The ME Association End of Week Research Round-Up | 08 May 2020


Charlotte Stephens, Research Correspondent, ME Association.

We show below brief summaries of the research studies about ME/CFS that have been published in the last week, followed by the abstracts from those studies.

At the end of each month, we enter all the published research into the central Research Index which is freely available as a download.

This is an A-Z index of the most important published research studies and selected key documents and articles, listed by subject matter, on myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS).

You can also find the Research Index in the Research section of the website together with a list of Research Summaries from the ME Association that provide lay explanations of the more important and interesting work that has been published to date.

ME/CFS Research Published 1st – 7th May 2020

This week, 6 new research studies have been published, highlights include:

1. Researchers in China used a rat model of chronic fatigue to study the effects of long-term fatigue on thermoregulation (maintaining a normal body temperature). They found that long-term fatigue affected the rat’s ability to maintain their body temperature, indicating this may also be a problem in humans.

2. Australian researchers looked at mitochondrial function in a type of immune cell in 51 ME/CFS patients. They found that they have a ‘complex V defect’, meaning that the rate of ATP (energy) production in this specific part of the energy production chain is reduced. They also found that other parts of the energy production chain are working over-time in order to compensate for the deficiency in ‘complex V’. This ‘compensatory upregulation’ means that the overall ATP (energy) levels appear as ‘normal’ in resting cells, but it may leave them unable to keep up with increases in energy demand.

3. The results of a phase II open-label trial in Norway of a cancer drug called cyclophosphamide in 40 patients with ME/CFS have been published. The researchers (Drs. Fluge and Mella) concluded that treatment with 6 intravenous infusions of cyclophosphamide was feasible for ME/CFS patients and believe their results warrant a randomized clinical trial. More than half of the patients responded and with prolonged follow-up over 4 years, a considerable proportion of patients reported ongoing remission. However, without a placebo control group, these results must be interpreted with caution.

ME/CFS Research References and Abstracts

1. Jason LA and Johnson M (2020)
Solving the ME/CFS criteria and name conundrum: the aftermath of IOM.
Fatigue: Biomedicine, Health and Behaviour [Epub ahead of print].

Abstract
In 2015, the Institute of Medicine (IOM) proposed a new name and set of clinical criteria for what had previously been referred to as Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS).

This committee recommended the adoption of the term systemic exertion intolerance disease (SEID) and clinical criteria that required specific symptoms such as post-exertional malaise and unrefreshing sleep. This article reviews efforts to evaluate the revised criteria as well as reactions to the new criteria and name.

Since these recommendations have been made, the proposed name change has not been widely adopted by the scientific or patient community. Even though the IOM’s proposed criteria were intended to be a clinical rather than a research case definition, over the past few years, an increasing number of studies have employed these criteria for research purposes. One unwitting consequence of the IOM criteria, which excludes few other illnesses, is the broadening of the number of individuals who are diagnosed and included in research studies.

There is still a need to implement the IOM’s recommendation to form a multidisciplinary committee to review research and policy changes following the release of the new criteria. We conclude by presenting a possible roadmap for overcoming barriers in order to make progress on developing a consensus for a name and criteria.

2. Li D et al. (2020)
Homeostatic disturbance of thermoregulatory functions in rats with chronic fatigue.
Neuroscience Research [Epub ahead of print].

Abstract
Chronic fatigue syndrome (CFS) is characterized by long-lasting fatigue, and a range of symptoms, and is involved in homeostasis disruption. CFS patients frequently complain of low grade fever or chill even under normal body temperature indicating that thermosensory or thermoregulatory functions might be disturbed in CFS. However, little is known about the detailed mechanisms.

To elucidate whether and how thermoregulatory function was altered during the development of chronic fatigue, we investigated temporal changes in body temperature with advance of fatigue accumulation in a chronic fatigue rat model using a wireless transponder.

Our findings demonstrated that the body temperature was adaptively increased in response to fatigue loading in the early phase, but unable to retain in the late phase. The tail heat dissipation was often observed and the frequency of tail heat dissipation gradually increased initially, then decreased. In the late phase of fatigue loading, the body temperature for the tail heat dissipation phase decreased to a value lower than that for the non-dissipation phase.

These results suggest that adaptive changes in thermoregulatory function occurred with fatigue progression, but this system might be disrupted by long-lasting fatigue, which may underlie the mechanism of fatigue chronification.

3. Maksound R (2020)
A systematic review of neurological impairments in myalgic encephalomyelitis/ chronic fatigue syndrome using neuroimaging techniques.
PLoS One 15 (4).

Abstract
Background: Myalgic encephalomyelitis/ Chronic Fatigue Syndrome (ME/CFS) is a multi-system illness characterised by a diverse range of debilitating symptoms including autonomic and cognitive dysfunction.

The pathomechanism remains elusive, however, neurological and cognitive aberrations are consistently described. This systematic review is the first to collect and appraise the literature related to the structural and functional neurological changes in ME/CFS patients as measured by neuroimaging techniques and to investigate how these changes may influence onset, symptom presentation and severity of the illness.

Methods: A systematic search of databases Pubmed, Embase, MEDLINE (via EBSCOhost) and Web of Science (via Clarivate Analytics) was performed for articles dating between December 1994 and August 2019. Included publications report on neurological differences in ME/CFS patients compared with healthy controls identified using neuroimaging techniques such as magnetic resonance imaging, positron emission tomography and electroencephalography. Article selection was further refined based on specific inclusion and exclusion criteria. A quality assessment of included publications was completed using the Joanna Briggs Institute checklist.

Results: A total of 55 studies were included in this review. All papers assessed neurological or cognitive differences in adult ME/CFS patients compared with healthy controls using neuroimaging techniques. The outcomes from the articles include changes in gray and white matter volumes, cerebral blood flow, brain structure, sleep, EEG activity, functional connectivity and cognitive function. Secondary measures including symptom severity were also reported in most studies.

Conclusions: The results suggest widespread disruption of the autonomic nervous system network including morphological changes, white matter abnormalities and aberrations in functional connectivity. However, these findings are not consistent across studies and the origins of these anomalies remain unknown. Future studies are required confirm the potential neurological contribution to the pathology of ME/CFS.

4. Missailidis D et al. (2020)
An Isolated Complex V Inefficiency and Dysregulated Mitochondrial Function in Immortalized Lymphocytes from ME/CFS Patients.
International Journal of Molecular Science 21 (3) 1074.

Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is an enigmatic condition characterized by exacerbation of symptoms after exertion (post-exertional malaise or “PEM”), and by fatigue whose severity and associated requirement for rest are excessive and disproportionate to the fatigue-inducing activity. There is no definitive molecular marker or known underlying pathological mechanism for the condition.

Increasing evidence for aberrant energy metabolism suggests a role for mitochondrial dysfunction in ME/CFS. Our objective was therefore to measure mitochondrial function and cellular stress sensing in actively metabolizing patient blood cells.

We immortalized lymphoblasts isolated from 51 ME/CFS patients diagnosed according to the Canadian Consensus Criteria and an age- and gender-matched control group. Parameters of mitochondrial function and energy stress sensing were assessed by Seahorse extracellular flux analysis, proteomics, and an array of additional biochemical assays.

As a proportion of the basal oxygen consumption rate (OCR), the rate of ATP synthesis by Complex V was significantly reduced in ME/CFS lymphoblasts, while significant elevations were observed in Complex I OCR, maximum OCR, spare respiratory capacity, nonmitochondrial OCR and “proton leak” as a proportion of the basal OCR.

This was accompanied by a reduction of mitochondrial membrane potential, chronically hyperactivated TOR Complex I stress signaling and upregulated expression of mitochondrial respiratory complexes, fatty acid transporters, and enzymes of the β-oxidation and TCA cycles. By contrast, mitochondrial mass and genome copy number, as well as glycolytic rates and steady state ATP levels were unchanged.

Our results suggest a model in which ME/CFS lymphoblasts have a Complex V defect accompanied by compensatory upregulation of their respiratory capacity that includes the mitochondrial respiratory complexes, membrane transporters and enzymes involved in fatty acid β-oxidation.

This homeostatically returns ATP synthesis and steady state levels to “normal” in the resting cells, but may leave them unable to adequately respond to acute increases in energy demand as the relevant homeostatic pathways are already activated.

5. Rekeland IG et al. (2020)
Intravenous Cyclophosphamide in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. An Open-Label Phase II Study.
Frontiers in Medicine 7: 162.

Abstract
Introduction: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a disease with high symptom burden, of unknown etiology, with no established treatment. We observed patients with long-standing ME/CFS who got cancer, and who reported improvement of ME/CFS symptoms after chemotherapy including cyclophosphamide, forming the basis for this prospective trial.

Materials and methods: This open-label phase II trial included 40 patients with ME/CFS diagnosed by Canadian criteria. Treatment consisted of six intravenous infusions of cyclophosphamide, 600–700 mg/m2, given at four-week intervals with follow-up for 18 months, extended to 4 years. Response was defined by self-reported improvements in symptoms by Fatigue score, supported by Short Form 36 (SF-36) scores, physical activity measures and other instruments. Repeated measures of outcome variables were assessed by General linear models. Responses were correlated with specific Human Leukocyte Antigen (HLA) alleles.

Results: The overall response rate by Fatigue score was 55.0% (22 of 40 patients). Fatigue score and other outcome variables showed significant improvements compared to baseline. The SF-36 Physical Function score increased from mean 33.0 at baseline to 51.5 at 18 months (all patients), and from mean 35.0 to 69.5 among responders. Mean steps per 24 h increased from mean 3,199 at baseline to 4,347 at 18 months (all patients), and from 3,622 to 5,589 among responders.

At extended follow-up to 4 years 68% (15 of 22 responders) were still in remission. Patients positive for HLA-DQB1*03:03 and/or HLA-C*07:04 (n = 12) had significantly higher response rate compared to patients negative for these alleles (n = 28), 83 vs. 43%, respectively. Nausea and constipation were common grade 1–2 adverse events. There were one suspected unexpected serious adverse reaction (aggravated POTS) and 11 serious adverse events in eight patients.

Conclusion: Intravenous cyclophosphamide treatment was feasible for ME/CFS patients and associated with an acceptable toxicity profile. More than half of the patients responded and with prolonged follow-up, a considerable proportion of patients reported ongoing remission. Without a placebo group, clinical response data must be interpreted with caution. We nevertheless believe a future randomized trial is warranted.

6. Umay E et al. (2020)
What happens to muscles in fibromyalgia syndrome.
International Journal of Medical Science 189 (2): 749-756.

Abstract
Background: The main somatic symptoms of fibromyalgia syndrome (FMS) are chronic musculoskeletal pain, stiffness, and fatigue, all of which are related to the muscle system and its functioning.

Aims: The aim of this study was to evaluate whether the asymptomatic upper and lower extremity muscles evaluated using ultrasonography (US) were different from healthy controls in both newly diagnosed and established FMS and to assess whether muscle measurements were related to fatigue and disease severity, as well as quality of life.

Methods: This study was conducted on 152 subjects (102 patients and 50 healthy controls) as a cross-sectional controlled trial. Real-time imaging of cross-sectional thickness (CST) (for deltoid, biceps brachii, triceps brachii, forearm flexor, tibialis anterior, and gastrocnemius medialis), and cross-sectional areas (CSAs) (quadriceps femoris (QF)) measurements were performed using US. Fatigue and disease severity as well as quality of life scales were given to all participants.

Results: In both patient groups, decreased QF muscle CSA was significantly correlated with increased fatigue severity and decreased overall quality of life and energy levels. Moreover, in patients with established disease, there was a significant correlation between the decrease in QF muscle CSA and increased social isolation and between the decrease in biceps brachii muscle CST and increased fatigue severity.

Conclusions: Whether in newly diagnosed or established disease, muscle measurement values and quality of life parameters were significantly decreased in patients with FMS compared with healthy controls.

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