2016 – Page 8 – American ME and CFS Society

Cognitive behaviour therapy for chronic fatigue syndrome: Differences in treatment outcome between a tertiary treatment centre in the United Kingdom and the Netherlands

Abstract:

OBJECTIVE: Cognitive behaviour therapy (CBT) reduces fatigue and disability in chronic fatigue syndrome (CFS). However, outcomes vary between studies, possibly because of differences in patient characteristics, treatment protocols, diagnostic criteria and outcome measures. The objective was to compare outcomes after CBT in tertiary treatment centres in the Netherlands (NL) and the United Kingdom (UK), using different treatment protocols but identical outcome measures, while controlling for differences in patient characteristics and diagnostic criteria.

METHODS: Consecutively referred CFS patients who received CBT were included (NL: n=293, UK: n=163). Uncontrolled effect sizes for improvement in fatigue (Chalder Fatigue Questionnaire), physical functioning (SF-36 physical functioning subscale) and social functioning (Work and Social Adjustment Scale) were compared. Multiple regression analysis was used to examine whether patient differences explained outcome differences between centres.

RESULTS: Effect sizes differed between centres for fatigue (Cohen’s D NL=1.74, 95% CI=1.52-1.95; UK=0.99, CI=0.73-1.25), physical functioning (NL=0.99, CI=0.81-1.18; UK=0.33, CI=0.08-0.58) and social functioning (NL=1.47, CI=1.26-1.69; UK=0.61, CI=0.35-0.86). Patients in the UK had worse physical functioning at baseline and there were minor demographic differences. These could not explain differences in centre outcome.

CONCLUSION: Effectiveness of CBT differed between treatment centres. Differences in treatment protocols may explain this and should be investigated to help further improve outcomes.

Source: Worm-Smeitink M, Nikolaus S, Goldsmith K, Wiborg J, Ali S, Knoop H, Chalder T. Cognitive behaviour therapy for chronic fatigue syndrome: Differences in treatment outcome between a tertiary treatment centre in the United Kingdom and the Netherlands. J Psychosom Res. 2016 Aug;87:43-9. doi: 10.1016/j.jpsychores.2016.06.006. Epub 2016 Jun 11. https://www.ncbi.nlm.nih.gov/pubmed/27411751

Complementary and alternative healthcare use by participants in the PACE trial of treatments for chronic fatigue syndrome

Abstract:

BACKGROUND: Chronic Fatigue Syndrome (CFS) is characterised by persistent fatigue, disability and a range of other symptoms. The PACE trial was randomised to compare four non-pharmacological treatments for patients with CFS in secondary care clinics. The aims of this sub study were to describe the use of complementary and alternative medicine (CAM) in the trial sample and to test whether CAM use correlated with an improved outcome.

METHOD: CAM use was recorded at baseline and 52weeks. Logistic and multiple regression models explored relationships between CAM use and both patient characteristics and trial outcomes.

RESULTS: At baseline, 450/640 (70%) of participants used any sort of CAM; 199/640 (31%) participants were seeing a CAM practitioner and 410/640 (64%) were taking a CAM medication. At 52weeks, those using any CAM fell to 379/589 (64%). Independent predictors of CAM use at baseline were female gender, local ME group membership, prior duration of CFS and treatment preference. At 52weeks, the associated variables were being female, local ME group membership, and not being randomised to the preferred trial arm. There were no significant associations between any CAM use and fatigue at either baseline or 52weeks. CAM use at baseline was associated with a mean (CI) difference of 4.10 (1.28, 6.91; p=0.024) increased SF36 physical function score at 52weeks, which did not reach the threshold for a clinically important difference.

CONCLUSION: CAM use is common in patients with CFS. It was not associated with any clinically important trial outcomes.

Source: Lewith G, Stuart B, Chalder T, McDermott C, White PD. Complementary and alternative healthcare use by participants in the PACE trial of treatments for chronic fatigue syndrome. J Psychosom Res. 2016 Aug;87:37-42. doi: 10.1016/j.jpsychores.2016.06.005. Epub 2016 Jun 10. https://www.ncbi.nlm.nih.gov/pubmed/27411750

Reduced cardiac volumes in chronic fatigue syndrome associate with plasma volume but not length of disease: a cohort study

Abstract:

OBJECTIVES: To explore potential mechanisms that underpin the cardiac abnormalities seen in chronic fatigue syndrome (CFS) using non-invasive cardiac impedance, red cell mass and plasma volume measurements.

METHODS: Cardiac MR (MR) examinations were performed using 3 T Philips Intera Achieva scanner (Best, NL) in participants with CFS (Fukuda; n=47) and matched case-by-case controls. Total volume (TV), red cell volume (RCV) and plasma volume (PV) measurements were performed (41 CFS and 10 controls) using the indicator dilution technique using simultaneous 51-chromium labelling of red blood cells and 125-iodine labelling of serum albumin.

RESULTS: The CFS group length of history (mean±SD) was 14±10 years. Patients with CFS had significantly reduced end-systolic and end-diastolic volumes together with reduced end-diastolic wall masses (all p<0.0001). Mean±SD RCV was 1565±443 mL with 26/41 (63%) having values below 95% of expected. PV was 2659±529 mL with 13/41 (32%) <95% expected. There were strong positive correlations between TV, RCV and PV and cardiac end-diastolic wall mass (all p<0.0001; r(2)=0.5). Increasing fatigue severity correlated negatively with lower PV (p=0.04; r(2)=0.2). There were no relationships between any MR or volume measurements and length of history, suggesting that deconditioning was unlikely to be the cause of these abnormalities.

CONCLUSIONS: This study confirms an association between reduced cardiac volumes and blood volume in CFS. Lack of relationship between length of disease, cardiac and plasma volumes suggests findings are not secondary to deconditioning. The relationship between plasma volume and severity of fatigue symptoms suggests a potential therapeutic target in CFS.

Source: Newton JL, Finkelmeyer A, Petrides G, Frith J, Hodgson T, Maclachlan L, MacGowan G, Blamire AM. Reduced cardiac volumes in chronic fatigue syndrome associate with plasma volume but not length of disease: a cohort study. Open Heart. 2016 Jun 24;3(1):e000381. doi: 10.1136/openhrt-2015-000381. ECollection 2016. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4932290/ (Full article)

Down-regulation of renin-aldosterone and antidiuretic hormone systems in patients with myalgic encephalomyelitis/chronic fatigue syndrome

Abstract:

BACKGROUND: Central nervous system dysfunction associated with myalgic encephalomyelitis (ME) has been postulated as the cause of chronic fatigue syndrome (CFS). A small heart or reduced left ventricular volume with reduced cardiac output has been reported to be common in patients with ME. The main circulatory blood volume regulators may be down-regulated.

METHODS: Plasma levels of the neurohumoral factors that regulate circulatory blood volume were determined in 18 patients with ME and 15 healthy subjects (Controls).

RESULTS: The echocardiographic examination revealed that the mean values for the left ventricular end-diastolic diameters, stroke volume index, and cardiac index as well as the mean blood pressure were all significantly smaller in the ME group than in the Controls. The mean plasma renin activity (1.6±1.0ng/ml/h vs. 2.5±1.5ng/ml/h, p=0.06) was considerably lower in the ME group than in the Controls. Both the mean plasma aldosterone (104±37pg/ml vs. 157±67pg/ml, p=0.004) and antidiuretic hormone (ADH) (2.2±1.0pg/ml vs. 3.3±1.5pg/ml, p=0.02) concentrations were significantly lower in the ME group than in the Controls.

Desmopressin (120μg), a synthetic version of arginine vasopressin, was orally administered for five successive days to 10 patients with ME. In five patients (50%), the symptoms of orthostatic intolerance during a 10min active standing test were ameliorated in association with a significant increase in urinary osmotic pressure and decrease in heart rate. Furthermore, in five patients (50%), the performance status scores for the activities of daily living were improved.

CONCLUSIONS: Both the renin-aldosterone and ADH systems were down-regulated despite the existence of reduction in cardiac preload and output in patients with ME. Desmopressin improved symptoms in half of the patients.

Source: Miwa K. Down-regulation of renin-aldosterone and antidiuretic hormone systems in patients with myalgic encephalomyelitis/chronic fatigue syndrome. J Cardiol. 2016 Jul 8. pii: S0914-5087(16)30120-4. doi: 10.1016/j.jjcc.2016.06.003. [Epub ahead of print] https://www.ncbi.nlm.nih.gov/pubmed/27401397

Managed Activity Graded Exercise iN Teenagers and pre-Adolescents (MAGENTA) feasibility randomised controlled trial: study protocol

Abstract:

INTRODUCTION: Paediatric chronic fatigue syndrome or myalgic encephalomyelitis (CFS/ME) is a relatively common and disabling condition, yet there is a limited evidence base for treatment. There is good evidence that graded exercise therapy is moderately effective in adults with CFS/ME, but there is little evidence for the effectiveness, cost-effectiveness, acceptability or best method of delivery for paediatric CFS/ME. This study aims to investigate the acceptability and feasibility of carrying out a multicentre randomised controlled trial investigating the effectiveness of graded exercise therapy compared with activity management for children/teenagers who are mildly or moderately affected with CFS/ME.

METHODS AND ANALYSIS: 100 paediatric patients (8-17 years) with CFS/ME will be recruited from 3 specialist UK National Health Service (NHS) CFS/ME services (Bath, Cambridge and Newcastle). Patients will be randomised (1:1) to receive either graded exercise therapy or activity management. Feasibility analysis will include the number of young people eligible, approached and consented to the trial; attrition rate and treatment adherence; questionnaire and accelerometer completion rates. Integrated qualitative methods will ascertain perceptions of feasibility and acceptability of recruitment, randomisation and the interventions. All adverse events will be monitored to assess the safety of the trial.

ETHICS AND DISSEMINATION: The trial has received ethical approval from the National Research Ethics Service (South West-Frenchay 15/SW/0124).

TRIAL REGISTRATION NUMBER: ISRCTN23962803; Pre-results.

Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

Source: Brigden A, Beasant L, Hollingworth W, Metcalfe C, Gaunt D, Mills N, Jago R, Crawley E. Managed Activity Graded Exercise iN Teenagers and pre-Adolescents (MAGENTA) feasibility randomised controlled trial: study protocol. BMJ Open. 2016 Jul 4;6(7):e011255. doi: 10.1136/bmjopen-2016-011255. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4947787/ (Full article)

Long-term methylphenidate intake in chronic fatigue syndrome

Abstract:

OBJECTIVE: Concentration disturbances are frequent in chronic fatigue syndrome (CFS). In a placebo-controlled double-blind crossover study, methylphenidate over 4 weeks was superior to placebo in the relief of fatigue and concentration disturbance. This observational study describes the effect of long-term methylphenidate intake on fatigue, concentration, and daily life activities, as reported by the patients themselves.

METHODS: A questionnaire was sent to all CFS patients who were prescribed methylphenidate at the general internal medicine department of a university hospital between August 2004 and February 2007, for possible improvement of concentration difficulties and fatigue.

RESULTS: Out of 194 consecutive patients, 149 (76.8%) sent the questionnaire back. At the time of the questionnaire, 65.3% had stopped the intake of methylphenidate, 34.7% still took it daily or occasionally. Among the patients who continued methylphenidate, 48% reported an at least 50% improvement of fatigue, and 62% reported an at least 50% improvement of concentration difficulties. This continued intake of methylphenidate resulted in more working hours in these patients. Side effects (agitation, palpitations, and dry mouth) were reported significantly more in patients who had stopped methylphenidate than in those who still took it.

CONCLUSION: The long-term intake of methylphenidate by CFS patients with concentration difficulties has a positive effect in about one out of three patients.

Source: Blockmans D, Persoons P. Long-term methylphenidate intake in chronic fatigue syndrome. Acta Clin Belg. 2016 Dec;71(6):407-414. Epub 2016 Jun 27. https://www.ncbi.nlm.nih.gov/pubmed/27351244

Killer Cell Immunoglobulin-like Receptor Genotype and Haplotype Investigation of Natural Killer Cells from an Australian Population of Chronic Fatigue Syndrome/Myalgic Encephalomyelitis Patients

Abstract:

Killer cell immunoglobulin-like receptor (KIR) genes encode for activating and inhibitory surface receptors, which are correlated with the regulation of Natural Killer (NK) cell cytotoxic activity. Reduced NK cell cytotoxic activity has been consistently reported in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME) patients, and KIR haplotypes and allelic polymorphism remain to be investigated.

The aim of this article was to conduct a pilot study to examine KIR genotypes, haplotypes, and allelic polymorphism in CFS/ME patients and nonfatigued controls (NFCs). Comparison of KIR and allelic polymorphism frequencies revealed no significant differences between 20 CFS/ME patients and 20 NFCs.

A lower frequency of the telomeric A/B motif (P < 0.05) was observed in CFS/ME patients compared with NFCs. This pilot study is the first to report the differences in the frequency of KIR on the telomeric A/B motif in CFS/ME patients. Further studies with a larger CFS/ME cohort are required to validate these results.

Source: Huth TK, Brenu EW, Staines DR, Marshall-Gradisnik SM. Killer Cell Immunoglobulin-like Receptor Genotype and Haplotype Investigation of Natural Killer Cells from an Australian Population of Chronic Fatigue Syndrome/Myalgic Encephalomyelitis Patients. Gene Regul Syst Bio. 2016 Jun 19;10:43-9. doi: 10.4137/GRSB.S39861. ECollection 2016. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4913894/ (Full article)

Nitrosative Stress, Hypernitrosylation, and Autoimmune Responses to Nitrosylated Proteins: New Pathways in Neuroprogressive Disorders Including Depression and Chronic Fatigue Syndrome

Abstract:

Nitric oxide plays an indispensable role in modulating cellular signaling and redox pathways. This role is mainly effected by the readily reversible nitrosylation of selective protein cysteine thiols. The reversibility and sophistication of this signaling system is enabled and regulated by a number of enzymes which form part of the thioredoxin, glutathione, and pyridoxine antioxidant systems.

Increases in nitric oxide levels initially lead to a defensive increase in the number of nitrosylated proteins in an effort to preserve their function. However, in an environment of chronic oxidative and nitrosative stress (O&NS), nitrosylation of crucial cysteine groups within key enzymes of the thioredoxin, glutathione, and pyridoxine systems leads to their inactivation thereby disabling denitrosylation and transnitrosylation and subsequently a state described as “hypernitrosylation.”

This state leads to the development of pathology in multiple domains such as the inhibition of enzymes of the electron transport chain, decreased mitochondrial function, and altered conformation of proteins and amino acids leading to loss of immune tolerance and development of autoimmunity. Hypernitrosylation also leads to altered function or inactivation of proteins involved in the regulation of apoptosis, autophagy, proteomic degradation, transcription factor activity, immune-inflammatory pathways, energy production, and neural function and survival.

Hypernitrosylation, as a consequence of chronically elevated O&NS and activated immune-inflammatory pathways, can explain many characteristic abnormalities observed in neuroprogressive disease including major depression and chronic fatigue syndrome/myalgic encephalomyelitis. In those disorders, increased bacterial translocation may drive hypernitrosylation and autoimmune responses against nitrosylated proteins.

Source: Morris G, Berk M, Klein H, Walder K, Galecki P, Maes M. Nitrosative Stress, Hypernitrosylation, and Autoimmune Responses to Nitrosylated Proteins: New Pathways in Neuroprogressive Disorders Including Depression and Chronic Fatigue Syndrome. Mol Neurobiol. 2016 Jun 23. [Epub ahead of print] https://www.ncbi.nlm.nih.gov/pubmed/27339878

Reduced diversity and altered composition of the gut microbiome in individuals with myalgic encephalomyelitis/chronic fatigue syndrome

Abstract:

BACKGROUND: Gastrointestinal disturbances are among symptoms commonly reported by individuals diagnosed with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). However, whether ME/CFS is associated with an altered microbiome has remained uncertain. Here, we profiled gut microbial diversity by sequencing 16S ribosomal ribonucleic acid (rRNA) genes from stool as well as inflammatory markers from serum for cases (n = 48) and controls (n = 39). We also examined a set of inflammatory markers in blood: C-reactive protein (CRP), intestinal fatty acid-binding protein (I-FABP), lipopolysaccharide (LPS), LPS-binding protein (LBP), and soluble CD14 (sCD14).

RESULTS: We observed elevated levels of some blood markers for microbial translocation in ME/CFS patients; levels of LPS, LBP, and sCD14 were elevated in ME/CFS subjects. Levels of LBP correlated with LPS and sCD14 and LPS levels correlated with sCD14. Through deep sequencing of bacterial rRNA markers, we identified differences between the gut microbiomes of healthy individuals and patients with ME/CFS. We observed that bacterial diversity was decreased in the ME/CFS specimens compared to controls, in particular, a reduction in the relative abundance and diversity of members belonging to the Firmicutes phylum.

In the patient cohort, we find less diversity as well as increases in specific species often reported to be pro-inflammatory species and reduction in species frequently described as anti-inflammatory. Using a machine learning approach trained on the data obtained from 16S rRNA and inflammatory markers, individuals were classified correctly as ME/CFS with a cross-validation accuracy of 82.93 %.

CONCLUSIONS: Our results indicate dysbiosis of the gut microbiota in this disease and further suggest an increased incidence of microbial translocation, which may play a role in inflammatory symptoms in ME/CFS.

Source: Giloteaux L, Goodrich JK, Walters WA, Levine SM, Ley RE, Hanson MR. Reduced diversity and altered composition of the gut microbiome in individuals with myalgic encephalomyelitis/chronic fatigue syndrome. Microbiome. 2016 Jun 23;4(1):30. doi: 10.1186/s40168-016-0171-4. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4918027/ (Full article)

Is chronic fatigue syndrome truly associated with haplogroups or mtDNA single nucleotide polymorphisms?

Letter to the Editor:

With interest we read the article by Billing-Ross et al. [1] about 193 patients with chronic fatigue syndrome (CFS) diagnosed according to the Fukuda or Canadian Consensus criteria and undergoing sequencing of the mtDNA, the DePaul Symptom questionnaire and the Medical Outcome Survey Short Form-36. The study showed that CFS is associated with mtDNA haplogroups J, U and H, that 8 mtDNA single nucleotide polymorphisms (SNPs) were associated with 16 symptom categories, and that three haplogroups were associated with six symptom categories [1]. We have the following comments and concerns.

The main limitation of this study is that only the mtDNA was investigated for sequence variants. Since it is well-known that mitochondrial disorders (MIDs) may be also caused by mutations in nDNA-located genes, particularly in children [2], disease-causing mutations or SNPs facilitating the development of CFS may have been missed. Furthermore, MIDs may not only be due to respiratory chain dysfunction but also due to disruption of other mitochondrial pathways, such as the beta-oxidation, the hem synthesis, the calcium handling, the coenzyme-Q metabolism, or the urea cycle. There is also consensus that investigations of mtDNA mutations or SNPs in mtDNA from lymphocytes may not be constructive since some mutations may not be present or heteroplasmy rates may be lower than in more severely affected tissues [3].

You can read the rest of this letter here: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4912808/

Source: Finsterer J, Zarrouk-Mahjoub S. Is chronic fatigue syndrome truly associated with haplogroups or mtDNA single nucleotide polymorphisms? J Transl Med. 2016 Jun 18;14(1):182. doi: 10.1186/s12967-016-0939-0. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4912808/ (Full article)