinois, USA). Normality of data was assessed with the one-sample Kolmogorov-Smirnov test. Equality of variances was evaluated with Levene’s test. Outcome measures were compared between the CFS groups, the MS group, and the control group with a oneway ANOVA with post hoc Bonferroni analyses. To reveal differences within the CFS groups, independent t tests were used. For this purpose, all variables were compared X X X X X X X X Total X X X X X X X X Non-FM 18 FM 30 48 CDC Center for Disease Control, ME myalgic encephalomyelitis, FM fibromyalgia Author's personal copy Clin Rheumatol Table 2 Demographic characteristics of the 1994 CFS group, subgrouped by clinical criteria 1994 CFS Canadian N (n=48) ♀ (n=46) Age (years) Illness duration (months) 24 23 ♀ Non-Canadian ME 24 23 ♀ 38 37 ♀ 38.21±12 37.33±12 110.38±74 173.88±178 Non-ME 10 9♀ 37.77±12 36.26±12 43.50±9 142.13±138.86 144.95±151 131.40±85 FM Non-FM 30 29 ♀ 18 17 ♀ 37.43±12 38.33±12 134.97±104 154.06±187 CON MS 39 24 ♀ 42.41±11 19 13 ♀ 38.05±15 / 83.35±69 FM fibromyalgia, CON healthy subjects, MS multiple sclerosis comparisons, interested readers are referred to the “Online supplement” to study the data in more detail. gray zones in Table 3. Those with FM had more pain and more sleeping problems (p<.017). Quality of life (SF-36) Fatigue severity (CIS) Contrasting CFS, ME and healthy controls Contrasting CFS, ME, and healthy controls Regarding the quality of life, as measured with the SF-36, CFS patients scored significantly worse on overall total scores (p<.017) compared to the control group and compared to the MS groups. Also, the MS group had significantly lower scores (p<.017) compared to the control subjects, as presented in Table 3. CFS patients had more severe fatigue as measured with the different subscales of the CIS, compared to healthy controls and MS patients. Only for the subscale motivation, CFS patients were equal to the MS patients (p=1.000). MS patients had overall higher fatigue scores compared to the healthy controls (p<.017), except for motivation (p=.048). Contrasting diagnostic criteria Contrasting diagnostic criteria When comparing the various diagnostic criteria for CFS, no significant differences were found between those fulfilling the ME criteria and those who did not. When comparing the patients fulfilling the Canadian criteria with the other groups, no differences were revealed (see all data in the “Online supplement”). But, the comorbidity of FM seems to worsen the quality of life significantly, as measured with the physical and the total SF-36 score (p<.017) (Table 3). Fulfilling the ME or Canadian criteria did not make a difference on the CIS (Online supplement). Only the comorbidity of FM led to higher fatigue scores, as presented in Table 3. Symptom severity Contrasting CFS, ME, and healthy controls As presented in Table 3, CFS patients reported significantly more severe symptoms (p<.017) compared to control subjects and MS patients. MS patients reported similar symptom severity compared to controls. Contrasting diagnostic criteria The only differences that were found were between the groups with comorbid FM and those without FM, as presented in the Psychological correlates Contrasting CFS, ME, and healthy controls No significant differences were found for hypervigilance (PVAQ) and for the subitem disease benefits of the ICQ, as presented in Table 3. CFS patients had significantly higher scores on the BDI-PC compared to controls (p<.001), and also, together with the MS patients, higher levels of kinesiophobia compared to healthy controls (p<.001 and p=.009). Contrasting diagnostic criteria Those fulfilling the ME criteria presented less kinesiophobia (37.82±6.65 vs 44.80±9.46; p=.010), as presented in the “Online Supplement.” No differences were found between those with or without comorbid FM (Table 3). Author's personal copy Clin Rheumatol Table 3 Contrasting patients and CFS with or without comorbid FM (all data concerning contrasting diagnostic criteria are presented in an Online Supplement) 1994 CFS Outcome measure FM CON MS p-value 342.36 ± 45 244.58 ± 85 .000* 331.98 ± 46 276.35 ± 76 .000* 676.91 ± 72 520.93 ±149 .000* 10.94 ± 14 15.74 ± 23 .000§ 18.72 ± 18 33.55 ± 29 .000§ 2.19 ± 5 5.24 ± 11 .000§ 1.86 ± 4 2.92 ± 12 .000§ 17.76 ± 17 35.82 ± 33 .000§ 11.46 ± 17 18.92 ± 23 .000§ 11.12 ± 18 14.68 ± 20 .000§ 10.23 ± 17 15.82 ± 21 .000§ 11.45 ± 17 19.71 ± 21 .000§ 2.99 ± 5 7.29 ± 14 .000§ 10.64 ± 16 18.74 ± 23 .000§ 13.26 ± 18 26.95 ± 30 .000§ 8.51 ± 14 26.55 ± 26 .000§ Non-FM 127.10 ± 46 Total Physical score (on 400) SF-36 111.97 ± 35 152.33 ± 53 195.17 ± 72 Total Mental score (on 400) 181.30 ± 68 218.28 ± 73 321.52 ± 104 Total score (on 800) 292.07 ± 90 370.61 ± 109 44.58 ± 16.11 Pain 51.97 ± 23 33.31 ± 27 65.33 ± 24 Fatigue 69.50 ± 23 58.39 ± 24 26.16 ± 30 Headache 29.58 ± 31 20.44 ± 29 18.84 ± 26 Sore throat 19.67 ± 25 17.47 ± 28 69.39 ± 21 Symptomlist CFS (VAS in mm) Post-exertional fatigue 71.82 ± 21 65.33 ± 22 56.84 ± 26 Attention deficits 60.15 ± 25 51.33 ± 28 52.94 ± 26 Memory problems 57.87 ± 26 44.72 ± 26 48.33 ± 29 Difficulties calculating 51.71 ± 27 42.69 ± 31 51.17 ± 24 Difficulties finding words 53.97 ± 20 46.50 ± 28 28.79 ± 30 Personality disorders 34.17 ± 29 19.83 ± 30 35.08 ± 29 Mood swings 38.97 ± 29 28.61 ± 28 80.48 ± 20 Non-restoring sleep 85.67 ± 13 71.83 ± 27 70.95 ± 29 Sleeping problems 78.88 ± 20 57.72 ± 37 Author's personal copy Clin Rheumatol 63.07 ± 24 Muscle weakness 66.50 ± 19 8.15 ± 15 23.79 ± 24 .000§ 17.97 ± 22 20.97 ± 31 .000§ 5.81 ± 12 10.37 ± 17 .000§ 9.54 ± 17 13.63 ± 21 .000§ 15.87 ± 23 13.79 ± 16 .000§ 6.67 ± 10 11.37 ± 16 .000§ 22.39 ± 11 36.11± 11 .000# 12.69 ± 7 20.90 ± 7 .000# 9.36 ± 5 13.26 ± 5 .001£ 7.62 ± 4 11.26 ± 5 .000# 38.03 ± 9 35.36 ± 11 .444 1.15 ± 2 1.68 ± 2 .000£ 29.85 ± 6 35.63 ± 6 .000¥ 0 10.89 ± 4 .000∆ 0 16.74 ± 3 .010∆ 0 14.26 ± 4 .694 57.36 ± 30 49.24 ± 35 Cold hands and feet 52.05 ± 35 44.56 ± 34 46.59 ± 30 Flue like symptoms 51.95 ± 28 37.67 ± 31 48.74 ± 30 Gastro-intestinal complaints 52.47 ± 27 42.53 ± 33 56.85 ± 30 Dyspnea 62.40 ± 27 47.61 ± 33 54.01 ± 29 Hypersensitivity light 60.43 ± 26 43.31 ± 32 50.02 ± 6 Fatigue 52.17 ± 4 46.44 ± 7 27.65 ± 6 Concentration CIS 29.00 ± 4 25.39 ± 8 13.98 ± 6 Motivation 15.17 ± 6 12.00 ± 6 14.71 ± 5 Activity 15.47 ± 4 13.44 ± 5 38.34 ± 13 Hypervigilance (PVAQ) 40.05 ± 10 35.50 ± 16 3.54 ± 4 Psychological correlates Depression (BDI-PC) 4.10 ± 4 2.61 ± 3 39.27 ± 8 Kinesiophobia (TSK-CFS) 38.83 ± 7 40.00 ± 8 16.19 ± 4 ICQ helplessness 16.77 ± 3 15.22 ± 4 13.77 ± 4 ICQ acceptance 13.13 ± 4 14.83 ± 5 14.75 ± 5 ICQ disease benefits 13.70 ± 4 16.50 ± 5 Scores in the gray zones are those that are significantly different between the FM versus non-FM CFS patients CFS chronic fatigue syndrome, FM fibromyalgia, CON healthy subjects, MS multiple sclerosis, CIS Checklist Individual Strength, PVAC Pain Vigilance and Awareness Questionnaire, BDI-PC Beck Depression Inventory-Primary Care, a Bonferroni post hoc tests revealed significant differences for all comparisons→CFS<MS<CON b Bonferroni post hoc tests revealed CFS>MS=CON c Bonferroni post hoc tests revealed significant differences for all comparisons→CFS>MS>CON d Bonferroni post hoc tests revealed CFS=MS>CON e Bonferroni post hoc tests revealed CFS=MS, CFS>CON, and MS=CON f Based on independent t test, because control subjects did not complete this questionnaire Author's personal copy Clin Rheumatol Objective measures Physical activity level Maximum voluntary contraction and muscle recovery Contrasting CFS, ME, and healthy controls Contrasting CFS, ME, and healthy controls Overall, the activity level of the CFS group was quite similar to that of the MS group, with, in comparison to the healthy controls, lower average activity counts (p=.003) and less time spent on light activity (p=.001) and, inversely, more time spent sedentary (p=.000). Time spent moderately or intensively active was not different, but average activity counts were, however, lower in the CFS group compared to the healthy controls (respectively p=.006 and p=.003), indicating a similar time span but at a lower intensity. Regarding the maximal voluntary contraction (MVC) of the non-dominant hand with the hand held dynamometer, the MVC of the CFS (30.40±7.65) group was significantly lower than that of MS patients (38.60±11.96; p=.013) and that of controls (37.72±12.31; p=.004). For the recovery values, expressed as percentages of the MVC, there was a significant time effect and a significant group effect (p<.001). Recovery values in the CFS group were lower compared to those of the healthy controls at every post-exercise interval (0 up to 45 min post-exercise) and compared to MS patients, immediately after the fatiguing exercise, as presented in Fig. 1. But, there was no interaction effect (p=.448). Contrasting diagnostic criteria No differences were found between the different diagnostic criteria (p>.017). Contrasting diagnostic criteria Cognitive tests No differences were found for MVC (p>.017). Also, for the repeated measures ANOVAs analyzing the muscle recovery, a time effect was found, but group effects were not found when subgrouping CFS patients on the basis of Canadian or non-Canadian criteria or ME criteria or non-ME criteria. Only a trend was found for slower/ incomplete recovery when comparing the CFS patients with and without FM (p=.056). MVCRecovery and MVC45 were indeed near significantly different between the two groups (p = .033 and p = .049), but MVC 0 was similar (p=.417). Interaction effects were again not found, indicating similar slopes. Contrasting CFS, ME, and healthy controls 110 p = .001 p = .003 100 90 % of MVC Fig. 1 Muscle recovery slope. CFS=1994 CDC diagnosed, CON=healthy subjects, MS= multiple sclerosis. MVC= maximum voluntary contraction, MVC0 =MVC immediately postexercise, MVCRecovery =mean MVC measured at 5-min intervals in the 45 min after exercise, MVC45 =MVC 45 min after exercise. Dotted arrows indicate significant differences between CFS patients and controls. Full arrows indicate significant differences between CFS patients and MS patients On the PVT, CFS patients presented significant slower reaction times compared to controls (p=.000), and MS patients also presented slower reaction times compared to healthy controls (p=.011). CFS patients had significantly more lapses (reacting outside 500 ms) than MS patients (p=.012) and controls (p=.000). For the Stroop test, significant differences were only found for reaction times and not for accuracy. CFS patients were significantly slower than MS patients and controls (p<.017). No differences were observed for the OSPAN test. 80 CFS MS 70 CON p = .019 60 p = .044 50 40 MVC0 MVCRecovery MVC45 Author's personal copy Clin Rheumatol Contrasting diagnostic criteria No significant differences were found in mean reaction times or lapses between the different criteria and between those with and without FM (p>.017). Discussion Controversy regarding the diagnosis of CFS continues to exist among patients and researchers. The outcome of the present study is the first to address the issue of CFS diagnosis by comparing the CFS group with health controls and MS patients, and additionally by comparing different diagnostic CFS criteria and evaluating the impact of comorbid FM, both for self-reports and objective measures. Contrasting CFS, ME, and healthy controls Overall, it seems that the CFS group reported more intense symptoms, more severe fatigue, and a worse quality of life compared to both the MS group and the healthy control group. Apart from hypervigilance which did not differ significantly between groups, the CFS group scored worse on the psychological correlates (depression, kinesiophobia, and illness cognitions). Regarding objective measures, CFS patients had lower MVC values for handgrip strength and displayed slower and incomplete recovery in the 45 min after a fatiguing exercise, compared to both the MS group and the control group. However, the CFS group and the MS group were similar regarding physical behavior and activity level, which were consistently lower than those in the control group. On the cognitive tests, CFS patients were slower than the other two groups. These results are consistent with previous studies that compared CFS patients with MS patients, indicating similar activity patterns in both groups [34, 46]. Also, the slower reaction times compared to those of healthy controls and MS patients are in line with previous findings [47]. The comparison of MVC and muscle recovery between those with CFS and those with MS is innovative to our knowledge and reveals the interesting finding that despite similar activity patterns, CFS patients were weaker and recovered slower. Given the etiology of MS, weakness is common and is the consequence of altered central motor drive, atrophy exceeding that observed with short-term disuse and approaching that reported in spinal cord injury, fewer type I fibers, smaller fibers of all types with reduced enzyme activity, etc. (for review, see [48]). Nevertheless, CFS patients exhibited lower isometric muscle strength and slower recovery, although the pattern of recovery was equal in all groups. It may be, however, that less impaired MS patients were included in this study (mean EDSS score 1.64) and that more impaired MS patients would exhibit higher levels of weakness. Contrasting diagnostic criteria It seems that the comorbidity of FM is a better discriminator between CFS patients with a high and low symptom burden than the various classifications of CFS, ME, and ME/CFS. Those with comorbid FM had more severe fatigue and other symptoms (pain and sleeping problems) and worse quality of life. For the objective measures, besides a near significantly slower recovery in those with comorbid FM, no major differences were found for cognitive performance and activity level, although more subtle differences regarding those with and without FM are discussed in Ickmans et al. [49]. Fulfilling the 2003 Canadian criteria or the ME criteria did not significantly alter the clinical picture. Only those fulfilling the ME criteria reported less kinesiophobia These findings are not consistent with previous studies. In earlier studies, researchers found differences within the CFS group dependent on the diagnostic criteria that were used, whereas in the present study, only a few differences between subgroups were observed. Because of the lack of differences, a post hoc power analysis was performed, resulting in a general power for the FM comparisons around 70–80 %, 70 % for the comparisons between those fulfilling the Canadian criteria and those who did not, but only 15 % for the comparisons according to the ME criteria. The latter is not surprising as only 10 patients did not fulfill the ME criteria. So before drawing strong conclusion regarding the ME criteria, further study with a larger sample size not fulfilling the ME criteria is necessary. In accord with previous studies, our results show that only a proportion of 1994 CFS-defined patients also met the criteria for ME or Canadian ME/CFS. Fifty percent of the CFS patients in this study also fulfilled the Canadian ME/CFS criteria, and this accords with the findings of other studies in which 50 % [50], 52.5 % [51], and 62.5 % [13] of patients fulfilled both rubrics. The similarities in proportions between investigations probably reflect the standardized diagnostic protocols available to researchers and clinicians when assessing patients using the Canadian case definition [8], allowing a consistency in assessment across populations and studies. By contrast, more than three quarters of the CFS patients in our study also fulfilled ME criteria, a higher proportion than that reported by other investigators. For example, in the large PACE trial involving 641 CFS patients in the UK [53], 51 % of participants overall conformed to both ME and CFS criteria, and in three smaller studies, the equivalent proportions were 45.8 % [54], 43.8 % [14], and 23.7 % [15]. The large variation between these estimates undoubtedly reflects the lack of power in most of the studies (implying that pure Author's personal copy Clin Rheumatol chance can account for a large part of the observed heterogeneity), and the lack of sensitive standardized protocols for the assessment of ME, including the absence of guidelines on the required frequency or severity of particular symptoms or symptom clusters. In addition, there is a number of different definitions which investigators can use (reviewed in [10]), and each of the four studies quoted above defined ME in a different way, making between-study comparisons of proportions of CFS patients also fulfilling ME criteria extremely difficult. Clearly, the ideal would be for there to be consensus-based standardized diagnostic and treatment protocols for ME, similar to those that exist for Canadian ME/CFS criteria. Consistent with earlier studies is that those fulfilling the ME criteria presented less psychological impairment (TSK), which is in line with the lack of differences on the psychiatric items and the suggestion that the ME criteria selects individuals with less psychiatric comorbidity and mental health issues than the Canadian ME/CFS criteria [15]. However, the present study was only able to compare CFS patients who fulfilled ME criteria with those who did not, given the great overlap in the groups, so a direct comparison between an ME group and a Canadian group was not possible. In brief, we observed few significant differences between CFS, ME/CFS, and ME criteria as regards to either selfreported symptoms or objective measures, despite the fact that CFS patients as a whole had a more severe illness burden than either MS patients or healthy subjects. These results accord with the findings of the large PACE trial [53], in which there were no apparent differences in either fatigue or physical function at baseline between patients meeting ME criteria and the CFS group as a whole. However, other investigators [15, 51, 52, 54] have found both Canadian ME/CFS- and MEdefined patients to have a greater symptomatic burden than CFS patients not meeting these criteria. Differences in the way ME was defined between studies may account for these anomalies, although the clear differences we observed in symptom burden between the CFS group as a whole versus MS patients and healthy controls, allied with the high incidence of comorbid fibromyalgia observed (62.5 % of patients), may point to a more severe illness burden in our group of Belgian CFS patients compared with CFS patients selected for other studies, leading to a high degree of symptomatology irrespective of the CFS, ME/CFS, or ME criteria used. The fact that those with comorbid FM scored worse on the self-reports of pain and disability is in line with previous research [23, 25]. Also, the lack of difference in mean reaction time and lapses on cognitive tests confirms the findings of Cook [25]. However, in the study of Ickmans et al. [49], those with and without comorbid FM were compared to healthy controls, and these analyses revealed that comorbid FM further decreases cognitive performance. Similar results were found for muscle recovery, being far worse in those with comorbid FM, compared to healthy controls. This suggests that it is indeed important to account for FM comorbidity to reduce heterogeneity in CFS patient groups. Regarding the fact that different diagnostic criteria do not seem to select different patients, it is indeed true that the CFS group, diagnosed by the 1994 CDC criteria, is a very heterogeneous population, particularly since the Fukuda criteria are less stringent than the original CDC-1988 criteria [55]. Therefore, it was suggested by De Becker et al. [55] that the addition of certain symptoms and removal of others might strengthen the ability to select well-defined groups of CFS patients. Furthermore, these authors state that a symptom severity index would be recommended, rather than just symptom occurrence alone, because virtually all symptoms are commonly found to occur. Our results suggest that the different diagnostic criteria commonly proposed for use in CFS patients may not, in practice, be sensitive enough to select symptomatically different groups of patients. Future research could focus on improving the specificity of existing criteria for CFS, using symptom severity indices and very specific diagnostic protocols to reduce the impact of clinician interpretation during diagnosis and allow subgrouping based on symptom clusters and symptom severity to reduce heterogeneity. For clinical practice, it seems that patients with comorbid FM are the most disabled and that also fatigue and sleeping problems are more prominent in those patients, besides the most obvious complaint of pain. So, instead of thinking that the therapy should rather be focused on the pain complaints in those with comorbid FM, special attention should be addressed to fatigue and sleeping hygiene as well. Besides that, it seems that clinicians should not bother too much about the diagnostic criteria, as long as either the 1994 CDC criteria or the Canadian are used, but rather be aware of the fact that CFS patients are really disabled in many aspects, even more than a generally well-accepted and recognized illness like MS. Many bodily functions and activities are restricted or impaired and should all be targeted in a multidisciplinary approach: cognitive function, exercise capacity and response, fatigue, pain, psychological issues, etc. Strengths and limitations The strength of the present study is that CFS patients were compared to another fatigued “disease control” group of MS patients and a healthy control group and that the role of different diagnostic criteria for CFS and the role of comorbid FM were evaluated in terms of both self-reports and objective measures. Moreover, the CFS patients in the present study were all diagnosed by the same physician, with extensive experience (over 20 years) with (differential) diagnosis and treatment of patients with CFS. The main limitations of the study were that it was impossible to directly compare, for example, an ME-defined group of CFS patients with a Author's personal copy Clin Rheumatol Canadian-defined group, nor to differentiate within the CFS subgroups between those with and without FM. Also, the lack of power to compare those fulfilling the ME criteria and those who did not prohibits drawing firm conclusions regarding these criteria. Conclusion This is the first study to compare both self-reported measures and objective measures in CFS patients and MS patients and to compare the role of different diagnostic criteria for CFS and the impact of comorbid FM. Both on self-reports and on objective measures, CFS patients performed worse overall compared with MS patients and healthy controls. The comparison of the different diagnostic criteria, however, did not reveal major differences between those fulfilling the Canadian or the ME criteria and those who did not. The comorbidity of FM with CFS, however, led to worse symptom severity, functioning, and quality of life. Acknowledgments Kelly Ickmans is a research fellow of ME Research UK, a national charity funding biomedical research into myalgic encephalomyelitis/chronic fatigue syndrome. The study was funded by a research grant ME Research UK, a national charity funding biomedical research into myalgic encephalomyelitis/chronic fatigue syndrome, awarded to the Vrije Universiteit Brussel, Brussels, Belgium. Jo Nijs is holder of the Chair “Exercise immunology and chronic fatigue in health and disease” funded by the European College for Decongestive Lymphatic Therapy, The Netherlands. Disclosures None References 1. 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