In silico analysis in ME/CFS: exercise worsens the situation considerably

@ pubmed:

Biophys Chem. 2015 Jul;202:21-31. doi: 10.1016/j.bpc.2015.03.009. Epub 2015 Apr 4.

In silico analysis of exercise intolerance in myalgic encephalomyelitis/chronic fatigue syndrome.

Lengert N1, Drossel B2.

Author information

Abstract

Post-exertional malaise is commonly observed in patients with myalgic encephalomyelitis/chronic fatigue syndrome, but its mechanism is not yet well understood. A reduced capacity for mitochondrial ATP synthesis is associated with the pathogenesis of CFS and is suspected to be a major contribution to exercise intolerance in CFS patients. To demonstrate the connection between a reduced mitochondrial capacity and exercise intolerance, we present a model which simulates metabolite dynamics in skeletal muscles during exercise and recovery. CFS simulations exhibit critically low levels of ATP, where an increased rate of cell death would be expected. To stabilize the energy supply at low ATP concentrations the total adenine nucleotide pool is reduced substantially causing a prolonged recovery time even without consideration of other factors, such as immunological dysregulations and oxidative stress. Repeated exercises worsen this situation considerably. Furthermore, CFS simulations exhibited an increased acidosis and lactate accumulation consistent with experimental observations.

Copyright © 2015 Elsevier B.V. All rights reserved.

KEYWORDS:

ATP synthesis; Chronic fatigue syndrome; Exercise intolerance; Exercise recovery; Myalgic encephalomyelitis; Post-exertional malaise

PMID:

 

25899994

 

[PubMed - in process]

The new diagnostic criteria for SEID are based upon important methodological shortcomings

@ informahealthcare.com, April 27, 2015:

A critical analysis of the proposal of the Institute of Medicine to replace Myalgic Encephalomyelitis and Chronic Fatigue Syndrome by a new diagnostic entity called Systemic Exertion Intolerance Disease Posted online on April 27, 2015. (doi:10.1185/03007995.2015.1045472) Frank NM Twisk ME-de-patiënten Foundation, The Netherlands Address for correspondence: Frank NM Twisk MBA BEd BEc, Zonnedauw 15, 1905 HB Limmen, The Netherlands. Tel. +31-72-505 4775; frank.twisk@hetnet.nl Abstract

 The Institute of Medicine (IOM) recently published their report in response to an assignment ‘to define diagnostic criteria for Myalgic Encephalomyelitis (ME)/chronic fatigue syndrome (CFS), to propose a process for reevaluation of these criteria in the future, and to consider whether a new name for this disease is warranted’. The basic preassumption of the IOM committee for the development of evidence-based diagnostic criteria for ME/CFS was that ME and CFS denote conditions with similar symptoms, hence ME/CFS.

The IOM committee recommends
1) that ME/CFS will be renamed “systemic exertion intolerance disease” (SEID); and that a new code should be assigned to SEID in the International Classification of Diseases (ICD), replacing the existing codes for ME (a neurological disease: G93.3) and CFS (“signs, symptoms, and abnormal clinical and laboratory findings, not elsewhere classified”: R53.82).

2) that a diagnosis SEID should be made if the new diagnostic criteria are met;

3) that the Department of Health and Human Services develops a toolkit appropriate for screening and diagnosing patients; and

4) that a multidisciplinary group re-examines the new diagnostic criteria when necessary.

This editorial reviews the working procedure of the IOM and two of the outcomes: the recommendation to introduce a new clinical entity (SEID) and new diagnostic criteria.

Based upon the contents of the report, and the arguments of the IOM, a search of PubMed and the archive of the Journal of Chronic Fatigue using the search terms ME (and old synonyms) and CFS, and a search of PubMed related to the five core symptoms of SEID was conducted.

Reviewing the working method and the recommendations, it is concluded that the new diagnostic criteria for SEID are based upon important methodological shortcomings and that the introduction of SEID to replace both ME and CFS has several profound negative consequences outweighing the advantages.

Keywords Myalgic Encephalomyelitis, chronic fatigue syndrome, systemic exertion intolerance disease, diagnosis, assessment, methodology

Four metabolic changes associated with exercise in cultured skeletal muscle cells in CFS compared to healthy controls

@plosone, April 2, 2015:


RESEARCH ARTICLE

Abnormalities of AMPK Activation and Glucose Uptake in Cultured Skeletal Muscle Cells from Individuals with Chronic Fatigue Syndrome

Audrey E. Brown,David E. Jones,Mark Walker,Julia L. Newton
PLOS
Published: April 2, 2015DOI: 10.1371/journal.pone.0122982
Abstract

Background

Post exertional muscle fatigue is a key feature in Chronic Fatigue Syndrome (CFS). Abnormalities of skeletal muscle function have been identified in some but not all patients with CFS. To try to limit potential confounders that might contribute to this clinical heterogeneity, we developed a novel in vitro system that allows comparison of AMP kinase (AMPK) activation and metabolic responses to exercise in cultured skeletal muscle cells from CFS patients and control subjects.
Methods

Skeletal muscle cell cultures were established from 10 subjects with CFS and 7 age-matched controls, subjected to electrical pulse stimulation (EPS) for up to 24h and examined for changes associated with exercise.
Results

In the basal state, CFS cultures showed increased myogenin expression but decreased IL6 secretion during differentiation compared with control cultures. Control cultures subjected to 16h EPS showed a significant increase in both AMPK phosphorylation and glucose uptake compared with unstimulated cells. In contrast, CFS cultures showed no increase in AMPK phosphorylation or glucose uptake after 16h EPS. However, glucose uptake remained responsive to insulin in the CFS cells pointing to an exercise-related defect. IL6 secretion in response to EPS was significantly reduced in CFS compared with control cultures at all time points measured.
Conclusion

EPS is an effective model for eliciting muscle contraction and the metabolic changes associated with exercise in cultured skeletal muscle cells. We found four main differences in cultured skeletal muscle cells from subjects with CFS; increased myogenin expression in the basal state, impaired activation of AMPK, impaired stimulation of glucose uptake and diminished release of IL6. The retention of these differences in cultured muscle cells from CFS subjects points to a genetic/epigenetic mechanism, and provides a system to identify novel therapeutic targets.

Psychiatrist Dr Henderson: ME/CFS: in 85% (92% in adolescents) symptoms resolve in 3-5 months on valacyclovir

Theodore Henderson, MD, PhD, March 25, 2015:

A recent consensus review on Chronic Fatigue Syndrome (CFS) and Myalgic Encephalomyelitis (ME)1 concluded that CFS/ME is significantly underdiagnosed and that the condition is likely caused, in part, by viruses. These findings are in line with my clinical work. Together, these two sources of data point to a pathway which may help the 2.5 million sufferers of this disease in the United States.

In February, the Institute of Medicine (IOM) completed its committee review on CFS/ME. This study was sponsored by the Department of Health and Human Services, the National Institutes of Health, and the Centers for Disease Control, among others.1

A comprehensive literature review and critique was completed by the Agency for Healthcare Research and Quality in December  as part of this process.2 Many important advancements in the medical conceptualization of CFS/ME are included in this 282 page document.

Perhaps the most important evolutionary step was the clear message delivered on page 15 of the introduction: CFS/ME is underdiagnosed and misunderstood. More than 80% of patients go undiagnosed, while 65% of patients spend more than a year seeking the correct diagnosis. A lack of understanding of this disorder has contributed to many patients feeling maligned, blamed, and undertreated.

Some patients told the committee that they felt belittled, dismissed, and ignored by their health care professionals. Patients also have reported that some treatment strategies, including the oft-cited graded exercise regimen, exacerbated their symptoms.3

Equally striking in this report was the clear assertion that CFS/ME likely has an infectious etiology and that viruses, in particular Epstein-Barr virus (EBV), are high on the list of suspected agents.1

My clinical work has focused on the viral and immunological pathogenesis of CFS/ME. In my clinic, I have treated over 200 adults and over 30 adolescents with what the IOM now says should be called Systemic Exertion Intolerance Disease (SEID). While I have not published my adult cases, a case series of adolescents was published last year.4 What has emerged from my work is that over 85% of patients with SEID (diagnosed by Fukuda criteria5) respond to antiviral therapy. Among adolescents, the outcome is better with 92% responding.

A critical second conclusion of my work is that a subset of patients diagnosed with depression — particularly treatment-resistant depression — actually had SEID. The adolescents in the case series were all referred for evaluation of depression or mood disorder. They all presented with marked fatigue, exertion induced malaise, brain fog, and impaired academic performance.

In addition, most reported daily naps and unrefreshing sleep.4 They had not responded to adequate trials of antidepressants and the duration of symptoms ranged from 6-96 months. There was no history of abuse or neglect, although this has been suggested as an etiology of SEID in the past.6,7 Patients completed the Children's Depression Inventory8 and the mean score was 14 (+2.83), below the typical cut-off for depression.

Patients were treated with the antiviral, valacyclovir (Valtrex), at a dose of 1000 mg twice a day. Only one patient experienced nausea and discontinued the antiviral. Improvement occurred over the course of 3-5 months. Eighty-six percent of the patients responded by 3 months, and 92% responded by 5 months. Symptoms of fatigue, exertion induced malaise, excessive sleep, napping, unrefreshing sleep, headaches, cognitive symptoms, and emotional symptoms all resolved.

Oncologists squash Mats Reimer's Wesselyan psycho blah blah

By deleder2k, 20.3.2015:

Norwegian Daily Medicine 2015.03.20 

dr. Øystein Fluge and dr. Olav Mella comments on Reimer's concern regarding the upcoming cylophosphamide study

Can ME / CFS patients respond to immunomodulatory treatment?

We conduct our study because we believe ME / CFS is a serious illness, and because we have hypothesized that sufferers may respond to immunomodulatory treatment.


Olav Mella, Kari Sørland and Olav Dahl, all at Department of Cancer, Haukeland University Hospital
Alexander Fosså, Department of Cancer treatment, Oslo University Hospital (Norwegian Radium Hospital)

On Dagens Medisin webpage (Norwegian Daily Medicine) paediatrician Mats Reimer commented on a new, open phase II study using cyclophosphamide in ME / CFS. The study was reviewed and approved without objection in the Regional Ethical Committee, a decision Reimer discredits and characterizes as "strange."

Read Reimer's article: Experimental tests and treatments for CFS / ME

If one's starting point is that ME / CFS is a psychosomatic illness, the result of psychosocial problems, or a fashion phenomenon, any intervention with drugs that may have adverse effects would be both wrong and unethical.

Why are the Cancer Department at Haukeland University Hospital working to understand ME / CFS and tentatively develop possible treatment?

Hypothesis. We work on the basis of a hypothesis: that ME / CFS in a sub-group of patients may be a variant of an autoimmune disease. The pattern of response and relapse after rituximab intervention match the response seen in other recognized autoimmune diseases. ME / CFS is often triggered by infections, there is a clear predominance of women, and that there seems to be a genetic predisposition (1)

Older ME / CFS patients have shown increased risk of B-cell lymphoma (2), especially a type (marginal zone) associated with chronic infections or with autoimmunity. Occurrence of autoimmune disease among first-degree relatives of ME / CFS patients are in our studies (3) clearly higher than in the general population. These findings are not evidence that ME / CFS is an immunological disease, but constitutes one of the reasons for our hypothesis.

NO DEFEAT. We believe the results of the conducted clinical studies with rituximab treatment strengthen the basis for further testing. Should the ongoing Norwegian, multi-centre, randomized, double-blind phase III study with rituximab versus placebo not show a treatment effect, we can assure that the medical world will know the result.

A study with a negative result will not be a defeat for us. We want to make an adequate study to clarify knowledge about a possible effect of the drug.

UNCERTAIN FINDINGS. Many studies on ME / CFS are characterized by uncertain findings. We are still looking for clear pathogenic mechanisms. It is not easy to explain the complex clinical picture patients are presenting. The first (random) observations of clinical response for patients with ME / CFS after treatment with cytostatics or rituximab in patients who had both ME / CFS and cancer have anecdotal character. Such observations may still be legitimate and lead to a hypothesis.

It is the same with the planned phase II study with cyclophosphamide. The protocol is based on the observation of clinical meaningful responses to prolonged ME / CFS disease after adjuvant chemotherapy for breast cancer, as well as observation by cyclophosphamide treatment of three pilot patients with ME / CFS - without concurrent cancer. No one knows yet whether these observations will be representative of a larger group of ME / CFS patients.

Why? Why will we perform a study of cyclophosphamide in ME / CFS?

The rationale is an acknowledgment that ME / CFS for many patients, is a highly disabling disease with a variety of distressing symptoms that deprives patients much of their lives. Many previously healthy people have suffer from a miserable quality of life and are completely deprived of the opportunity to participate in familiar and social life, education and employment.

We conduct this study precisely because we believe ME / CFS is a serious illness, and because we have hypothesized that the disease may respond to immunomodulatory treatment.

RESPONSE. With the limitations imposed by an open design without placebo group, this study does not provide heavy support for any use of cyclophosphamide in ME / CFS. The purpose of this study is to evaluate the response pattern and response rates (or lack thereof), feasibility and side effects.

Cyclophosphamide has been used in autoimmune diseases for years. Although the cumulative doses of cyclophosphamide in this study is low, one cannot with certainty exclude rare but serious side effects. Patients are therefore well informed of the aspects of the treatment and are selected with respect to the severity and duration of illness.

THE CORRECT THING TO DO. ME / CFS affects many people, perhaps 0.1-0.2 percent of the population, equivalent to 5,000-100,00 patients in Norway. The disease has major implications for the patients themselves and their families, and there are large economic costs to society. The IOM report (5) estimates the cost of ME / CFS to be 17-24 billion dollars in the US alone.

For us working in the oncology field, the contrast in attitude, investments, research and understanding of disease mechanisms in ME / CFS are striking, and we have concluded that it is appropriate to conduct clinical trials, based on our clinical observations and consequent hypotheses. We are pleased, but not surprised, that the Regional Committees for Medical and Health Research Ethics is supporting our vision.

Conflicts of interest:
• Haukeland University Hospital have sought, and partially granted, the patent for treatment principle B-cell depletion in ME / CFS. Øystein Fluge and Olav Mella named in the application as "inventors".
• When Haukeland University has applied for a patent for the use of drugs in ME / CFS, it is it is because it is important so that as many patients as possible can benefit from treatment
• Bergen Teknologioverføring, owned by Haukeland University Hospital, University of Bergen and Marine Research, points out that the copyright for the indication is necessary to get treatment implemented if further clinical trials would show that treatment has clear benefits for patients.



References:
1. Albright F, Light K, Light A, Bateman L, Cannon-Albright LA. Evidence for a heritable predisposition to Chronic Fatigue Syndrome. BMC Neurol. 2011;11: 62.
2. Chang CM, Warren JL, Engels EA. Chronic fatigue syndrome and subsequent risk of cancer among elderly US adults. Cancer. 2012;118: 5929-5936.
3. Fluge O, Bruland O, Risa K, Storstein A, Kristoffersen EK, et al. Benefit from B-Lymphocyte Depletion Using the Anti-CD20 Antibody Rituximab in Chronic Fatigue Syndrome. A Double-Blind and Placebo-Controlled Study. PLoS One. 2011;6: e26358.
4. Fluge O, Risa K, Lunde S, Alme K, Rekeland IG, et al. B-lymphocyte depletion in Myalgic Encephalopathy/ Chronic Fatigue Syndrome. An open-label phase II study with rituximab maintenance treatment. (Under approval)
5. http://www.iom.edu/Reports/2015/ME-CFS.aspx

Original article in Norwegian: http://www.dagensmedisin.no/debatt/-kan-mecfse-respondere-pa-immunmodulerende-behandling/
Translated by Google Translate and 

deleder2k

Reduced CD2, CD4 and CD8 lymphocytes and also reduced immunoglobulin (Ig) in ME / CFS

@ PubMed:

  Med J Aust.  1989 Aug 7;151(3):122-4.Immunological abnormalities in the chronic fatigue syndrome.Lloyd AR 1, Wakefield D , Boughton CR , Dwyer JM .Author information

  Abstract The chronic fatigue syndrome is a disorder of unknown aetiology which is characterized by debilitating fatigue. Recent evidence has suggested that viruses may persist in the tissues of patients with chronic fatigue syndrome. A concurrent immunological disturbance is likely to be associated with the persistence of viral antigens. Therefore, the humoral and cellular immunity of 100 patients who were suffering from chronic fatigue syndrome and that of 100 healthy, age- and sex-matched control subjects were compared.

  This study documents the frequent occurrence of abnormalities within the cellular and humoral immune systems of patients with well-defined chronic fatigue syndrome. Disordered immunity may be central to the pathogenesis of chronic fatigue syndrome.

  In patients with chronic fatigue syndrome, a significant (P less than 0.01) reduction was found in the absolute number of peripheral blood lymphocytes in the total T-cell (CD2), the helper/inducer T-cell (CD4) and the suppressor/cytotoxic T-cell (CD8) subsets. A significant (P less than 0.001) reduction also was found in T-cell function, which was measured: in vivo by delayed-type hypersensitivity skin-testing (reduced responses were recorded in 50 [88%] of 57 patients); and in vitro by phytohaemagglutinin stimulation.

  Reduced immunoglobulin (Ig) levels were common (56% of patients), with the levels of serum IgG3- and IgG1-subclasses particularly (P less than 0.05) affected.

The NewYorker: People with ME/CFS are more “functionally impaired” than those with MS and congestive heart failure

BY MEGHAN O’ROURKE, FEBRUARY 27, 2015:

  "People with ME/CFS, the report noted, are more “functionally impaired” than those with Type 2 diabetes, multiple sclerosis, and congestive heart failure—diseases that we know to be very grave indeed."

  more @ newyorker.com

IOM: ME/CFS "is a medical—not a psychiatric or psychological—illness"

@ PubMed:

 

Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an Illness.

Editors

Committee on the Diagnostic Criteria for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome; Board on the Health of Select Populations; Institute of Medicine.

Source

Washington (DC): National Academies Press (US); 2015.
The National Academies Collection: Reports funded by National Institutes of Health.

Excerpt

Myalgic encephalomyelitis (ME) and chronic fatigue syndrome (CFS) are serious, debilitating conditions that affect millions of people in the United States and around the world. ME/CFS can cause significant impairment and disability. Despite substantial efforts by researchers to better understand ME/CFS, there is no known cause or effective treatment. Diagnosing the disease remains a challenge, and patients often struggle with their illness for years before an identification is made. Some health care providers have been skeptical about the serious physiological—rather than psychological—nature of the illness. Once diagnosed, patients often complain of receiving hostility from their health care provider as well as being subjected to treatment strategies that exacerbate their symptoms. 

Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome proposes new diagnostic clinical criteria for ME/CFS and a new term for the illness - systemic exertion intolerance disease(SEID). According to this report, the term myalgic encephalomyelitis does not accurately describe this illness, and the term chronic fatigue syndrome can result in trivialization and stigmatization for patients afflicted with this illness. Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome stresses that SEID is a medical—not a psychiatric or psychological—illness. This report lists the major symptoms of SEID and recommends a diagnostic process. One of the report's most important conclusions is that a thorough history, physical examination, and targeted work-up are necessary and often sufficient for diagnosis. 

The new criteria will allow a large percentage of undiagnosed patients to receive an accurate diagnosis and appropriate care. Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome will be a valuable resource to promote the prompt diagnosis of patients with this complex, multisystem, and often devastating disorder; enhance public understanding; and provide a firm foundation for future improvements in diagnosis and treatment.

Copyright © 2015, National Academy of Sciences.

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PMID:

 

25695122

 

[PubMed] 

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