The ME Association ME/CFS Research Round-up

Emma Northwood, Research Correspondent, ME Association

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

All research relating to ME/CFS can be located in the ME Association: Index of ME/CFS Published Research.

This extensive library of research is updated at the end of each month and is correct to 02 November 2020. It is a free resource and available to anyone.

The Index provides an A-Z of published research studies and selected key documents and articles, listed by subject matter, on myalgic encephalomyelitis, myalgic encephalopathy, and/or chronic fatigue syndrome (ME/CFS).

You can use it to easily locate and read any research in a particular area that you might be interested in, e.g. epidemiology, infection, neurology, post-exertional malaise etc.

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

ME/CFS Research Published 28 Nov – 04 Dec 2020

In the past week, five new research studies on ME/CFS have been published. We highlight two of them below:

Some ME/CFS sufferers, as well coping with chronic fatigue and exhaustion, have to contend with pain. The first paper (1) presented here looks into a possible reason for this pain.  

Perineural cysts, which are also known as Tarlov cysts, are fluid-filled sacs that form on the nerve root sheath, most commonly in the lower area of the spine. They form around the roots of nerves and result from pathologically increased cerebrospinal fluid pressure. The cysts may or may not cause pain, but if symptoms are felt, initially they produce sensory symptoms.

From 197 fibromyalgia and/or CFS-patient scans examined retrospectively, 39% had Tarlov cysts. This is three times the rate seen in the general population. The authors believe that this observation supports the hypothesis that STCs, FM, and CFS may share the same pathophysiological mechanism of moderately increased cerebrospinal fluid pressure.

In the second research study (2), a multi-omics approach was used to assess similarities of CFS and patients with Q fever fatigue syndrome (QFS).

Multi-omics is where the structure and function of the whole makeup of a given biological function is measured such as genes, proteins, or products of reactions called metabolites.

Technology was employed to assess the microbiome (genetic material of all microbes in or on the body), the blood metabolome (chemicals found within the blood), and inflammatory proteome (proteins expressed during the inflammatory process).

There were no significant differences in ME/CFS patients and QFS patients across the three different omics layers. Inflammatory markers such as 4E-BP1 and MMP-1 may, however, be able to effectively distinguish between healthy controls and both CFS and QFS patients.

ME/CFS Research References and Abstracts

1. High Prevalence of Perineural Cysts in Patients with Fibromyalgia and Chronic Fatigue Syndrome
Hulens M, Bruyninckx F, Dankaerts W, Rasschaert R, De Mulder P, Stalmans I, Vansant G, Bervoets C.
Pain Med. 2020 Dec 1:pnaa410.

Abstract
Objective: Pain in fibromyalgia (FM) and chronic fatigue syndrome (CFS) is assumed to originate from central sensitization.

Perineural cysts or Tarlov cysts (TCs) are nerve root dilations resulting from pathologically increased cerebrospinal fluid pressure. These cysts initially affect sensory neurons and axons in dorsal root ganglia and produce sensory symptoms (pain and paresthesia).

Symptomatic TC (STC) patients often complain about widespread pain and fatigue. Consequently, STC patients may initially be diagnosed with FM, CFS, or both. The objective of this study was to document the prevalence of TCs in patients diagnosed with FM or CFS.

Design: A retrospective study.
Setting: An outpatient clinic for musculoskeletal disorders.
Subjects: Patients diagnosed with FM according to the 1990 American College of Rheumatology criteria or with CFS according to the 1994 Centers for Disease Control criteria were selected.
Methods: Review of lumbar and sacral magnetic resonance imaging scans including TCs ≥5 mm in size.

Results: In total, 197 patients with FM, CFS, or both underwent magnetic resonance imaging. Ninety-one percent were women. The mean age was 48.1 (±11.9) years. TCs were observed in 39% of patients, with a mean size of 11.8 (±5.2) mm. In males, the prevalence was 12%, vs. 42% in females.

Conclusions: In patients diagnosed with FM or CFS, the prevalence of TCs was three times higher than that in the general population. This observation supports the hypothesis that STCs, FM, and CFS may share the same pathophysiological mechanism, i.e., moderately increased cerebrospinal fluid pressure, causing irritation of neurons and axons in dorsal root ganglia.

2. Multi-omics examination of Q fever fatigue syndrome identifies similarities with chronic fatigue syndrome
Raijmakers RPH, Roerink ME, Jansen AFM, Keijmel SP, Gacesa R, Li Y, Joosten LAB, van der Meer JWM, Netea MG, Bleeker-Rovers CP, Xu CJ.
J Transl Med. 2020 Nov 26;18(1):448

Abstract
Background: Q fever fatigue syndrome (QFS) is characterised by a state of prolonged fatigue that is seen in 20% of acute Q fever infections and has major health-related consequences.

The molecular mechanisms underlying QFS are largely unclear. In order to better understand its pathogenesis, we applied a multi-omics approach to study the patterns of the gut microbiome, blood metabolome, and inflammatory proteome of QFS patients, and compared these with those of chronic fatigue syndrome (CFS) patients and healthy controls (HC).

Methods: The study population consisted of 31 QFS patients, 50 CFS patients, and 72 HC. All subjects were matched for age, gender, and general geographical region (South-East part of the Netherlands). The gut microbiome composition was assessed by Metagenomic sequencing using the Illumina HiSeq platform. A total of 92 circulating inflammatory markers were measured using Proximity Extension Essay and 1607 metabolic features were assessed with a high-throughput non-targeted metabolomics approach.

Results: Inflammatory markers, including 4E-BP1 (P = 9.60-16 and 1.41-7) and MMP-1 (P = 7.09-9and 3.51-9), are significantly more expressed in both QFS and CFS patients compared to HC. Blood metabolite profiles show significant differences when comparing QFS (319 metabolites) and CFS (441 metabolites) patients to HC, and are significantly enriched in pathways like sphingolipid (P = 0.0256 and 0.0033) metabolism.

When comparing QFS to CFS patients, almost no significant differences in metabolome were found. Comparison of microbiome taxonomy of QFS and CFS patients with that of HC, shows both in- and decreases in abundancies in Bacteroidetes (with emphasis on Bacteroides and Alistiples spp.), and Firmicutes and Actinobacteria (with emphasis on Ruminococcus and Bifidobacterium spp.).

When we compare QFS patients to CFS patients, there is a striking resemblance and hardly any significant differences in microbiome taxonomy are found.

Conclusions: We show that QFS and CFS patients are similar across three different omics layers and 4E-BP1 and MMP-1 have the potential to distinguish QFS and CFS patients from HC.

3. Patients’ hopes for recovery from myalgic encephalomyelitis and chronic fatigue syndrome: Toward a “recovery in” framework
Devendorf AR, Rown AA, Jason LA.
Chronic Illn. 2020 Dec;16(4):307-321.

Abstract
Objective: There is no consensus on recovery from myalgic encephalomyelitis and chronic fatigue syndrome, which has spawned debates when interpreting outcome research. Within these debates, the patient voice is often neglected. This study aimed to understand how patients conceptualize recovery – regarding the definition and possibility of recovery.

Method: We conducted in-depth, semi-structured interviews with 10 older (above age 50) female patients with myalgic encephalomyelitis or chronic fatigue syndrome. Data were analyzed using a deductive thematic analysis.

Results: Our sample viewed recovery as functioning without fear of relapse, returning to previous roles and identities, and achieving a sustained absence of symptoms.

Participants expressed skepticism that reaching recovery from myalgic encephalomyelitis and chronic fatigue syndrome exists but working toward significant improvement through coping is a viable goal.

Although many accepted they would never reclaim full functioning, participants continued to experience uncertainty about their future with unclear prognostic goals and limited treatment options.

Discussion: Recovery is more than just symptom reduction. Outcome research should incorporate well-being measures like identity, meaning and quality of life, and personal empowerment to enhance recovery definitions.

When communicating treatment goals, providers might convey cautious optimism for complete symptom remission, while emphasizing that living a fulfilling life through effective coping strategies is possible.

4. Elevated Perceived Exertion in People with Myalgic Encephalomyelitis with Chronic Fatigue Syndrome and Fibromyalgia: A Meta-analysis
Barhorst EE, Andrae WE, Rayne TJ, Falvo MJ, Cook DB, Lindheimer JB.
Med Sci Sports Exerc. 2020 Dec;52(12):2615-2627.

Abstract
Purpose: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and fibromyalgia (FM) are two debilitating illnesses primarily characterized by chronic symptoms of fatigue and musculoskeletal pain, respectively.

Some investigators have observed an elevated sense of effort in these patient groups; however, this effect has not been substantiated via quantitative review. As such, we conducted a meta-analysis of RPE responses to aerobic exercise in ME/CFS and FM compared with healthy adults.

Methods: Case-control studies involving adults with ME/CFS or FM that measured RPE and heart rate responses to acute aerobic exercise were included.

Data sources included PubMed, Scopus/Embase, CINAHL, CENTRAL, and Google Scholar. Risk of bias was assessed by evaluating each study’s description of participant characteristics, matching procedures, and administration of RPE scales. Hedges’ d effect sizes for RPE were calculated and aggregated using random-effects models, and potential moderators were explored with meta-regression analysis.

Results: Forty-one effects were extracted from 37 studies involving 1016 patients and 686 healthy controls. We observed a large (Hedges’ d = 0.85, 95% confidence interval = 0.62-1.08) effect indicating higher RPE in patients than controls.

The mean effect size was significantly moderated (P < 0.001, R = 0.38) by whether RPE data were analyzed at a peak or submaximal intensity (b = 0.60, z = 4.6, P < 0.001) and the type of patient group that was studied (b = 0.25, z = 2.08, P = 0.04).

Conclusions: People with ME/CFS and FM perceive aerobic exercise as more effortful than healthy adults, but the exact causes are unclear.

The large magnitude of this effect merits further exploration of underlying mechanisms that could provide insight into the pathophysiology of ME/CFS and FM or the broader debate about the nature of central and/or peripheral signals that influence RPE.

5. Patients’ experiences and effects of non-pharmacological treatment for myalgic encephalomyelitis/chronic fatigue syndrome – a scoping mixed methods review
Mengshoel AM, Helland IB, Meeus M, Castro-Marrero J, Pheby D, Bolle Strand E.
Int J Qual Stud Health Well-being. 2020 Dec;15(1):1764830

Abstract
Purpose: The EU COST Action 15111 collaboration on myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) aims to assess current research and identify knowledge gaps in Europe. Presently, our purpose is to map the effects of non-pharmacological therapies (NPTs) for ME/CFS, and what patients find important in the treatment process.

Methods: A scoping mixed methods literature review of European studies identified 16 papers fulfilling our inclusion criteria. The quantitative and qualitative studies were synthesized separately in tables. Additionally, extracts from the qualitative studies were subjected to translational analysis.

Results: Effect studies addressed cognitive behavioural therapy (CBT, n = 4), multimodal rehabilitation (n = 2) and activity-pacing (n = 2). CBT reduced fatigue scores more than usual care or waiting list controls.

The effects of rehabilitation and activity-pacing were inconsistent. The contents, assessment methods and effects of rehabilitation and activity pacing studies varied.

For patients, health professionals’ recognition of ME/CFS and support were crucial, but they expressed ambiguous experiences of what the NPTs entail.

Conclusions: Methodological differences make comparisons across NPTs impossible, and from a patient perspective the relevance of the specific contents of NPTs are unclear.

Future well-designed studies should focus on developing NPTs tailored to patients’ concerns and evaluation tools reflecting what is essential for patients.

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