Using plasma autoantibodies of Central Nervous System proteins to distinguish veterans with Gulf War Illness from healthy & symptomatic controls

Using plasma autoantibodies of Central Nervous System proteins to distinguish veterans with Gulf War Illness from healthy and symptomatic controls, by Mohamed B Abou-Donia, Elizabeth S Lapadula, Maxine H Krengel, Emily Quinn, Jessica LeClair, Joseph Massaro, Lisa A Conboy, Efi Kokkotou, Maria Abreu, Nancy G Klimas, Daniel D Nguyen and Kimberly Sullivan in Brain Sci. 2020, 10(9), 610; [doi.org/10.3390/brainsci10090610]  5 September 2020

 

Research abstract:

For the past 30 years, there has been a lack of objective tools for diagnosing Gulf War Illness (GWI), which is largely characterized by central nervous system (CNS) symptoms emerging from 1991 Gulf War (GW) veterans. In a recent preliminary study, we reported the presence of autoantibodies against CNS proteins in the blood of veterans with GWI, suggesting a potential objective biomarker for the disorder.

Now, we report the results of a larger, confirmatory study of these objective biomarkers in 171 veterans with GWI compared to 60 healthy GW veteran controls and 85 symptomatic civilian controls (n = 50 myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and n = 35 irritable bowel syndrome (IBS)).

Specifically, we compared plasma markers of CNS autoantibodies for diagnostic characteristics of the four groups (GWI, GW controls, ME/CFS, IBS). For veterans with GWI, the results showed statistically increased levels of nine of the ten autoantibodies against neuronal “tubulin, neurofilament protein (NFP), Microtubule Associated Protein-2 (MAP-2), Microtubule Associated Protein-Tau (Tau), alpha synuclein (α-syn), calcium calmodulin kinase II (CaMKII)” and glial proteins “Glial Fibrillary Acidic Protein (GFAP), Myelin Associated Glycoprotein (MAG), Myelin Basic Protein (MBP), S100B” compared to healthy GW controls as well as civilians with ME/CFS and IBS.

Next, we summed all of the means of the CNS autoantibodies for each group into a new index score called the Neurodegeneration Index (NDI). The NDI was calculated for each tested group and showed veterans with GWI had statistically significantly higher NDI values than all three control groups. The present study confirmed the utility of the use of plasma autoantibodies for CNS proteins to distinguish among veterans with GWI and other healthy and symptomatic control groups.

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Characterization of post–exertional malaise in patients with ME/CFS

Characterization of post–exertional malaise in patients with Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome, by Barbara Stussman, Ashley Williams, Joseph Snow, Angelique Gavin, Remle Scott, Avindra Nath and Brian Walitt in Front. Neurol., 18 September 2020 [doi.org/10.3389/fneur.2020.01025]

 

Research abstract:

Background:

Myalgic encephalomyelitis/chronic fatigue syndrome is characterized by persistent and disabling fatigue, exercise intolerance, cognitive difficulty, and musculoskeletal/joint pain. Post–exertional malaise is a worsening of these symptoms after a physical or mental exertion and is considered a central feature of the illness. Scant observations in the available literature provide qualitative assessments of post–exertional malaise in patients with myalgic encephalomyelitis/ chronic fatigue syndrome. To enhance our understanding, a series of outpatient focus groups were convened.

Methods:

Nine focus groups totaling 43 patients who reported being diagnosed with myalgic encephalomyelitis/ chronic fatigue syndrome were held between November 2016 and August 2019. Focus groups queried post–exertional malaise in daily life and participants’ retrospective memory of post–exertional malaise that followed an exercise provocation with a cardiopulmonary exercise test. Data analysis followed the grounded theory method to systematically code and categorize the data to find meaningful patterns. A qualitative software package was used to move text into categories during data coding.

Results:

A wide range of symptoms were attributed to exertion both in daily lives and following cardiopulmonary exercise testing. While three core symptoms emerged (exhaustion, cognitive difficulties, and neuromuscular complaints), participants’ descriptions were notable for their unique individual variations. Of 18 participants who responded to questions centered around symptoms following a cardiopulmonary exercise test, 17 reported that symptoms started within 24 h and peaked in severity within 72 h following the cardiopulmonary exercise test. Patients described post–exertional malaise as interfering with their ability to lead a “normal” life.

Conclusion:

The experience of post–exertional malaise in myalgic encephalomyelitis/chronic fatigue syndrome varies greatly between individuals and leads to a diminished quality of life. myalgic encephalomyelitis/ chronic fatigue syndrome patients describe post–exertional malaise as all-encompassing with symptoms affecting every part of the body, difficult to predict or manage, and requiring complete bedrest to fully or partially recover. Given the extensive variability in patients, further research identifying subtypes of post–exertional malaise could lead to better targeted therapeutic options.

Excerpts from Results

Theme 1. PEM Was Triggered by Three Broad Categories of Events
We asked focus group participants to give examples of activities that caused them to have PEM. Notably, there were three broad categories of activities: physical activity, cognitive effort, and emotion precipitated, although there was overlap across the three groups. These categories included triggers such as household chores, social activities, errands outside of the home, physical exercise, cognitive activities, and emotional moments (Figure 1).

Theme 2. Effects of PEM Were Impacted by Baseline Pre-exertional Symptoms
When focus group participants were asked to describe PEM following exertion, many expressed the importance of understanding their “starting point” or “baseline.” Participants described the pliable nature of symptoms and how successive exertion can compound symptoms.

Theme 3. PEM Had a Wide Symptom Range With Few Differences Between Daily PEM and Following CPET, With Three Core Symptoms (Exhaustion, Cognitive Difficulties, and Neuromuscular Complaints)…

Theme 3a. Exhaustion
Participants explained that the exhaustion from PEM is different than what they experienced before having ME/CFS…

Theme 3b. Cognitive Difficulties
Cognitive difficulties were described as both difficulty thinking clearly/paying attention and difficulty speaking or finding words…

Theme 3c. Neuromuscular Complaints
Patients often complained of neuromuscular symptoms, which included muscle pain/aches and muscle weakness…

Theme 4. PEM Following CPET Was More Immediate and of Longer Duration Than PEM in Daily Life

Theme 5. The Manner of Onset of PEM Symptoms Varied
Separate from when PEM began (as shown in Figures 4, 5), we also determined whether participants perceived the onset of symptoms as sudden or gradual…

Theme 6. Complete Rest Was Necessary to Gain Any Relief in PEM Symptoms
When asked what could alleviate PEM symptoms, virtually every participant agreed that while in an episode of PEM, complete rest was absolutely necessary to reduce symptoms…

Theme 7. Planning and Moderation of Energy Expenditure Was Essential to Avoiding PEM
An interesting theme that emerged during focus group discussions centered around the steps taken by participants to manage activity levels in their daily lives to minimize the effects of PEM…

Theme 8. The Uncertainty and Debility of PEM Created Despair
…Participants talked at length about living with the unpredictability of PEM and having to adjust their lives to try to avoid severe PEM…

Conclusion
ME/CFS patients describe PEM as all-encompassing with symptoms affecting every part of the body, difficult to predict or manage, and requiring complete bedrest to fully or partially recover. Through in-depth focus group discussions, ME/CFS patients describe PEM as disruptive to living a self-described “normal” life, sometimes leading to hopelessness or despair. Given the extensive variability in PEM symptoms and timeframes for onset, peak, and recovery, further research identifying subtypes of PEM could lead to better targeted therapeutic options…

 

MECFSSkeptic blog post,  by Michiel Tack: Summary of the NIH’s exploration of post-exertional malaise

Press release: NIH study details self-reported experiences with post-exertional malaise in ME/CFS

Medical newsResearchers explore clinical and biological aspects of myalgic encephalomyelitis/ chronic fatigue syndrome

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An analysis of 2‐day cardiopulmonary exercise testing to assess unexplained fatigue

An analysis of 2‐day cardiopulmonary exercise testing to assess unexplained fatigue, by Jacob B Lindheimer, Thomas Alexander, Wei Qian, Jacquelyn C Klein‐Adams, Gudrun Lange, Benjamin H Natelson, Dane B Cook, Helene Z Hill, Michael J Falvo in Physiological Reports, Vol 8, Issue 17, Sep 2020 [doi.org/10.14814/phy2.14564]

 

Research abstract:

Two consecutive maximal cardiopulmonary exercise tests (CPETs) performed 24 hr apart (2‐day CPET protocol) are increasingly used to evaluate post‐exertional malaise (PEM) and related disability among individuals with myalgic encephalomyelitis/ chronic fatigue syndrome (ME/CFS).

This protocol may extend to other fatiguing illnesses with similar characteristics to ME/CFS; however, 2‐day CPET protocol reliability and minimum change required to be considered clinically meaningful (i.e., exceeding the standard error of the measure) are not well characterized.

To address this gap, we evaluated the 2‐day CPET protocol in Gulf War Illness (GWI) by quantifying repeatability of seven CPET parameters, establishing their thresholds of clinically significant change, and determining whether changes differed between veterans with GWI and controls. Excluding those not attaining peak effort criteria (n = 15), we calculated intraclass correlation coefficients (ICCs), the smallest real difference (SRD%), and repeated measures analysis of variance (RM‐ANOVA) at the ventilatory anaerobic threshold (VAT) and peak exercise in 15 veterans with GWI and eight controls.

ICC values at peak ranged from moderate to excellent for veterans with GWI (mean [range]; 0.84 [0.65 – 0.92]) and were reduced at the VAT (0.68 [0.37 – 0.78]). Across CPET variables, the SRD% at peak exercise for veterans with GWI (18.8 [8.8 – 28.8]) was generally lower than at the VAT (28.1 [9.5 – 34.8]). RM‐ANOVAs did not detect any significant group‐by‐time interactions (all p > .05).

The methods and findings reported here provide a framework for evaluating 2‐day CPET reliability, and reinforce the importance of carefully considering measurement error in the population of interest when interpreting findings.

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Mitochondria & immunity in CFS

Mitochondria and Immunity in Chronic Fatigue Syndrome, by G Anderson, Michael Maes in Prog Neuropsychopharmacol Biol Psychiatry 2020 May 26 [DOI:10.1016/j.pnpbp.2020.109976]

 

Review abstract:

It is widely accepted that the pathophysiology and treatment of myalgic encephalomyelitis/ chronic fatigue syndrome (ME/CFS) could be considerably improved. The heterogeneity of ME/CFS and the confusion over its classification have undoubtedly contributed to this, although this would seem a consequence of the complexity of the array of ME/CFS presentations and high levels of diverse comorbidities.

This article reviews the biological underpinnings of ME/CFS presentations, including the interacting roles of the gut microbiome/permeability, endogenous opioidergic system, immune cell mitochondria, autonomic nervous system, microRNA-155, viral infection/re-awakening and leptin as well as melatonin and the circadian rhythm. This details not only relevant pathophysiological processes and treatment options, but also highlights future research directions.

Due to the complexity of interacting systems in ME/CFS pathophysiology, clarification as to its biological underpinnings is likely to considerably contribute to the understanding and treatment of other complex and poorly managed conditions, including fibromyalgia, depression, migraine, and dementia. The gut and immune cell mitochondria are proposed to be two important hubs that interact with the circadian rhythm in driving ME/CFS pathophysiology.

Read the full paper

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Postviral fatigue syndrome and creatine: a piece of the puzzle?

Postviral fatigue syndrome and creatine: a piece of the puzzle?, by Sergej M Ostojic in Nutritional Neuroscience pp. 1–2, 19 Aug 2020 [doi.org/10.1080/1028415X.2020.1809880]

 

Letter conclusion:

Creatine supplementation may recharge creatine stores (at least in the skeletal muscles) but this does not inevitably lead to better clinical features in all PFS (postviral fatigue syndrome) patients. It might help some patients to perform more physical work without negative consequences yet creatine is probably less effective to tackle general fatigue and/or nervous system-specific signs and symptoms of PFS. We are still short of information. Does supplemental creatine even  reach the brain in PFS, a major stumbling block for creatine delivery in clinical neurology.

The appropriate daily dose, dosing interval, and treatment duration, gender-specific pharmacokinetic and pharmacodynamic considerations, possible interactions with other disease-modifying agents, long-term side effects of creatine – all details missing for PFS patients.

Creatine supplementation, therefore, requires much more research credentials before being endorsed in PFS, with correcting creatine might be just a piece of solving the big jigsaw puzzle of metabolic turmoil in this baffling disease. Finally, to answer to a PFS patient’s question about creatine – play safe and wait for better evidence!

Read the full letter

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Physios for ME podcast: a case study of post viral fatigue/ long Covid/ chronic Covid 19

 

Podcast: Physios for ME present a case study of Post Viral Fatigue/Long Covid/Chronic Covid 19.

A conversation about key aspects of pacing, avoiding PEM and how a skilled physiotherapist can be of help. [31 mins]

 

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WAMES AGM 26th Sep 2020

Annual General Meeting of WAMES

 

The annual business meeting of the Welsh Association of ME & CFS Support will be held virtually to review past events and plan future activities. Covid-19 has changed our landscape and our future, so there will be lots to discuss!

This year we will be welcoming a new secretary and treasurer!

Please contact jan@wames.org.uk if you have anything to report to WAMES, or topics you wish us to discuss or more importantly, if you would like to join the team or volunteer in any way.  Let Jan know if you wish to attend.

 

When:

Saturday 26th September 2020 at  10.30am

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Factors affecting the characterization of Post-Exertional Malaise derived from patient input

Factors affecting the characterization of Post-Exertional Malaise derived from patient input by Carly S Holtzman, Claire Fisher, Shaun Bhatia, Leonard A Jason, in Journal of Health Disparities Research and Practice: Vol. 13 : Iss. 2 , Article 5.

Research abstract:

The National Institutes of Health/Center for Disease Control and Prevention (NIH/CDC) Common Data Elements (CDE) established a post-exertional malaise (PEM) workgroup with the task of describing PEM and recommending a standardized way of assessing it in patients with myalgic encephalomyelitis and chronic fatigue syndrome (ME/CFS).

As a stigmatized group, patients with ME/CFS are in need of instruments which can properly describe their symptomatic experiences, which can help reduce the disparity between illness seriousness and appropriate attention from healthcare.

The current study explored attitudes and preferences among 115 patients with ME/CFS who participated in the creation of a patient-driven instrument to measure PEM, the key symptom of the illness. Themes that emerged from the qualitative analyses of patient feedback focused on how their illness was experienced; their access to care; problems with physicians, researchers, and research methods; and expressions of gratitude for the collaborative process.

Domains that were most important to the patient community were identified in the effort to create a comprehensive measure of PEM. Benefits of community-based action research are discussed.

Four themes emerged from the Facebook discussions regarding PEM:
(1) illness experience;
(2) consequences;
(3) issues in the field;
(4) attitudes and interactions.
We explain the components of each theme and illustrate how patients’ Facebook comments were taken into consideration during the participatory process of creating a PEM questionnaire.

Study conclusion:

Overall, analyzing Facebook comments related to the experience of PEM has led to new
insights, which in turn allowed us to create a comprehensive, patient-driven questionnaire assessing PEM. Our goal was to identify the most important aspects of PEM, as well as how the patient community interacted with each other via Facebook.

This action-oriented process has led us to believe that it is crucial to collaborate with the patient community which can result in a more insightful, accurate and valid perspective of the illness.

This qualitative analysis using community based action research has made substantial contributions to the study of PEM, and ME/CFS in general. It is our hope to provide a model of how scientists and patients in this area can work together in the development of methods and instruments to better assess this illness.

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Association between quadrivalent human papillomavirus vaccination & selected syndromes with autonomic dysfunction in Danish females

Association between quadrivalent human papillomavirus vaccination and selected syndromes with autonomic dysfunction in Danish females: population based, self-controlled, case series analysis, by Anders Hviid, Nicklas M Thorsen, Palle Valentiner-Branth, Morten Frisch, Kåre Mølbak in BMJ Vol 370, p. m2930, Sep 2, 2020 [doi.org/10.1136 bmj.m2930]

 

What is already known on this topic

  • Anecdotal links between human papillomavirus vaccination and syndromes with autonomic dysfunction, such as chronic fatigue syndrome, complex regional pain
    syndrome, and postural orthostatic tachycardia syndrome, have been reported
  • Concerns about human papillomavirus vaccine persist and challenge cancer prevention in several countries through disappointing uptake of the vaccine

What this study adds

  • Our study did not support the hypothesis that quadrivalent human
    papillomavirus vaccine increases the risk of selected syndromes with autonomic
    dysfunction (chronic fatigue syndrome, complex regional pain syndrome, and
    postural orthostatic tachycardia syndrome) in Danish girls and women
  • A moderate to large increase in the rate (more than 32%) of any syndrome
    associated with vaccination is unlikely given the statistical power of our study

Research abstract:

Objective
To evaluate the association between quadrivalent human papillomavirus vaccination and syndromes with autonomic dysfunction, such as chronic fatigue syndrome, complex regional pain syndrome, and postural orthostatic tachycardia syndrome.

Design
Population-based self-controlled case series.

Setting
Information on human papillomavirus vaccinations and selected syndromes with autonomic dysfunction (chronic fatigue syndrome, complex regional pain syndrome, and postural orthostatic tachycardia syndrome) identified using ICD-10 (international classification of diseases, revision 10) diagnostic codes from Danish nationwide registers.

Participants
869 patients with autonomic dysfunction syndromes from a cohort of 1 375 737 Danish born female participants aged 10 to 44 years during 2007-16.

Main outcome measures
Self-controlled case series rate ratios (95% confidence intervals) of the composite outcome of chronic fatigue syndrome, complex regional pain syndrome, and postural orthostatic tachycardia syndrome, adjusted for age and season, comparing female participants vaccinated and unvaccinated with the quadrivalent human papillomavirus vaccine. Chronic fatigue syndrome, complex regional pain syndrome, and postural orthostatic tachycardia syndrome were also considered separately in secondary analyses.

Results
During 10 581 902 person years of follow-up, 869 female participants with syndromes of autonomic dysfunction (136 with chronic fatigue syndrome, 535 with complex regional pain syndrome, and 198 with postural orthostatic tachycardia syndrome) were identified. Quadrivalent human papillomavirus vaccination did not statistically significantly increase
the rate of a composite outcome of all syndromes with autonomic dysfunction in a 365 day risk period following vaccination (rate ratio 0.99, 95% confidence interval 0.74 to 1.32) or the rate of any individual syndrome in the risk period (chronic fatigue syndrome (0.38,
0.13 to 1.09), complex regional pain syndrome (1.31, 0.91 to 1.90), or postural orthostatic tachycardia syndrome (0.86, 0.48 to 1.54)).

Conclusions
When vaccination is introduced, adverse events could occur in close temporal relation to the vaccine purely by chance. These results do not support a causal association between quadrivalent human papillomavirus vaccination and chronic fatigue syndrome, complex regional pain syndrome, or postural orthostatic tachycardia syndrome, either individually or as a composite outcome. An increased risk of up to 32% cannot be formally excluded, but the statistical power of the study suggests that a larger increase in the rate of any syndrome associated with vaccination is unlikely.

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Using structural & functional MRI as a neuroimaging technique to investigate CFS/ME: a systematic review

Using structural and functional MRI as a neuroimaging technique to investigate chronic fatigue syndrome/myalgic encephalopathy: a systematic review, by in BMJ Open Vol 10, #8, p e031672, August 30, 2020 [doi.org/10.1136/bmjopen-2019-031672]

 

Strengths and limitations of this study

  • To the best of our knowledge, this is the first systematic review of neuroimaging studies that have investigated chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) using MRI.
  • We reviewed both structural MRI and functional MRI (fMRI) studies of CFS/ME.
  • We identified common limitations across the neuroimaging studies and make recommendations for future research.
  • We were unable to find conclusive evidence for neural biomarkers of CFS/ME.
  • The main limitation of the current systematic review is that a meta-analysis was not possible because of the different methodologies across the studies, such as fMRI studies using a variety of tasks to assess different cognitive functions.

Research abstract

Objective
This systematic review aims to synthesise and evaluate structural MRI (sMRI) and functional MRI (fMRI) studies in chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME).

Methods
We systematically searched Medline and Ovid and included articles from 1991 (date of Oxford diagnostic criteria for CFS/ME) to first April 2019. Studies were selected by predefined inclusion and exclusion criteria. Two reviewers independently reviewed the titles and abstracts to determine articles for inclusion, full text and quality assessment
for risk of bias.

Results
sMRI studies report differences in CFS/ME brain anatomy in grey and white matter volume, ventricular enlargement and hyperintensities. Three studies report no neuroanatomical differences between CFS/ME and healthy controls. Task-based fMRI investigated working memory, attention, reward and motivation, sensory information processing and emotional conflict. The most consistent finding was CFS/ME exhibited increased activations and recruited additional brain regions. Tasks with increasing load or
complexity produced decreased activation in task-specific brain regions.

Conclusions
There were insufficient data to define a unique neural profile or biomarker of CFS/ME. This may be due to inconsistencies in finding neuroanatomical differences in CFS/ME and the variety of different tasks employed by fMRI studies. But there are also limitations with
neuroimaging. All brain region specific volumetric differences in CFS/ME were derived from voxel-based statistics that are biased towards group differences that are highly localised in space. fMRI studies demonstrated both increases and decreases in activation patterns in CFS/ME, this may be related to task demand. However, fMRI signal cannot
differentiate between neural excitation and inhibition or function-specific neural processing.

Many studies have small sample sizes and did not control for the heterogeneity of this clinical population. We suggest that with robust study design, subgrouping and
larger sample sizes, future neuroimaging studies could potentially lead to a breakthrough in our understanding of the disease.

[NB a broad definition of CFS was used – the patients are not homogeneous.]

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