ME/CFS diagnosis & management in young people: a primer

Posted on 06/21/2017 by wames

Review article:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Diagnosis and Management in Young People: a Primer, by Peter C. Rowe,  Rosemary A. Underhill,  Kenneth J. Friedman,  Alan Gurwitt,  Marvin S. Medow,  Malcolm S. Schwartz,  Nigel Speight,  Julian M. Stewart,  Rosamund Vallings and  Katherine S. Rowe in Front. Pediatr., 19 June 2017

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex disease that affects children and adolescents as well as adults. The etiology has not been established.

While many pediatricians and other health-care providers are aware of ME/CFS, they often lack essential knowledge that is necessary for diagnosis and treatment. Many young patients experience symptoms for years before receiving a diagnosis.

This primer, written by the International Writing Group for Pediatric ME/CFS, provides information necessary to understand, diagnose, and manage the symptoms of ME/CFS in children and adolescents.

ME/CFS is characterized by overwhelming fatigue with a substantial loss of physical and mental stamina. Cardinal features are malaise and a worsening of symptoms following minimal physical or mental exertion. These post-exertional symptoms can persist for hours, days, or weeks and are not relieved by rest or sleep. Other symptoms include cognitive problems, unrefreshing or disturbed sleep, generalized or localized pain, lightheadedness, and additional symptoms in multiple organ systems.

While some young patients can attend school, on a full or part-time basis, many others are wheelchair dependent, housebound, or bedbound. Prevalence estimates for pediatric ME/CFS vary from 0.1 to 0.5%. Because there is no diagnostic test for ME/CFS, diagnosis is purely clinical, based on the history and the exclusion of other fatiguing illnesses by physical examination and medical testing. Co-existing medical conditions including orthostatic intolerance (OI) are common.

Successful management is based on determining the optimum balance of rest and activity to help prevent post-exertional symptom worsening. Medications are helpful to treat pain, insomnia, OI and other symptoms.

The published literature on ME/CFS and specifically that describing the diagnosis and management of pediatric ME/CFS is very limited. Where published studies are lacking, recommendations are based on the clinical observations and practices of the authors.

Read more

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Could we finally have a definitive biomarker for ME/CFS?

Posted on 06/20/2017 by wames

ME Research UK blog post, 9 June 2017: Could we finally have a definitive biomarker for ME/CFS?

It’s a recurring theme, but the diagnosis of ME/CFS is severely hampered by the lack of a test that can distinguish people with the illness from those without. This is a challenge in many diseases, but particularly in ME/CFS which affects so many different systems of the body.

ME/CFS is currently identified by the presence of specific signs and symptoms, but there are several different criteria in use, and much debate over which are the most precise or appropriate. The quest for a biomarker is therefore a top priority since an accurate diagnosis is essential for patients to receive the medical care they need.

Generally speaking, biomarkers are measurable substances or processes in the body that can indicate the risk, presence or severity of a disease, or how well it will respond to a specific treatment.

For example, a high white blood cell count may indicate the presence of an infection, while raised levels of prostate-specific antigen in the blood are associated with an increased risk of prostate cancer.

Researchers have looked at a number of different measures as potential biomarkers for ME/CFS, including brain imaging findings, ECG abnormalities, and immunosignatures based on antibodies in the blood.

In fact, ME Research UK has recently funded work to look for an immunosignature that can predict patients’ responses to rituximab therapy.

New research from a team in Australia, led by Prof. Brett Lidbury at the Australian National University in Canberra, has added another potential biomarker to this list.

Prof. Lidbury has a longstanding interest in the search for biomarkers for ME/CFS, and ME Research UK recently awarded his group funding to analyse genetic data which might provide clues about the mechanisms of the disease.

But in this recent study, published in the Journal of Translational Medicine, the team focused on a different potential biomarker: activin.

The two types of activin (A and B) are produced in several organs in the body, and have a number of different roles, including regulation of the menstrual cycle, and involvement in metabolism and wound repair.

Prof. Lidbury is interested in two of its functions which have particular relevance to ME/CFS, namely the control of inflammation and muscle mass. Inflammation is important because the immune system is thought to be involved in the illness, while muscle mass will have an obvious influence on muscle weakness and pain.

The researchers took blood samples from 45 patients with ME/CFS (as defined by the Canadian Diagnostic Criteria) and from 17 healthy controls. Concentrations of both activin A and activin B were measured (as they have some different functions), as well as follistatin (a binding protein that regulates levels of activin).

Levels of activin B in the blood were markedly higher in the ME/CFS patients than in the healthy individuals (and also higher than in a previously studied normal group), whereas activin A and follistatin levels were no different.

This exciting finding suggests that the combination of elevated activin B and normal activin A may represent a useful biomarker for the presence of ME/CFS, although this would need to be validated in larger groups of patients.

Another intriguing prospect is whether follistatin might have some value as a treatment for ME/CFS since it can inhibit the actions of activin B. In fact, follistatin could have a two-pronged attack because it also blocks myostatin, a protein that inhibits muscle cell growth.

Prof. Lidbury’s study has certainly borne fruit, giving us a potential diagnostic biomarker for ME/CFS, as well as some hope for a new treatment. It’s early days on both fronts, however, so we will be keeping a close eye on further developments from this group.

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Dysregulation of cytokine pathways in CFS & MS

Posted on 06/15/2017 by wames

Research abstract:

Dysregulation of cytokine pathways in chronic fatigue syndrome and multiple sclerosis by Matthew Sorenson, Jacob Furst, Herbert Mathews & Leonard A. Jason in Fatigue: Biomedicine Heath & Behavior pp1-14 [Published online 7 Jun 2017]

Background:

Cytokine studies in chronic fatigue syndrome (CFS) have yielded mixed findings.

Purpose:

This investigation evaluated whether network analysis of cytokine production differs between patients with CFS and multiple sclerosis (MS) as compared to a reference group of healthy controls.

Methods:

Three subgroups (N = 109) were included: 15 participants who met diagnostic criteria for CFS, 57 participants meeting criteria for MS, and 37 controls. Peripheral blood was obtained and production of a select cytokine profile was determined from stimulated and unstimulated mononuclear cells. Data were generated through the use of a multi-analyte bead suspension array. Pairwise associations were determined for each group, and these associations were used to create a graphical representation of the data. The graph was clustered using an eigenvector community algorithm and results visualized using edges to model the correlations by color and thickness to show direction and strength.

Results:

The control and MS groups produced a three-neighborhood relationship regardless of cell condition. While producing a three-neighborhood relationship, the MS group differed significantly from the control group as it displayed stronger relationships among pro-inflammatory cytokines. In contrast, the CFS group displayed a three-neighborhood solution when unstimulated. However, when cells from the CFS group were stimulated, a two-neighborhood model was found that exhibited stronger inter-cytokine correlations. The model found in CFS was significantly different from that found in the control and MS groups.

Conclusion:

CFS was characterized by a pattern of global immunologic activation using network analysis, fundamentally different from those found for either MS or control groups.

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Clinical similarities between ME/CFS & d-lactic acidosis: a systematic review

Posted on 06/14/2017 by wames

Review abstract:

Examining clinical similarities between myalgic encephalomyelitis/chronic fatigue syndrome and d-lactic acidosis: a systematic review, by Amy Wallis, Michelle Ball,
Sandra McKechnie, Henry Butt, Donald P. Lewis and Dorothy Bruck in Journal of Translational Medicine 2017 15:129 [Published: 7 June 2017]

Background:
The pursuit for clarity in diagnostic and treatment pathways for the complex, chronic condition of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) continues. This systematic review raises a novel question to explore possible overlapping aetiology in two distinct conditions. Similar neurocognitive symptoms and evidence of d-lactate producing bacteria in ME/CFS raise questions about shared mechanisms with the acute condition of d-lactic acidosis (d-la).

Methods:
d-la case reports published between 1965 and March 2016 were reviewed for episodes describing both neurological symptoms and high d-lactate levels. Fifty-nine d-la episodes were included in the qualitative synthesis comparing d-la symptoms with ME/CFS diagnostic criteria. A narrative review of d-la mechanisms and relevance for ME/CFS was provided.

Results:
The majority of neurological disturbances reported in d-la episodes overlapped with ME/CFS symptoms. Of these, the most frequently reported d-la symptoms were motor disturbances that appear more prominent during severe presentations of ME/CFS. Both patient groups shared a history of gastrointestinal abnormalities and evidence of bacterial dysbiosis, although only preliminary evidence supported the role of lactate-producing bacteria in ME/CFS.

Limitations:
Interpretation of results are constrained by both the breadth of symptoms included in ME/CFS diagnostic criteria and the conservative methodology used for d-la symptom classification. Several pathophysiological mechanisms in ME/CFS were not examined.

Conclusions:
Shared symptomatology and underlying microbiota–gut–brain interactions raise the possibility of a continuum of acute (d-la) versus chronic (ME/CFS) presentations related to d-lactate absorption. Measurement of d-lactate in ME/CFS is needed to effectively evaluate whether subclinical d-lactate levels affect neurological symptoms in this clinical population.

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Is “bad energy” core problem in FM & ME/CFS?

Posted on 06/08/2017 by wames

Health rising blogpost, by Cort Johnson, 31 May 2017: Study Suggests “Bad Energy” is Core Problem in Fibromyalgia and Chronic Fatigue Syndrome (ME/CFS)

Lactate has become a big deal in both chronic fatigue syndrome (ME/CFS) and fibromyalgia (FM).  A by-product of anaerobic energy metabolism, lactate ordinarily gets pumped out of our cells in large amounts during exertion. The lactate findings suggest that the energy needs of ME/CFS/FM patients are largely being addressed by glycolysis or anaerobic energy production. Anaerobic energy production plays an important role in energy production, but when aerobic energy production is not available and it becomes the major source of energy it produces metabolites that produce the burning muscles, fatigue and other symptoms we associate with over-exercise.

That makes it all the more shocking and puzzling to find high lactate levels in two diseases in which exercise is often hardly tolerated. That suggests that something is profoundly off with ME/CFS and possibly FM patients’ energy productions systems. The fact that increased lactate levels have been found in several different compartments of the body in these diseases only sharpens the interest.

We mostly focus on lactate in the muscles and blood, but high lactate levels have also been found in the brains of people with chronic fatigue syndrome (ME/CFS). Over the past ten years Dr. Shungu and Dr. Natelson have documented large lactate increases in the ventricles in the brains of ME/CFS patients. They’ve also found large decreases in brain glutathione levels as well.  In their latest study, they went a step further and examined lactate levels in the brains of FM patients as well.

Ventricular Lactate and the Cerebrospinal Fluid
The ventricles, which sit at the bottom of the brain, are filled with cerebral spinal fluid
When Shungu and Dr. Natelson refer to ventricular lactate, they’re also referring to the cerebral spinal fluid – a “tissue” that is becoming increasing important in ME/CFS and FM. The ventricles are four cavities sitting at the bottom of the brain where the cerebral spinal fluid (CSF) is produced. The CSF functions as a kind of cushion, a blood flow and neuro-endocrine-immune regulator and as an important waste removal outlet.

Analyzing the cerebral spinal fluid is the closest we can get to the brain short of a biopsy. CSF studies are able to uncover several different kinds of pathologies associated with the brain including bleeding, infection, inflammation and autoimmunity. Protein analyses of CSF have identified unique protein signatures for multiple sclerosis, lupus and other diseases.

CSF studies from the Simmaron Research Foundation and the Center for Infection and Immunity uncovered a pattern of immune upregulation / exhaustion and identified an atypical ME/CFS subset.  Other CSF studies found a different protein signature in ME/CFS vs. Lyme disease and evidence of increased intracranial pressure in ME/CFS. Low levels of glutathione suggest the brain’s antioxidant defenses are down.

This study examined the makeup of CSF – aka the brain ventricles – in ME/CFS, FM, and healthy controls

Read more about the study

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Controversy over exercise therapy for chronic fatigue syndrome: key lessons for clinicians and academics

Posted on 06/07/2017 by wames

Article summary:

Controversy over exercise therapy for chronic fatigue syndrome: key lessons for clinicians and academics, by Alex J. Mitchell in BJPsych Advances May 2017, 23 (3) 145-148

Chronic fatigue syndrome (CFS) is syndrome of unremitting fatigue of at least 6 months’ duration that causes significant disability. Exercise therapy has a proven track record in medicine and could be effective for some patients with CFS.

An updated Cochrane review of eight studies appeared to suggest that exercise helps fatigue symptoms, but with only a small probability of recovery and/or improvement in daily function. Provisional data on acceptability suggest that most patients are willing to participate.

However, one key study (PACE), which was well powered and influential in the Cochrane review, has been met with considerable controversy owing to lack of clarity on outcomes. Following release of the PACE study primary data, re-analysis suggested smaller effect sizes than initially reported.

Pheonix rising comment

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Bias, misleading information & lack of respect for alternative views have distorted perceptions of ME/CFS & its treatment

Posted on 06/05/2017 by wames

Article abstract:

Bias, misleading information and lack of respect for alternative views have distorted perceptions of myalgic encephalomyelitis/chronic fatigue syndrome and its treatment, by Ellen Goudsmit, Sandra Howes in Journal of Health Psychology [First Published May 29, 2017]

The PACE trial is one of the most recent studies evaluating cognitive behavioural therapy and graded exercise therapy for myalgic encephalomyelitis/chronic fatigue syndrome. These interventions are based on a model which assumes that symptoms are perpetuated by factors such as misguided beliefs and a lack of activity. Our analysis indicates that the researchers have shown significant bias in their accounts of the literature and may also have overstated the effectiveness of the above treatments. We submit that their approach to criticisms undermines the scientific process and is inconsistent with best practice.

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Endogenous pain facilitation rather than inhibition differs between people with CFS, MS, and controls

Posted on 06/01/2017 by wames

Research abstract:

Endogenous pain facilitation rather than inhibition differs between people with Chronic Fatigue Syndrome, Multiple Sclerosis, and controls: An observational study, by Simon M. Collin, Jo Nijs, Mira Meeus, Andrea Polli, Barbara Willekens, Kelly Ickmans in Pain Physician, May 2017, Volume 20, Issue 4 ppE489-E497 [Published 20 May 2017]

Background:
Commonalities in the core symptoms of fatigue and cognitive dysfunction experienced by chronic fatigue syndrome (CFS, also known as ME) and multiple sclerosis (MS) patients have been described. Many CFS and MS patients also experience chronic pain, which has been attributed to central sensitization in both groups of patients. However, the  characteristics of pain in CFS and MS patients have not been compared.

Objectives:
To compare experimental pain measurements in patients with CFS or MS and healthy controls.

Study design:
Observational study.

Setting:
This study took place in Belgium at Vrije Universiteit Brussel and the University of Antwerp.

Methods
Pressure pain thresholds, temporal summation, conditioned pain modulation, and occlusion cuff pressure thresholds rated as painful (1st cuff pressure threshold) and as 3/10 on a verbal numerical scale (2nd cuff pressure threshold) were measured in patients with CFS (n=48), MS (n=19) and healthy pain-free controls (n=30). Adjusted between-group differences were estimated using linear regression models.

Results
Finger pain pressure thresholds of patients with CFS, compared with patients with MS, were 25% lower (difference ratio 0.75 [95% CI 0.59, 0.95], P=0.02) and shoulder pain pressure thresholds were 26% lower (difference ratio 0.74 [0.52, 1.04], P=0.08).

Compared with patients with MS, patients with CFS had 29% lower first cuff pressure threshold (difference ratio 0.71 [0.53, 0.94], P=0.02) and 41% lower 2nd cuff pressure threshold (0.59 [0.41, 0.86], P=0.006). Finger temporal summation was higher in patients with CFS than in patients with MS (mean difference 1.15 [0.33, 1.97], P=0.006), but there were no differences in shoulder temporal summation or conditioned pain modulation at either site.

Differences between patients with CFS and MS tended to be greater than between either patient group and healthy controls. Pain pressure thresholds and cuff pressure thresholds tended to be positively correlated, and temporal summation negatively correlated, with higher physical function and lower fatigue in both groups of patients.

Subjective pain in patients with CFS but not in patients with MS was strongly negatively correlated with pain pressure thresholds and cuff pressure thresholds, and positively correlated with temporal summation.

Limitations:
The main limitations of our study are the relatively small sample sizes, its cross-sectional design, and its exploratory nature.

Conclusions:
We found differences in the characteristics of pain symptoms reported by patients with CFS and patients with MS, which suggest different underlying mechanisms. Specifically, overactive endogenous pain facilitation was characteristic of pain in patients with CFS but not in patients with MS, suggesting a greater role for central sensitization in CFS

Comment: Phoenix Rising Forum

 

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Dr Byron Hyde and ‘the terrible tale of Amy Brown’

Posted on 05/26/2017 by wames

Amy Brown is the pseudonym of an English child whose story is recounted by Dr Byron Hyde, a Canadian doctor who has been actively researching and treating people with ME for decades.

Dr Hyde describes the years 9 year old ‘Amy’ spent visiting many doctors without obtaining an accurate diagnosis, and the diagnosis he reached after her parents requested his help. He believes the story demonstrates:

‘convincing evidence that M.E. , distinct from CFS, is an enteroviral illness. This paper also demonstrates the stages of M.E.  illness… Amy’s story also points out what is generally not discussed, the severe and alarming explosive headaches which can occur at the M.E. disease onset, heralding an acute M.E. encephalopathy.’

Dr Hyde believes in the importance of adequate testing to make an accurate diagnosis. He uses the SEGAMI brain software (a uniform reading and processing environment for all SPECT and PET cameras) to demonstrate the significant hypo-perfusion brain injury of the left temporal region and the cingulate gyrus of the limbic system seen in all his ME patients.

An introduction to the work of Dr Hyde, followed by Amy’s tale can be read on the Health Rising website: The Doctors and Mr. Hyde: Amy Brown’s M.E Enterovirus Story

Dr Hyde founded the The Nightingale Research Foundation,  a Canadian registered charitable organization dedicated to the study and treatment of Myalgic Encephalomyelitis (M.E.) and Chronic Fatigue Syndrome (CFS) and related illnesses.

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A comparison of neuroimaging abnormalities in MS, Depression & CFS (ME)

Posted on 05/25/2017 by wames

Article abstract:

A Comparison of Neuroimaging Abnormalities in Multiple Sclerosis, Major Depression and Chronic Fatigue Syndrome (Myalgic Encephalomyelitis): is There a Common Cause?, by Gerwyn Morris, Michael Berk, Basant K Puri in Mol Neurobiol. pp 1-18 [Published online 17 May 2017]

There is copious evidence of abnormalities in resting-state functional network connectivity states, grey and white matter pathology and impaired cerebral perfusion in patients afforded a diagnosis of multiple sclerosis, major depression or chronic fatigue syndrome (CFS) (myalgic encephalomyelitis).

Systemic inflammation may well be a major element explaining such findings. Inter-patient and inter-illness variations in neuroimaging findings may arise at least in part from regional genetic, epigenetic and environmental variations in the functions of microglia and astrocytes.

Regional differences in neuronal resistance to oxidative and inflammatory insults and in the performance of antioxidant defences in the central nervous system may also play a role.

Importantly, replicated experimental findings suggest that the use of high-resolution SPECT imaging may have the capacity to differentiate patients afforded a diagnosis of CFS from those with a diagnosis of depression. Further research involving this form of neuroimaging appears warranted in an attempt to overcome the problem of aetiologically heterogeneous cohorts which probably explain conflicting findings produced by investigative teams active in this field. However, the ionising radiation and relative lack of sensitivity involved probably preclude its use as a routine diagnostic tool.

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