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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.

Background: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), Gulf War Illness (GWI) and control subjects underwent 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 a 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 subjects showed greater activation during cognition than ME/CFS in the left pedunculotegmental nucleus. Post exercise, ME/CFS subjects showed greater activation than GWI ones 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. The controls had no changes. Conclusions: Exercise caused the 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 most patients recover from acute COVID-19, some experience postacute sequelae of severe acute respiratory syndrome coronavirus 2 infection (PASC). One subgroup of PASC is a syndrome called “long COVID-19,” reminiscent of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). ME/CFS is a debilitating condition, often triggered by viral and bacterial infections, leading to years-long debilitating symptoms including profound fatigue, postexertional malaise, unrefreshing sleep, cognitive deficits, and orthostatic intolerance. Some are skeptical that either ME/CFS or long COVID-19 involves underlying biological abnormalities. However, in this review, we summarize the evidence that people with acute COVID-19 and with ME/CFS have biological abnormalities including redox imbalance, systemic inflammation and neuroinflammation, an impaired ability to generate adenosine triphosphate, and a general hypometabolic state. These phenomena have not yet been well studied in people with long COVID-19, and each of them has been reported in other diseases as well, particularly neurological diseases. We also examine the bidirectional relationship between redox imbalance, inflammation, energy metabolic deficits, and a hypometabolic state. We speculate as to what may be causing these abnormalities. Thus, understanding the molecular underpinnings of both PASC and ME/CFS may lead to the development of novel therapeutics.

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.

Background and aims The interaction between the immune system and pain has been thoroughly explored in the recent decades. The release of inflammatory mediators from immune cells has the capability of activating neurons and glial cells, in turn sensitizing the nervous system. Both immune system alterations and pain modulation dysfunctions have been shown in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) following exercise. However, no studies tried to explore whether these two phenomena are linked and can explain exercise-induced symptoms worsening in people with ME/CFS. We hypothesized that exercise-induced changes in descending pain modulation is associated to changes in immune system functions. We used complement system product C4a and elastase activity as indicators of immune system activity. Methods The study design was a secondary analysis of controlled experimental studies. Twenty-two patients with ME/CFS and 22 healthy sedentary controls were enrolled. In experiment 1, subjects performed an aerobic submaximal exercise test; in experiment 2 they underwent a self-paced exercise test. One week of rest period were set between the two exercise tests. Before and after each experiment, subjects underwent clinical assessment, pain thresholds (PPTs) measurement, and blood sampling. Immune system function was assessed measuring complement system C4a products and elastase activity. Results Changes in elastase activity were not associated to changes in PPTs. Associations were observed in the ME/CFS group between changes in PPTs and C4a products, following both types of exercise. After submaximal exercise, the change in C4a products was associated with the change in PPT at the thumb in patients (r=0.669, p=0.001). Similarly, after self-paced exercise the change in C4a products was associated witht the change in PPT at the calf in patients (r=0.429, p=0.047). No such correlations were found in healthy controls. Regression analysis showed that C4a changes after the submaximal exercise significantly predicted the change in PPTs (R2=0.236; p=0.02). Conclusions Moderate associations between exercise-induced changes in PPTs and immune system activity were found only in ME/CFS. The change in the complement system following submaximal exercise might be able to explain part of the change in patient’s pain thresholds, providing evidence for a potential link between immune system alteration and dysfunctional endogenous pain modulation. These results have to be taken with caution, as only one out of three measures of PPTs was found associated with C4a changes. We cannot reject the hypothesis that C4a might therefore be a confounding factor, and changes during exercise might be mediated by other mechanism. Implications Immune system changes following exercise might contribute to exercise-induced symptoms worsening in patients with ME/CFS. However, the role of the complement system is questionable.

​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.

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.

Autoimmune disorders are known to affect a substantial number of people worldwide and in some cases may be fatal. They occur in the presence of unregulated inflammatory re‐ sponses including failure in self-tolerance. Some unexplained disorders with immune com‐ promises may demonstrate certain characteristics that suggest an autoimmune disorder including Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME). CFS/ME re‐ mains an unsolved disorder with multiple symptoms and no single causative factor. These symptoms may include but are not limited to incapacitating fatigue, weakened short term memory or attentiveness, sore throat, tender cervical or axillary lymph nodes, muscle pain, severe headaches, impaired sleep and postexertional malaise. To date succinct and concise mechanisms that underlie this disorder have not yet being identified although, many hy‐ potheses have been put forward. CFS/ME often occurs as a consequence of a post-infectious episode accompanied by compromises in the immune, endocrine and nervous systems. The sequences of these events have not being clearly identified. Importantly, immune deteriora‐ tion in CFS/ME is related to heightened or suppressed cell function, differential gene expres‐ sion, equivocal levels of immune cell numbers and protein secretion promoting adverse inflammatory activation. Both innate and adaptive immune system perturbations persist in CFS/ME. These characteristics are in many respects similar to mechanisms of disease in au‐ toimmune disorders suggesting that the changes in immune response may develop from cellular and molecular changes in immune cells and proteins. We propose here that as the mechanism of CFS/ME may involve certain immunological factors that have been shown to be compromised in other autoimmune diseases, CFS/ME may in some cases have an autoim‐

This article reviews a Myalgic Encephalomyelitis (ME) case definition based on criteria offered over the past five decades. The current paper looks to review case definitions for ME based on Ramsay’s definition [41], the “London” criteria [45], Hyde’s Nightingale definition [16], and Goudsmit et al.’s criteria [11]. In general, these theorists have argued that ME is now defined differently than chronic fatigue syndrome because ME involves an acute onset, postexertional malaise and neurocognitive problems, and fatigue is not a major criteria. We will compare these theorists to the recently published International Consensus Criteria for Myalgic Encephalomyelitis [3]. We will also attempt to consolidate aspects of different current definitions in order to suggest possible core features of ME. This article will also recommend the importance of providing explicit, objective criteria on specific key symptoms. In addition, structured interview schedules along with specific medical tests are recommended to assure this illness is assessed in a consistent way across settings. It is hoped these developments will lead to increased reliability of the ME case definition, as well as more frequent use of these criteria by investigators.

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.