Research Digest 30/07/21

Welcome to the 74th Emerge Australia Research Digest, where you will find summaries of some of the latest research and information about ME/CFS, with links to the complete articles.

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Systematic Review of Sleep Characteristics in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Authors: Maksoud R, Eaton-Fitch N, Matula M, Cabanas H, Staines D, Marshall-Gradisnik S (Griffith University, Australia)
Publication: Healthcare
Over 90% of people with ME/CFS and no primary sleep disorder report unrefreshing or disturbed sleep. This paper systematically reviewed studies that objectively measured sleep quality in ME/CFS using polysomnography and/or multiple sleep latency testing (MSLT).

In addition to containing key search terms, studies were included if they were published between January 1995 and February 2021, had human participants aged 18 years or older, were in English, observational, and if they defined ME/CFS by either the Fukuda criteria, Canadian Consensus Criteria, International Consensus Criteria, or Institute of Medicine criteria. Twenty papers were identified which met the inclusion criteria. Eighty percent of papers were observational case-control studies, with all studies using the Fukuda criteria.

There was inconsistency in the results across studies for most measures, including slow-wave sleep duration, apnoea-hypopnoea index (number of apnoea and hypopnea events), spectral activity, and MSLT (ability to fall asleep in controlled conditions). No significant differences were found in sleep onset latency (time between fully awake and fully asleep) and non-REM sleep between ME/CFS and HC. All studies that investigated microarousal index, a sleep fragmentation measure, showed an increase level in ME/CFS.

Many studies also reported secondary outcome measures. Thirteen studies reporting subjective sleep quality or sleepiness showed significant differences between ME/CFS and HC. Significant differences also existed in depression, anxiety, insomnia, and fatigue levels, with higher scores seen in ME/CFS. 
The authors noted that the use of broad diagnostic criteria, small sample size, and confounding factors (such as alcohol or caffeine intake, or first night effects) contributed to the inconsistent results and made recommendations for future research, including the use of stricter diagnostic criteria and strategies to control confounding variables.

Effect of Melatonin Plus Zinc Supplementation on Fatigue Perception in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Randomized, Double-Blind, Placebo-Controlled Trial

Authors: Castro-Marrero J, Zaragozá MC, López-Vílchez I, Galmés JL, Cordobilla B, Maurel S, Domingo JC, Alegre-Martín J (Vall d’Hebron University Hospital, Spain)
Publication: Antioxidants
Several marginal nutritional deficiencies (such as B complex, vitamin C, melatonin, zinc and L-tryptophan) have been reported in ME/CFS and may be involved in the etiology of the disease. Melatonin is a hormone that regulates circadian rhythms, and is involved in immune function, neuroendocrine processes, and acts as an antioxidant. The essential trace element, zinc, has roles in synaptic neuroplasticity, immune function, and reducing oxidative stress. This study is the first pilot trial of oral melatonin and zinc supplementation in ME/CFS and their impact on fatigue perception, sleep disturbance, anxiety, depression and health-related quality of life.

Sixty females aged between 18-65 years with ME/CFS (Fukuda criteria), who did not have other active fatigue-causing medical conditions or psychiatric disorders, were included in the study. Participants were randomised to a placebo control group or to the intervention group (1mg melatonin plus 10mg zinc).The primary outcome measure was self-reported fatigue. Data was obtained at baseline, during treatment (at 8 and 16 weeks), as well as at four weeks post-treatment. Ten participants were either lost to follow-up or requested to leave the study before the end of the trial at 20 weeks. None of these were due to adverse events.

At 16-weeks, the intervention group had significant improvements in the perception of physical fatigue, though this was not maintained at follow-up. The intervention group also had significant improvements at 8 and 16 weeks in the physical component summary of health-related quality of life. No significant improvements were observed in sleep quality, depression or anxiety.

This pilot study showed that 16-weeks of oral melatonin and zinc supplement was safe, tolerated, and improved fatigue perception in those with ME/CFS. Further studies are called for to address the limitations of this trial, including small sample size, participant gender, dose-response effect, and to account for confounding factors.

Comparing Idiopathic Chronic Fatigue and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) in Males: Response to Two-Day Cardiopulmonary Exercise Testing Protocol

Authors: van Campen CLMC, Visser FC (Stichting CardioZorg, Netherlands)
Publication: Healthcare
Cardiopulmonary exercise testing (CPET) measures the severity of physical activity intolerance. Previous studies have found that most ME/CFS patients show similar or slightly lower peak volume oxygen consumption (VO2) compared to healthy controls on day one of a CPET, whereas on day two ME/CFS patients have significantly lower VO2. This study aimed to examine exercise intolerance in a two day CPET protocol in male patients with ME/CFS compared to male patients with idiopathic chronic fatigue (ICF). 
Data from 26 patients with ME/CFS and 25 patients with ICF who had completed a two-day CPET at a specialist cardiology clinic were included in this study. All participants were male (female results reported in a separate study). Patients were excluded if they had severe ME/CFS (as defined by the International Consensus Criteria), there was an alternative explanation for their symptoms, or the two CPETs were not completed on consecutive days. Physical measurements, disease severity, and duration were comparable between the two groups, however there was a higher rate of fibromyalgia in the ME/CFS group. Throughout the CPET, measurements were taken of VO2, volume of carbon dioxide released, oxygen saturation, blood pressure and heart rate.
The authors found no significant differences in resting heart rate between the groups, and minimal differences in measurement values between groups on day-one. VO2 and workload parameters declined significantly in the ME/CFS group from day-one to day-two, whereas the ICF group showed an increase on day-two.  
The authors recognised that not including healthy sedentary controls was a limitation of this study.
The authors conclude that the findings of lower VO2 at peak exercise in the ME/CFS group on day-two are suggestive of metabolic abnormalities, not deconditioning, and may represent early signs of post-exertional malaise. In contrast, the general improvement seen on day-two in the ICF group show a pattern similar to sedentary and healthy controls, which suggests the findings are ME/CFS specific.

Pathomechanisms and possible interventions in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)

Authors: Fluge Ø, Tronstad KJ, Mella O (Haukeland University Hospital, Norway)
Publication: The Journal of Clinical Investigation
The authors of this paper note that, while several hypotheses about the pathophysiology of ME/CFS have been put forward, a pathomechanism has yet to be established. In this paper, the authors propose a framework model for the initiation and maintenance of ME/CFS, and identify potential therapeutic opportunities.
The authors proposed three steps to the framework model for the initiation and maintenance of ME/CFS (see figure below): (1) an initial immune response that follows an infection (a trigger response), with involvement of B-cells and autoantibodies; (2) autoantibodies potentially target the vascular system, which may affect endothelium or neuromuscular control and autonomic small nerve fibres creating disturbed homeostasis and tissue hypoxia; (3) secondary compensatory adaptations present in response to inadequate blood flow regulation upon exertion, including autonomic adaptations, increased sympathetic tone, metabolic adaptations, all further compromising homeostasis and energy strain. The authors suggested that the first and third stages of this framework model each provide potential opportunities for therapeutic intervention.
With their model, the authors’ have proposed that the clinical symptoms of ME/CFS may result from inadequate autoregulation of blood flow yielding tissue hypoxia on exertion, and associated compensatory adaptations from increased sympathetic output and metabolic shifts.
The authors conclude that the proposed pathomechanistic model is consistent with the lack of tissue histologic inflammation, lack of obvious organ damage, and potential for spontaneous recovery sometimes seen in ME/CFS, and that future research should seek to identify disease mechanisms and targets for intervention.

Figure: Proposed model for ME/CFS pathomechanisms

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