Environmental, neuro-immune & neuro-oxidative stress interactions in CFS

Environmental, neuro-immune, and neuro-oxidative stress interactions in Chronic Fatigue Syndrome, by Geir Bjørklund, Maryam Dadar, Lyudmila Pivina, Monica Daniela Doşa, Yuliya Semenova & Michael Maes in Molecular Neurobiology (2020) [doi.org/10.1007/s12035-020-01939-w]

 

Review abstract:

Chronic fatigue syndrome/myalgic encephalomyelitis (CFS) is a complex, multisystem disease that is characterized by long-term fatigue, exhaustion, disabilities, pain, neurocognitive impairments, gastrointestinal symptoms, and post-exertional malaise, as well as lowered occupational, educational, and social functions.

The clinical and biomarker diagnosis of this disorder is hampered by the lack of validated diagnostic criteria and laboratory tests with adequate figures of merit, although there are now many disease biomarkers indicating the pathophysiology of CFS.

Here, we review multiple factors, such as immunological and environmental factors, which are associated with CFS and evaluate current concepts on the involvement of immune and environmental factors in the pathophysiology of CFS. The most frequently reported immune dysregulations in CFS are modifications in immunoglobulin contents, changes in B and T cell phenotypes and cytokine profiles, and decreased cytotoxicity of natural killer cells. Some of these immune aberrations display a moderate diagnostic performance to externally validate the clinical diagnosis of CFS, including the expression of activation markers and protein kinase R (PKR) activity. Associated with the immune aberrations are activated nitro-oxidative pathways, which may explain the key symptoms of CFS.

Fig. 1 The pathogenesis of
CFS due to
exposure to infections, metals,
& environmental factors

This review shows that viral and bacterial infections, as well as nutritional deficiencies, may further aggravate the immune-oxidative pathophysiology of CFS. Targeted treatments with antioxidants and lipid replacement treatments may have some clinical efficacy in CFS. We conclude that complex interactions between immune and nitro-oxidative pathways, infectious agents, environmental factors, and nutritional deficiencies play a role in the pathophysiology of CFS.

Read full paper

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Exercise alters brain activation in Gulf War Illness & ME/CFS

Exercise alters brain activation in Gulf War Illness and Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome, by Stuart D Washington, Rakib U Rayhan, Richard Garner, Destie Provenzano, Kristina Zajur, Florencia Martinez Addiego, John W VanMeter, James N Baraniuk in Brain Communications, Vol 2, Issue 2, 2020, fcaa070 [doi.org/10.1093/braincomms/fcaa070] Published: 10 August 2020

 

Research abstract:

Gulf War Illness affects 25–30% of American veterans deployed to the 1990–91 Persian Gulf War and is characterized by cognitive post-exertional malaise following physical effort. Gulf War Illness remains controversial since cognitive post-exertional malaise is also present in the more common Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.

An objective dissociation between neural substrates for cognitive post-exertional malaise in Gulf War Illness and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome would represent a biological basis for diagnostically distinguishing these two illnesses.

Here, we used functional magnetic resonance imaging to measure neural activity in healthy controls and patients with Gulf War Illness and Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome during an N-back working memory task both before and after exercise. Whole brain activation during working memory (2-Back > 0-Back) was equal between groups prior to exercise.

Exercise had no effect on neural activity in healthy controls yet caused deactivation within dorsal midbrain and cerebellar vermis in Gulf War Illness relative to Myalgic Encephalomyelitis/Chronic Fatigue Syndrome patients. Further, exercise caused increased activation among Myalgic Encephalomyelitis/Chronic Fatigue Syndrome patients within the dorsal midbrain, left operculo-insular cortex (Rolandic operculum) and right middle insula.

These regions-of-interest underlie threat assessment, pain, interoception, negative emotion and vigilant attention. As they only emerge post-exercise, these regional differences likely represent neural substrates of cognitive post-exertional malaise useful for developing distinct diagnostic criteria for Gulf War Illness and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.

 

The Science Times: Chronic Fatigue Syndrome and Gulf War Illness Distinguished by Brain Activity

The functional magnetic resonance imaging (fMRI) results showed that the brain activity of Gulf War veterans behaved differently from CFS patients after exercise and memory tasks. GWI patients had lower brain activity in the part of the brain that processes pain (periaqueductal gray) as well as in the cerebellum. The cerebellum controls motor skills, cognition, and emotions.

The opposite was found in patients CFS, with increased activity in the two brain areas which increased attention and vigilance. Despite no changes in brain activity, CFS still suffered several physical symptoms and episodes of brain fog. Previous evidence has shown how the molecular structure of the cerebrospinal fluid in patients of both conditions alter after moderate exercise.

Medical Express: Gulf War illness, chronic fatigue syndrome distinct illnesses, study suggests

The two illnesses share many symptoms, including cognitive and memory problems (often described as “brain fog”), pain, and fatigue following mild to moderate exercise. Some medical institutions, including the U.S. Department of Veterans Affairs (the VA), list CFS as a symptom of GWI (called chronic multisymptom illness associated with service in the Gulf War by the VA).

“Our results strongly suggest that GWI and CFS represent two distinct disorders of the brain and therefore CFS is not a symptom of GWI,” says Stuart Washington, Ph.D., a post-doctoral fellow and first author on the study. “Combining of two different disorders could lead to improper treatment of both.” Washington works in the laboratory of James Baraniuk, MD, professor of medicine at Georgetown.

 

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Orthostatic Intolerance explained – videos from Bateman Horne Center

What is orthostatic intolerance (OI)?

 

Two videos from the Bateman Horne Center in Utah, USA set out to explain orthostatic intolerance for health professionals and it’s role in ME/CFS.

There is sufficient evidence to suggest a high prevalence of orthostatic intolerance (OI) exists in those with ME/CFS. OI is measurable, and the ability to identify and manage OI can greatly improve patient outcomes and daily functioning.

Video 1: Defines OI, and discusses the physiology and testing for OI.

Video 2:  Describes findings of reduced cerebral blood flow. Treatments include hydration, compression clothing and medications. Possible causes of OI in ME/CFS are listed. [Duration 6 minutes each]

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Mapping of pathological change in CFS using the ratio of T1- & T2-weighted MRI scans

Mapping of pathological change in chronic fatigue syndrome using the ratio of T1- and T2-weighted MRI scans, by Kiran Thapaliya, Sonya Marshall-Gradisnik, Don Staines, Leighton Barnden in NeuroImage: Clinical Vol 28, 2020, 102366 [doi.org/10.1016/j.nicl.2020.102366]

 

Research highlights

  • We showed increased T1w/T2w in ME/CFS in contrast to other neurodegenerative diseases.
  • Higher T1w/T2w occurred in basal ganglia and white matter tracts.
  • Increased T1w/T2w indicates increased myelin and/or iron levels.
  • T1w/T2w regressions vs clinical measures were abnormal in cingulate cortex and white matter foci.

Research abstract:

Myalgic Encephalomyelitis or Chronic Fatigue Syndrome (ME/CFS) subjects suffer from a variety of cognitive complaints indicating that the central nervous system plays a role in its pathophysiology.

Recently, the ratio T1w/T2w has been used to study changes in tissue myelin and/or iron levels in neurodegenerative diseases such as multiple sclerosis and schizophrenia.

In this study, we applied the T1w/T2w method to detect changes in tissue microstructure in ME/CFS patients relative to healthy controls. We mapped the T1w/T2w signal intensity values in the whole brain for forty-five ME/CFS patients who met Fukuda criteria and twenty-seven healthy controls and applied both region- and voxel-based quantification. We also performed interaction-with-group regressions with clinical measures to test for T1w/T2w relationships that are abnormal in ME/CFS at the population level.

Region-based analysis showed significantly elevated T1w/T2w values (increased myelin and/or iron) in ME/CFS in both white matter (WM) and subcortical grey matter. The voxel-based group comparison with sub-millimetre resolution voxels detected very significant clusters with increased T1w/T2w in ME/CFS, mostly in subcortical grey matter, but also in brainstem and projection WM tracts. No areas with decreased T1w/T2w were found in either analysis. ME/CFS T1w/T2w regressions with heart-rate variability, cognitive performance, respiration rate and physical well-being were abnormal in both gray and white matter foci.

Our study demonstrates that the T1w/T2w approach is very sensitive and shows increases in myelin and/or iron in WM and basal ganglia in ME/CFS.

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Genetic risk factors of ME/CFS: a critical review

Genetic risk factors of ME/CFS: a critical review, by in Human Molecular Genetics, ddaa169, 3 Aug 2020 [doi.org/10.1093/hmg/ddaa169]

 

Review abstract:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex multisystem illness that lacks effective therapy and a biomedical understanding of its causes.

Despite a prevalence of approximately 0.2–0.4% and its high public health burden, and evidence that it has a heritable component, ME/CFS has not yet benefited from the advances in technology and analytical tools that have improved our understanding of many other complex diseases.

Here we critically review existing evidence that genetic factors alter ME/CFS risk before concluding that most ME/CFS candidate gene associations are not replicated by the larger CFS cohort within UK Biobank. Multiple genome-wide association studies of this cohort also have not yielded consistently significant associations.

Ahead of upcoming larger genome-wide association studies we discuss how these could generate new lines of enquiry into the DNA variants, genes and cell-types that are causally involved in ME/CFS disease.

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It’s still ME – Kara Jane’s album launched for Severe ME Day

Kara Jane’s album launch – It’s still M.E.

 

At last I can say it – my album, It’s Still M.E., is out now! Please, please share the news with everyone you know. My story is told today on the BBC News site.

Where to buy my album

It’s Still M.E can be downloaded and streamed from major platforms.

My story

I’m seriously ill with a severe form of ME. I’ve been bed bound for many years and am dependent on oxygen and 24 hour nursing care. I’m frequently admitted to hospital with serious infections, and a few years ago doctors warned me that my life expectancy could be very limited.

From this place of suffering and despair, my album was born.

I began writing music to express my pain, and a family friend helped me to record the songs from my bed.  As I’m too ill to sing more than a line or two at a time, completing the vocals took a couple of years.

Recording from my bed

In May 2020, a BBC appeal resulted in over 100 musicians and producers coming forward to offer their help in completing the album.  An amazing team have dedicated the last few months to working on my music.  Thanks to them, my dream of releasing an album has now come true.

I’m aiming to raise £100,000 for research into severe ME. (More information here.)

How you can help

There are several ways that you can support me.

1 – Buy my album!  Every penny raised will go towards research into the severest cases of ME.    It will also help raise awareness of just how serious this illness can be.

2 – Donate to my fund.  If you wish to make a donation in addition to purchasing the album, please visit my Just Giving page.

3 – Spread the word about my album, on social media and in person.  (All my social media links are at the bottom of the page.) The more people we can reach, the greater the success of the project.

Album taster

 

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Severe ME resources for health and social care professionals

New WAMES website page for severe ME resources

 

A new page has been added to the professionals section of the website:

Severe ME Care Resources

The page highlights the need for a compassionate approach to care for a group of patients who are extremely hypersensitive to their environment and vulnerable to harm.

The Videos, books and information come from experienced sources such as Stonebird, Dialogues from ME, Dr Nigel Speight, Emily Collingridge etc.

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Severe ME Day – 8 August 2020

A day to remember everyone who is suffering or who has ever suffered from Severe and Very Severe Myalgic Encephalomyelitis.

 


Severe ME Understanding & Remembrance Day :

This day aims to bring public attention to the illness for the sake of all those presently suffering from Severe Myalgic Encephalomyelitis and to remember all those who have died from ME.

A day to honour the strength of spirit of all those who have endured and continue to endure decades of suffering and profound physical dysfunction and yet receive little, or no recognition or help, but rather continue to experience gross misrepresentation and misinterpretation of their illness and profound disability.

 

What’s the significance of 8th August?

This is the birth date of Sophia Mirza.  Sophia was bed-bound with severe Myalgic Encephalomyelitis and was a victim of medical abuse.  Her doctors did not believe that Myalgic Encephalomyelitis was a physical disease and so she was forcibly taken from her bed/home by social workers, police officers and doctors, and kept in a psychiatric facility where she received inappropriate treatment and care.  Sophia subsequently died of ME at the age of 32.  Her post-mortem revealed widespread inflammation in the spinal cord.  This same inexcusable abuse still goes on.

 

We remember all those died of ME/CFS in Wales, and those who gave up the fight:

  • Annabel Senior , 2003 – first known person in the UK to have CFS on the death certificate
  • Sarah Ann Tyler, 2017
  • Dr Martin Rhisiart, 2017

Please let us know if you’d like someone’s name to be added to the list.

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Autonomic phenotypes in CFS are associated with illness severity: a cluster analysis

Autonomic phenotypes in Chronic Fatigue Syndrome (CFS) are associated with illness severity: a cluster analysis, by Joanna Słomko, Fernando Estevez-Lopez, Sławomir Kujawski, Monika Zawadka-Kunikowska, Małgorzata Tafil-Klawa, Modra Murovska, Julia L Newton, Paweł Zalewski on behalf of the European Network on ME/CFS (EUROMENE) in J. Clin. Med. 2020, 9(8), 2531; [doi.org/10.3390/jcm9082531]

 

Research abstract:

In this study we set out to define the characteristics of autonomic subgroups of patients with Chronic Fatigue Syndrome (CFS). The study included 131 patients with CFS (Fukuda criteria).

Participants completed the following screening symptom assessment tools: Chalder Fatigue Scale, Fatigue Impact Scale, Fatigue Severity Scale, Epworth Sleepiness Scales,
the self-reported Composite Autonomic Symptom Scale.

Autonomic parameters were measured at rest with a Task Force Monitor (CNS Systems) and arterial stiffness using an Arteriograph (TensioMed Kft.).

Principal axis factor analysis yielded four factors: fatigue, subjective and objective autonomic dysfunction and arterial stiffness. Using cluster analyses, these factors were grouped in four autonomic profiles: 34% of patients had sympathetic symptoms with dysautonomia, 5% sympathetic alone, 21% parasympathetic and 40% had issues with sympathovagal balance.

Those with a sympathetic-dysautonomia phenotype were associated with more severe disease, reported greater subjective autonomic symptoms with sympathetic over-modulation and had the lowest quality of life. The highest quality of life was observed in the balance subtype where subjects were the youngest, had lower levels of fatigue and the lowest values for arterial stiffness. Future studies will aim to design autonomic profile-specific treatment interventions to determine links between autonomic phenotypes CFS and a specific treatment.

 

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Autoantibodies to Beta-Adrenergic & muscarinic cholinergic receptors in ME patients – a validation study in plasma & cerebrospinal fluid from two Swedish cohorts

Autoantibodies to Beta-Adrenergic and Muscarinic cholinergic receptors in Myalgic Encephalomyelitis (ME) patients – a validation study in plasma and cerebrospinal fluid from two Swedish cohorts, by Annie Bynke, Per Julin, Carl-Gerhard Gottfries, Harald Heidecke, Carmen Scheibenbogen, Jonas Bergquist in Brain, Behavior, & Immunity – Health Vol 7, August 2020 [doi.org/10.1016/j.bbih.2020.100107]

 

HIGHLIGHTS

  • Myalgic Encephalomyelitis (ME) is a devastating disorder (with millions of patients worldwide) with unclear etiology and no clear diagnostic biomarker available.
  • This study support previous findings that there exists a general pattern of increased antibody levels to adrenergic and muscarinic receptors within the ME patient group.
  • No evidence for intrathecal antibody production was found in cerebrospinal fluid. The role of increased autoantibodies in the pathogenesis of ME is still uncertain and further research is needed to evaluate the clinical significance of these findings.

Research abstract:

Myalgic encephalomyelitis (ME) also known as ME/CFS (Chronic Fatigue Syndrome) or ME/SEID (Systemic Exertion Intolerance Disorder), is a disabling and often long-lasting disease that can drastically impair quality of life and physical/social functioning of the patients.

Muscarinic acetylcholine receptor

Underlying pathological mechanisms are to a large extent unknown, but the presence of autoantibodies, cytokine pattern deviations and the presentation of cognitive and autonomic nervous system related symptoms provide evidence for ME being an immunological disorder with elements of autoimmunity. Increased levels of autoantibodies binding to adrenergic and muscarinic receptors in ME-patients have been reported. It is hypothesized that these autoantibodies have pathological significance and contribute to the ME-specific symptoms, however, these observations need to be validated.

This study was designed to investigate potential differences in adrenergic and muscarinic receptor autoantibody levels in plasma and cerebrospinal fluid (CSF) samples between ME patients and gender and age-matched healthy controls, and to correlate the autoantibody levels to disease severity.

We collected body fluids and health-related questionnaires from two Swedish ME cohorts, plasma and CSF from one of the cohorts (n=24), only plasma from the second cohort (n=24) together with plasma samples (n=24) and CSF (n=6) from healthy controls.

All samples were analyzed for IgG autoantibodies directed against Alpha- (α1, α2) and Beta- (β1-3) adrenergic receptors and Muscarinic (M) 1-5 acetylcholine receptors using an ELISA technique. The questionnaires were used as measures of disease severity.

Significant increases in autoantibody levels in ME patients compared to controls were found for M3 and M4 -receptors in both cohorts and β1, β2, M3 and M4- receptors in one cohort. No significant correlations were found between autoantibody levels and disease severity. No significant levels of autoantibodies were detected in the CSF samples. These findings support previous findings that there exists a general pattern of increased antibody levels to adrenergic and muscarinic receptors within the ME patient group. However, the role of increased adrenergic and muscarinic receptor autoantibodies in the pathogenesis of ME is still uncertain and further research is needed to evaluate the clinical significance of these findings.

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