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Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a medically unexplained illness characterized by severe fatigue limiting normal daily activities for at least 6 months accompanied by problems with unrefreshing sleep, exacerbation of symptoms following physical or mental efforts (postexertional malaise [PEM]), and either cognitive reports or physiological evidence of orthostatic intolerance in the form of either orthostatic tachycardia and/or hypocapnia. Although rarely considered to have cardiac dysfunction, ME/CFS patients frequently have reduced stroke volume with a significant inverse relation between cardiac output and PEM severity. Magnetic resonance imaging of ME/CFS patients compared with normal control subjects found significantly reduced stroke, end-systolic, and end-diastolic volumes together with reduced end-diastolic wall mass. Another cardiovascular abnormality is reduced nocturnal blood pressure assessed by 24-hour monitoring. Autonomic dysfunction is also frequently observed with postural orthostatic tachycardia and/or hypocapnia. Two consecutive cardiopulmonary stress tests may provide metabolic data substantiating PEM.

Background: Myalgic Encephalomyelitis / Chronic Fatigue Syndrome (ME/CFS), Gulf War Ill-ness (GWI) and control subjects had fMRI during difficult cognitive tests performed before and after submaximal exercise provocation (Washington 2020). Exercise caused increased activation in ME/CFS but decreased activation for GWI in the dorsal midbrain, left Rolandic operculum and right middle insula. Midbrain and isthmus nuclei participate in threat assessment, attention, cognition, mood, pain, sleep, and autonomic dysfunction Methods: Activated midbrain nuclei were inferred by re-analysis of data from 31 control, 36 ME/CFS and 78 GWI subjects using a seed region approach and the Harvard Ascending Arousal Network. Results: Before exercise, control and GWI had greater activation during cognition than ME/CFS in left pedunculotegmental nucleus. Postexercise ME/CFS had greater activation than GWI for midline periaqueductal gray, dorsal and median raphe, and right midbrain reticular formation, parabrachial complex and locus coeruleus. The change between days (delta) was positive for ME/CFS but negative for GWI indicating reciprocal patterns of activation. Controls had no changes. Conclusions: Exercise caused opposite effects with increased activation in ME/CFS but decreased activation in GWI indicating different pathophysiological responses to exertion and mechanisms of disease. Midbrain and isthmus nuclei contribute to postexertional malaise in ME/CFS and GWI.

Primary and specialty care clinicians strive to base diagnoses and treatment on specific, measurable abnormalities. Yet those with invisible, controversial illnesses such as myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) often have symptoms not explained by standard laboratory values. For instance, one of the cardinal features of ME/CFS is postexertional malaise, the exacerbation of symptoms-fatigue, pain, cognitive dysfunction-following exertion, which contradicts studies showing the health benefits of exercise. In these cases, overly physicalist approaches to caring for patients are not likely to be helpful, and a clinician's willingness to listen to a patient's experience of illness becomes essential.

Although autonomic nervous system (ANS) dysfunction in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) has been proposed, conflicting evidence makes it difficult to draw firm conclusions regarding ANS activity at rest in ME/CFS patients. Although severe exercise intolerance is one of the core features of ME/CFS, little attempts have been made to study ANS responses to physical exercise. Therefore, impairments in ANS activation at rest and following exercise were examined using a case-control study in 20 ME/CFS patients and 20 healthy people. Different autonomous variables, including cardiac, respiratory, and electrodermal responses were assessed at rest and following an acute exercise bout. At rest, parameters in the time-domain represented normal autonomic function in ME/CFS, while frequency-domain parameters indicated the possible presence of diminished (para)sympathetic activation. Reduced parasympathetic reactivation during recovery from exercise was observed in ME/CFS. This is the first study showing reduced parasympathetic reactivation during recovery from physical exercise in ME/CFS. Delayed HR recovery and/or a reduced HRV as seen in ME/CFS have been associated with poor disease prognosis, high risk for adverse cardiac events, and morbidity in other pathologies, implying that future studies should examine whether this is also the case in ME/CFS and how to safely improve HR recovery in this population.

Background: The diagnosis of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is problematic due to the lack of established objective measurements. Postexertional malaise (PEM) is a hallmark of ME/CFS, and the two-day cardiopulmonary exercise test (CPET) has been tested as a tool to assess functional impairment in ME/CFS patients. This study aimed to estimate the potential of the CPET. Methods: We reviewed studies of the two-day CPET and meta-analyzed the differences between ME/CFS patients and controls regarding four parameters: volume of oxygen consumption and level of workload at peak (VO2peak, Workloadpeak) and at ventilatory threshold (VO2@VT, Workload@VT). Results: The overall mean values of all parameters were lower on the 2nd day of the CPET than the 1st in ME/CFS patients, while it increased in the controls. From the meta-analysis, the difference between patients and controls was highly significant at Workload@VT (overall mean: −10.8 at Test 1 vs. −33.0 at Test 2, p < 0.05), which may reflect present the functional impairment associated with PEM. Conclusions: Our results show the potential of the two-day CPET to serve as an objective assessment of PEM in ME/CFS patients. Further clinical trials are required to validate this tool compared to other fatigue-inducing disorders, including depression, using well-designed large-scale studies.

Naltrexone is used as an off-label treatment in low doses for several chronic immune-modulated disorders in many countries. Although only small-scale clinical trials have been performed, these suggest efficacy in several diseases including Crohn’s disease, fibromyalgia and Gulf War Illness. Despite numerous internet reports of response to low-dose naltrexone (LDN), no clinical trials exist in people with chronic fatigue syndrome. This condition is characterised by chronic profound fatigue, postexertional malaise, pain and autonomic and neurocognitive disturbances. This series of three case reports compiled by people with long-term ill-health due to chronic fatigue syndrome shows the range of responses they observed when taking LDN, from life changing to a reduction in some symptoms only. Treatment doses ranged from 4 to 12 mg. Clinical trials may be warranted to explore the potential use of naltrexone in people with these debilitating illnesses which currently have no licensed treatments available.

​BackgroundCognitive–behavioural therapy (CBT) is effective in chronic fatigue syndrome. However, CBT has not been investigated in postinfectious chronic fatigue (CF), nor is it known whether addition of therapeutic elements from other disciplines might be feasible. We studied the feasibility of a combined CBT and music therapy intervention for CF following Epstein-Barr virus (EBV) infection in adolescents.​MethodsAdolescents (12–20 years old) participating in a postinfectious cohort study who developed CF 6 months after an acute EBV infection were eligible for the present feasibility study. A combined CBT and music therapy programme (10 therapy sessions and related homework) was compared with care as usual in a randomised controlled design. Therapists and participants were blinded to outcome evaluation. Endpoints included physical activity (steps/day), symptom scores, recovery rate and possible harmful effects, but the study was underpowered regarding efficacy. Total follow-up time was 15 months.​ResultsA total of 43 individuals with postinfectious CF were included (21 intervention group, 22 control group). Seven individuals left the study during the first 3 months, leaving 15 in the intervention group and 21 in the control group at 3 months’ follow-up. No harmful effects were recorded, and compliance with appointment was high. In intention-to-treat analyses, number of steps/day tended to decrease (difference=−1158, 95% CI −2642 to 325), whereas postexertional malaise tended to improve (difference=−0.4, 95% CI −0.9 to 0.1) in the intervention group at 3 months. At 15 months’ follow-up, there was a trend towards higher recovery rate in the intervention group (62% vs 37%).​ConclusionAn intervention study of combined CBT and music therapy in postinfectious CF is feasible, and appears acceptable to the participants. The tendencies towards positive effects on patients’ symptoms and recovery might justify a full-scale clinical trial.​Trial registration numberNCT02499302.

PURPOSE: Oxidative stress has been proposed as a contributor to pain in patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). During incremental exercise in patients with ME/CFS, oxidative stress enhances sooner and antioxidant response is delayed. We explored whether oxidative stress is associated with pain symptoms or pain changes following exercise, and the possible relationships between oxidative stress and parasympathetic vagal nerve activity in patients with ME/CFS versus healthy, inactive controls. METHODS: The present study reports secondary outcomes from a previous work. Data from 36 participants were studied (women with ME/CFS and healthy controls). Subjects performed a submaximal exercise test with continuous cardiorespiratory monitoring. Levels of thiobarbituric acid-reactive substances (TBARSs) were used as a measure of oxidative stress, and heart rate variability was used to assess vagal activity. Before and after the exercise, subjects were asked to rate their pain using a visual analogic scale. FINDINGS: Significant between-group differences in pain at both baseline and following exercise were found (both, P

Chronic fatigue syndrome in the emergency department Christian R Timbol,* James N Baraniuk* Division of Rheumatology, Immunology and Allergy, Georgetown University, Washington, DC, USA *Both authors contributed equally to this work Purpose: Chronic fatigue syndrome (CFS) is a debilitating disease characterized by fatigue, postexertional malaise, cognitive dysfunction, sleep disturbances, and widespread pain. A pilot, online survey was used to determine the common presentations of CFS patients in the emergency department (ED) and attitudes about their encounters.Methods: The anonymous survey was created to score the severity of core CFS symptoms, reasons for going to the ED, and Likert scales to grade attitudes and impressions of care. Open text fields were qualitatively categorized to determine common themes about encounters.Results: Fifty-nine percent of respondents with physician-diagnosed CFS (total n=282) had gone to an ED. One-third of ED presentations were consistent with orthostatic intolerance; 42% of participants were dismissed as having psychosomatic complaints. ED staff were not knowledgeable about CFS. Encounters were unfavorable (3.6 on 10-point scale). The remaining 41% of subjects did not go to ED, stating nothing could be done or they would not be taken seriously. CFS subjects can be identified by a CFS questionnaire and the prolonged presence (>6 months) of unremitting fatigue, cognitive, sleep, and postexertional malaise problems.Conclusion: This is the first investigation of the presentation of CFS in the ED and indicates the importance of orthostatic intolerance as the most frequent acute cause for a visit. The self-report CFS questionnaire may be useful as a screening instrument in the ED. Education of ED staff about modern concepts of CFS is necessary to improve patient and staff satisfaction. Guidance is provided for the diagnosis and treatment of CFS in these challenging encounters. Keywords: patient satisfaction, orthostatic intolerance, postexertional malaise, myalgic encephalomyelitis, systemic exertion intolerance disease, SEID

Myalgic encephalomyelitis (ME) often also called chronic fatigue syndrome (ME/CFS) is a common, debilitating, disease of unknown origin. Although a subject of controversy and a considerable scientific literature, we think that a solid understanding of ME/CFS pathogenesis is emerging. In this study, we compiled recent findings and placed them in the context of the clinical picture and natural history of the disease. A pattern emerged, giving rise to an explanatory model. ME/CFS often starts after or during an infection. A logical explanation is that the infection initiates an autoreactive process, which affects several functions, including brain and energy metabolism. According to our model for ME/CFS pathogenesis, patients with a genetic predisposition and dysbiosis experience a gradual development of B cell clones prone to autoreactivity. Under normal circumstances these B cell offsprings would have led to tolerance. Subsequent exogenous microbial exposition (triggering) can lead to comorbidities such as fibromyalgia, thyroid disorder, and orthostatic hypotension. A decisive infectious trigger may then lead to immunization against autoantigens involved in aerobic energy production and/or hormone receptors and ion channel proteins, producing postexertional malaise and ME/CFS, affecting both muscle and brain. In principle, cloning and sequencing of immunoglobulin variable domains could reveal the evolution of pathogenic clones. Although evidence consistent with the model accumulated in recent years, there are several missing links in it. Hopefully, the hypothesis generates testable propositions that can augment the understanding of the pathogenesis of ME/CFS. Funding Agencies|SolveME/CFS Initiative; Swedish ME Association; Open Medicine Foundation [1011454]; Uppsala Academic Hospital [FOU2017-0039]; Invest in ME Foundation, London

Nijs J, Van Oosterwijck J, Meeus M, Lambrecht L, Metzger K, Fremont M, Paul L (Vrije Universiteit Brussel, Brussels; University College Antwerp, Antwerp; University Hospital Brussels, Brussels; Private Practice for Internal Medicine, Gent/Aalst; and RED Laboratories N.V., Zellik; Belgium, and University of Glasgow, Glasgow, UK). Unravelling the nature of postexertional malaise in myalgic encephalomyelitis/chronic fatigue syndrome: the role of elastase, complement C4a and interleukin-1β. J Intern Med 2010; 267: 418–435. Objectives. Too vigorous exercise or activity increase frequently triggers postexertional malaise in people with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), a primary characteristic evident in up to 95% of people with ME/CFS. The present study aimed at examining whether two different types of exercise results in changes in health status, circulating elastase activity, interleukin (IL)-1β and complement C4a levels. Design. Comparative experimental design. Setting. University. Subjects. Twenty-two women with ME/CFS and 22 healthy sedentary controls Interventions: participants were subjected to a submaximal exercise (day 8) and a self-paced, physiologically limited exercise (day 16). Each bout of exercise was preceded and followed by blood sampling, actigraphy and assessment of their health status. Results. Both submaximal exercise and self-paced, physiologically limited exercise resulted in postexertional malaise in people with ME/CFS. However, neither exercise bout altered elastase activity, IL-1β or complement C4a split product levels in people with ME/CFS or healthy sedentary control subjects (P > 0.05). Postexercise complement C4a level was identified as a clinically important biomarker for postexertional malaise in people with ME/CFS. Conclusions. Submaximal exercise as well as self-paced, physiologically limited exercise triggers postexertional malaise in people with ME/CFS, but neither types of exercise alter acute circulating levels of IL-1β, complement C4a split product or elastase activity. Further studying of immune alterations in relation to postexertional malaise in people with ME/CFS using multiple measurement points postexercise is required.

VanOosterwijckJ,NijsJ,MeeusM,LefeverI,HuybrechtsL,LambrechtL,PaulL(VrijeUniversiteitBrussel, Brussels; Artesis University CollegeAntwerp, Antwerp; University Hospital Brussels,Brussels; Private Practice For Internal Medicine,Ghent⁄Aalst; CVS Contactgroep, Bruges; Belgium;andUniversityofGlasgow,Glasgow,UK).Paininhibi-tion and postexertional malaise in myalgic encepha-lomyelitis⁄chronic fatigue syndrome. J Intern Med2010;268: 265–278.Objectives. Toexaminetheefficacyofthepaininhibitorysystems in patients with myalgic encephalomyeli-tis⁄chronic fatigue syndrome (ME⁄CFS) during twodifferenttypesofexerciseandtoexaminewhetherthe(mal)functioningofpaininhibitorysystemsisassoci-atedwithsymptomincreasesfollowingexercise.Design.Acontrolledexperimentalstudy.Setting and subjects. Twenty-two women with ME⁄CFSand 22 healthy sedentary controls were studied attheDepartmentofHumanPhysiology,VrijeUniversi-teitBrussel.Interventions. All subjects performed a submaximalexercisetestandaself-paced,physiologicallylimitedexercise test on a cycle ergometer. The exercise testswere undertaken with continuous cardiorespiratorymonitoring.Beforeandaftertheexercisebouts,sub-jectsfilledoutquestionnairestoassesshealthstatus,and underwent pressure pain threshold measure-ments.Throughoutthestudy,subjects’activitylevelswereassessedusingaccelerometry.Results. In patients with ME⁄CFS, pain thresholds de-creasedfollowingbothtypesofexercise,whereastheyincreasedinhealthysubjects.Thiswasaccompaniedby a worsening of the ME⁄CFS symptom complexpost-exercise.Decreasedpressurethresholdsduringsubmaximal exercise were associated with postexer-tional fatigue in the ME⁄CFS group (r =0.454;P =0.034).Conclusions. These observations indicate the presenceof abnormal central pain processing during exercisein patients with ME⁄CFS and demonstrate that bothsubmaximal exercise andself-paced,physiologicallylimited exercise trigger postexertional malaise inthese patients. Further study is required to identifyspecific modes and intensity of exercise that can beperformedinpeoplewithME⁄CFSwithoutexacerbat-ingsymptoms.Keywords: algometry, ME⁄CFS, pain, postexertionalmalaise,submaximalexercise.IntroductionPatients with myalgic encephalomyelitis⁄chronicfatiguesyndrome(ME ⁄CFS)experienceadebilitatingfatigueaccompaniedbysecondarysymptomsinclud-ing sore throat, memory and concentration impair-ments, headache, sleep disorders and, most often,muscle and joint pain. Not only do people withME⁄CFS often report a fluctuating pattern to theirsymptoms and physical and cognitive capabilities,they also show severe symptom and pain exacerba-tion following physical exercise [1, 2]. This postexer-tional malaise is present in 95% of ME⁄CFS patients[3] and isone ofthe bestpredictors ofthedifferentialdiagnosis of ME⁄CFS and major depressive disorder[4]. The severe exacerbation of symptoms followingexercise, as seen in ME⁄CFS patients, is not presentin other disorders where fatigue is a predominant

Persons with Myalgic Encephalomyelitis/chronic fatigue syndrome (ME/CFS) often complain of fatigue states (e.g. post-exertional malaise, brain fog) that are qualitatively different than normal, daily fatigue. Given the heterogeneous nature of ME/CFS, it is likely that individuals with this illness experience these fatigue types differently in terms of severity and frequency. It is also possible that meaningful subgroups of patients exist regarding different patterns of the fatigue experience. The purpose of this study was to investigate whether individuals with ME/CFS can be classified in a meaningful way according to the different types of fatigue they experience. One hundred individuals with ME/CFS participated in the study. Individuals that met inclusion criteria were administered the Multiple Fatigue Types Questionnaire (MFTQ), a five-factor instrument that distinguishes between different types of fatigue. A cluster analysis was used to classify patients into various clusters based upon factor subscale scores. Using a three-factor solution, individuals were classified according to illness severity (low, moderate, severe) across the different fatigue factors. However, a 5-cluster solution enabled participants with moderate to severe fatigue levels to fall out into more differentiated clusters and demonstrate distinct fatigue state patterns. These results suggest that fatigue patterns of individuals with ME/CFS are heterogeneous and patients may be classified into meaningful subgroups.

Postexertional malaise (PEM) is a defining characteristic of chronic fatigue syndrome (CFS) that remains a source of some controversy. The purpose of this study was to explore the effects of an exercise challenge on CFS symptoms from a patient perspective.This study included 25 female CFS patients and 23 age-matched sedentary controls. All participants underwent a maximal cardiopulmonary exercise test. Subjects completed a health and well-being survey (SF-36) 7 days postexercise. Subjects also provided, approximately 7 days after testing, written answers to open-ended questions pertaining to physical and cognitive responses to the test and length of recovery. SF-36 data were compared using multivariate analyses. Written questionnaire responses were used to determine recovery time as well as number and type of symptoms experienced.Written questionnaires revealed that within 24 hours of the test, 85% of controls indicated full recovery, in contrast to 0 CFS patients. The remaining 15% of controls recovered within 48 hours of the test. In contrast, only 1 CFS patient recovered within 48 hours. Symptoms reported after the exercise test included fatigue, light-headedness, muscular/joint pain, cognitive dysfunction, headache, nausea, physical weakness, trembling/instability, insomnia, and sore throat/glands. A significant multivariate effect for the SF-36 responses (p0.001) indicated lower functioning among the CFS patients, which was most pronounced for items measuring physiological function.The results of this study suggest that PEM is both a real and an incapacitating condition for women with CFS and that their responses to exercise are distinctively different from those of sedentary controls.

The Institute of Medicine (IOM) in the United States has recently proposed that the term systemic exertion intolerance disease (SEID) replace chronic fatigue syndrome. In addition, the IOM proposed a new case definition for SEID, which includes substantial reductions or impairments in the ability to engage in pre‑illness activities, unrefreshing sleep, postexertional malaise, and either cognitive impairment or orthostatic intolerance. Unfortunately, these recommendations for a name change were not vetted with patient and professional audiences, and the new criteria were not evaluated with data sets of patients and controls. A recent poll suggests that the majority of patients reject this new name. In addition, studies have found that prevalence rates will dramatically increase with the new criteria, particularly due to the ambiguity revolving around exclusionary illnesses. Findings suggest that the new criteria select more patients who have less impairment and fewer symptoms than several other criteria. The implications of these findings are discussed in the current review.

Objective This study examined predictors of fatigue severity and predictors of continued chronic fatigue status at wave 2 follow-up within a random, community-based sample of individuals previously evaluated in a wave 1 prevalence study of chronic fatigue and chronic fatigue syndrome that originally took place between 1995 and 1997. Methods Wave 1 data were from a larger community-based prevalence study of chronic fatigue syndrome. In the present study, a second wave of data were collected by randomly selecting a sample of participants from the wave 1 sample of 18,675 adults and readministering a telephone screening questionnaire designed to assess symptoms of chronic fatigue syndrome. Results Findings revealed that wave 1 fatigue severity was a predictor of fatigue severity at wave 2 in the overall sample of individuals with and without chronic fatigue. In the smaller sample of individuals with chronic fatigue, wave 1 fatigue severity, worsening of fatigue with physical exertion, and feeling worse for 24 hours or more after exercise significantly predicted continued chronic fatigue status (vs. improvement) at wave 2 follow-up. Conclusions These findings underscore the prognostic validity of postexertional malaise in predicting long-term chronic fatigue and also highlight the importance of using population-based, representative random samples when attempting to identify long-term predictors of chronic fatigue at follow-up.

The 1994 case definition of chronic fatigue syndrome is widely used not only for diagnosis but also for clinical and laboratory-based observations of this clinical entity. The criteria for the 1994 case definition are based primarily on symptoms and not on physical signs or chemical or immunological tests. This situation has resulted in conflicting clinical and laboratory observations that in all likelihood is due to different populations of patients being studied in different centers. Based on some of the recent publications, there appears to be an emerging picture of this disease entity that we propose could be used to subgroup chronic fatigue syndrome into four different subclasses. These subclasses would consist of chronic fatigue with primarily nervous system disorders such as impaired memory or concentration and headache, chronic fatigue with primarily endocrine system disorders such as unrefreshing sleep and postexertional malaise, chronic fatigue with musculoskeletal system disorders such as muscle pain and joint pain, and chronic fatigue with immune system/infectious disorders such as sore throat and tender lymph nodes. It is suggested that if clinical and laboratory-based studies on chronic fatigue syndrome were conducted on more homogeneous subgroups of patients, the data from one center to the other might not be as conflicting and more insights can be shed on the nature of this clinical condition.

Aim The diagnosis and management of paediatric chronic fatigue syndrome (CFS) remain ongoing challenges for paediatric clinicians, particularly given its unknown aetiology and the little research on effective treatments for this condition. The aim of this study was to describe the presenting features of new patients attending a specialist chronic fatigue clinic at a tertiary-level Australian children's hospital. Method The medical records of all patients with an initial consultation at the chronic fatigue clinic over a 12-month period were reviewed using a standardised data collection template. Functional impact was based on school attendance and classified according to the National Institute of Health and Clinical Excellence guidelines (2007). Results A total of 99 patients attending the clinic were identified. Of these, 59 were diagnosed with CFS. Median age was 15.4 years with almost two-thirds of patients of female sex. Median time between symptom onset and diagnosis was 15.5 months. There was a high occurrence of fatigue, sleep disturbance, pain, postexertional malaise, and autonomic and cognitive symptoms in the group. The functional impact of CFS was classified as mild for 20%, moderate for 66% and severe for 14% of patients. Conclusions Most young people diagnosed with CFS experience symptoms for a protracted period, with considerable functional impact prior to initial tertiary service consultation. This audit has identified important areas for research, practice development and education in relation to the management of patients with CFS.

Myalgic encephalomyelitis (ME), chronic fatigue syndrome (CFS) and chronic fatigue (CF) are distinct diagnostic categories with regard to clinical symptoms, severity of illness and biomarkers. Patients with ME and CFS show higher scores on fatigue, neurocognitive disorders, hyperalgesia, autonomic symptoms, postexertional malaise and a subjective feeling of infection than patients with CF. ME is characterized by increased postexertional malaise, a subjective feeling of infection and neurocognitive disorders and is a more severe variant than CFS. Fukuda's 1994 CDC criteria are adequate to make a distinction between patients with ME/CFS and CF, while ME/CFS patients should be subdivided into those with and without postexertional malaise into ME and CFS, respectively. Different interrelated pathophysiological mechanisms play a role in ME/CFS, i.e. (1) inflammation and immune activation, (2) oxidative and nitrosative stress and lowered antioxidant defenses, (3) activation of cell signaling networks, e.g. nuclear factor ĸβ, the 2 9 ,5 9 -oligoadenylate/RNase-L and/or protein kinase R pathway, (4) a transition towards autoimmune reactions, and (5) bacterial translocation. The inflammatory biomarkers are higher in ME/CFS than in CF and higher in ME than in CFS. The above-mentioned pathways may explain the onset of characteristic ME/CFS symptoms, such as fatigue, malaise, autonomic symptoms, hyperalgesia, and neurocognitive symptoms. Different etiological factors may trigger ME/CFS/CF, e.g. viral and bacterial infections, and (auto)immune and inflammatory disorders, while psychosocial and physical stressors act as modulating factors. New pathophysiologically driven drug candidates for ME and CFS are discussed which target the pathways that play a role in ME/CFS.

This review summarizes the symptoms and signs seen in patients with chronic fatigue syndrome (CFS). It is based on the authors' experience with two cohorts of approximately 510 patients with chronic debilitating fatigue and on the reported experience of other investigators with similar patients. The most characteristic symptoms of CFS are the sudden onset of an infectious-type illness, the subsequent chronic and debilitating fatigue, and postexertional malaise; many patients also have recurrent fevers, pharyngitis, adenopathy, myalgias, sleep disorders, and cognitive impairment.

The goal of this study was to identify variables that successfully differentiated patients with chronic fatigue syndrome, major depressive disorder, and controls. Fifteen participants were recruited for each of these three groups, and discriminant function analyses were conducted. Using symptom occurrence and severity data from the Fukuda et al. (1994) definitional criteria, the best predictors were postexertional malaise, unrefreshing sleep, and impaired memory-concentration. Symptom occurrence variables only correctly classified 84.4% of cases, whereas 91.1% were correctly classified when using symptom severity ratings. Finally, when using percentage of time fatigue reported, postexertional malaise severity, unrefreshing sleep severity, confusion-disorientation severity, shortness of breath severity, and self-reproach to predict group membership, 100% were classified correctly.

Patients with chronic fatigue syndrome (CFS) experience chronic musculoskeletal pain which is even more debilitating than fatigue. Scientific research data gathered around the world enables clinicians to understand, at least in part, chronic musculoskeletal pain in CFS patients. Generalized joint hypermobility and benign joint hypermobility syndrome appear to be highly prevalent among CFS sufferers, but they do not seem to be of any clinical importance. On the other hand, pain catastrophizing accounts for a substantial portion of musculoskeletal pain and is a predictor of exercise performance in CFS patients. The evidence concerning pain catastrophizing is supportive of the indirect evidence of a dysfunctional pain processing system in CFS patients with musculoskeletal pain. CFS sufferers respond to incremental exercise with a lengthened and accentuated oxidative stress response, explaining muscle pain, postexertional malaise, and the decrease in pain threshold following graded exercise in CFS patients. Applying the scientific evidence to the manual physiotherapy profession, pacing self-management techniques and pain neurophysiology education are indicated for the treatment of musculoskeletal pain in CFS patients. Studies examining the effectiveness of these strategies for CFS patients are warranted.

The aetiology of chronic fatigue syndrome (CFS) is unknown; however, recent evidence suggests excessive free radical (FR) generation may be involved. This study investigated for the first time levels of 8-iso-prostaglandin-F(2 alpha)-isoprostanes alongside other plasma markers of oxidative stress in CFS patients and control subjects. Forty-seven patients (18 males, 29 females, mean age 48 [19--63] years) who fulfilled the Centres for Disease Control classification for CFS and 34 healthy volunteers (13 males, 21 females, 46 [19--63] years) were enrolled in the study. The CFS patients were divided into two groups; one group had previously defined cardiovascular (CV) risk factors of obesity and hypertension (group 1) and the second were normotensive and nonobese (group 2). Patients had significantly increased levels of isoprostanes (group 1, P=0.007; group 2, P=0.03, unpaired t test compared to controls) and oxidised low-density lipoproteins (group 2, P=0.02) indicative of a FR attack on lipids. CFS patients also had significantly lower high-density lipoproteins (group 1, P=0.011; group 2, P=0.005). CFS symptoms correlated with isoprostane levels, but only in group 2 low CV risk CFS patients (isoprostanes correlated with; total symptom score P=0.005; joint pain P=0.002; postexertional malaise P=0.027, Pearson). This is the first time that raised levels of the gold standard measure of in vivo oxidative stress (isoprostanes) and their association with CFS symptoms have been reported.

We would like to comment on Van Cauwenbergh et al. [1] in which the authors outline guidelines for graded exercise therapy (GET) and cognitive behavioural therapy (CBT) for ME ⁄CFS. In this context, it is essential to make a distinction between ME [2], CFS and chronic fatigue (CF). While postexertional malaise, a long-lasting increase in symptoms, like pain and cognitive impairment, after a minor exertion is mandatory for ME, it is not obligatory for the diagnosis of CFS. Van Cauwenbergh et al. [1] stipulate that the rationale for CBT and GET is kinesiophobia, resulting into the avoidance of behaviour and deconditioning. However, there is no correlation between kinesiophobia and exercise capacity, activity limitations, or participation restrictions in CFS patients with widespread muscle or joint pain [3]. Deconditioning and psychological variables also do not account for the symptoms [3]. The authors [1] claim that CBT ⁄GET is an evidence-based effective therapy for CFS. However, most of the studies reviewed in [1] are studies on the effectiveness of CBT ⁄GET in chronic fatigue (CF), not in CFS, let alone ME [2]. A recent large-scale trial in the UK showed that the effectiveness of CBT and GET in CF [1] in terms of ‘fatigue’ is 30% and 28%, respectively, while fatigue decreases in 15% of the cases by standard medical care. While CBT ⁄GET results into a decrease in fatigue in some CF patients [3], there is no substantial clinical improvement in objective measures, for example activity levels, exercise capacity ⁄ oxygen uptake or distance walked in 6 minutes [1,3]. Even more, CBT ⁄GET is often counterproductive. A longlasting negative impact of exertion on in ME ⁄CFS has been observed repetitively [3]. Data of Nijs et al. [4], for example, show that an one-off walking exercise with intensity and duration limits results in an increase in pain lasting more than 24 h. Research [3] has demonstrated that exercise has a (strong) negative effect on the physiological exercise capacity 24 h later and that CFS patients are unable to sustain low target activity levels, indicated by reduced total activity after 4–10 days. A randomized controlled trial [5] observed that pain had increased and physical function had declined 12 months after CBT ⁄GET. A distinction between ME, CFS and CF is essential. CBT ⁄GET is not an evidence-based effective approach and often has a negative effect in ME ⁄CFS [3]. Future studies should explore the biological abnormalities in ME and CFS in more detail and the effect of exertion in well-defined subgroups to avoid iatrogenic harm.

Chronic fatigue syndrome (CFS) belongs in the medically unexplained illnesses. It affects approximately 0.2-0.7% of the population in Western countries. It is characterised by unexplained fatigue, lasting 6 months or more, impairment of neurocognitive functions and quality of sleep, and of somatic symptoms, such as recurrent sore throat, muscle aches, arthralgias, headache and postexertional malaise. No link between infections and CFS has been clearly established but the immune system is activated, there are aberrations in several hypothalamic-pituitary axes and involvement of other parts of the central nervous system. No specific treatment has been found. Cognitive behavioural therapy is established to be of value to improve quality of life. More effective treatment should result, as advances in biomedical as well as psychological research continue.

Chronic fatigue syndrome (CFS) is a condition characterized by impairment of neurocognitive functions and quality of sleep and of somatic symptoms such as recurrent sore throat, muscle aches, arthralgias, headache, and postexertional malaise. A majority of patients describe an infectious onset but the link between infections and CFS remains uncertain. Findings show an activation of the immune system, abberations in several hypothalamic-pituitary axes and involvement of other parts of the central nervous system. The origin is bound to be complex and it may well be that the solution will come together with a more generally altered view about mind-body dualism, and the concept of illness and disease.

The paper “Fear of movement and avoidance behaviour toward physical activity in chronic-fatigue syndrome and fibromyalgia: state of the art and implications for clinical practice” [1] is interesting but problematic. We agree that mild exercise is good but over exercise can cause relapse. Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and fibromyalgia patients suffer from relapse when is subjected to over exercise. We at the ME/CFS Center at Mount Sinai School of Medicine, New York are investigating the postexertional malaise seen in (ME/CFS). This is one of the criteria in the Canadian Consensus of diagnosis of ME/CFS. [2] The notion that ME/CFS is caused by poor conditioning is no longer widely accepted. It is thought that it is an immune system dysfunction, which after onset can be provoked by stress, over exercise or overwork [3]. Indeed, there can be depression, but this depression is secondary to the disease much like any other chronic disease. Cognitive behavioral therapy may be helpful to reverse the secondary depression but one must understand that this depression is indeed secondary and the initial disease entity is in the immune system and must be identified and treated.