ME Association September Summary of ME/CFS Published Research | 05 October 2019

Charlotte Stephens, Research Correspondent, ME Association.

The Index of Published ME/CFS Research has been updated to take account of the research published during September 2019.

The Index is a convenient way to locate and read the most recent studies and also those that were published previously.

The Index lists studies by subject matter and author, with links to PubMed or the relevant Journal.

It is free to download, comes with an interactive contents table and is an A-Z list of all the most important studies (and selected key documents and articles).

You can also find the index in the Research section of the website together with all the summary research reviews that the ME Association has published.

ME/CFS Research Published in September 2019

1. Burke M (2019)
“It’s All in Your Head”—Medicine’s Silent Epidemic.
JAMA Network [Epub ahead of print].

Abstract
“It’s all in your head” is a phrase sometimes said by physicians to patients presenting with symptoms unexplained by medical disease.
As a neurologist specializing in neuropsychiatry, nothing bothers me more than overhearing medical colleagues proclaim this one-liner at the bedside or snicker about these patients during rounds.
Unbeknownst to them, I also hear my patients’ version of being on the other end of this phrase and find myself constantly trying to repair the damage that these words can cause.
Whether physicians like to admit it or not, medically unexplained symptoms encompass a vast terrain of clinical practice. In neurology, these symptoms fall under functional neurological disorder, but every specialty has their own variants and favored terminologies (e.g. chronic fatigue syndrome, fibromyalgia).
The inadequate management of this segment of medicine represents a silent epidemic that is slowly eroding patient-physician relationships, perpetuating unnecessary disability, and straining health care resources.

2. Eyskens J et al. (2019)
Assessing chronic fatigue syndrome: Self-reported physical functioning and correlations with physical testing.
Journal of Bodywork and Movement Therapies 23 (3): 598-603.

Abstract
The pathophysiology of chronic fatigue syndrome (CFS) remains unclear; no biomarkers have thus far been identified or physical tests designed to underpin its diagnosis. Assessment mainly uses Fukuda's criteria and is based on the exclusion of symptoms related to other diseases/syndromes, subjective self-reporting, and outcomes of self-report questionnaires.
In order to improve the baseline assessment and progress evaluation of individuals suspected of CFS and using an association-oriented research strategy and a cross-correlational design, this study investigates possible associations between the performance on two physical tests, i.e. ‘Timed Loaded Standing’ (TLS), assessing trunk-arm endurance, and the ‘Stops Walking with Eyes Closed while performing a secondary Cognitive Task’ (SWECCT), measuring impaired automaticity of gait, and the results of two self-report questionnaires, the Checklist Individual Strength (CIS, total score and fatigue subscale score) and the physical functioning and vitality subscales of the Short Form Health Survey (SF-36) to gauge the participants' subjective feelings of fatigue and beliefs regarding their abilities to perform daily-life activities.
Comparisons of the outcomes obtained in 27 female patients with a confirmed diagnosis of CFS revealed that trunk-arm endurance as measured with the TLS correlated with the SF-36 physical functioning subscale only (raw p value: 0.004). None of the other correlations were statistically significant.
It is concluded that the TLS may have potential as an objective assessment tool to support the diagnosis and monitoring of treatment effects in CFS.

3. Friedman K et al. (2019)
Editorial: Advances in ME/CFS Research and Clinical Care.
Frontiers in Pediatrics [Epub ahead of print].

Abstract
Advances in ME/CFS Research and Clinical Care spotlights Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): a maligned, stigmatized, under-researched disease, which lacks a definitive, objective clinical test for its diagnosis, and definitive palliative and curative treatments.
A few brave physicians attempt to alleviate the suffering of the afflicted. They rely upon the patients' symptoms to guide them. Physicians can provide symptomatic relief and improve upon patients' abnormal physiological and metabolic parameters by intervening to cause the latter to approach normal limits.
Documented to be more severely disabling than HIV-AIDS, ME/CFS receives disturbingly little funding in the United States and around the world. ME/CFS patients constitute an identifiable, underserved population that is in need of the recognition which would raise them from their current, underserved or non-served patient status into the mainstream of healthcare worldwide.
ME/CFS is a common disease worldwide, affecting approximately 1 percent of the world's population. Despite these obstacles, and as evidenced by the articles contained herein, ME/CFS research is being conducted, and patient care issues are being addressed. Today, researchers and clinicians communicate rapidly via the internet to overcome conventional impediments to knowledge and patient care.

4. Groven KS and Dahl-Michelsen T (2019)
Recovering from chronic fatigue syndrome as an intra-active process.
Health Care Women International 12: 1-12.

Abstract
In this article, we draw on the narrative of a woman who has recovered from chronic fatigue syndrome (CFS) to explore the process of recovering from a debilitating illness.
Inspired by Julia Kristeva's notion of the body as a complex biocultural fact and by Karen Barad's posthuman theory (also termed agential realism), we adopt an intra-active approach to the woman's recovery process, revealing the role played by human as well as nonhuman entities.
In so doing, we move beyond “dualistic,” often polarized debates in the medical literature (and mainstream media) regarding the causes of CFS: debates in which “biological/physiological” factors tend to be set against “mental/cognitive/psychological” ones. We argue for a medical perspective in which the intra-action of human and nonhuman agents is recognized as contributing to an individual's recovery process.

5. Joung JY et al. (2019)
The Efficacy and Safety of Myelophil, an Ethanol Extract Mixture of Astragali Radix and Salviae Radix, for Chronic Fatigue Syndrome: A Randomized Clinical Trial.
Frontiers in Pharmacology 10: 991.

Abstract
Background: There is a strong demand for therapeutics to treat chronic fatigue syndrome (CFS), although there are limitations. Myelophil, which is a combination of extracts from Astragali Radix and Salviae Miltiorrhizae Radix, has been clinically used to treat fatigue-related disorders in South Korea. We conducted a randomized controlled clinical trial of Myelophil in patients with CFS and evaluated its efficacy and safety in two hospitals. 
Methods: We enrolled 98 participants (M: 38, F: 60) with CFS in a phase 2 trial of oral Myelophil (2 g daily) or placebo for 12 weeks. The primary end point was a change in the Chalder fatigue scale, as scored by a numeric rating scale (NRS). The secondary end points included changes in the visual analogue scale, fatigue severity scale (FSS), and 36-item short-form health survey (SF-36). Biomarkers of oxidative stress and cytokines were evaluated by blood tests. 
Results: Ninety-seven participants (48 in the Myelophil group and 49 in the placebo group) completed the trial. An analysis of all participants showed that Myelophil slightly improved fatigue symptoms compared with those of the placebo, but this effect was not statistically significant (p > 0.05 for the NRS, VAS, FSS, and SF-36). By contrast, an analysis of the subpopulation (53 participants, M: 24, F: 29) with severe symptoms (≥63, median NRS value of total participants) showed a statistically significant improvement in fatigue symptoms in the Myelophil group compared with the placebo (p < 0.05 for NRS, FSS, and SF-36). There were no significant changes in the biomarkers for oxidative stress and cytokines before or after the treatment. No Myelophil-related adverse response was observed during the trial.
Conclusion: These results support the hypothesis that Myelophil can be a therapeutic candidate to manage CFS and provide the rationale for its progression to a phase 3 clinical trial.

6. Melamed K et al. (2019)
Unexplained exertional intolerance associated with impaired systemic oxygen extraction.
European Journal of Applied Physiology 119 (10): 2375-2389.

Abstract
Purpose: The clinical investigation of exertional intolerance generally focuses on cardiopulmonary diseases, while peripheral factors are often overlooked. We hypothesize that a subset of patients exists whose predominant exercise limitation is due to abnormal systemic oxygen extraction (SOE).
Methods: We reviewed invasive cardiopulmonary exercise test (iCPET) results of 313 consecutive patients presenting with unexplained exertional intolerance. An exercise limit due to poor SOE was defined as peak exercise (Ca-vO2)/[Hb] ≤ 0.8 and VO2max < 80% predicted in the absence of a cardiac or pulmonary mechanical limit. Those with peak (Ca-vO2)/[Hb] > 0.8, VO2max ≥ 80%, and no cardiac or pulmonary limit were considered otherwise normal. The otherwise normal group was divided into hyperventilators (HV) and normals (NL). Hyperventilation was defined as peak PaCO2 < [1.5 × HCO3 + 6].
Results: Prevalence of impaired SOE as the sole cause of exertional intolerance was 12.5% (32/257). At peak exercise, poor SOE and HV had less acidemic arterial blood compared to NL (pHa = 7.39 ± 0.05 vs. 7.38 ± 0.05 vs. 7.32 ± 0.02, p < 0.001), which was explained by relative hypocapnia (PaCO2 = 29.9 ± 5.4 mmHg vs. 31.6 ± 5.4 vs. 37.5 ± 3.4, p < 0.001). For a subset of poor SOE, this relative alkalemia, also seen in mixed venous blood, was associated with a normal PvO2 nadir (28 ± 2 mmHg vs. 26 ± 4, p = 0.627) but increased SvO2 at peak exercise (44.1 ± 5.2% vs. 31.4 ± 7.0, p < 0.001).
Conclusions: We identified a cohort of patients whose exercise limitation is due only to systemic oxygen extraction, due to either an intrinsic abnormality of skeletal muscle mitochondrion, limb muscle microcirculatory dysregulation, or hyperventilation and left shift the oxyhemoglobin dissociation curve.

7. Morris G et al. (2019)
Myalgic encephalomyelitis/chronic fatigue syndrome: From pathophysiological insights to novel therapeutic opportunities.
Pharmacological Research [Epub ahead of print].

Abstract
Myalgic encephalomyelitis (ME) or chronic fatigue syndrome (CFS) is a common and disabling condition with a paucity of effective and evidence-based therapies, reflecting a major unmet need. Cognitive behavioural therapy and graded exercise are of modest benefit for only some ME/CFS patients, and many sufferers report aggravation of symptoms of fatigue with exercise.
The presence of a multiplicity of pathophysiological abnormalities in at least the subgroup of people with ME/CFS diagnosed with the current international consensus “Fukuda” criteria, points to numerous potential therapeutic targets. Such abnormalities include extensive data showing that at least a subgroup has a pro-inflammatory state, increased oxidative and nitrosative stress, disruption of gut mucosal barriers and mitochondrial dysfunction together with dysregulated bioenergetics.
In this paper, these pathways are summarised, and data regarding promising therapeutic options that target these pathways are highlighted; they include coenzyme Q10, melatonin, curcumin, molecular hydrogen and N-acetylcysteine. These data are promising yet preliminary, suggesting hopeful avenues to address this major unmet burden of illness.

8. Numata T et al. (2019)
Successful Treatment of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome with Chronic Febricula Using the Traditional Japanese Medicine Shosaikoto.
International Medicine [Epub ahead of print].

Abstract
We herein report the case of a 14-year-old girl who had been experiencing chronic fatigue, febricula, and social withdrawal for 20 months. No notable abnormalities were identified during routine check-ups at a general pediatric hospital; symptomatic treatments did not affect her condition. She was diagnosed with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).
Based on the concepts of Japanese traditional medicine, she was administered shosaikoto-based treatment. After several weeks of treatment, all of the symptoms had been dramatically alleviated, consequently resolving the issue of non-attendance at school.
Shosaikoto-based medication may be a therapeutic option for treating ME/CFS in patients presenting with chronic febricula.

9. Oaklander A and Nolano M (2019)
Scientific Advances in and Clinical Approaches to Small-Fiber Polyneuropathy.
JAMA Network [Epub ahead of print].

Abstract
Small-fiber polyneuropathy involves preferential damage to the thinly myelinated A-delta fibers, unmyelinated C sensory fibers, or autonomic or trophic fibers. Although this condition is common, most patients still remain undiagnosed and untreated because of lagging medical and public awareness of research advances. Chronic bilateral neuropathic pain, fatigue, and nausea are cardinal symptoms that can cause disability and dependence, including pain medication dependence.
Biomarker confirmation is recommended, given the nonspecificity of symptoms. The standard test involves measuring epidermal neurite density within a 3-mm protein gene product 9.5 (PGP9.5)–immunolabeled lower-leg skin biopsy. Biopsies and autonomic function testing confirm that small-fiber neuropathy not uncommonly affects otherwise healthy children and young adults, in whom it is often associated with inflammation or dysimmunity.
A recent meta-analysis concluded that small-fiber neuropathy underlies 49% of illnesses labeled as fibromyalgia. Initially, patients with idiopathic small-fiber disorders should be screened by medical history and blood tests for potentially treatable causes, which are identifiable in one-third to one-half of patients. Then, secondary genetic testing is particularly important for familial and childhood cases. Treatable genetic causes include Fabry disease, transthyretin and primary systemic amyloidosis, hereditary sensory autonomic neuropathy-1, and ion-channel mutations.
Immunohistopathologic evidence suggests that small-fiber dysfunction and denervation, especially of blood vessels, contributes to diverse symptoms, including postexertional malaise, postural orthostatic tachycardia, and functional gastrointestinal distress.
Preliminary evidence implicates acute or chronic autoreactivity in some cases, particularly in female patients and otherwise healthy children and young adults. Different temporal patterns akin to Guillain-Barré syndrome and chronic inflammatory demyelinating polyneuropathy have been described; here, corticosteroids and immunoglobulins, which are often efficacious for inflammatory neuropathic conditions, are increasingly considered.
Because small fibers normally grow throughout life, improving contributory conditions may permit regrowth, slow progression, and prevent permanent damage. The prognosis is often hopeful for improving quality of life and sometimes for abatement or resolution, particularly in the young and otherwise healthy individuals. Examples include diabetic, infectious, toxic, genetic, and inflammatory causes.
The current standard of care requires prompt diagnosis and treatment, particularly in children and young adults, to restore life trajectory. Consensus diagnostic and tracking metrics should be established to facilitate treatment trials.

10. Vink M and Vink-Niese F (2019)
Work Rehabilitation and Medical Retirement for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patients. A Review and Appraisal of Diagnostic Strategies.
Diagnostics 9 (4).

Abstract
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome leads to severe functional impairment and work disability in a considerable number of patients. The majority of patients who manage to continue or return to work, work part-time instead of full time in a physically less demanding job. The prognosis in terms of returning to work is poor if patients have been on long-term sick leave for more than two to three years. Being older and more ill when falling ill are associated with a worse employment outcome.
Cognitive behavioural therapy and graded exercise therapy do not restore the ability to work. Consequently, many patients will eventually be medically retired depending on the requirements of the retirement policy, the progress that has been made since they have fallen ill in combination with the severity of their impairments compared to the sort of work they do or are offered to do.
However, there is one thing that occupational health physicians and other doctors can do to try and prevent chronic and severe incapacity in the absence of effective treatments. Patients who are given a period of enforced rest from the onset, have the best prognosis. Moreover, those who work or go back to work should not be forced to do more than they can to try and prevent relapses, long-term sick leave and medical retirement.

11. Yang M et al. (2019)
Psychometric properties of the PROMIS® Fatigue Short Form 7a among adults with myalgic encephalomyelitis/chronic fatigue syndrome.
Quality of Life Research [Epub ahead of print].

Abstract
Purpose: To evaluate the psychometric properties of the Patient-Reported Outcome Measurement Information System® Fatigue Short Form 7a (PROMIS F-SF) among people with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS).
Methods: Analyses were conducted using data from the Multi-Site Clinical Assessment of ME/CFS study, which recruited participants from seven ME/CFS specialty clinics across the US. Baseline and follow-up data from ME/CFS participants and healthy controls were used. Ceiling/Floor effects, internal consistency reliability, differential item functioning (DIF), known-groups validity, and responsiveness were examined.
Results: The final sample comprised 549 ME/CFS participants at baseline, 386 of whom also had follow-up. At baseline, the sample mean of PROMIS F-SF T-score was 68.6 (US general population mean T-score of 50 and standard deviation of 10). The PROMIS F-SF demonstrated good internal consistency reliability (Cronbach's α = 0.84) and minimal floor/ceiling effects. No DIF was detected by age or sex for any item. This instrument also showed good known-groups validity with medium-to-large effect sizes (η2 = 0.08-0.69), with a monotonic increase of the fatigue T-score across ME/CFS participant groups with low, medium, and high functional impairment as measured by three different variables (p < 0.01), and with significantly higher fatigue T-scores among ME/CFS participants than healthy controls (p < 0.0001). Acceptable responsiveness was found with small-to-medium effect sizes (Guyatt's Responsiveness Statistic = 0.28-0.54).
Conclusions: Study findings support the reliability and validity of PROMIS F-SF as a measure of fatigue for ME/CFS and lend support to the drug development tool submission for qualifying this measure to evaluate therapeutic effect in ME/CFS clinical trials.

12. Yang G et al. (2019)
Is the efficacy of repetitive transcranial magnetic stimulation influenced by baseline severity of fatigue symptom in patients with myalgic encephalomyelitis.
International Journal of Neuroscience [Epub ahead of print].

Abstract
Objectives: Recently, repetitive transcranial magnetic stimulation (rTMS) has been therapeutically applied for patients with myalgic encephalomyelitis (ME). However, it is still unclear which clinical factors could influence the efficacy of rTMS for ME patients. The purpose of this study is to clarify whether baseline severity of fatigue symptom would influence the efficacy of rTMS applied for ME patients. 
Methods: Twenty-two patients with ME were studied. Each patient was hospitalized to receive 6-8 sessions of rTMS. In this study, high-frequency rTMS of 10 Hz was applied over prefrontal cortex. To evaluate the severity of fatigue symptom, Brief Fatigue Inventory (BFI) score and Visual Analogue Scale (VAS) rate were applied before and after rTMS application. Based on the BFI score before rTMS, the patients were divided into two groups: ‘severe group' (n = 9) and ‘mild group' (n = 13). We compared the extent of the improvements of fatigue symptom between two groups. 
Results: In severe group, compared to before rTMS, VAS rate was significantly lower not only at discharge but also 2 weeks after discharge. Similarly, mild group also showed significant decrease in VAS rate at the same timepoints. However, the extent of VAS rate change did not differ between two groups. In addition, no significant correlation between baseline score of BFI and the changes in VAS rate was indicated. 
Conclusions: It can be concluded that rTMS can improve fatigue symptom in ME patients regardless of baseline severity of fatigue symptom. It is expected that rTMS can be a novel therapeutic intervention for ME patients.

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