Elevations of ventricular lactate levels occur in both chronic fatigue syndrome and fibromyalgia
January 23, 2018
New research published in Fatigue: Biomedicine, Health & Behavior found ventricular lactate (lactate present in cerebrospinal fluid) might serve as a biological marker of underlying brain dysfunction for patients with chronic fatigue syndrome (CFS), fibromyalgia (FM), and those with a dual diagnosis. The study, titled “Elevations of ventricular lactate levels occur in both chronic fatigue syndrome and fibromyalgia”, also found evidence for a unitary hypothesis of the pathophysiology of CFS and FM – that is, they are different presentations of the same condition.
The study was authored by Dr. Natelson, of the Pain & Fatigue Study Center at Beth Israel Medical Center, in conjunction with pain specialists, clinicians, and quantitative experts. The team used neuroimaging to measure ventricular lactate in subjects across three diagnostic groups – FM only, CFS only, or CFS plus FM – and compared to healthy controls. A modified version of the 1994 Fukuda (CDC) criteria was used to select CFS patients.
The group found that, relative to healthy controls, ventricular lactate was higher in all illness groups included in the study. Elevations in ventricular lactate suggests a shift to anaerobic processes and a problem with brain-related mitochondrial metabolism across the CFS-FM spectrum. The authors conclude that, while there is evidence that ventricular lactate measured by neuroimaging can be used as a biomarker of syndromes characterized by medically unexplained pain or fatigue, this result does not indicate it can be used to differentiate CFS from FM.
Previous work from 2008 considering the relationship between ventricular lactate and ME/CFS also used a condition with symptomatic overlap as a study comparison group. The researchers looked at ventricular lactate levels in individuals with CFS (diagnosed with the 1994 guidelines) and Generalized Anxiety Disorder (GAD) – a condition that includes fatigue with an unknown origin as a hallmark symptom. However, this study found an abnormal increase in ventricular lactate in CFS relative to the comparison group (GAD). Unlike the connection between FM and CFS supported by Dr. Natelson’s study, this finding suggests distinct neurobiological differences between CFS and GAD.
CFS and FM were found to have statistically indistinguishable levels of lactate in the recent finding detailed in Fatigue, but we don’t have proof this reflects the same underlying cause. Nonetheless, ventricular lactate is indicated as a viable biomarker of underlying brain dysfunction for some patients with either or both diagnoses. The authors note that further research will be needed to further address if CFS and FM are different illnesses or variations of the same condition.
New Therapies in Irritable Bowel Syndrome: What Works and WhenOrla Craig
Curr Opin Gastroenterol. 2018;34(1):50-56.
Abstract and IntroductionPurpose of review. The purpose of this review is to examine the evidence supporting the use of recently developed pharmacological treatments for IBS together with new evidence supporting more traditional therapies in order to understand where the new agents are best used in the treatment pathway.
Recent findings. There is evidence to support the use of traditional treatments such as antispasmodics, antidepressants and dietary alteration in IBS. New therapeutic agents such as Linaclotide, Lubiprostone, Plecanatide, Rifaxamin and Eluxadoline are all more effective than placebo in treating symptoms of IBS with Tenapanor being a promising new agent. The majority of patients, however, treated with these medications remain symptomatic and they are not suitable for use in all patients.
Summary. Traditional treatments such as antispasmodics, antidepressants, dietary and lifestyle modifications retain their importance in the treatment of IBS with the newer agents to be considered wherever these treatments are ineffective or poorly tolerated.
Stigma in Myalgic Encephalomyelitis and its association with functioning
Don M. Baken, Shane T. Harvey, David L. Bimler & Kirsty J. Ross
Pages 30-40 | Received 20 Oct 2016, Accepted 17 Dec 2017, Published online: 04 Jan 2018
https://doi.org/10.1080/21641846.2018.1419553
ABSTRACT
Background: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is categorised by the World Health Organisation as a neurological condition. It is poorly understood and people with ME/CFS report experiencing stigma. Research suggests that stigma might be linked to functional ability.
Purpose: This study investigated the relationship of stigma to factors associated with functional ability. Additionally, the use of standardised measures allowed for comparison of stigma severity in ME/CFS to other neurological conditions.
Method: A convenience sample of 206 people diagnosed with ME/CFS completed mailed or online self-report standardised measures of stigma, health, ability to participate in social roles and activities, and their satisfaction with this ability. Findings were compared to published data for three neurological conditions.
Results: Stigma scores were significantly correlated (p < .0001) with all self-report health and functional measures (range: −.30 to −.42). The ME/CFS sample reported higher levels of stigma (d = 1.30) and lower levels of health (d = 1.86–2.16) and functioning (d = 1.63) than the comparison conditions.
Conclusions: Consistent with studies over the last two decades, people with ME/CFS report higher levels of stigma when compared to the other conditions. The stigma is not just associated with health but also with specific measures of functional ability.
Gen Med Open, 2017 doi: 10.15761/GMO.1000117 Volume 1(3): 1-13
ISSN: 2515-4737
An analysis of Dutch hallmark studies confirms the outcome of the PACE trial: cognitive behaviour therapy with a graded activity protocol is not effective for chronic fatigue syndrome and Myalgic Encephalomyelitis
FNM Twisk1* and LAMM Corsius2 1ME-de-patiënten Foundation, Limmen, the Netherlands 2 Independent researchers, Etten-Leur, The Netherlands
Abstract Myalgic Encephalomyelitis (ME) and Chronic Fatigue Syndrome (CFS) are considered to be enigmatic diseases. Several studies propose that the combination of cognitive behaviour therapy with a graded activity protocol (CBT+), justified by a so-called (bio)psychosocial (explanatory) model, is an effective treatment option for CFS (ME).
Objective A critical review of five Dutch hallmark studies that allegedly support this claim.
Methods An analysis of the five CBT+ studies with special attention to the patients studied, the criteria (subjective and objective measures and cut-off scores) used to select participants and to define improvement and recovery, the consistency of the definitions of caseness (being diagnosed as a CFS patient at entry) versus the definitions of improvement and recovery after CBT+, and the objective effects.
Results The studies investigated suffer from various methodological flaws. Apart from these methodological shortcomings, the claim that CBT+ is an effective treatment option for CFS is not substantiated by the data reported. Some studies investigated CFS patients, other studies investigated CF patients, labelled as CFS patients, or combinations of CFS and CF patients. No study investigated the effect of CBT+ in a group of patients meeting the (original) diagnostic criteria for ME. The effects of CBT+ on subjective measures, for example fatigue and disability, if present, are insufficient to achieve normal values. Impressive recovery and improvement rates are based on very loose criteria for subjective measures. Cut-off scores for subjective measures used to define improvement and recovery in studies show overlap with cut-off scores for CFS caseness in one or more of the other studies. More importantly, looking at the objective measures, the proof of clinical improvement after CBT+ is lacking.
Conclusion Solid evidence of effectiveness of CBT+ for CFS, let alone ME, is lacking in the five hallmark studies. The lack of objective improvement indicates CBT+ is ineffective. This finding confirms the outcome of the large-scale PACE-trial in the UK.
Elevated brain natriuretic peptide levels in chronic fatigue syndrome associate with cardiac dysfunction: a case control studyAuthorsCara Tomas, Andreas Finkelmeyer, Tim Hodgson, Laura MacLachlan, Guy A MacGowan, Andrew M Blamire, Julia L Newton
Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK
AbstractObjectives: To explore levels of the brain natriuretic peptide (BNP) and how these associate with the cardiac abnormalities recently identified in chronic fatigue syndrome (CFS).
Methods: Cardiac magnetic resonance examinations were performed using 3T Philips Intera Achieva scanner (Best, Netherlands) in CFS (Fukuda) participants and sedentary controls matched group wise for age and sex. BNP was also measured by using an enzyme immunoassay in plasma from 42 patients with CFS and 10 controls.
Results: BNP levels were significantly higher in the CFS cohort compared with the matched controls (P=0.013). When we compared cardiac volumes (end-diastolic and end-systolic) between those with high BNP levels (BNP >400 pg/mL) and low BNP (<400 pg/mL), there were significantly lower cardiac volumes in those with the higher BNP levels in both end-systolic and end-diastolic volumes (P=0.05). There were no relationships between fatigue severity, length of disease and BNP levels (P=0.2) suggesting that our findings are unlikely to be related to deconditioning.
Conclusion: This study confirms an association between reduced cardiac volumes and BNP in CFS. Lack of relationship between length of disease suggests that findings are not secondary to deconditioning. Further studies are needed to explore the utility of BNP to act as a stratification paradigm in CFS that directs targeted treatments.
PublicationTomas et al, Open Heart, 2017 Dec 27; 4(2):e000697
Ticks transmitting Lyme disease are found in a third of Britain, mainly the south
BMJ 2018; 360 doi: https://doi.org/10.1136/bmj.k692 (Published 12 February 2018) Cite this as: BMJ 2018;360:k692
Ticks responsible for transmitting Lyme disease are distributed widely around the UK, a team from Public Health England has found.1
Data from a surveillance scheme that has been running since 2005 showed that the number of sites where ticks have been found have nearly doubled from 2010 to 2016. Dividing Britain into squares of 10 km on each side, the 2016 data show that ticks were reported in 36% of the squares, up from 20% before 2010. In Greater London 80% of the grid squares contained ticks, compared with 67% in southeast England. The Midlands, by contrast, seemed relatively free of ticks.
The increases may result from better awareness of ticks, said the study authors, led by Benjamin Cull,
Pain Physician. 2018 Jan;21(1):E13-E24Cerebral Blood Flow and Heart Rate Variability in Chronic Fatigue Syndrome: A Randomized Cross-Over Study.Malfliet A1, Pas R2, Brouns R3, De Win J4, Hatem SM5, Meeus M6, Ickmans K7, van Hooff RJ3, Nijs J8.
AbstractBACKGROUND: Pain, fatigue, and concentration difficulties are typical features of chronic fatigue syndrome (CFS). The exact underlying mechanisms of these symptoms are still unknown, but available evidence suggests an important role for impaired pain modulation. As evidence also suggests that pain modulation is related to cardiovascular mechanisms, it seems logical to investigate whether cerebral blood flow (CBF) and heart rate variability (HRV) are altered in these patients.
OBJECTIVES:
We aimed to investigate the role of the cardiovascular system in pain modulation and symptoms of CFS; the response of CBF and HRV to physical stress and their relation to the change in temporal summation (TS) of pressure pain and self-reported symptoms was evaluated.
STUDY DESIGN: A controlled, randomized cross-over trial.
SETTING: University Hospital Brussels.
METHODS:
Twenty CFS patients and 20 sedentary healthy controls were included in this study. In both of the groups, the change in TS of pressure pain, CBF (using transcranial Doppler), and HRV (using finger plethysmography) was examined during physical and emotional stress (to control for potential bias), as well as their association mutually and with self-reported symptoms of pain, fatigue, and concentrations difficulties.
RESULTS:
There was no significant interaction or group (F-values ranging from .100 to 1.862, P-values ranging from .754 to .181) effect in CBF or HRV parameters. HRV and CBF did change during physical exercise, but the changes did not differ between patients and controls. While pain scores during TS at the trapezius site reduced in the control group after the physical exercise protocol (P = .037), they did not change in the CFS group (P = .108), suggesting impaired pain modulation. There were no significant correlations between CBF, HRV, TS, and self-reported symptoms (all P-values of correlation analyses > .01).
LIMITATIONS: Although effect sizes were medium to large, the study sample was relatively low. Also, the mild nature of the exercise bout is discussable. Nonetheless, this mild exercise was able to provoke endogenous pain modulation in the control group, which endorsed a proper execution of the cycling exercise. Moreover, mild exercises are more applicable to daily physical activities in CFS patients than vigorous exercises.
CONCLUSION: These results seem to refute the previously suggested alterations of CBF/HRV in CFS patients. These cardiovascular parameters appear not to explain pain before, during, and following exercise.Brain Nerve. 2018 Jan;70(1):35-40. doi: 10.11477/mf.1416200947
[Immunopathogenesis of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)].[Article in Japanese]Yamamura T1, Ono H, Sato W.
AbstractA recent study on the pathogenesis of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) has revealed an elevation of inflammatory and anti-inflammatory cytokines in the sera and cerebrospinal fluids of the patients and presence of autoantibodies in subgroups of ME/CFS patients. Furthermore, investigator-initiated clinical trials have proved the efficacy of anti-CD20 antibody (rituximab), that eliminate B cells, in the treatment of ME/CFS. Based on these findings, we hypothesize that immune abnormalities, such as enhanced autoimmune responses, may play an essential role in the neuroinflammatory pathogenesis of ME/CFS.
PMID:29348373
DOI:10.11477/mf.1416200947
Clin Physiol Funct Imaging. 2018 Jan;38(1):128-137. doi: 10.1111/cpf.12393. Epub 2016 Sep 28
Static and dynamic functional connectivity in patients with chronic fatigue syndrome: use of arterial spin labelling fMRI.Boissoneault J1, Letzen J1, Lai S2, Robinson ME1, Staud R3.
Author informationAbstractStudies using arterial spin labelling (ASL) have shown that individuals with chronic fatigue syndrome (CFS) have decreased regional cerebral blood flow, which may be associated with changes in functional neural networks. Indeed, recent studies indicate disruptions in functional connectivity (FC) at rest in chronically fatigued patients including perturbations in static FC (sFC), that is average FC at rest between several brain regions subserving neurocognitive, motor and affect-related networks. Whereas sFC often provides information of functional network reorganization in chronic illnesses, investigations of temporal changes in functional connectivity between multiple brain areas may shed light on the dynamic characteristics of brain network activation associated with such maladies. We used ASL fMRI in 19 patients with CFS and 15 healthy controls (HC) to examine both static and dynamic changes in FC among several a priori selected brain regions during a fatiguing cognitive task. HC showed greater increases than CFS in static FC (sFC) between insula and temporo-occipital structures and between precuneus and thalamus/striatum. Furthermore, inferior frontal gyrus connectivity to cerebellum, occipital and temporal structures declined in HC but increased in CFS. Patients also showed lower dynamic FC (dFC) between hippocampus and right superior parietal lobule. Both sFC and dFC correlated with task-related fatigue increases. These data provide the first evidence that perturbations in static and dynamic FC may underlie chronically fatigued patients' report of task-induced fatigue. Further research will determine whether such changes in sFC and dFC are also characteristic for other fatigued individuals, including patients with chronic pain, cancer and multiple sclerosis.
KEYWORDS:
MRI ; arterial spin labelling; chronic fatigue; dynamic functional connectivity
PMID:27678090
PMCID:PMC5373941[Available on 2019-01-01]
DOI:10.1111/cpf.12393
J Psychosom Res. 2018 Jan;104:55-60. doi: 10.1016/j.jpsychores.2017.11.011. Epub 2017 Nov 20
Glucocorticoid receptor DNA methylation and childhood trauma in chronic fatigue syndrome patients.Vangeel EB1, Kempke S2, Bakusic J3, Godderis L4, Luyten P5, Van Heddegem L6, Compernolle V6, Persoons P7, Lambrechts D8, Izzi B9, Freson K10, Claes S11.
Author informationAbstractOBJECTIVE:
Although the precise mechanisms are not yet understood, previous studies have suggested that chronic fatigue syndrome (CFS) is associated with hypothalamic-pituitary-adrenal (HPA) axis dysregulation and trauma in early childhood. Consistent with findings suggesting that early life stress-induced DNA methylation changes may underlie dysregulation of the HPA axis, we previously found evidence for the involvement of glucocorticoid receptor (GR) gene (NR3C1) methylation in whole blood of CFS patients.
METHODS:
In the current study, we assessed NR3C1-1F region DNA methylation status in peripheral blood from a new and independent sample of 80 female CFS patients and 91 female controls. In CFS patients, history of childhood trauma subtypes was evaluated using the Childhood Trauma Questionnaire short form (CTQ-SF).
RESULTS:
Although absolute methylation differences were small, the present study confirms our previous findings of NR3C1-1F DNA hypomethylation at several CpG sites in CFS patients as compared to controls. Following multiple testing correction, only CpG_8 remained significant (DNA methylation difference: 1.3% versus 1.5%, p<0.001). In addition, we found associations between DNA methylation and severity of fatigue as well as with childhood emotional abuse in CFS patients, although these findings were not significant after correction for multiple testing.
CONCLUSIONS:
In conclusion, we replicated findings of NR3C1-1F DNA hypomethylation in CFS patients versus controls. Our results support the hypothesis of HPA axis dysregulation and enhanced GR sensitivity in CFS.
Copyright © 2017 Elsevier Inc. All rights reserved.
KEYWORDS:
Childhood trauma; Chronic fatigue syndrome; DNA methylation; Glucocorticoid receptor; HPA axis; NR3C1
PMID:29275786
DOI:10.1016/j.jpsychores.2017.11.011
Int J Radiat Biol. 2018 Jan 10:1-17. doi: 10.1080/09553002.2018.1422871. [Epub ahead of printChronic fatigue and immune deficiency syndrome (CFIDS), cellular metabolism, and ionizing radiation: a review of contemporary scientific literature and suggested directions for future research.Rusin A1, Seymour C2, Mothersill C1.
Author informationAbstractPURPOSE:
To investigate biochemical pathways known to be involved in radiation response and in CFIDS to determine if there might be common underlying mechanisms leading to symptoms experienced by those accidentally or deliberately exposed to radiation and those suffering from CFIDS. If such a link was established to suggest testable hypotheses to investigate the mechanisms with the aim of identifying new therapeutic targets.
CONCLUSIONS:
Evidence for involvement of the alpha-synuclein, cytochrome c oxidase, αB-crystallin, RNase L, and lactate dehydrogenase/STAT1 pathways is strong and suggests a common underlying mechanism involving mitochondrial dysfunction mediated by ROS and disruption of ATP production. The downstream effect of this is compromised energy production. Testable hypotheses are suggested to investigate the involvement of these pathways further.
KEYWORDS:
Chronic fatigue syndrome; atomic veterans; bystander effects of radiation; post-radiation syndrome; reactive oxygen species (ROS)
PMID:29297728
DOI:10.1080/09553002.2018.1422871
Brain Nerve. 2018 Jan;70(1):11-18. doi: 10.11477/mf.1416200944
[Diagnosis and Treatment of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome].[Article in Japanese]
Kuratsune H1.
AbstractWe present here the Japanese clinical diagnostic criteria for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) that were proposed in 2016 by the Japanese Ministry of Health, Labour and Welfare study group. The clinical diagnosis criteria of ME/CFS were created to be used by healthcare agencies in charge of primary care practice. We also explain the current prognosis in ME/CFS and medical treatments used in major medical institutions in Japan.
PMID:29348370
DOI:10.11477/mf.1416200944
J Psychosom Res. 2018 Jan;104:29-34. doi: 10.1016/j.jpsychores.2017.11.007. Epub 2017 Nov 8
Chronic fatigue syndrome (CFS/ME) symptom-based phenotypes and 1-year treatment outcomes in two clinical cohorts of adult patients in the UK and The Netherlands.Collin SM1, Heron J2, Nikolaus S3, Knoop H3, Crawley E2.
AbstractOBJECTIVE:
We previously described symptom-based chronic fatigue syndrome (CFS/ME) phenotypes in clinical assessment data from 7041 UK and 1392 Dutch adult CFS/ME patients. Here we aim to replicate these phenotypes in a more recent UK patient cohort, and investigate whether phenotypes are associated with 1-year treatment outcome.
METHODS:
12 specialist CFS/ME services (11 UK, 1 NL) recorded the presence/absence of 5 symptoms (muscle pain, joint pain, headache, sore throat, and painful lymph nodes) which can occur in addition to the 3 symptoms (post-exertional malaise, cognitive dysfunction, and disturbed/unrefreshing sleep) that are present for almost all patients. Latent Class Analysis (LCA) was used to assign symptom profiles (phenotypes). Multinomial logistic regression models were fitted to quantify associations between phenotypes and overall change in health 1year after the start of treatment.
RESULTS:
Baseline data were available for N=918 UK and N=1392 Dutch patients, of whom 416 (45.3%) and 912 (65.5%) had 1-year follow-up data, respectively. 3- and 4-class phenotypes identified in the previous UK patient cohort were replicated in the new UK cohort. UK patients who presented with 'polysymptomatic' and 'pain-only' phenotypes were 57% and 67% less likely (multinomial odds ratio (MOR) 0.43 (95% CI 0.19-0.94) and 0.33 (95% CI 0.13-0.84)) to report that their health was "very much better" or "much better" than patients who presented with an 'oligosymptomatic' phenotype. For Dutch patients, polysymptomatic and pain-only phenotypes were associated with 72% and 55% lower odds of improvement (MOR 0.28 (95% CI 0.11, 0.69) and 0.45 (95% CI 0.21, 0.99)) compared with oligosymptomatic patients.
CONCLUSIONS:
Adult CFS/ME patients with multiple symptoms or pain symptoms who present for specialist treatment are much less likely to report favourable treatment outcomes than patients who present with few symptoms.
Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.
KEYWORDS:
Chronic fatigue syndrome; Latent class analysis; Phenotypes; Symptom profiles; Treatment outcomes
PMID:29275782
DOI:10.1016/j.jpsychores.2017.11.007
J Sch Health. 2018 Jan;88(1):74-89. doi: 10.1111/josh.12580.
Measuring School Functioning in Students With Chronic Fatigue Syndrome: A Systematic Review.Tollit M1, Politis J2, Knight S1.
Author informationAbstractBACKGROUND:
It is often surmised that school functioning is significantly impacted in chronic fatigue syndrome (CFS); however, how this phenomenon manifests itself has rarely been characterized.
METHODS:
This systematic review synthesized and critically appraised methods, constructs, and instruments used to assess school functioning in students with CFS. Searches were conducted in electronic databases (CINAHL, MEDLINE, PubMed, ERIC, and PsycINFO) to locate empirical studies that measured school functioning in children and adolescents with CFS.
RESULTS:
A total of 36 papers met the inclusion criteria. By far the most commonly reported school functioning construct measured related to school attendance. This was followed by academic functioning, achievement motivation, and educational services received. Little consistency was found in the measurement of these constructs across studies.
CONCLUSIONS:
The current review revealed that the school experiences of children and adolescents with CFS have rarely been characterized beyond school absenteeism. Improvements in current assessment methods are required to comprehensively understand the impact of CFS on school functioning. Completely understanding the multiple aspects of school functioning will help to inform targeted strategies to optimize educational outcomes for students with CFS.
© 2018, American School Health Association.
KEYWORDS:
child and adolescent health; chronic diseases; chronic fatigue syndrome; school functioning; school psychology
PMID:29224219
DOI:10.1111/josh.12580
Improvement of severe myalgic encephalomyelitis/chronic fatigue syndrome symptoms following surgical treatment of cervical spinal stenosis
https://doi.org/10.1186/s12967-018-1397-7
Received: 14 November 2017
Accepted: 24 January 2018
Published: 2 February 2018
Abstract
Background
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a potentially disabling disorder. Little is known about the contributors to severe forms of the illness. We describe three consecutive patients with severe ME/CFS whose symptoms improved after recognition and surgical management of their cervical spinal stenosis.
Methods
All patients satisfied clinical criteria for ME/CFS and orthostatic intolerance, and were later found to have cervical spinal stenosis. Overall function was assessed before and after surgery using the Karnofsky score and the SF-36 physical function subscale score.
Results
Neurological findings included > 3+ deep tendon reflexes in 2 of 3, a positive Hoffman sign in 2 of 3, tremor in 2 of 3, and absent gag reflex in 1 of 3. The cervical spine canal diameter in the three patients ranged from 6 to 8.5 mm. One had congenital cervical stenosis with superimposed spondylosis, and two had single- or two-level spondylosis. Anterior cervical disc replacement surgery in two patients and a hybrid anterior cervical disc fusion and disc replacement in the third was associated with a marked improvement in myelopathic symptoms, resolution of lightheadedness and hemodynamic dysfunction, improvement in activity levels, and improvement in global ME/CFS symptoms.
Conclusions
The prompt post-surgical restoration of more normal function suggests that cervical spine stenosis contributed to the pathogenesis of refractory ME/CFS and orthostatic symptoms. The improvements following surgery emphasize the importance of a careful search for myelopathic examination findings in those with ME/CFS, especially when individuals with severe impairment are not responding to treatment.
Keywords
Cervical stenosisCervical myelopathyChronic fatigue syndromeMyalgic encephalomyelitisPostural tachycardia syndromeOrthostatic intolerance
https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-018-1397-7
Eukaryotes in the gut microbiota in myalgic encephalomyelitis/chronic fatigue syndromeAlexandra H. Mandarano1, Ludovic Giloteaux1, Betsy A. Keller2, Susan M. Levine1, Maureen R. Hanson1
Published January 22, 2018
PubMed 29375937
Abstract
Patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) often suffer from gastrointestinal symptoms and many are diagnosed with irritable bowel syndrome (IBS). Previous studies, including from our laboratory, have demonstrated that the ME/CFS gut bacterial composition is altered and less diverse when compared to healthy individuals. Patients have increased biomarkers of inflammation and leaky gut syndrome. To further investigate dysbiosis in the ME/CFS gut microbiome, we sought to characterize the eukaryotes present in the gut of 49 individuals with ME/CFS and 39 healthy controls. Using 18S rRNA sequencing, we have identified eukaryotes in stool samples of 17 healthy individuals and 17 ME/CFS patients. Our analysis demonstrates a small, nonsignificant decrease in eukaryotic diversity in ME/CFS patients compared to healthy individuals. In addition, ME/CFS patients show a nonsignificant increase in the ratio of fungal phyla Basidiomycota to Ascomycota, which is consistent with ongoing inflammation in ME/CFS. We did not identify specific eukaryotic taxa that are associated with ME/CFS disease status.
Cite this as
Mandarano AH, Giloteaux L, Keller BA, Levine SM, Hanson MR. (2018) Eukaryotes in the gut microbiota in myalgic encephalomyelitis/chronic fatigue syndrome. PeerJ 6:e4282 https://doi.org/10.7717/peerj.4282
Front. Immunol., 15 February 2018 | https://doi.org/10.3389/fimmu.2018.00229
Infection Elicited Autoimmunity and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: An Explanatory Model
Jonas Blomberg1*, Carl-Gerhard Gottfries2, Amal Elfaitouri3, Muhammad Rizwan1 and Anders Rosén4
Probiotics Antimicrob Proteins.
2018 Feb 20. doi: 10.1007/s12602-018-9397-8. [Epub ahead of print]
A Systematic Review of Probiotic Interventions for Gastrointestinal Symptoms and Irritable Bowel Syndrome in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME).Corbitt M1, Campagnolo N2,3, Staines D2,3, Marshall-Gradisnik S2,3.
AbstractGastrointestinal (GI) symptoms and irritable bowel (IB) symptoms have been associated with chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME). The aim of this study was to conduct a systematic review of these symptoms in CFS/ME, along with any evidence for probiotics as treatment. Pubmed, Scopus, Medline (EBSCOHost) and EMBASE databases were searched to source relevant studies for CFS/ME. The review included any studies examining GI symptoms, irritable bowel syndrome (IBS) and/or probiotic use. Studies were required to report criteria for CFS/ME and study design, intervention and outcome measures. Quality assessment was also completed to summarise the level of evidence available. A total of 3381 publications were returned using our search terms. Twenty-five studies were included in the review. Randomised control trials were the predominant study type (n = 24). Most of the studies identified examined the effect of probiotic supplementation on the improvement of IB symptoms in IBS patients, or IB symptoms in CFS/ME patients, as well as some other significant secondary outcomes (e.g. quality of life, other gastrointestinal symptoms, psychological symptoms). The level of evidence identified for the use of probiotics in IBS was excellent in quality; however, the evidence available for the use of probiotic interventions in CFS/ME was poor and limited. There is currently insufficient evidence for the use of probiotics in CFS/ME patients, despite probiotic interventions being useful in IBS. The studies pertaining to probiotic interventions in CFS/ME patients were limited and of poor quality overall. Standardisation of protocols and methodology in these studies is required.
KEYWORDS:
Chronic fatigue syndrome; Gastrointestinal symptoms; Irritable bowel symptoms; Myalgic encephalomyelitis; Probiotics
PMID: 29464501 DOI:10.1007/s12602-018-9397-8
Metabolomics and Chronic Fatigue Syndrome—Testing an Exciting New Technology for Diagnosis and Management for ME/CFS and other illnessesThe OMF and the North American ME/CFS Metabolomics Study
Mitochondria – “Mitochondria” is not quite a household word, but when it comes to understanding complex chronic disease, it should be. Mitochondria are the hub of the wheel of metabolism.
More than 90% of the pathways that break down food into building blocks and 70% of the pathways that make new building blocks have at least one reaction that passes through mitochondria. These little bioreactors use the oxygen we breathe to turn food and drink into energy and to perform over 500 other important chemical reactions in the cell.
Mitochondria also have another key function: They stand guard over the cell, ready to defend it when things go wrong. When a virus attacks, or a toxin is detected, mitochondria stop what they were doing, change their shape and cellular locations, and take up arms to help defend the cell. Mitochondria then send messages in the form of metabolites to the nucleus of the cell and to neighboring cells to signal the danger so gene expression can be changed and neighboring cells can prepare for battle. Different signals are sent when the danger has passed to alert the cell that healing can proceed.
“Metabolomics is a new lens that allows us to ‘see’ this inner world of the cell in a new way that lends itself to scientific discovery. This new vision is leading to breakthroughs in our understanding of why patients with ME/CFS get stuck in a cycle of pain and suffering and disability.”– Dr. Robert Naviaux
Recent scientific discoveries in our lab have shown that several different chronic complex diseases can result when this “cell danger response” (CDR) gets stuck in the “on” position for too long. When the CDR gets stuck, normal healing can’t proceed. If this happens, it could theoretically lead to Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS).
Metabolomics – Metabolomics is one of the hottest rising stars in the high tech race to gain a molecular understanding of health and disease. Metabolomics uses a machine called a “mass spectrometer” to measure hundreds of chemicals in our blood.
In our lab, at the University of California San Diego, with a single blood specimen, we can measure over 500 of these chemicals from over 60 different biochemical pathways.
These chemicals are the building blocks that cells use to grow and function, to fight and to heal. Like a Hubble telescope for medicine, metabolomics is allowing us to see deeper and with greater clarity into the universe of the cell than has ever been possible before. In a drop of blood, we can “eavesdrop” on the collective conversations of all the cells in the body.
In ME/CFS, as in many complex chronic diseases, many genes interact with many environmental factors encountered at times of vulnerability. Complex diseases are not predestined by our genes alone. Complex diseases are ecogenetic—resulting from the interaction of genes inherited from our ancestors and environmental factors we encounter in a lifetime. Our metabolism is the real-time readout of the gene-environment interaction. Metabolomics is a new lens that allows us to “see” this inner world of the cell in a new way that lends itself to scientific discovery.
This new vision is leading to breakthroughs in our understanding of why patients with ME/CFS get stuck in a cycle of pain and suffering and disability. But more importantly, metabolomics is also shedding light on how rational therapies designed to trigger a return to health might be just around the corner.
Association of chronic fatigue syndrome with premature telomere attrition
https://doi.org/10.1186/s12967-018-1414-x
2018 Received: 23 October 2017 Accepted: 16 February 2018 Published: 27 February 2018
Abstract
Background
Chronic fatigue syndrome (CFS), also known as myalgic encephalomyelitis (ME), is a severely debilitating condition of unknown etiology. The symptoms and risk factors of ME/CFS share features of accelerated aging implicated in several diseases. Using telomere length as a marker, this study was performed to test the hypothesis that ME/CFS is associated with accelerated aging.
Methods
Participant (n = 639) data came from the follow-up time point of the Georgia CFS surveillance study. Using the 1994 CFS Research Case Definition with questionnaire-based subscale thresholds for fatigue, function, and symptoms, participants were classified into four illness groups: CFS if all criteria were met (n = 64), CFS-X if CFS with exclusionary conditions (n = 77), ISF (insufficient symptoms/fatigue) if only some criteria were met regardless of exclusionary conditions (n = 302), and NF (non-fatigued) if no criteria and no exclusionary conditions (n = 196). Relative telomere length (T/S ratio) was measured using DNA from whole blood and real-time PCR. General linear models were used to estimate the association of illness groups or T/S ratio with demographics, biological measures and covariates with significance set at p < 0.05.
Results
The mean T/S ratio differed significantly by illness group (p = 0.0017); the T/S ratios in CFS (0.90 ± 0.03) and ISF (0.94 ± 0.02) were each significantly lower than in NF (1.06 ± 0.04). Differences in T/S ratio by illness groups remained significant after adjustment for covariates of age, sex, body mass index, waist–hip ratio, post-exertional malaise and education attainment. Telomere length was shorter by 635, 254 and 424 base pairs in CFS, CFS-X and ISF, respectively, compared to NF. This shorter telomere length translates to roughly 10.1–20.5, 4.0–8.2 and 6.6–13.7 years of additional aging in CFS, CFS-X and ISF compared to NF respectively. Further, stratified analyses based on age and sex demonstrated that the association of ME/CFS with short telomeres is largely moderated by female subjects < 45 years old.
Conclusions
This study found a significant association of ME/CFS with premature telomere attrition that is largely moderated by female subjects < 45 years old. Our results indicate that ME/CFS could be included in the list of conditions associated with accelerated aging. Further work is needed to evaluate the functional significance of accelerated aging in ME/CFS.
Original Research ARTICLE
Front. Endocrinol. | doi: 10.3389/fendo.2018.00097
Higher prevalence of ‘low T3 syndrome’ in patients with chronic fatigue syndrome: A case-control study
Begoña Ruiz-Núñez1, 2*, Rabab Tarasse1, Emar Vogelaar3, Janneke Dijck-Brouwer1 and Frits Muskiet1
Keywords: chronic fatigue syndrome, thyroid, ‘low T3 syndrome’, Triiodothyronine, Reverse triiodothyronine, Urinary iodine, Inflammation, high sensitivity CRP.
Received: 28 Nov 2017; Accepted: 27 Feb 2018.
An Eye on "The Mitochondria Man" : Robert Naviaux and Chronic Fatigue Syndrome (ME/CFS)
Top of Form
This is the start of an "Eye On" series focusing on researchers new to the chronic fatigue syndrome/fibromyalgia research fields. Few researchers present more exciting possibilities for ME/CFS than Dr. Robert Naviaux at UC San Diego (UCSD).
Naviaux recently joined the Scientific Advisory Board of the Open Medicine Foundation (OMF) and he's believed to have co-authored a paper that is under review. Early reports suggest the Severe Patient Big Data study may, in its early stages, uncovered significant about the mitochondria in ME/CFS
In some ways Naviaux seems tailor-made for ME/CFS. Naviaux runs the Robert Naviaux Laboratory at UC San Diego, is the founder/ co-director of UCSD's Mitochondrial and Metabolic Disease Center, and co-founder and a former president of the Mitochondrial Medicine Society. This man is clearly a pioneer in the relatively new and emerging field of mitochondrial research but he has an interesting immune side as well.
Naviaux trained at the NIH in tumor immunology and natural killer cell biology, and at the Salk Institute in virology and gene therapy. If ME/CFS or FM turns out to have a viral/inflammation/mitochondrial connection it's hard to imagine someone better placed to take advantage of that.
Naviaux gained some renown in 2013 when he was able to reverse autism in a mouse model using a hypothesis that could help explain chronic fatigue syndrome and fibromyalgia as well. He proposed that a sustained "cell danger response" is causing the cells in autism to essentially to shut down, stop communicating with other cells and go into hibernation.
Naviaux believes that cells damaged by viruses, or toxins react defensively causing their membranes stiffen and the
“When cells are exposed to classical forms of dangers, such as a virus, infection or toxic environmental substance, a defense mechanism is activated. This results in changes to metabolism and gene expression, and reduces the communication between neighboring cells. Simply put, when cells stop talking to each other, children stop talking.” Naviaux
(That's an intriguing idea given the evidence of "immune exhaustion" in ME/CFS and FM, and the rather massive alterations of immune cell networks Gordon Broderick and Dr. Klimas have found in ME/CFS. Could immune cell shut downs be behind those network alterations? )
Everybody seems to believe that the innate or early immune response which causes inflammation is involved in ME/CFS but Naviaux has taken the conversation a step further by tying in the mitochondria. Naviaux knew the mitochondria were involved in inflammation - they can be huge emitters of free radicals - and looked for ways in which they interacted with the immune system. He found them in substances called "mitokines" such as ATP and adenosine that cells with distressed mitochondrial emit.
The purines and pyrimidines ( ATP, ADP, UTP, and UDP), produced by these damaged cells can effect everything from inflammation, neurotransmission, pain production, and autonomic nervous system activity. They bind to purinergic and other receptors on cells found from the circulatory to digestive to immune systems to the brain.
Sleeping Sickness Drug
Naviaux used a drug called suramin that battled sleeping sickness to reverse autism in his mouse model. An anti-purinergic signaling drug, suramin, Naviaux believes, stops the cell danger signal in its tracks. In two studies he's been able to show that the drug rebuilt the mouse's brain synapses, re -enabled stalled cell-to-cell signaling, improved its social behavior and motor coordination and normalized it's mitochondrial metabolism. The drug is now being tested in a small trial of autistic children.
Suramin is more of use for what it reveals than as a treatment possibility than a full-flung treatment. It can only be taken for couple of months but newer antipurinergic medicines might be able to be taken for longer or might just need to be taken intermittently.
As Naviaux developed his hypothesis that damaged cells are triggering purinergic signaling cascades in autism, Donald Staines in Australia was proposing vasoactive neuropeptides were doing much the same thing in ME/CFS. Staines also proposed that ATP and adenosine releases from cells with mitochondrial problems may be causing the purinergic signaling to go bananas in ME/CFS.
Meanwhile Alan Light's examination of physiological pathways linked to stress and distress in ME/CFS was uncovering issues with purinergic signaling as well. Light found that increased purinergic receptor activity was highly associated with post exertional fatigue after exercise in ME/CFS (but not MS). He, too, suggested that purinergic receptors in ME/CFS patients were reacting to ATP molecules emanating from stressed cells. Back in 2012 he proposed that purinergic receptor upregulation in ME/CFS was turning the microglia in the brain on and producing pain and fatigue in ME/CFS.
Naviaux and other ME/CFS researchers, then, may be coming from different directions and ending up in much the same place.
We don't know what Naviaux has found in ME/CFS - we're waiting on his publication for that; it could be something entirely different but his past research alone suggests that he is someone to watch.
A member of the Health Rising Forums, Rachel Riggs, knows this first hand. After visiting Dr. Naviaux's lab she described a researcher who was very enthusiastic about ME/CFS, who mentioned linkages between autism and the disease - a disease, he thought, which put ME/CFS bodies in a kind of hibernation. Dr. Naviaux said his paper on ME/CFS will, if and when it is published, surprise a lot of people. Rachel had a palpable sense that the lab was on the cusp of something big.
Naviaux's got some big accomplishments behind him and some big toys to play with. His lab developed two advanced technologies; biocavity laser spectroscopy and mtDNA mutation detection by mass spectrometry, and recently created new bioinformatic methods that allow them to better analyze genetic data. Put all that together and Naviaux says he has the ability to "dissect the metabolic and molecular features of virtually any disease".
Naviaux appears to be all in ME/CFS. His biggest hurdle may be finding the money to fully study it. Hopefully the new approach by the NIH or the growing ability of ME/CFS donors to support exciting research will be enough.
Naviaux is part of an increasing focus on the mitochondria in ME/CFS research circles. The Chronic Fatigue Initiative has engaged Maureen Hanson to do a series of ME/CFS mitochondrial studies. Richard Deth, a mitochondrial expert, is working with Dr. Klimas at the Institute for Neuroimmune Institute in Florida. Dr. Saligan, a P2P report participant, and member of the NIH Intramural study is a bit of a wild card. His work on the stress response and catastrophizing has raised concerns, but his main research interest is focused on the physiological aspects of cancer fatigue.
Saligan has done studies on murine models of radiation induced fatigue, gene expression and cancer fatigue, prostate cancer and fatigue, inflammation and cancer fatigue, BDNF and fatigue, immunogenomic markers and fatigue, mitochondria and prostate fatigue, biomarkers and cancer fatigue and on and on and he's done one review on catastrophizing and fatigue.
Effect of tai chi versus aerobic exercise for fibromyalgia: comparative effectiveness randomized controlled trial
BMJ 2018; 360 doi: https://doi.org/10.1136/bmj.k851 (Published 21 March 2018)
Chenchen Wang, director and professor of medicine1,Christopher H Schmid, professor of biostatistics and co-director2,Roger A Fielding, director and professor of medicine3,William F Harvey, assistant professor of medicine1,Kieran F Reid, scientist III3,Lori Lyn Price, statistician4,Jeffrey B Driban, assistant professor of medicine1,Robert Kalish, associate professor of medicine5,Ramel Rones, tai chi instructor6,Timothy McAlindon, division chief and professor of medicine1
Abstract
Objectives To determine the effectiveness of tai chi interventions compared with aerobic exercise, a current core standard treatment in patients with fibromyalgia, and to test whether the effectiveness of tai chi depends on its dosage or duration.
Design Prospective, randomized, 52 week, single blind comparative effectiveness trial.
Setting Urban tertiary care academic hospital in the United States between March 2012 and September 2016.
Participants 226 adults with fibromyalgia (as defined by the American College of Rheumatology 1990 and 2010 criteria) were included in the intention to treat analyses: 151 were assigned to one of four tai chi groups and 75 to an aerobic exercise group.
Interventions Participants were randomly assigned to either supervised aerobic exercise (24 weeks, twice weekly) or one of four classic Yang style supervised tai chi interventions (12 or 24 weeks, once or twice weekly). Participants were followed for 52 weeks. Adherence was rigorously encouraged in person and by telephone.
Main outcome measures The primary outcome was change in the revised fibromyalgia impact questionnaire (FIQR) scores at 24 weeks compared with baseline. Secondary outcomes included changes of scores in patient’s global assessment, anxiety, depression, self efficacy, coping strategies, physical functional performance, functional limitation, sleep, and health related quality of life.
Results FIQR scores improved in all five treatment groups, but the combined tai chi groups improved statistically significantly more than the aerobic exercise group in FIQR scores at 24 weeks (difference between groups=5.5 points, 95% confidence interval 0.6 to 10.4, P=0.03) and several secondary outcomes (patient’s global assessment=0.9 points, 0.3 to 1.4, P=0.005; anxiety=1.2 points, 0.3 to 2.1, P=0.006; self efficacy=1.0 points, 0.5 to 1.6, P=0.0004; and coping strategies, 2.6 points, 0.8 to 4.3, P=0.005). Tai chi treatment compared with aerobic exercise administered with the same intensity and duration (24 weeks, twice weekly) had greater benefit (between group difference in FIQR scores=16.2 points, 8.7 to 23.6, P<0.001). The groups who received tai chi for 24 weeks showed greater improvements than those who received it for 12 weeks (difference in FIQR scores=9.6 points, 2.6 to 16.6, P=0.007). There was no significant increase in benefit for groups who received tai chi twice weekly compared with once weekly. Participants attended the tai chi training sessions more often than participants attended aerobic exercise. The effects of tai chi were consistent across all instructors. No serious adverse events related to the interventions were reported.
Conclusion Tai chi mind-body treatment results in similar or greater improvement in symptoms than aerobic exercise, the current most commonly prescribed non-drug treatment, for a variety of outcomes for patients with fibromyalgia. Longer duration of tai chi showed greater improvement. This mind-body approach may be considered a therapeutic option in the multidisciplinary management of fibromyalgia.
January 23, 2018
New research published in Fatigue: Biomedicine, Health & Behavior found ventricular lactate (lactate present in cerebrospinal fluid) might serve as a biological marker of underlying brain dysfunction for patients with chronic fatigue syndrome (CFS), fibromyalgia (FM), and those with a dual diagnosis. The study, titled “Elevations of ventricular lactate levels occur in both chronic fatigue syndrome and fibromyalgia”, also found evidence for a unitary hypothesis of the pathophysiology of CFS and FM – that is, they are different presentations of the same condition.
The study was authored by Dr. Natelson, of the Pain & Fatigue Study Center at Beth Israel Medical Center, in conjunction with pain specialists, clinicians, and quantitative experts. The team used neuroimaging to measure ventricular lactate in subjects across three diagnostic groups – FM only, CFS only, or CFS plus FM – and compared to healthy controls. A modified version of the 1994 Fukuda (CDC) criteria was used to select CFS patients.
The group found that, relative to healthy controls, ventricular lactate was higher in all illness groups included in the study. Elevations in ventricular lactate suggests a shift to anaerobic processes and a problem with brain-related mitochondrial metabolism across the CFS-FM spectrum. The authors conclude that, while there is evidence that ventricular lactate measured by neuroimaging can be used as a biomarker of syndromes characterized by medically unexplained pain or fatigue, this result does not indicate it can be used to differentiate CFS from FM.
Previous work from 2008 considering the relationship between ventricular lactate and ME/CFS also used a condition with symptomatic overlap as a study comparison group. The researchers looked at ventricular lactate levels in individuals with CFS (diagnosed with the 1994 guidelines) and Generalized Anxiety Disorder (GAD) – a condition that includes fatigue with an unknown origin as a hallmark symptom. However, this study found an abnormal increase in ventricular lactate in CFS relative to the comparison group (GAD). Unlike the connection between FM and CFS supported by Dr. Natelson’s study, this finding suggests distinct neurobiological differences between CFS and GAD.
CFS and FM were found to have statistically indistinguishable levels of lactate in the recent finding detailed in Fatigue, but we don’t have proof this reflects the same underlying cause. Nonetheless, ventricular lactate is indicated as a viable biomarker of underlying brain dysfunction for some patients with either or both diagnoses. The authors note that further research will be needed to further address if CFS and FM are different illnesses or variations of the same condition.
New Therapies in Irritable Bowel Syndrome: What Works and WhenOrla Craig
Curr Opin Gastroenterol. 2018;34(1):50-56.
Abstract and IntroductionPurpose of review. The purpose of this review is to examine the evidence supporting the use of recently developed pharmacological treatments for IBS together with new evidence supporting more traditional therapies in order to understand where the new agents are best used in the treatment pathway.
Recent findings. There is evidence to support the use of traditional treatments such as antispasmodics, antidepressants and dietary alteration in IBS. New therapeutic agents such as Linaclotide, Lubiprostone, Plecanatide, Rifaxamin and Eluxadoline are all more effective than placebo in treating symptoms of IBS with Tenapanor being a promising new agent. The majority of patients, however, treated with these medications remain symptomatic and they are not suitable for use in all patients.
Summary. Traditional treatments such as antispasmodics, antidepressants, dietary and lifestyle modifications retain their importance in the treatment of IBS with the newer agents to be considered wherever these treatments are ineffective or poorly tolerated.
Stigma in Myalgic Encephalomyelitis and its association with functioning
Don M. Baken, Shane T. Harvey, David L. Bimler & Kirsty J. Ross
Pages 30-40 | Received 20 Oct 2016, Accepted 17 Dec 2017, Published online: 04 Jan 2018
https://doi.org/10.1080/21641846.2018.1419553
ABSTRACT
Background: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is categorised by the World Health Organisation as a neurological condition. It is poorly understood and people with ME/CFS report experiencing stigma. Research suggests that stigma might be linked to functional ability.
Purpose: This study investigated the relationship of stigma to factors associated with functional ability. Additionally, the use of standardised measures allowed for comparison of stigma severity in ME/CFS to other neurological conditions.
Method: A convenience sample of 206 people diagnosed with ME/CFS completed mailed or online self-report standardised measures of stigma, health, ability to participate in social roles and activities, and their satisfaction with this ability. Findings were compared to published data for three neurological conditions.
Results: Stigma scores were significantly correlated (p < .0001) with all self-report health and functional measures (range: −.30 to −.42). The ME/CFS sample reported higher levels of stigma (d = 1.30) and lower levels of health (d = 1.86–2.16) and functioning (d = 1.63) than the comparison conditions.
Conclusions: Consistent with studies over the last two decades, people with ME/CFS report higher levels of stigma when compared to the other conditions. The stigma is not just associated with health but also with specific measures of functional ability.
Gen Med Open, 2017 doi: 10.15761/GMO.1000117 Volume 1(3): 1-13
ISSN: 2515-4737
An analysis of Dutch hallmark studies confirms the outcome of the PACE trial: cognitive behaviour therapy with a graded activity protocol is not effective for chronic fatigue syndrome and Myalgic Encephalomyelitis
FNM Twisk1* and LAMM Corsius2 1ME-de-patiënten Foundation, Limmen, the Netherlands 2 Independent researchers, Etten-Leur, The Netherlands
Abstract Myalgic Encephalomyelitis (ME) and Chronic Fatigue Syndrome (CFS) are considered to be enigmatic diseases. Several studies propose that the combination of cognitive behaviour therapy with a graded activity protocol (CBT+), justified by a so-called (bio)psychosocial (explanatory) model, is an effective treatment option for CFS (ME).
Objective A critical review of five Dutch hallmark studies that allegedly support this claim.
Methods An analysis of the five CBT+ studies with special attention to the patients studied, the criteria (subjective and objective measures and cut-off scores) used to select participants and to define improvement and recovery, the consistency of the definitions of caseness (being diagnosed as a CFS patient at entry) versus the definitions of improvement and recovery after CBT+, and the objective effects.
Results The studies investigated suffer from various methodological flaws. Apart from these methodological shortcomings, the claim that CBT+ is an effective treatment option for CFS is not substantiated by the data reported. Some studies investigated CFS patients, other studies investigated CF patients, labelled as CFS patients, or combinations of CFS and CF patients. No study investigated the effect of CBT+ in a group of patients meeting the (original) diagnostic criteria for ME. The effects of CBT+ on subjective measures, for example fatigue and disability, if present, are insufficient to achieve normal values. Impressive recovery and improvement rates are based on very loose criteria for subjective measures. Cut-off scores for subjective measures used to define improvement and recovery in studies show overlap with cut-off scores for CFS caseness in one or more of the other studies. More importantly, looking at the objective measures, the proof of clinical improvement after CBT+ is lacking.
Conclusion Solid evidence of effectiveness of CBT+ for CFS, let alone ME, is lacking in the five hallmark studies. The lack of objective improvement indicates CBT+ is ineffective. This finding confirms the outcome of the large-scale PACE-trial in the UK.
Elevated brain natriuretic peptide levels in chronic fatigue syndrome associate with cardiac dysfunction: a case control studyAuthorsCara Tomas, Andreas Finkelmeyer, Tim Hodgson, Laura MacLachlan, Guy A MacGowan, Andrew M Blamire, Julia L Newton
Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK
AbstractObjectives: To explore levels of the brain natriuretic peptide (BNP) and how these associate with the cardiac abnormalities recently identified in chronic fatigue syndrome (CFS).
Methods: Cardiac magnetic resonance examinations were performed using 3T Philips Intera Achieva scanner (Best, Netherlands) in CFS (Fukuda) participants and sedentary controls matched group wise for age and sex. BNP was also measured by using an enzyme immunoassay in plasma from 42 patients with CFS and 10 controls.
Results: BNP levels were significantly higher in the CFS cohort compared with the matched controls (P=0.013). When we compared cardiac volumes (end-diastolic and end-systolic) between those with high BNP levels (BNP >400 pg/mL) and low BNP (<400 pg/mL), there were significantly lower cardiac volumes in those with the higher BNP levels in both end-systolic and end-diastolic volumes (P=0.05). There were no relationships between fatigue severity, length of disease and BNP levels (P=0.2) suggesting that our findings are unlikely to be related to deconditioning.
Conclusion: This study confirms an association between reduced cardiac volumes and BNP in CFS. Lack of relationship between length of disease suggests that findings are not secondary to deconditioning. Further studies are needed to explore the utility of BNP to act as a stratification paradigm in CFS that directs targeted treatments.
PublicationTomas et al, Open Heart, 2017 Dec 27; 4(2):e000697
Ticks transmitting Lyme disease are found in a third of Britain, mainly the south
BMJ 2018; 360 doi: https://doi.org/10.1136/bmj.k692 (Published 12 February 2018) Cite this as: BMJ 2018;360:k692
Ticks responsible for transmitting Lyme disease are distributed widely around the UK, a team from Public Health England has found.1
Data from a surveillance scheme that has been running since 2005 showed that the number of sites where ticks have been found have nearly doubled from 2010 to 2016. Dividing Britain into squares of 10 km on each side, the 2016 data show that ticks were reported in 36% of the squares, up from 20% before 2010. In Greater London 80% of the grid squares contained ticks, compared with 67% in southeast England. The Midlands, by contrast, seemed relatively free of ticks.
The increases may result from better awareness of ticks, said the study authors, led by Benjamin Cull,
Pain Physician. 2018 Jan;21(1):E13-E24Cerebral Blood Flow and Heart Rate Variability in Chronic Fatigue Syndrome: A Randomized Cross-Over Study.Malfliet A1, Pas R2, Brouns R3, De Win J4, Hatem SM5, Meeus M6, Ickmans K7, van Hooff RJ3, Nijs J8.
AbstractBACKGROUND: Pain, fatigue, and concentration difficulties are typical features of chronic fatigue syndrome (CFS). The exact underlying mechanisms of these symptoms are still unknown, but available evidence suggests an important role for impaired pain modulation. As evidence also suggests that pain modulation is related to cardiovascular mechanisms, it seems logical to investigate whether cerebral blood flow (CBF) and heart rate variability (HRV) are altered in these patients.
OBJECTIVES:
We aimed to investigate the role of the cardiovascular system in pain modulation and symptoms of CFS; the response of CBF and HRV to physical stress and their relation to the change in temporal summation (TS) of pressure pain and self-reported symptoms was evaluated.
STUDY DESIGN: A controlled, randomized cross-over trial.
SETTING: University Hospital Brussels.
METHODS:
Twenty CFS patients and 20 sedentary healthy controls were included in this study. In both of the groups, the change in TS of pressure pain, CBF (using transcranial Doppler), and HRV (using finger plethysmography) was examined during physical and emotional stress (to control for potential bias), as well as their association mutually and with self-reported symptoms of pain, fatigue, and concentrations difficulties.
RESULTS:
There was no significant interaction or group (F-values ranging from .100 to 1.862, P-values ranging from .754 to .181) effect in CBF or HRV parameters. HRV and CBF did change during physical exercise, but the changes did not differ between patients and controls. While pain scores during TS at the trapezius site reduced in the control group after the physical exercise protocol (P = .037), they did not change in the CFS group (P = .108), suggesting impaired pain modulation. There were no significant correlations between CBF, HRV, TS, and self-reported symptoms (all P-values of correlation analyses > .01).
LIMITATIONS: Although effect sizes were medium to large, the study sample was relatively low. Also, the mild nature of the exercise bout is discussable. Nonetheless, this mild exercise was able to provoke endogenous pain modulation in the control group, which endorsed a proper execution of the cycling exercise. Moreover, mild exercises are more applicable to daily physical activities in CFS patients than vigorous exercises.
CONCLUSION: These results seem to refute the previously suggested alterations of CBF/HRV in CFS patients. These cardiovascular parameters appear not to explain pain before, during, and following exercise.Brain Nerve. 2018 Jan;70(1):35-40. doi: 10.11477/mf.1416200947
[Immunopathogenesis of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)].[Article in Japanese]Yamamura T1, Ono H, Sato W.
AbstractA recent study on the pathogenesis of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) has revealed an elevation of inflammatory and anti-inflammatory cytokines in the sera and cerebrospinal fluids of the patients and presence of autoantibodies in subgroups of ME/CFS patients. Furthermore, investigator-initiated clinical trials have proved the efficacy of anti-CD20 antibody (rituximab), that eliminate B cells, in the treatment of ME/CFS. Based on these findings, we hypothesize that immune abnormalities, such as enhanced autoimmune responses, may play an essential role in the neuroinflammatory pathogenesis of ME/CFS.
PMID:29348373
DOI:10.11477/mf.1416200947
Clin Physiol Funct Imaging. 2018 Jan;38(1):128-137. doi: 10.1111/cpf.12393. Epub 2016 Sep 28
Static and dynamic functional connectivity in patients with chronic fatigue syndrome: use of arterial spin labelling fMRI.Boissoneault J1, Letzen J1, Lai S2, Robinson ME1, Staud R3.
Author informationAbstractStudies using arterial spin labelling (ASL) have shown that individuals with chronic fatigue syndrome (CFS) have decreased regional cerebral blood flow, which may be associated with changes in functional neural networks. Indeed, recent studies indicate disruptions in functional connectivity (FC) at rest in chronically fatigued patients including perturbations in static FC (sFC), that is average FC at rest between several brain regions subserving neurocognitive, motor and affect-related networks. Whereas sFC often provides information of functional network reorganization in chronic illnesses, investigations of temporal changes in functional connectivity between multiple brain areas may shed light on the dynamic characteristics of brain network activation associated with such maladies. We used ASL fMRI in 19 patients with CFS and 15 healthy controls (HC) to examine both static and dynamic changes in FC among several a priori selected brain regions during a fatiguing cognitive task. HC showed greater increases than CFS in static FC (sFC) between insula and temporo-occipital structures and between precuneus and thalamus/striatum. Furthermore, inferior frontal gyrus connectivity to cerebellum, occipital and temporal structures declined in HC but increased in CFS. Patients also showed lower dynamic FC (dFC) between hippocampus and right superior parietal lobule. Both sFC and dFC correlated with task-related fatigue increases. These data provide the first evidence that perturbations in static and dynamic FC may underlie chronically fatigued patients' report of task-induced fatigue. Further research will determine whether such changes in sFC and dFC are also characteristic for other fatigued individuals, including patients with chronic pain, cancer and multiple sclerosis.
KEYWORDS:
MRI ; arterial spin labelling; chronic fatigue; dynamic functional connectivity
PMID:27678090
PMCID:PMC5373941[Available on 2019-01-01]
DOI:10.1111/cpf.12393
J Psychosom Res. 2018 Jan;104:55-60. doi: 10.1016/j.jpsychores.2017.11.011. Epub 2017 Nov 20
Glucocorticoid receptor DNA methylation and childhood trauma in chronic fatigue syndrome patients.Vangeel EB1, Kempke S2, Bakusic J3, Godderis L4, Luyten P5, Van Heddegem L6, Compernolle V6, Persoons P7, Lambrechts D8, Izzi B9, Freson K10, Claes S11.
Author informationAbstractOBJECTIVE:
Although the precise mechanisms are not yet understood, previous studies have suggested that chronic fatigue syndrome (CFS) is associated with hypothalamic-pituitary-adrenal (HPA) axis dysregulation and trauma in early childhood. Consistent with findings suggesting that early life stress-induced DNA methylation changes may underlie dysregulation of the HPA axis, we previously found evidence for the involvement of glucocorticoid receptor (GR) gene (NR3C1) methylation in whole blood of CFS patients.
METHODS:
In the current study, we assessed NR3C1-1F region DNA methylation status in peripheral blood from a new and independent sample of 80 female CFS patients and 91 female controls. In CFS patients, history of childhood trauma subtypes was evaluated using the Childhood Trauma Questionnaire short form (CTQ-SF).
RESULTS:
Although absolute methylation differences were small, the present study confirms our previous findings of NR3C1-1F DNA hypomethylation at several CpG sites in CFS patients as compared to controls. Following multiple testing correction, only CpG_8 remained significant (DNA methylation difference: 1.3% versus 1.5%, p<0.001). In addition, we found associations between DNA methylation and severity of fatigue as well as with childhood emotional abuse in CFS patients, although these findings were not significant after correction for multiple testing.
CONCLUSIONS:
In conclusion, we replicated findings of NR3C1-1F DNA hypomethylation in CFS patients versus controls. Our results support the hypothesis of HPA axis dysregulation and enhanced GR sensitivity in CFS.
Copyright © 2017 Elsevier Inc. All rights reserved.
KEYWORDS:
Childhood trauma; Chronic fatigue syndrome; DNA methylation; Glucocorticoid receptor; HPA axis; NR3C1
PMID:29275786
DOI:10.1016/j.jpsychores.2017.11.011
Int J Radiat Biol. 2018 Jan 10:1-17. doi: 10.1080/09553002.2018.1422871. [Epub ahead of printChronic fatigue and immune deficiency syndrome (CFIDS), cellular metabolism, and ionizing radiation: a review of contemporary scientific literature and suggested directions for future research.Rusin A1, Seymour C2, Mothersill C1.
Author informationAbstractPURPOSE:
To investigate biochemical pathways known to be involved in radiation response and in CFIDS to determine if there might be common underlying mechanisms leading to symptoms experienced by those accidentally or deliberately exposed to radiation and those suffering from CFIDS. If such a link was established to suggest testable hypotheses to investigate the mechanisms with the aim of identifying new therapeutic targets.
CONCLUSIONS:
Evidence for involvement of the alpha-synuclein, cytochrome c oxidase, αB-crystallin, RNase L, and lactate dehydrogenase/STAT1 pathways is strong and suggests a common underlying mechanism involving mitochondrial dysfunction mediated by ROS and disruption of ATP production. The downstream effect of this is compromised energy production. Testable hypotheses are suggested to investigate the involvement of these pathways further.
KEYWORDS:
Chronic fatigue syndrome; atomic veterans; bystander effects of radiation; post-radiation syndrome; reactive oxygen species (ROS)
PMID:29297728
DOI:10.1080/09553002.2018.1422871
Brain Nerve. 2018 Jan;70(1):11-18. doi: 10.11477/mf.1416200944
[Diagnosis and Treatment of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome].[Article in Japanese]
Kuratsune H1.
AbstractWe present here the Japanese clinical diagnostic criteria for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) that were proposed in 2016 by the Japanese Ministry of Health, Labour and Welfare study group. The clinical diagnosis criteria of ME/CFS were created to be used by healthcare agencies in charge of primary care practice. We also explain the current prognosis in ME/CFS and medical treatments used in major medical institutions in Japan.
PMID:29348370
DOI:10.11477/mf.1416200944
J Psychosom Res. 2018 Jan;104:29-34. doi: 10.1016/j.jpsychores.2017.11.007. Epub 2017 Nov 8
Chronic fatigue syndrome (CFS/ME) symptom-based phenotypes and 1-year treatment outcomes in two clinical cohorts of adult patients in the UK and The Netherlands.Collin SM1, Heron J2, Nikolaus S3, Knoop H3, Crawley E2.
AbstractOBJECTIVE:
We previously described symptom-based chronic fatigue syndrome (CFS/ME) phenotypes in clinical assessment data from 7041 UK and 1392 Dutch adult CFS/ME patients. Here we aim to replicate these phenotypes in a more recent UK patient cohort, and investigate whether phenotypes are associated with 1-year treatment outcome.
METHODS:
12 specialist CFS/ME services (11 UK, 1 NL) recorded the presence/absence of 5 symptoms (muscle pain, joint pain, headache, sore throat, and painful lymph nodes) which can occur in addition to the 3 symptoms (post-exertional malaise, cognitive dysfunction, and disturbed/unrefreshing sleep) that are present for almost all patients. Latent Class Analysis (LCA) was used to assign symptom profiles (phenotypes). Multinomial logistic regression models were fitted to quantify associations between phenotypes and overall change in health 1year after the start of treatment.
RESULTS:
Baseline data were available for N=918 UK and N=1392 Dutch patients, of whom 416 (45.3%) and 912 (65.5%) had 1-year follow-up data, respectively. 3- and 4-class phenotypes identified in the previous UK patient cohort were replicated in the new UK cohort. UK patients who presented with 'polysymptomatic' and 'pain-only' phenotypes were 57% and 67% less likely (multinomial odds ratio (MOR) 0.43 (95% CI 0.19-0.94) and 0.33 (95% CI 0.13-0.84)) to report that their health was "very much better" or "much better" than patients who presented with an 'oligosymptomatic' phenotype. For Dutch patients, polysymptomatic and pain-only phenotypes were associated with 72% and 55% lower odds of improvement (MOR 0.28 (95% CI 0.11, 0.69) and 0.45 (95% CI 0.21, 0.99)) compared with oligosymptomatic patients.
CONCLUSIONS:
Adult CFS/ME patients with multiple symptoms or pain symptoms who present for specialist treatment are much less likely to report favourable treatment outcomes than patients who present with few symptoms.
Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.
KEYWORDS:
Chronic fatigue syndrome; Latent class analysis; Phenotypes; Symptom profiles; Treatment outcomes
PMID:29275782
DOI:10.1016/j.jpsychores.2017.11.007
J Sch Health. 2018 Jan;88(1):74-89. doi: 10.1111/josh.12580.
Measuring School Functioning in Students With Chronic Fatigue Syndrome: A Systematic Review.Tollit M1, Politis J2, Knight S1.
Author informationAbstractBACKGROUND:
It is often surmised that school functioning is significantly impacted in chronic fatigue syndrome (CFS); however, how this phenomenon manifests itself has rarely been characterized.
METHODS:
This systematic review synthesized and critically appraised methods, constructs, and instruments used to assess school functioning in students with CFS. Searches were conducted in electronic databases (CINAHL, MEDLINE, PubMed, ERIC, and PsycINFO) to locate empirical studies that measured school functioning in children and adolescents with CFS.
RESULTS:
A total of 36 papers met the inclusion criteria. By far the most commonly reported school functioning construct measured related to school attendance. This was followed by academic functioning, achievement motivation, and educational services received. Little consistency was found in the measurement of these constructs across studies.
CONCLUSIONS:
The current review revealed that the school experiences of children and adolescents with CFS have rarely been characterized beyond school absenteeism. Improvements in current assessment methods are required to comprehensively understand the impact of CFS on school functioning. Completely understanding the multiple aspects of school functioning will help to inform targeted strategies to optimize educational outcomes for students with CFS.
© 2018, American School Health Association.
KEYWORDS:
child and adolescent health; chronic diseases; chronic fatigue syndrome; school functioning; school psychology
PMID:29224219
DOI:10.1111/josh.12580
Improvement of severe myalgic encephalomyelitis/chronic fatigue syndrome symptoms following surgical treatment of cervical spinal stenosis
- Peter C. Rowe, Colleen L. Marden, Scott Heinlein and Charles C. EdwardsII
https://doi.org/10.1186/s12967-018-1397-7
Received: 14 November 2017
Accepted: 24 January 2018
Published: 2 February 2018
Abstract
Background
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a potentially disabling disorder. Little is known about the contributors to severe forms of the illness. We describe three consecutive patients with severe ME/CFS whose symptoms improved after recognition and surgical management of their cervical spinal stenosis.
Methods
All patients satisfied clinical criteria for ME/CFS and orthostatic intolerance, and were later found to have cervical spinal stenosis. Overall function was assessed before and after surgery using the Karnofsky score and the SF-36 physical function subscale score.
Results
Neurological findings included > 3+ deep tendon reflexes in 2 of 3, a positive Hoffman sign in 2 of 3, tremor in 2 of 3, and absent gag reflex in 1 of 3. The cervical spine canal diameter in the three patients ranged from 6 to 8.5 mm. One had congenital cervical stenosis with superimposed spondylosis, and two had single- or two-level spondylosis. Anterior cervical disc replacement surgery in two patients and a hybrid anterior cervical disc fusion and disc replacement in the third was associated with a marked improvement in myelopathic symptoms, resolution of lightheadedness and hemodynamic dysfunction, improvement in activity levels, and improvement in global ME/CFS symptoms.
Conclusions
The prompt post-surgical restoration of more normal function suggests that cervical spine stenosis contributed to the pathogenesis of refractory ME/CFS and orthostatic symptoms. The improvements following surgery emphasize the importance of a careful search for myelopathic examination findings in those with ME/CFS, especially when individuals with severe impairment are not responding to treatment.
Keywords
Cervical stenosisCervical myelopathyChronic fatigue syndromeMyalgic encephalomyelitisPostural tachycardia syndromeOrthostatic intolerance
https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-018-1397-7
Eukaryotes in the gut microbiota in myalgic encephalomyelitis/chronic fatigue syndromeAlexandra H. Mandarano1, Ludovic Giloteaux1, Betsy A. Keller2, Susan M. Levine1, Maureen R. Hanson1
Published January 22, 2018
PubMed 29375937
Abstract
Patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) often suffer from gastrointestinal symptoms and many are diagnosed with irritable bowel syndrome (IBS). Previous studies, including from our laboratory, have demonstrated that the ME/CFS gut bacterial composition is altered and less diverse when compared to healthy individuals. Patients have increased biomarkers of inflammation and leaky gut syndrome. To further investigate dysbiosis in the ME/CFS gut microbiome, we sought to characterize the eukaryotes present in the gut of 49 individuals with ME/CFS and 39 healthy controls. Using 18S rRNA sequencing, we have identified eukaryotes in stool samples of 17 healthy individuals and 17 ME/CFS patients. Our analysis demonstrates a small, nonsignificant decrease in eukaryotic diversity in ME/CFS patients compared to healthy individuals. In addition, ME/CFS patients show a nonsignificant increase in the ratio of fungal phyla Basidiomycota to Ascomycota, which is consistent with ongoing inflammation in ME/CFS. We did not identify specific eukaryotic taxa that are associated with ME/CFS disease status.
Cite this as
Mandarano AH, Giloteaux L, Keller BA, Levine SM, Hanson MR. (2018) Eukaryotes in the gut microbiota in myalgic encephalomyelitis/chronic fatigue syndrome. PeerJ 6:e4282 https://doi.org/10.7717/peerj.4282
Front. Immunol., 15 February 2018 | https://doi.org/10.3389/fimmu.2018.00229
Infection Elicited Autoimmunity and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: An Explanatory Model
Jonas Blomberg1*, Carl-Gerhard Gottfries2, Amal Elfaitouri3, Muhammad Rizwan1 and Anders Rosén4
- 1Department of Medical Sciences, Uppsala University, Clinical Microbiology, Academic Hospital, Uppsala, Sweden
- 2Gottfries Clinic AB, Mölndal, Sweden
- 3Department of Infectious Disease and Tropical Medicine, Faculty of Public Health, Benghazi University, Benghazi, Libya
- 4Department of Clinical and Experimental Medicine, Division of Cell Biology, Linköping University, Linköping, Sweden
Probiotics Antimicrob Proteins.
2018 Feb 20. doi: 10.1007/s12602-018-9397-8. [Epub ahead of print]
A Systematic Review of Probiotic Interventions for Gastrointestinal Symptoms and Irritable Bowel Syndrome in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME).Corbitt M1, Campagnolo N2,3, Staines D2,3, Marshall-Gradisnik S2,3.
AbstractGastrointestinal (GI) symptoms and irritable bowel (IB) symptoms have been associated with chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME). The aim of this study was to conduct a systematic review of these symptoms in CFS/ME, along with any evidence for probiotics as treatment. Pubmed, Scopus, Medline (EBSCOHost) and EMBASE databases were searched to source relevant studies for CFS/ME. The review included any studies examining GI symptoms, irritable bowel syndrome (IBS) and/or probiotic use. Studies were required to report criteria for CFS/ME and study design, intervention and outcome measures. Quality assessment was also completed to summarise the level of evidence available. A total of 3381 publications were returned using our search terms. Twenty-five studies were included in the review. Randomised control trials were the predominant study type (n = 24). Most of the studies identified examined the effect of probiotic supplementation on the improvement of IB symptoms in IBS patients, or IB symptoms in CFS/ME patients, as well as some other significant secondary outcomes (e.g. quality of life, other gastrointestinal symptoms, psychological symptoms). The level of evidence identified for the use of probiotics in IBS was excellent in quality; however, the evidence available for the use of probiotic interventions in CFS/ME was poor and limited. There is currently insufficient evidence for the use of probiotics in CFS/ME patients, despite probiotic interventions being useful in IBS. The studies pertaining to probiotic interventions in CFS/ME patients were limited and of poor quality overall. Standardisation of protocols and methodology in these studies is required.
KEYWORDS:
Chronic fatigue syndrome; Gastrointestinal symptoms; Irritable bowel symptoms; Myalgic encephalomyelitis; Probiotics
PMID: 29464501 DOI:10.1007/s12602-018-9397-8
Metabolomics and Chronic Fatigue Syndrome—Testing an Exciting New Technology for Diagnosis and Management for ME/CFS and other illnessesThe OMF and the North American ME/CFS Metabolomics Study
Mitochondria – “Mitochondria” is not quite a household word, but when it comes to understanding complex chronic disease, it should be. Mitochondria are the hub of the wheel of metabolism.
More than 90% of the pathways that break down food into building blocks and 70% of the pathways that make new building blocks have at least one reaction that passes through mitochondria. These little bioreactors use the oxygen we breathe to turn food and drink into energy and to perform over 500 other important chemical reactions in the cell.
Mitochondria also have another key function: They stand guard over the cell, ready to defend it when things go wrong. When a virus attacks, or a toxin is detected, mitochondria stop what they were doing, change their shape and cellular locations, and take up arms to help defend the cell. Mitochondria then send messages in the form of metabolites to the nucleus of the cell and to neighboring cells to signal the danger so gene expression can be changed and neighboring cells can prepare for battle. Different signals are sent when the danger has passed to alert the cell that healing can proceed.
“Metabolomics is a new lens that allows us to ‘see’ this inner world of the cell in a new way that lends itself to scientific discovery. This new vision is leading to breakthroughs in our understanding of why patients with ME/CFS get stuck in a cycle of pain and suffering and disability.”– Dr. Robert Naviaux
Recent scientific discoveries in our lab have shown that several different chronic complex diseases can result when this “cell danger response” (CDR) gets stuck in the “on” position for too long. When the CDR gets stuck, normal healing can’t proceed. If this happens, it could theoretically lead to Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS).
Metabolomics – Metabolomics is one of the hottest rising stars in the high tech race to gain a molecular understanding of health and disease. Metabolomics uses a machine called a “mass spectrometer” to measure hundreds of chemicals in our blood.
In our lab, at the University of California San Diego, with a single blood specimen, we can measure over 500 of these chemicals from over 60 different biochemical pathways.
These chemicals are the building blocks that cells use to grow and function, to fight and to heal. Like a Hubble telescope for medicine, metabolomics is allowing us to see deeper and with greater clarity into the universe of the cell than has ever been possible before. In a drop of blood, we can “eavesdrop” on the collective conversations of all the cells in the body.
In ME/CFS, as in many complex chronic diseases, many genes interact with many environmental factors encountered at times of vulnerability. Complex diseases are not predestined by our genes alone. Complex diseases are ecogenetic—resulting from the interaction of genes inherited from our ancestors and environmental factors we encounter in a lifetime. Our metabolism is the real-time readout of the gene-environment interaction. Metabolomics is a new lens that allows us to “see” this inner world of the cell in a new way that lends itself to scientific discovery.
This new vision is leading to breakthroughs in our understanding of why patients with ME/CFS get stuck in a cycle of pain and suffering and disability. But more importantly, metabolomics is also shedding light on how rational therapies designed to trigger a return to health might be just around the corner.
Association of chronic fatigue syndrome with premature telomere attrition
- Mangalathu S. Rajeevan Janna Murray, Lisa Oakley, Jin-Mann S. Lin and Elizabeth R. Unger
https://doi.org/10.1186/s12967-018-1414-x
2018 Received: 23 October 2017 Accepted: 16 February 2018 Published: 27 February 2018
Abstract
Background
Chronic fatigue syndrome (CFS), also known as myalgic encephalomyelitis (ME), is a severely debilitating condition of unknown etiology. The symptoms and risk factors of ME/CFS share features of accelerated aging implicated in several diseases. Using telomere length as a marker, this study was performed to test the hypothesis that ME/CFS is associated with accelerated aging.
Methods
Participant (n = 639) data came from the follow-up time point of the Georgia CFS surveillance study. Using the 1994 CFS Research Case Definition with questionnaire-based subscale thresholds for fatigue, function, and symptoms, participants were classified into four illness groups: CFS if all criteria were met (n = 64), CFS-X if CFS with exclusionary conditions (n = 77), ISF (insufficient symptoms/fatigue) if only some criteria were met regardless of exclusionary conditions (n = 302), and NF (non-fatigued) if no criteria and no exclusionary conditions (n = 196). Relative telomere length (T/S ratio) was measured using DNA from whole blood and real-time PCR. General linear models were used to estimate the association of illness groups or T/S ratio with demographics, biological measures and covariates with significance set at p < 0.05.
Results
The mean T/S ratio differed significantly by illness group (p = 0.0017); the T/S ratios in CFS (0.90 ± 0.03) and ISF (0.94 ± 0.02) were each significantly lower than in NF (1.06 ± 0.04). Differences in T/S ratio by illness groups remained significant after adjustment for covariates of age, sex, body mass index, waist–hip ratio, post-exertional malaise and education attainment. Telomere length was shorter by 635, 254 and 424 base pairs in CFS, CFS-X and ISF, respectively, compared to NF. This shorter telomere length translates to roughly 10.1–20.5, 4.0–8.2 and 6.6–13.7 years of additional aging in CFS, CFS-X and ISF compared to NF respectively. Further, stratified analyses based on age and sex demonstrated that the association of ME/CFS with short telomeres is largely moderated by female subjects < 45 years old.
Conclusions
This study found a significant association of ME/CFS with premature telomere attrition that is largely moderated by female subjects < 45 years old. Our results indicate that ME/CFS could be included in the list of conditions associated with accelerated aging. Further work is needed to evaluate the functional significance of accelerated aging in ME/CFS.
Original Research ARTICLE
Front. Endocrinol. | doi: 10.3389/fendo.2018.00097
Higher prevalence of ‘low T3 syndrome’ in patients with chronic fatigue syndrome: A case-control study
Begoña Ruiz-Núñez1, 2*, Rabab Tarasse1, Emar Vogelaar3, Janneke Dijck-Brouwer1 and Frits Muskiet1
- 1Laboratory Medicine, University Medical Center Groningen, Netherlands
- 2Healthy Institute, Spain
- 3European Laboratory of Nutriënts (ELN), Netherlands
Keywords: chronic fatigue syndrome, thyroid, ‘low T3 syndrome’, Triiodothyronine, Reverse triiodothyronine, Urinary iodine, Inflammation, high sensitivity CRP.
Received: 28 Nov 2017; Accepted: 27 Feb 2018.
An Eye on "The Mitochondria Man" : Robert Naviaux and Chronic Fatigue Syndrome (ME/CFS)
Top of Form
This is the start of an "Eye On" series focusing on researchers new to the chronic fatigue syndrome/fibromyalgia research fields. Few researchers present more exciting possibilities for ME/CFS than Dr. Robert Naviaux at UC San Diego (UCSD).
Naviaux recently joined the Scientific Advisory Board of the Open Medicine Foundation (OMF) and he's believed to have co-authored a paper that is under review. Early reports suggest the Severe Patient Big Data study may, in its early stages, uncovered significant about the mitochondria in ME/CFS
In some ways Naviaux seems tailor-made for ME/CFS. Naviaux runs the Robert Naviaux Laboratory at UC San Diego, is the founder/ co-director of UCSD's Mitochondrial and Metabolic Disease Center, and co-founder and a former president of the Mitochondrial Medicine Society. This man is clearly a pioneer in the relatively new and emerging field of mitochondrial research but he has an interesting immune side as well.
Naviaux trained at the NIH in tumor immunology and natural killer cell biology, and at the Salk Institute in virology and gene therapy. If ME/CFS or FM turns out to have a viral/inflammation/mitochondrial connection it's hard to imagine someone better placed to take advantage of that.
Naviaux gained some renown in 2013 when he was able to reverse autism in a mouse model using a hypothesis that could help explain chronic fatigue syndrome and fibromyalgia as well. He proposed that a sustained "cell danger response" is causing the cells in autism to essentially to shut down, stop communicating with other cells and go into hibernation.
Naviaux believes that cells damaged by viruses, or toxins react defensively causing their membranes stiffen and the
“When cells are exposed to classical forms of dangers, such as a virus, infection or toxic environmental substance, a defense mechanism is activated. This results in changes to metabolism and gene expression, and reduces the communication between neighboring cells. Simply put, when cells stop talking to each other, children stop talking.” Naviaux
(That's an intriguing idea given the evidence of "immune exhaustion" in ME/CFS and FM, and the rather massive alterations of immune cell networks Gordon Broderick and Dr. Klimas have found in ME/CFS. Could immune cell shut downs be behind those network alterations? )
Everybody seems to believe that the innate or early immune response which causes inflammation is involved in ME/CFS but Naviaux has taken the conversation a step further by tying in the mitochondria. Naviaux knew the mitochondria were involved in inflammation - they can be huge emitters of free radicals - and looked for ways in which they interacted with the immune system. He found them in substances called "mitokines" such as ATP and adenosine that cells with distressed mitochondrial emit.
The purines and pyrimidines ( ATP, ADP, UTP, and UDP), produced by these damaged cells can effect everything from inflammation, neurotransmission, pain production, and autonomic nervous system activity. They bind to purinergic and other receptors on cells found from the circulatory to digestive to immune systems to the brain.
Sleeping Sickness Drug
Naviaux used a drug called suramin that battled sleeping sickness to reverse autism in his mouse model. An anti-purinergic signaling drug, suramin, Naviaux believes, stops the cell danger signal in its tracks. In two studies he's been able to show that the drug rebuilt the mouse's brain synapses, re -enabled stalled cell-to-cell signaling, improved its social behavior and motor coordination and normalized it's mitochondrial metabolism. The drug is now being tested in a small trial of autistic children.
Suramin is more of use for what it reveals than as a treatment possibility than a full-flung treatment. It can only be taken for couple of months but newer antipurinergic medicines might be able to be taken for longer or might just need to be taken intermittently.
As Naviaux developed his hypothesis that damaged cells are triggering purinergic signaling cascades in autism, Donald Staines in Australia was proposing vasoactive neuropeptides were doing much the same thing in ME/CFS. Staines also proposed that ATP and adenosine releases from cells with mitochondrial problems may be causing the purinergic signaling to go bananas in ME/CFS.
Meanwhile Alan Light's examination of physiological pathways linked to stress and distress in ME/CFS was uncovering issues with purinergic signaling as well. Light found that increased purinergic receptor activity was highly associated with post exertional fatigue after exercise in ME/CFS (but not MS). He, too, suggested that purinergic receptors in ME/CFS patients were reacting to ATP molecules emanating from stressed cells. Back in 2012 he proposed that purinergic receptor upregulation in ME/CFS was turning the microglia in the brain on and producing pain and fatigue in ME/CFS.
Naviaux and other ME/CFS researchers, then, may be coming from different directions and ending up in much the same place.
We don't know what Naviaux has found in ME/CFS - we're waiting on his publication for that; it could be something entirely different but his past research alone suggests that he is someone to watch.
A member of the Health Rising Forums, Rachel Riggs, knows this first hand. After visiting Dr. Naviaux's lab she described a researcher who was very enthusiastic about ME/CFS, who mentioned linkages between autism and the disease - a disease, he thought, which put ME/CFS bodies in a kind of hibernation. Dr. Naviaux said his paper on ME/CFS will, if and when it is published, surprise a lot of people. Rachel had a palpable sense that the lab was on the cusp of something big.
Naviaux's got some big accomplishments behind him and some big toys to play with. His lab developed two advanced technologies; biocavity laser spectroscopy and mtDNA mutation detection by mass spectrometry, and recently created new bioinformatic methods that allow them to better analyze genetic data. Put all that together and Naviaux says he has the ability to "dissect the metabolic and molecular features of virtually any disease".
Naviaux appears to be all in ME/CFS. His biggest hurdle may be finding the money to fully study it. Hopefully the new approach by the NIH or the growing ability of ME/CFS donors to support exciting research will be enough.
Naviaux is part of an increasing focus on the mitochondria in ME/CFS research circles. The Chronic Fatigue Initiative has engaged Maureen Hanson to do a series of ME/CFS mitochondrial studies. Richard Deth, a mitochondrial expert, is working with Dr. Klimas at the Institute for Neuroimmune Institute in Florida. Dr. Saligan, a P2P report participant, and member of the NIH Intramural study is a bit of a wild card. His work on the stress response and catastrophizing has raised concerns, but his main research interest is focused on the physiological aspects of cancer fatigue.
Saligan has done studies on murine models of radiation induced fatigue, gene expression and cancer fatigue, prostate cancer and fatigue, inflammation and cancer fatigue, BDNF and fatigue, immunogenomic markers and fatigue, mitochondria and prostate fatigue, biomarkers and cancer fatigue and on and on and he's done one review on catastrophizing and fatigue.
Effect of tai chi versus aerobic exercise for fibromyalgia: comparative effectiveness randomized controlled trial
BMJ 2018; 360 doi: https://doi.org/10.1136/bmj.k851 (Published 21 March 2018)
Chenchen Wang, director and professor of medicine1,Christopher H Schmid, professor of biostatistics and co-director2,Roger A Fielding, director and professor of medicine3,William F Harvey, assistant professor of medicine1,Kieran F Reid, scientist III3,Lori Lyn Price, statistician4,Jeffrey B Driban, assistant professor of medicine1,Robert Kalish, associate professor of medicine5,Ramel Rones, tai chi instructor6,Timothy McAlindon, division chief and professor of medicine1
Abstract
Objectives To determine the effectiveness of tai chi interventions compared with aerobic exercise, a current core standard treatment in patients with fibromyalgia, and to test whether the effectiveness of tai chi depends on its dosage or duration.
Design Prospective, randomized, 52 week, single blind comparative effectiveness trial.
Setting Urban tertiary care academic hospital in the United States between March 2012 and September 2016.
Participants 226 adults with fibromyalgia (as defined by the American College of Rheumatology 1990 and 2010 criteria) were included in the intention to treat analyses: 151 were assigned to one of four tai chi groups and 75 to an aerobic exercise group.
Interventions Participants were randomly assigned to either supervised aerobic exercise (24 weeks, twice weekly) or one of four classic Yang style supervised tai chi interventions (12 or 24 weeks, once or twice weekly). Participants were followed for 52 weeks. Adherence was rigorously encouraged in person and by telephone.
Main outcome measures The primary outcome was change in the revised fibromyalgia impact questionnaire (FIQR) scores at 24 weeks compared with baseline. Secondary outcomes included changes of scores in patient’s global assessment, anxiety, depression, self efficacy, coping strategies, physical functional performance, functional limitation, sleep, and health related quality of life.
Results FIQR scores improved in all five treatment groups, but the combined tai chi groups improved statistically significantly more than the aerobic exercise group in FIQR scores at 24 weeks (difference between groups=5.5 points, 95% confidence interval 0.6 to 10.4, P=0.03) and several secondary outcomes (patient’s global assessment=0.9 points, 0.3 to 1.4, P=0.005; anxiety=1.2 points, 0.3 to 2.1, P=0.006; self efficacy=1.0 points, 0.5 to 1.6, P=0.0004; and coping strategies, 2.6 points, 0.8 to 4.3, P=0.005). Tai chi treatment compared with aerobic exercise administered with the same intensity and duration (24 weeks, twice weekly) had greater benefit (between group difference in FIQR scores=16.2 points, 8.7 to 23.6, P<0.001). The groups who received tai chi for 24 weeks showed greater improvements than those who received it for 12 weeks (difference in FIQR scores=9.6 points, 2.6 to 16.6, P=0.007). There was no significant increase in benefit for groups who received tai chi twice weekly compared with once weekly. Participants attended the tai chi training sessions more often than participants attended aerobic exercise. The effects of tai chi were consistent across all instructors. No serious adverse events related to the interventions were reported.
Conclusion Tai chi mind-body treatment results in similar or greater improvement in symptoms than aerobic exercise, the current most commonly prescribed non-drug treatment, for a variety of outcomes for patients with fibromyalgia. Longer duration of tai chi showed greater improvement. This mind-body approach may be considered a therapeutic option in the multidisciplinary management of fibromyalgia.
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