Adamson et al. considered a 2-point decrease in Chalder Fatigue Questionnaire score to indicate improvement in fatigue and a 2-point increase in Chalder Fatigue Questionnaire score to indicate deterioration in fatigue.1 While intuitively appealing, data exist that suggest a more complex relationship between changes in Chalder Fatigue Questionnaire
scores and clinical change.
Collin and Crawley studied treatment outcomes at 11 specialist myalgic encephalomyelitis/ chronic fatigue syndrome clinics in England.2 The authors tabulated mean change in Chalder Fatigue Questionnaire score at one year against Clinical Global Impression scores (see additional file 1, table S3). A 2-point decrease in Chalder Fatigue Questionnaire score was reported patients who deemed their health as follows: ‘no change’, ‘a little worse’, ‘much worse’ and ‘very much worse’.
The mean changes in Chalder Fatigue Questionnaire score in those categories were similar, with overlapping 95% confidence intervals within the range [4.77, 2.29]. This suggests that a 2-point decrease in Chalder Fatigue Questionnaire score indicates deterioration or no change in the health of a person with myalgic encephalomyelitis/ chronic fatigue syndrome, not improvement.
Adamson et al. report a mean change in Chalder Fatigue Questionnaire score of 6.52, corresponding to the ‘a little better’ category in Collin and Crawley’s data. For comparison, the mean change of those ‘much better’ was an 11-point decrease in Chalder Fatigue Questionnaire score, and ‘very much better’ was a 14.9-point decrease.
Studies using the Chalder Fatigue Questionnaire as a primary outcome measure may miss or underestimate deterioration, because the Chalder Fatigue Questionnaire obscures it. Studies may overestimate improvement if a 2-point decrease on the Chalder Fatigue Questionnaire is used, when a 10-point decrease may be a more appropriate lower bound.
Anchoring one subjective measure to another can hint at cut-offs for clinically important differences, but the use of more objective outcome measures such as actigraphy would be preferable. The unpopularity of such measures among myalgic encephalomyelitis/ chronic fatigue syndrome researchers may be linked with the stubborn refusal of more objective outcome measures to budge with current specialist treatment.3
Posted inNews|TaggedChalder fatigue scale, Karen D Kirke|Comments Off on Measuring improvement & deterioration in ME/CFS: the pitfalls of the Chalder Fatigue Questionnaire
Background
Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is understood as a complex condition, likely triggered and sustained by an interplay of biological, psychological, and social factors. Little oversight exists of the field of causal research. This systematic scoping review explores potential causal factors of CFS/ME as researched by primary studies.
Methods
We searched eight databases for primary studies that examined potential causal factors of CFS/ME. Based on title/abstract review, two researchers independently sorted each study’s factors into nine main categories and 71 subordinate categories, using a system developed with input given during a 2018 ME conference, specialists and representatives from a ME patient advocacy group, and using BMJ Best Practice’s description of CFS/ME etiology. We also extracted data related to study design, size, diagnostic criteria and comparison groups.
Results
We included 1161 primary studies published between January 1979 and June 2019. Based on title/abstract analysis, no single causal factor dominated in these studies, and studies reported a mean of 2.73 factors. The four most common factors were: immunological (297 studies), psychological (243), infections (198), and neuroendocrinal (198). The most frequent study designs were case–control studies (894 studies) comparing CFS/ME patients with healthy participants. More than half of the studies (that reported study size in the title/abstract) included 100 or fewer participants.
Conclusion
The field of causal hypotheses of CFS/ME is diverse, and we found that the studies examined all the main categories of possible factors that we had defined a priori. Most studies were not designed to adequately explore causality, rather to establish hypotheses. We need larger studies with stronger study designs to gain better knowledge of causal factors of CFS/ME.
The post-exertional malaise of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) was modeled by comparing micro-RNA (miRNA) in cerebrospinal fluid from subjects who had no exercise versus submaximal exercise.
Materials and Methods:
Differentially expressed miRNAs were examined by informatics methods to predict potential targets and regulatory pathways affected by exercise.
Results:
miR-608, miR-328, miR-200a-5p, miR-93-3p, and miR-92a-3p had higher levels in subjects who rested overnight (nonexercise n=45) compared to subjects who had exercised before their lumbar punctures (n=15). The combination was examined in DIANA MiRpath v3.0, TarBase, Cytoscape, and Ingenuity software® to select the intersection of target mRNAs. DIANA found 33 targets that may be elevated after exercise, including TGFBR1, IGFR1, and CDC42. Adhesion and adherens junctions were the most frequent pathways. Ingenuity selected seven targets that had complementary mechanistic pathways involving GNAQ, ADCY3, RAP1B, and PIK3R3. Potential target cells expressing high levels of these genes included choroid plexus, neurons, and microglia.
Conclusion:
The reduction of this combination of miRNAs in cerebrospinal fluid after exercise suggested upregulation of phosphoinositol signaling pathways and altered adhesion during the post-exertional malaise of ME/CFS.
Clinical Trial Registration Nos.: NCT01291758 and NCT00810225.
Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating condition associated with several negative health outcomes. A hallmark of ME/CFS is decreased exercise capacity and often profound exercise intolerance. The causes of ME/CFS and its related symptoms are unknown, but there are indications of a dysregulated metabolism with impaired glycolytic vs oxidative energy balance.
In line with this, we recently demonstrated abnormal lactate accumulation among ME/CFS patients compared with healthy controls after exercise testing. Here we examined if cardiac dimensions and function were altered in ME/CFS, as this could lead to increased lactate production.
Methods: We studied 16 female ME/CFS patients and 10 healthy controls with supine and we assessed cardiac dimensions and function by conventional echocardiographic and Doppler analysis as well as novel tissue Doppler and strain variables.
Results: A detailed analyses of key variables of cardiac dimensions and cardiac function revealed no significant differences between the two study groups.
Conclusion: In this cohort of well-described ME/CFS patients, we found no significant differences in echocardiographic variables characterizing cardiac dimensions and function compared with healthy controls.
(This article belongs to the Special Issue ME/CFS – the Severely and Very Severely Affected)
Dr Nina Muirhead, a dermatology surgeon in Buckinghamshire & lecturer at Cardiff Medical School responds to an article in the British Medical Journal.
Dear Editor
I strongly echo this sentiment from my long COVID colleagues about assessing and investigating patients properly and would like to add that doctors must also diagnose patients properly. We should not treat long COVID as anxiety, nor confuse primary psychological sequalae of COVID with the multisystem disease ME/CFS.
COVID-19 can leave emboli, pulmonary fibrosis, organ damage and myocarditis in its wake. Many ‘long-haulers’ are struggling at home and still recording symptoms without a diagnosis or prognosis. Their acute COVID experience may have ranged from mild to severe, but they have not felt better after the expected twelve-day average. This heterogenous group are presenting with multiple symptoms: fatigue, headaches, ‘lung burn’, sore throats, chest pains, irritable bowel, night sweats, rashes, brain fog, muscle, bone and joint pains, changing sleep, palpitations, burning skin, dizziness, tingling, tinnitus, difficulty concentrating – the list goes on. Days have turned to weeks, and weeks have turned to months. Will months turn to years, or years to decades?
A subset of ‘chronic COVID-19’ patients do not have familiar organic pathology to explain their symptoms, they know their experience is not imagined, nor secondary to anxiety. Fit individuals walk or exercise, yet, on other days, struggle to climb the stairs or get out of bed.
Symptoms flare in the hours or days after trivial physical, emotional, or cognitive effort. Many are still functioning at a fraction of their pre-COVID normal. Others fluctuate between recovery and relapse.
Shockingly, some are facing difficulty being believed, or told their symptoms are secondary to anxiety or depression. The Royal College of GPs have produced a short module linking long COVID to anxiety and post-traumatic stress, but many long COVID patients would not be anxious if they felt well. There are calls for a new narrative. Are we on the verge of defining a new disease, or are many of these patients experiencing the reality of ME/CFS?
When the COVID-19 global viral pandemic hit, the online ME/CFS community went wild: “There will be an explosion of post-COVID patients with ME.” “How will the NHS deal with the impending ME tsunami?” ME/CFS is a common, complex, chronic, multisystem disease affecting tens of millions of patients worldwide. Many cases are triggered by a viral infection and up to a quarter of patients are bedbound or housebound. ME/CFS appears to be the neglected illness of the 21st Century, residing in a medical blind-spot. ME/CFS is widely misunderstood and should neither be a diagnosis of exclusion nor an exclusive diagnosis. Evidence shows patients suffer from inflammation, autonomic and metabolic dysregulation and altered mitochondrial function. Exertion results in an exacerbation of symptoms and exercise is not recommended as a treatment.
Identifying ME/CFS patients amongst, and alongside, those with ‘chronic COVID-19’ is vital. It is also crucial that we learn to differentiate between patients suffering from anxiety, depression and post-traumatic stress from those developing a complex multisystem disease, which as yet has no biomarker. I do not deny the interplay between body and mind, but depression and anxiety can be reduced with exercise whilst ME/CFS can be exacerbated. Unless we learn to recognise the difference, progress will not be made. The burden of illness should be recorded and epidemiological data collected to drive scientific and biomedical research. Some experienced ME/CFS clinicians are convinced that many long COVID patients are suffering from ME/CFS.
However not all long COVID patients fit the diagnostic criteria for ME/CFS and worse, there is widespread ignorance that ME/CFS is psychological, such that many who are anxious and depressed at this stage could be mislabeled as having ME/CFS.
Do long COVID and ME/CFS patients think they have the same disease?
There are reservations on both sides. Long COVID patients do not want their disease to be misjudged, underestimated, or ignored. Healthcare professionals with long COVID seem the most reticent that long COVID and ME/CFS are conflated. This is particularly the case for those who were taught the outdated biopsychosocial narrative for ME/CFS, they know exercise and psychotherapy are not the answer. ME/CFS patients think their lived experience of real, debilitating, chronic, complex disease could be a great source of support. After a diagnosis ME/CFS and long COVID patients all require appropriate support from their GP, employer, family and friends. They need regular review and may develop other comorbidities.
This debate has implications for guidelines, funding, government, policy and practice. Many healthcare professionals with long COVID have struggled to resume full time work. These reports are the tip of the iceberg, patients who ignore symptoms and push through may get worse. The peak of bedbound and housebound patients could hit at around 2-5 years, others may deteriorate over decades. The mean duration of ME/CFS in children and young people is five years but in adults as few as 5% are estimated to make a full recovery. Early advice to rest has been shown to reduce the future burden on work rehabilitation and medical retirement. ME/CFS is already estimated to cost the UK economy £3.3 billion per year, can we afford to add thousands of long COVID patients to the millions already missing?
When long COVID patients report that the harder they push to get better, the more their bodies fail them, we must listen and take note.
Fatigue, pain, sleep disturbance and brain fog are debilitating and have a major impact on quality of life. Exercise has the potential to exacerbate symptoms and may inhibit cellular energy delivery. NICE has wisely advised caution against using graded exercise therapy for post COVID patients. Objective assessments for orthostatic intolerance, neuroinflammation, altered cellular bioenergetics, grip strength and cardiopulmonary exercise testing (CPET) should be part of rehabilitation assessment. Repeat CPET may indicate if exercise is making patients better, or worse.
Long COVID and ME/CFS are complex and heterogeneous. Both need greater recognition and research. The worst outcome would be to ignore or dismiss both. There is a pressing need for better education so that we can take the right approach and avoid causing patients harm.
Competing interests: I have no financial conflict of interest. I have provided expert testimony to NICE on education, information and support for healthcare professionals on ME/CFS and am chair of the CFS/ME education working group (CMRC) I am a member of Forward ME, I am a doctor working for the NHS and a patient with ME/CFS.
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Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex neuroimmune disorder characterized by numerous symptoms of unknown etiology. The ME/CFS immune markers reported so far have failed to generate a clinical consensus, perhaps partly due to the limitations of biospecimen biobank.
To address this issue, we performed a comparative analysis of the impact of long-term biobanking on previously identified immune markers and also explored additional potential immune markers linked to infection in ME/CFS. A correlation analysis of marker cryostability across immune cell subsets based on flow cytometry immunophenotyping of fresh blood and frozen PBMC samples collected from individuals with ME/CFS (n = 18) and matched healthy controls (n = 18) was performed.
The functionality of biobanked samples was assessed on the basis of cytokine production assay after stimulation of frozen PBMCs. T cell markers defining Treg subsets and the expression of surface glycoprotein CD56 in T cells and the frequency of the effector CD8 T cells, together with CD57 expression in NK cells, appeared unaltered by biobanking. By contrast, NK cell markers CD25 and CD69 were notably increased, and NKp46 expression markedly reduced, by long-term cryopreservation and thawing. Further exploration of Treg and NK cell subsets failed to identify significant differences between ME/CFS patients and healthy controls in terms of biobanked PBMCs.
Our findings show that some of the previously identified immune markers in T and NK cell subsets become unstable after cell biobanking, thus limiting their use in further immunophenotyping studies for ME/CFS. These data are potentially relevant for future multisite intervention studies and cooperative projects for biomarker discovery using ME/CFS biobanked samples. Further studies are needed to develop novel tools for the assessment of biomarker stability in cryopreserved immune cells from people with ME/CFS.
Objective: Pain in fibromyalgia (FM) and chronic fatigue syndrome (CFS) is assumed to originate from central sensitization. Perineural cysts or Tarlov cysts (TCs) are nerve root dilations resulting from pathologically increased cerebrospinal fluid pressure. These cysts initially affect sensory neurons and axons in dorsal root ganglia and produce sensory symptoms (pain and paresthesia). Symptomatic TC (STC) patients often complain about widespread pain and fatigue. Consequently, STC patients may initially be diagnosed with FM, CFS, or both. The objective of this study was to document the prevalence of TCs in patients diagnosed with FM or CFS.
Design:
A retrospective study.
Setting:
An outpatient clinic for musculoskeletal disorders.
Subjects:
Patients diagnosed with FM according to the 1990 American College of Rheumatology criteria or with CFS according to the 1994 Centers for Disease Control criteria were selected.
Methods:
Review of lumbar and sacral magnetic resonance imaging scans including TCs ≥5 mm in size.
Results:
In total, 197 patients with FM, CFS, or both underwent magnetic resonance imaging. Ninety-one percent were women. The mean age was 48.1 (±11.9) years. TCs were observed in 39% of patients, with a mean size of 11.8 (±5.2) mm. In males, the prevalence was 12%, vs. 42% in females.
Conclusions:
In patients diagnosed with FM or CFS, the prevalence of TCs was three times higher than that in the general population. This observation supports the hypothesis that STCs, FM, and CFS may share the same pathophysiological mechanism, i.e., moderately increased cerebrospinal fluid pressure, causing irritation of neurons and axons in dorsal root ganglia.
The post-exertional malaise of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) was modeled by comparing 
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and we assessed cardiac dimensions and function by conventional echocardiographic and 
Dr Nina Muirhead, a dermatology surgeon in Buckinghamshire & lecturer at Cardiff Medical School responds to an article in the British Medical Journal.
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex 
Pain in fibromyalgia (FM) and chronic fatigue syndrome (CFS) is assumed to originate from central sensitization. 
