Welcome to the 56th 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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Neuroimaging characteristics of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS): a systematic review

Author: Shan ZY, Barnden LR, Kwiatek RA, Bhuta S, Hermens DF, Lagopoulos J
Links: https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-020-02506-6


In this literature review, researchers examined neuroimaging studies of ME/CFS from 1988 to 2018. A total of 63 studies were included in this review.

The studies in the review used a range of different diagnostic criteria for ME/CFS, including the CDC-Holmes criteria, Oxford criteria, CDC-Fukuda criteria, Canadian Consensus Criteria, paediatric ME/CFS definition, Reeves criteria and the International Consensus Criteria. The CDC-Fukuda criteria was by far the most commonly used criteria (used by 54 of the 63 studies). Some studies used a combination of criteria.   
 
Frequent observations across numerous studies by different research groups were additional brain area recruitment for cognitive tasks and abnormalities in the brain stem. Additionally, sluggish blood oxygenation level-dependent (BOLD) response to tasks, reduced serotonin transporters, and regional hypo-metabolism were consistently observed by more than two research teams. Single observations included abnormal brain tissue properties, regional metabolic abnormalities, and correlation between brain measures and ME/CFS symptoms. Changes in global and regional grey or white matter volume and changes in cerebral blood flow at rest were inconsistent across studies.

The authors conclude that the observations in neuroimaging studies could suggest abnormal neurovascular coupling in ME/CFS patients. 
 
The reviewers highlight potential limitations of reviewed studies, such as small sample sizes. They also note that 80% of the studies reviewed failed to control for lifestyle differences. Given that ME/CFS requires patients to reduce their activity due to post-exertional malaise, it is important to be able to distinguish between changes due to ME/CFS and changes due to reduced physical activity. The authors recommend the use of measures of physical activity in patients and healthy controls in future studies.


How Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Progresses: The Natural History of ME/CFS

Authors: Nacul L, O'Boyle S, Palla L, Nacul FE, Mudie K, Kingdon CC, Cliff JM, Clark TG, Dockrell HM, Lacerda EM
Link: https://www.frontiersin.org/articles/10.3389/fneur.2020.00826/full


While an understanding of the natural course of a disease is important for the design of effective preventative and intervention studies, these authors acknowledge that the natural course of ME/CFS has not been well understood, having been hampered by issues with inconsistent use of diagnostic criteria and a lack of longitudinal studies. 
 
There is often marked variability in presentation, severity, progression, and duration of disease among people with ME/CFS, and even within the same individual over time. These differences and changes have not been well-studied. This conceptual paper explores the long-term course of ME/CFS and how presentation and pathophysiological abnormalities may vary with time.

The authors propose a framework for understanding and interpreting the pathophysiology of ME/CFS that considers the many factors which impact on health and the variation in the condition over time. The framework incorporates distinct stages of the disease, as used in other conditions: asymptomatic predisposition, prodromal and symptomatic disease.  



The authors propose that ME/CFS may represent a failure of the body to return to homeostasis following an insult or stressor. They note that this state would affect a range of physiological systems and in non-uniform ways, explaining the diverse presentations and severity of the disease. They draw on sepsis and polytrauma, both of which involve impaired homeostasis but which have been extensively researched, to explore this hypothesis. 
 
The authors suggest that different pathophysiology at different disease stages may explain some of the inconsistencies found in ME/CFS research, and conclude that there is a clear need for well-designed longitudinal studies, especially research involving pre-illness individuals.


Hemodynamics during the 10-minute NASA Lean Test: evidence of circulatory decompensation in a subset of ME/CFS patients

Author: Lee J, Vernon SD, Jeys P, Ali W, Campos A, Unutmaz D, Yellman B, Bateman L
Link: https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-020-02481-y


Given the high rate of orthostatic intolerance (OI) in ME/CFS patients, there is a need for clinically useful tools to assess OI in these patients. These authors acknowledge that, while tilt table testing and continuous heart rate monitoring are used in research, they aren’t always available to clinicians, and that standardised assessment tools for ME/CFS patients are needed. The aim of this study was to determine the clinical utility of the 10-minute NASA Lean Test (NLT) as an assessment tool for OI in ME/CFS patients, and to understand the haemodynamic changes associated with OI in ME/CFS. 

The study included 150 ME/CFS patients (diagnosed according to the Fukuda criteria, Canadian Consensus Criteria and IOM criteria), and 75 healthy controls (HC). The patient group was subdivided into 75 who had been ill for less than 4 years (<4 ME/CFS) and 75 who had been ill for more than 10 years (>10 ME/CFS). All participants underwent the NLT, in which blood pressure and heart rate were measured initially during resting supine for 10 minutes and then every minute while standing for 10 minutes. 
 
The results demonstrated that a minimum of 5 minutes of standing is needed for haemodynamic changes to become evident. There was no significant difference in the rate of haemodynamic changes associated with postural orthostatic intolerance syndrome (POTS) in the ME/CFS and HC groups, though ME/CFS patients were more likely to report POTS symptoms than HCs. The authors describe this finding as “not anticipated but unsurprising” given the NLT leaves the body with only the neurovascular response to compensate for the orthostatic stress of standing. The authors also note that syncope is common in HC during the tilt table test. 
 
The <4 ME/CFS group had significantly higher heart rate and abnormally narrowed pulse pressure compared to >10 ME/CFS and HCs. This group also experienced significantly more OI symptoms  compared to both HCs and >10 ME/CFS group. This circulatory decompensation was not related to age or medication use.

The authors suggest that the observed circulatory decompensation found in the <4 ME/CFS group may reflect inadequate ventricular filling from low venous pressure. They also hypothesise that the >10 ME/CFS group may have less pronounced circulatory decompensation than the <4 ME/CFS as their bodies may have adapted over time. 
 
Finally, the authors note that, while OI symptoms are worsened with deconditioning, deconditioning cannot be the sole cause of OI in ME/CFS, as it is often present very early in the condition, even in patients who had been very fit prior to disease onset.


A systematic review of mitochondrial abnormalities in myalgic encephalomyelitis/chronic fatigue syndrome/systemic exertion intolerance disease

Authors: Holden S, Maksoud R, Eaton-Fitch N, Cabanas H, Staines D, Marshall-Gradisnik S.
Link: https://pubmed.ncbi.nlm.nih.gov/32727475/


Mitochondria are the organelles responsible for energy metabolism and are critical to immune responses. Mitochondrial aberrations have been implicated in the pathophysiology of ME/CFS and have been proposed as a possible biomarker for ME/CFS. The purpose of this systematic review was to evaluate the literature concerned with mitochondrial changes in ME/CFS patients compared to healthy controls.

The review covered studies published between January 1995 and February 2020. Studies were only included if they used either the Fukuda criteria, Canadian Consensus Criteria (CCC), International Consensus Criteria or Institute of Medicine criteria. Nineteen studies were included in the review, focussing on variations in mitochondrial DNA, messenger RNA, mitochondrial respiratory function, metabolites, and coenzymes. 
 
The authors found wide variations in results between studies, and the lack of standardised methodology made comparisons between studies difficult. The authors also note the predominant use of the Fukuda criteria, which is broad and likely to capture a heterogeneous sample with overlapping conditions, which may help explain some of the inconsistencies between studies. They note that more recent papers have tended to use more stringent criteria, like the CCC. 
 
The studies included in the review were also impeded by small sample sizes and other methodological issues, such as a failure to exclude smokers and a failure to match ME/CFS with healthy controls by age, sex and socioeconomic status. 
 
All of these methodological inconsistencies made it difficult for the authors to draw many firm conclusions about the role of mitochondria in the pathophysiology of ME/CFS.

Nonetheless, the results suggest that ME/CFS is not a primary mitochondrial disorder, due to the absence of disease-causing genetic variants. Changes in mitochondrial structure, DNA, RNA, respiratory function, metabolites and coenzymes were found, and the authors suggest that these might be due to secondary effects of other disrupted pathways. However, they also note the significant methodological inconsistencies and small sample sizes in these studies, and recommend that these findings be interpreted with caution.