This commentary identifies recent scientific and clinical milestones that appear to have increased legitimization of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).
These milestones include government-funded reports recognizing the seriousness of ME/CFS, new initiatives for biomedical research sponsored by the US National Institutes of Health, official endorsement of the ME/CFS name, publication of practitioner primers, and the launch of a new peer-review fatigue journal.
These positive developments are tempered by ongoing illness challenges including patient stigma, absence of diagnostic markers, a lack of established treatments, and a dearth of researchers and knowledgeable, interested clinicians.
In October 2019, Cochrane announced its commitment to a full update the Cochrane Review Exercise therapy for chronic fatigue syndrome. The statement noted plans for: “a comprehensive review of the protocol, which will be developed in consultation with an independent advisory group that we intend to convene. This group will involve partners from patient-advocacy groups from different parts of the world who will help us to embed a patient-focused, contemporary perspective on the review question, methods and findings.”
Cochrane is now pleased to announce that Hilda Bastian has been appointed to lead the independent advisory group. Hilda has been a health consumer advocate and researcher, and has held many roles with healthcare bodies. She is also author of the popular PLoS blog “Absolutely Maybe”, which looks at the uncertainties in medicine, and reported on the contents and conduct of the Cochrane Review Exercise therapy for chronic fatigue syndrome. Her knowledge and understanding of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), and the methodology of systematic reviews, saw broad support for her blog posts from consumers and researchers alike.
Rates of suicidal ideation, attempts, and completion are alarmingly high in chronic invisible illness communities. Suicide is the second leading cause of death for people with myalgic encephalomyelitis/chronic fatigue syndrome [1], with 20% of patients dying by suicide [2]. In postural orthostatic tachycardia syndrome, approximately 50% are at high risk for suicide, with 15-18% reporting past suicide attempts, and 13% stating that they will likely make a future suicide attempt [3,4].
In the fibromyalgia community, 33% report suicidal ideation [5], while 4% of people with hypermobile Ehlers-Danlos syndrome attempt suicide [6]. Finally, 1,200 chronic Lyme disease patients die by suicide in the United States annually [7]. Clearly, the chronic invisible illness community is highly affected by suicidal ideation.
There are several reasons that people with chronic invisible illness are at particularly high risk of suicide. Nearly half of the risk factors for suicide – major physical illness, sense of isolation, hopelessness, job or financial loss, loss of relationships, and lack of good health care – are prevalent in this population. Common symptoms for many with chronic illnesses have also been linked with increased suicide risk, including functional disability [8], chronic pain [9], and sleep disturbance [10]. However, most people with chronic illnesses do not have a mental health diagnosis [11].
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) affects approximately 250,000 people in the UK. The condition varies in severity causing long-term physical and cognitive fatigue which is not alleviated by rest. Whilst the pathology is not understood, recent evidence suggests metabolic abnormalities may be associated with the manifestation of symptoms, particularly involving the metabolism of glucose and energy production.
The use of ketone bodies as an alternative energy substrate may be beneficial to people with ME/CFS, in order to by-pass the glycolytic pathway, enhance energy production and reduce fatiguing outcomes.
Study Design and Methods:
Using a pragmatic collective case study with repeated measures methodology we investigated the feasibility of following a ketogenic diet and potential effects of the high fat, low carbohydrate diet on response to physical activity in people with ME/CFS (n=3) and healthy controls (n=3) using a submaximal exercise stress test both with and without dietary intervention. Exercise tolerance (mins), rate of oxygen consumption (VO2) to workload (75W), respiratory exchange ratio (RER), rate of perceived effort (RPE) and lactate response were measured throughout and descriptive statistics performed.
Results:
We found that the ketogenic diet was followed, with compliance higher in the pwME/CFS. Variations in response following the ketogenic diet was observed across individuals in minutes performed, VO2, HR, RER, and RPE post diet but the KD only limited exercise capacity in the control individuals. Individuals responded differently to the KD but group trends have been reported as means and standard deviation. The KD resulted in a decrease in RER at submax in the controls with a mean change of 0.07 from baseline (0.86 ± 0.1) to post intervention (0.79 ± 0.1) compared to a mean change of 0.02 in the ME/CFS from baseline (1.03 ± 0.1) to post intervention (1.01 ± 0.1).
A decrease in VO2 (L/min) at submax showed a mean change of 0.06 (L/min) in the pwME/CFS at baseline (1.34 ± 0.1) to post intervention (1.27 ± 0.2) compared to a mean change of 0.07 (L/min) in the controls at baseline (1.40 ± 0.3) to post intervention (1.33 ± 0.2). HR (bpm) at submax decreased in all individuals, with a mean change of 4 (bpm), with pwME/CFS at baseline (139 ± 8.2) to post intervention (135 ± 14) and control individuals at baseline (107 ± 7.8) to intervention (103 ± 3.2). RPE at submax decreased in the pwME/CFS from baseline (6 ± 1.0) to post intervention (5 ± 2.1) whereas the controls increased from baseline (2 ± 1.0) to post intervention (3 ± 1.5).
Conclusion:
Our observations suggest individualised but metabolic flexibility in healthy individuals is achievable via dietary manipulation showing the ability to switch from glucose to fats under controlled conditions. The different response in substrate utilisation in individuals with ME/CFS suggests that potential metabolic abnormalities may be present in ME/CFS. Further investigation is now warranted in order to assess whether the KD is beneficial for people with ME/CFS.
Comorbid depression is common in adolescents with chronic illness. We aimed to design and test a linguistic coding scheme for identifying depression in adolescents with Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME), by exploring features of e-consultations within online cognitive behavioural therapy treatment.
E-consultations of 16 adolescents (aged 11 – 17) receiving FITNET-NHS treatment in a national randomised controlled trial were examined. A theoretically-driven linguistic coding scheme was developed and used to categorise comorbid depression in e-consultations using computerised content analysis.
Linguistic coding scheme categorisation was subsequently compared to classification of depression using the Revised Children’s Anxiety and Depression Scale (RCADS) published cut-offs (t-scores ≥ 65, ≥ 70). Extra linguistic elements identified deductively and inductively were compared with self-reported depressive symptoms after unblinding.
The linguistic coding scheme categorised three (19%) of our sample consistently with self-report assessment. Of all 12 identified linguistic features, differences in language use by categorisation of self-report assessment were found for ‘past-focus’ words (mean rank frequencies: 1.50 for no depression, 5.50 for possible depression, and 10.70 for probable depression; p < .05) and ‘discrepancy’ words (mean rank frequencies: 16.00 for no depression, 11.20 for possible depression, and 6.40 for probable depression; p < .05).
The linguistic coding profile developed as a potential tool to support clinicians in identifying comorbid depression in e-consultations showed poor value in this sample of adolescents with CFS/ME. Some promising linguistic features were identified, warranting further research with larger samples.
Improving Access to Psychological Therapiesis a UK Government funded initiative to widen access to psychological treatment for a range of common mental health complaints, such as depression and anxiety. More recently, the service has begun to treat patients with medically unexplained symptoms.
This paper reports on a review of treatment protocols and early treatment data for medically unexplained symptoms, specifically the illness myalgic encephalomyelitis/ chronic fatigue syndrome.
Main text:
A series of seven core problems and failings are identified, including an unproven treatment rationale, a weak and contested evidence-base, biases in treatment promotion, exaggeration of recovery claims, under-reporting of drop-out rates, and a significant risk of misdiagnosis and inappropriate treatment.
Conclusions:
There is a pressing need for independent oversight of this service, specifically evaluation of service performance and methods used to collect and report treatment outcomes. This service offers uniform psycho-behavioural therapy that may not meet the needs of many patients with medically unexplained health complaints.
Psychotherapy should not become a default when patients’ physical symptoms remain unexplained, and patients should be fully informed of the rationale behind psychotherapy, before agreeing to take part. Patients who reject psychotherapy or do not meet selection criteria should be offered appropriate medical and psychological support.
Chronic Fatigue Syndrome (CFS) is a debilitating condition estimated to impact at least 1 million individuals in the United States, however there persists controversy about its existence.
Machine learning algorithms have become a powerful methodology for evaluating multi-regional areas of fMRI activation that can classify disease phenotype from sedentary control. Uncovering objective biomarkers such as an fMRI pattern is important for lending credibility to diagnosis of CFS.
fMRI scans were evaluated for 69 patients (38 CFS and 31 Control) taken before (Day 1) and after (Day 2) a submaximal exercise test while undergoing the n-back memory paradigm. A predictive model was created by grouping fMRI voxels into the Automated Anatomical Labeling (AAL) atlas, splitting the data into a training and testing dataset, and feeding these inputs into a logistic regression to evaluate differences between CFS and control.
Model results were cross-validated 10 times to ensure accuracy. Model results were able to differentiate CFS from sedentary controls at a 80% accuracy on Day 1 and 76% accuracy on Day 2 (Table 3). Recursive features selection identified 29 ROI’s that significantly distinguished CFS from control on Day 1 and 28 ROI’s on Day 2 with 10 regions of overlap shared with Day 1 (Figure 3). These 10 shared regions included the putamen, inferior frontal gyrus, orbital (F3O), supramarginal gyrus (SMG), temporal pole; superior temporal gyrus (T1P) and caudate ROIs.
Figure 3. Significantly elevated BOLD activity during the 2 > 0 back condition in CFS and control groups before and after exercise
This study was able to uncover a pattern of activated neurological regions that differentiated CFS from Control. This pattern provides a first step toward developing fMRI as a diagnostic biomarker and suggests this methodology could be emulated for other disorders. We concluded that a logistic regression model performed on fMRI data significantly differentiated CFS from Control.
Patients high in PEM endorse greater symptom burden than those low in PEM
Patients high in PEM endorse greater psychological adversity than those low in PEM
Results suggest the Fukuda case definition does not define a heterogeneous group
PEM may identify patients who would most benefit from psychological intervention
Research abstract:
Objective: Post-exertional malaise (PEM) is often considered a cardinal symptom of Chronic Fatigue Syndrome (CFS). There is no gold standard diagnostic method for CFS, however, and the Centers for Disease Control (CDC) Fukuda case definition does not require PEM. Research has identified differences in symptom burden between patients according to PEM, but whether it is associated with psychological distress has not been investigated.
Methods:
The CDC CFS Inventory, Fatigue Symptom Inventory, Profile of Mood States, Center for Epidemiologic Studies Depression Scale, Perceived Stress Scale, and subscales of the Sickness Impact Profile were administered to 261 patients diagnosed with the Fukuda criteria. PEM status (loPEM/hiPEM) was determined via self-reported post-exertional fatigue severity. Analyses of covariance (ANCOVA), controlling for age and gender, assessed cross-sectional group differences, and cross-sectional linear regressions using the continuous PEM severity predictor paralleled these analyses.
Results:
hiPEM patients reported greater symptom intensity, frequency, and interference than loPEM counterparts (p’s < .001). hiPEM patients also reported greater social disruption, depressive symptoms, and mood disturbance (p’s ≤ .011). Groups did not differ in recent negative life experiences, perceived stress, or demographic variables. The results of regression analyses mirrored those of ANCOVAs.
Conclusion:
This study replicates the association between PEM and symptom burden and additionally associates PEM with psychological distress; psychological distress could, however, be a consequence of symptom burden. Differences between hiPEM and loPEM CFS patients highlight the heterogeneity of diagnoses resulting from the Fukuda criteria. It is also possible that PEM identifies particularly distressed patients for whom psychological intervention would be most beneficial.
So as far as I can tell, the main message of this paper is, or should be, that the Fukuda case definition is inadequate because many of those who meet it do not appear to experience PEM as a debilitating factor, if they experience it at all. Given that PEM is already viewed as the cardinal symptom of the illness, the logical conclusion is that such patients don’t have ME, despite having been diagnosed with CFS per Fukuda. As it reads, the study’s main finding seems to be that CFS patients with PEM need psychological intervention—when in fact what they really need most is effective medical treatments for their ME.
Chronic fatigue syndrome (CFS) is one of the most intractable diseases and is characterized by severe central fatigue that impairs even daily activity. To date, the pathophysiological mechanisms are uncertain and no therapies exist. Therefore, a proper animal model reflecting the clinical features of CFS is urgently required.
We compared two CFS animal models most commonly used, by injection with lipopolysaccharide (LPS from Escherichia coli O111:B4) or polyinosinic: polycytidylic acid (poly I:C), along with bilateral adrenalectomy (ADX) as another possible model. Both LPS- and poly I:C-injected mice dominantly showed depressive behaviors, while ADX led to fatigue-like performances with high pain sensitivity.
In brain tissues, LPS injection notably activated microglia and the 5-hydroxytryptamine (HT)1A receptor in the prefrontal cortex and hippocampus. Poly I:C-injection also remarkably activated the 5-HT transporter and 5-HT1A receptor with a reduction in serotonin levels in the brain. ADX particularly activated astrocytes and transforming growth factor beta (TGF-β) 1 in all brain regions.
Our results revealed that LPS and poly I:C animal models approximate depressive disorder more closely than CFS. We suggest that ADX is a possible method for establishing a mouse model of CFS reflecting clinical features, especially in neuroendocrine system.
New Welsh Government Advisory Group for ME/CFS and pain
2014 Task & Finish Group Report
It is five years since the Welsh Government published a Task & Finish Report giving Health Boards an action plan for improving services for ME/CFS and Fibromyalgia.
WAMES has been a member of the national advisory group for the T&FG Report – the All Wales Implementation Group (AWIG) – which has met 4 times a year with representatives from Health Boards and government.
WAMES has also been actively challenging individual Health Boards to implement the recommendations, with little success. Health Boards have repeatedly ignored calls from patients and government to take ME service planning seriously.
New advisory group
The Welsh Government has now decided to take a different approach and merge three groups (Persistent Pain, Arthritis and ME/CFS and FM) into one advisory group. The aim will be to report to the Chief Medical Officer on issues the conditions share and bespoke issues relating to specific conditions. Established channels of communication will then be used to engage with Health Boards.
It is hoped the new group will be established by April 2020 and the new structure will be monitored for effectiveness after sufficient time has passed.
In addition Health Education and Improvement Wales (HEIW) will be in attendance at the new group so they understand the issues surrounding education, training and workforce development.
The Welsh Government research and development team – Health and Care Research Wales – have confirmed funding is available for well designed research projects.
Patient representation
WAMES has questions about whether this new group will be more effective in enlisting Health Board commitment to providing care for people with ME than previous approaches, but we are pleased that the Welsh Government recognises the need to find a better way of working.
Kevin Francis, the Policy lead for ME in the Welsh Government is happy to meet with groups who support people living with ME, FM and pain conditions. He wishes to better understand the issues for those living with these conditions. Please let Jan know if you wish to take up this offer. jan@wames.og.uk
These positive developments are tempered by ongoing illness challenges including patient stigma, absence of diagnostic markers, a lack of established treatments, and a dearth of researchers and knowledgeable, interested clinicians.
