Tag: 2014

Assessment of recovery status in chronic fatigue syndrome using normative data

Abstract:

INTRODUCTION: Adamowicz et al. have reviewed criteria previously employed to define recovery in chronic fatigue syndrome (CFS). They suggested such criteria have generally lacked stringency and consistency between studies and recommended future research should require “normalization of symptoms and functioning”.

METHODS: Options regarding how “normalization of symptoms and functioning” might be operationalized for CFS cohorts are explored.

RESULTS: A diagnosis of CFS excludes many chronic disabling illnesses present in the general population, and CFS cohorts can almost exclusively consist of people of working age; therefore, it is suggested that thresholds for recovery should not be based on population samples which include a significant proportion of sick, disabled or elderly individuals. It is highlighted how a widely used measure in CFS research, the SF-36 physical function subscale, is not normally distributed. This is discussed in relation to how recovery was defined for a large intervention trial, the PACE trial, using a method that assumes a normal distribution. Summary data on population samples are also given, and alternative methods to assess recovery are proposed.

CONCLUSIONS: The “normalization of symptoms and function” holds promise as a means of defining recovery from CFS at the current time. However, care is required regarding how such requirements are operationalized, otherwise recovery rates may be overstated, and perpetuate the confusion and controversy noted by Adamowicz et al.

Comment on

 

Source: Matthees A. Assessment of recovery status in chronic fatigue syndrome using normative data. Qual Life Res. 2015 Apr;24(4):905-7. doi: 10.1007/s11136-014-0819-0. Epub 2014 Oct 11. https://www.ncbi.nlm.nih.gov/pubmed/25304959 (Full article)

Comment:

Alem Matthees 2015 Aug 16 11:22 p.m.

In response to post-publication feedback, I wish to clarify some aspects of the abstract, so there are no further misunderstandings about the scope and content in the full text of this article:

a) Classification and naming issues aside, ME/CFS occurs at all ages, including young children and adolescents. [1] I never intended to suggest otherwise. The statement about patients being almost exclusively of working age was in context of research cohorts, particularly intervention trials which typically exclude patients under 18 years of age and rarely recruit those over 65 years. It is argued that studies consisting of such cohorts should not use normative data from general populations which include the elderly.

b) The physical function subscale of the Short Form 36 health survey (PF SF-36) is discussed because it is a commonly used measure in research and was used in the PACE trial. This article is not a defence of the PACE trial, but uses it to exemplify how the issues described earlier in the article can cause normative data to be misinterpreted or misapplied. Selected details on this issue can be found in an BMJ Rapid Response (open-access) which does not require subscription to view. [2]

c) This article is not meant to be a comprehensive analysis of recovery or case definitions, it is simply a commentary which focuses on using normative data from other comparison groups, one of the issues raised in the review by Adamowicz et al. [3] It explores the appropriate control groups or comparison populations, highlights a problem with using the mean ±1 SD as a threshold if the data does not follow a normal distribution, includes some summary statistics, mentions statistical testing at the group level, and encourages researchers to publish enough information so that others can accurately estimate the functional status of participants. Subjective self-reported measures are important but have potential biases (particularly in nonblinded trials lacking placebo control). Objective measures are also important, particularly when assertions that the intervention is effective at increasing function and activity are contradicted by a range of objective measures. See commentaries by Twisk [4] and others. [5-7]

References

1: Bakken IJ, Tveito K, Gunnes N, Ghaderi S, Stoltenberg C, Trogstad L, Håberg SE, Magnus P. Two age peaks in the incidence of chronic fatigue syndrome/myalgic encephalomyelitis: a population-based registry study from Norway 2008-2012. BMC Med. 2014 Oct 1;12:167. doi: 10.1186/s12916-014-0167-5. PMID 25274261. http://www.ncbi.nlm.nih.gov/pmc/articles/pmid/25274261

2: Matthees A. Re: Tackling fears about exercise is important for ME treatment, analysis indicates. BMJ Rapid Response, 21 January 2015. http://www.bmj.com/content/350/bmj.h227/rr-16

3: Adamowicz JL, Caikauskaite I, Friedberg F. Defining recovery in chronic fatigue syndrome: a critical review. Qual Life Res. 2014 Nov;23(9):2407-16. doi: 10.1007/s11136-014-0705-9. Epub 2014 May 3. PMID: 24791749. http://link.springer.com/article/10.1007/s11136-014-0705-9

4: Twisk FN. A definition of recovery in myalgic encephalomyelitis and chronic fatigue syndrome should be based upon objective measures. Qual Life Res. 2014 Nov;23(9):2417-8. doi: 10.1007/s11136-014-0737-1. Epub 2014 Jun 17. PMID: 24935018. http://link.springer.com/article/10.1007/s11136-014-0737-1

5: Kindlon TP. Objective measures found a lack of improvement for CBT & GET in the PACE Trial: subjective improvements may simply represent response biases or placebo effects in this non-blinded trial. BMJ Rapid Response, 18 January 2015. http://www.bmj.com/content/350/bmj.h227/rr-10

6: Wilshire CE. Re: Tackling fears about exercise is important for ME treatment, analysis indicates. BMJ Rapid Response, 19 January 2015. http://www.bmj.com/content/350/bmj.h227/rr-7

7: Faulkner G. In non-blinded trials, self-report measures could mislead. Lancet Psychiatry. Volume 2, No. 4, e7, April 2015. doi: 10.1016/S2215-0366(15)00089-9 http://www.thelancet.com/journals/lanpsy/article/PIIS2215-0366(15)00089-9/fulltext

Behavioral perturbation and sleep in healthy and virus-infected inbred mice

Abstract:

Murine gammaherpesvirus (MuGHV) is a natural pathogen of wild rodents that has been studied extensively in terms of host immune responses to herpesviruses during acute infection, latency, and reactivation from latency. Although herpesvirus infections in people can be associated with fatigue and excessive sleepiness during both acute and latent infection, MuGHV has not been assessed extensively as a model for studying the behavioral consequences of chronic latent herpesvirus infections.

To assess MuGHV infection as a model for evaluating fatigue and assessing potential mechanisms that underlie the exacerbation of fatigue during chronic viral disease, we evaluated sleep, temperature, and activity after exposure of healthy and latently MuGHV-infected mice to sleep fragmentation and social interaction. Neither treatment nor infection significantly affected temperature. However, at some time points, latently infected mice that underwent sleep fragmentation had less locomotor activity and more slow-wave sleep than did mice exposed to social interaction. In addition, delta-wave amplitude during slow-wave sleep was lower in infected mice exposed to sleep fragmentation compared with uninfected mice exposed to the same treatment.

Both reduced locomotor activity and increased time asleep could indicate fatigue in infected mice after sleep fragmentation; reduced delta-wave amplitude during slow-wave sleep indicates a light plane of sleep from which subjects would be aroused easily. Identifying the mechanisms that underlie sleep responses of mice with chronic latent MuGHV infection may increase our understanding of fatigue during infections and eventually contribute to improving the quality of life for people with chronic viral infections.

 

Source: Trammell RA, Toth LA. Behavioral perturbation and sleep in healthy and virus-infected inbred mice. Comp Med. 2014 Aug;64(4):283-92. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4170093/ (Full article)

 

Pain and pressure pain thresholds in adolescents with chronic fatigue syndrome and healthy controls: a cross-sectional study

Abstract:

OBJECTIVES: Although pain is a significant symptom in chronic fatigue syndrome (CFS), pain is poorly understood in adolescents with CFS. The aim of this study was to explore pain distribution and prevalence, pain intensity and its functional interference in everyday life, as well as pressure pain thresholds (PPT) in adolescents with CFS and compare this with a control group of healthy adolescents (HC).

METHODS: This is a case-control, cross-sectional study on pain including 120 adolescents with CFS and 39 HCs, aged 12-18 years. We measured pain frequency, pain severity and pain interference using self-reporting questionnaires. PPT was measured using pressure algometry. Data were collected from March 2010 until October 2012 as part of the Norwegian Study of Chronic Fatigue Syndrome in Adolescents: Pathophysiology and Intervention Trial.

RESULTS: Adolescents with CFS had significantly lower PPTs compared with HCs (p<0.001). The Pain Severity Score and the Pain Interference Score were significantly higher in adolescents with CFS compared with HCs (p<0.001). Almost all adolescents with CFS experienced headache, abdominal pain and/or pain in muscles and joints. Moreover, in all sites, the pain intensity levels were significantly higher than in HCs (p<0.001).

CONCLUSIONS: We found a higher prevalence of severe pain among adolescents with CFS and lowered pain thresholds compared with HCs. The mechanisms, however, are still obscure. Large longitudinal population surveys are warranted measuring pain thresholds prior to the onset of CFS.

TRIAL REGISTRATION NUMBER: Clinical Trials, NCT01040429; The Norwegian Study of Chronic Fatigue Syndrome in Adolescents: Pathophysiology and Intervention Trial (NorCAPITAL) http://www.clinicaltrials.gov.

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

 

Source: Winger A, Kvarstein G, Wyller VB, Sulheim D, Fagermoen E, Småstuen MC, Helseth S. Pain and pressure pain thresholds in adolescents with chronic fatigue syndrome and healthy controls: a cross-sectional study. BMJ Open. 2014 Oct 6;4(9):e005920. doi: 10.1136/bmjopen-2014-005920. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4187660/ (Full article)

 

Phenylephrine alteration of cerebral blood flow during orthostasis: effect on n-back performance in chronic fatigue syndrome

Abstract:

Chronic fatigue syndrome (CFS) with orthostatic intolerance is characterized by neurocognitive deficits and impaired working memory, concentration, and information processing. In CFS, upright tilting [head-up tilt (HUT)] caused decreased cerebral blood flow velocity (CBFv) related to hyperventilation/hypocapnia and impaired cerebral autoregulation; increasing orthostatic stress resulted in decreased neurocognition.

We loaded the baroreflex with phenylephrine to prevent hyperventilation and performed n-back neurocognition testing in 11 control subjects and 15 CFS patients. HUT caused a significant increase in heart rate (109.4 ± 3.9 vs. 77.2 ± 1.6 beats/min, P < 0.05) and respiratory rate (20.9 ± 1.7 vs. 14.2 ± 1.2 breaths/min, P < 0.05) and decrease in end-tidal CO2 (ETCO2; 42.8 ± 1.2 vs. 33.9 ± 1.1 Torr, P < 0.05) in CFS vs. control. HUT caused CBFv to decrease 8.7% in control subjects but fell 22.5% in CFS.

In CFS, phenylephrine prevented the HUT-induced hyperventilation/hypocapnia and the significant drop in CBFv with HUT (-8.1% vs. -22.5% untreated). There was no difference in control subject n-back normalized response time (nRT) comparing supine to HUT (106.1 ± 6.9 vs. 97.6 ± 7.1 ms at n = 4), and no difference comparing control to CFS while supine (97.1 ± 7.1 vs 96.5 ± 3.9 ms at n = 4). However, HUT of CFS subjects caused a significant increase in nRT (148.0 ± 9.3 vs. 96.4 ± 6.0 ms at n = 4) compared with supine.

Phenylephrine significantly reduced the HUT-induced increase in nRT in CFS to levels similar to supine (114.6 ± 7.1 vs. 114.6 ± 9.3 ms at n = 4). Compared with control subjects, CFS subjects are more sensitive both to orthostatic challenge and to baroreflex/chemoreflex-mediated interventions. Increasing blood pressure with phenylephrine can alter CBFv. In CFS subjects, mitigation of the HUT-induced CBFv decrease with phenylephrine has a beneficial effect on n-back outcome.

Copyright © 2014 the American Physiological Society.

 

Source: Medow MS, Sood S, Messer Z, Dzogbeta S, Terilli C, Stewart JM. Phenylephrine alteration of cerebral blood flow during orthostasis: effect on n-back performance in chronic fatigue syndrome. J Appl Physiol (1985). 2014 Nov 15;117(10):1157-64. doi: 10.1152/japplphysiol.00527.2014. Epub 2014 Oct 2. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4233252/ (Full article)

 

A Study of the Protective Effect of Triticum aestivum L. in an Experimental Animal Model of Chronic Fatigue Syndrome

Abstract:

BACKGROUND: Oxidative stress plays a major role in the pathogenesis of chronic fatigue syndrome (CFS). Keeping in view the proven antioxidant activity of Triticum aestivum L., this study has been undertaken to explore the potential therapeutic benefit of this plant in the treatment of CFS.

OBJECTIVE: To study the protective effect of the ethanolic extract of the leaves of Triticum aestivum (EETA) in an experimental mice model of CFS.

MATERIALS AND METHODS: Five groups of albino mice (20-25 g) were selected for the study, with five animals in each group. Group A served as the naïve control and Group B served as the stressed control. Groups C and D received EETA (100 mg/kg and 200 mg/kg b.w.). Group E received imipramine (20 mg/kg b.w.). Except for Group A, mice in each group were forced to swim 6 min each for 7 days to induce a state of chronic fatigue. Duration of immobility was measured on every alternate day. After 7 days, various behavioral tests (mirror chamber and elevated plus maize test for anxiety, open field test for locomotor activity) and biochemical estimations (malondialdehyde [MDA] and catalase activity) in mice brain were performed.

RESULTS: Forced swimming in the stressed group resulted in a significant increase in immobility period, decrease in locomotor activity and elevated anxiety level. The brain homogenate showed significantly increased MDA and decreased catalase levels. The extract-treated groups showed significantly (P < 0.05) improved locomotor activity, decreased anxiety level, elevated catalase levels and reduction of MDA.

CONCLUSION: The study confirms the protective effects of EETA in CFS.

 

Source: Borah M, Sarma P, Das S. A Study of the Protective Effect of Triticum aestivum L. in an Experimental Animal Model of Chronic Fatigue Syndrome. Pharmacognosy Res. 2014 Oct;6(4):285-91. Doi: 10.4103/0974-8490.138251. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4166815/ (Full article)

 

Two age peaks in the incidence of chronic fatigue syndrome/myalgic encephalomyelitis: a population-based registry study from Norway 2008-2012

Abstract:

BACKGROUND: The aim of the current study was to estimate sex- and age-specific incidence rates of chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) using population-based registry data. CFS/ME is a debilitating condition with large impact on patients and their families. The etiology is unknown, and the distribution of the disease in the general population has not been well described.

METHODS: Cases of CFS/ME were identified in the Norwegian Patient Register (NPR) for the years 2008 to 2012. The NPR is nationwide and contains diagnoses assigned by specialist health care services (hospitals and outpatient clinics). We estimated sex- and age-specific incidence rates by dividing the number of new cases of CFS/ME in each category by the number of person years at risk. Incidence rate ratios were estimated by Poisson regression with sex, age categories, and year of diagnosis as covariates.

RESULTS: A total of 5,809 patients were registered with CFS/ME during 2008 to 2012. The overall incidence rate was 25.8 per 100,000 person years (95% confidence interval (CI): 25.2 to 26.5). The female to male incidence rate ratio of CFS/ME was 3.2 (95% CI: 3.0 to 3.4). The incidence rate varied strongly with age for both sexes, with a first peak in the age group 10 to 19 years and a second peak in the age group 30 to 39 years.

CONCLUSIONS: Early etiological clues can sometimes be gained from examination of disease patterns. The strong female preponderance and the two age peaks suggest that sex- and age-specific factors may modulate the risk of CFS/ME.

 

Source: Bakken IJ, Tveito K, Gunnes N, Ghaderi S, Stoltenberg C, Trogstad L, Håberg SE, Magnus P. Two age peaks in the incidence of chronic fatigue syndrome/myalgic encephalomyelitis: a population-based registry study from Norway 2008-2012. BMC Med. 2014 Oct 1;12:167. doi: 10.1186/s12916-014-0167-5. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4189623/ (full article)

Comment:

Cortisol output in adolescents with chronic fatigue syndrome: pilot study on the comparison with healthy adolescents and change after cognitive behavioural guided self-help treatment

Abstract:

OBJECTIVE: This study examined cortisol in adolescents with chronic fatigue syndrome (CFS) compared to healthy adolescents and changes in cortisol after cognitive behavioural guided self-help treatment. Exploratory analyses investigated the association between cortisol output and psychological variables.

METHODS: Salivary cortisol was measured upon awakening, at 15, 30, 45 and 60 min afterwards and at 12 noon, 4:00 p.m. and 8:00 p.m., in adolescents with CFS and healthy controls (HC). Groups were matched for age, gender, menarche status, menstrual cycle and awakening time. Twenty-four adolescents with CFS provided saliva samples six months after treatment. The main outcome measure was total salivary output over the day, calculated by area under the curve (AUC). The salivary awakening response was also assessed.

RESULTS: Cortisol output over the day was significantly lower in the CFS group (n=46) than in healthy controls (n=33). Within the CFS group, lower daily cortisol output was associated with higher self-reported perfectionist striving and prosocial behaviour. There were no significant group differences in the awakening response (n=47 CFS versus n=34 HC). After treatment, adolescents with CFS (n=21) showed a significant increase in daily cortisol output, up to normal levels.

CONCLUSION: The reduced daily cortisol output in adolescents with CFS is in line with adult findings. Associations between reduced cortisol output and two psychological variables-perfectionism and prosocial behaviour-are consistent with cognitive behavioural models of chronic fatigue syndrome. The mild hypocortisolism is reversible; cortisol output had returned to healthy adolescent levels by six months after cognitive behavioural guided self-help treatment.

Copyright © 2014 Elsevier Inc. All rights reserved.

 

Source: Rimes KA, Papadopoulos AS, Cleare AJ, Chalder T. Cortisol output in adolescents with chronic fatigue syndrome: pilot study on the comparison with healthy adolescents and change after cognitive behavioural guided self-help treatment. J Psychosom Res. 2014 Nov;77(5):409-14. doi: 10.1016/j.jpsychores.2014.08.018. Epub 2014 Sep 8.https://www.ncbi.nlm.nih.gov/pubmed/25260861

 

Use of single-nucleotide polymorphisms (SNPs) to distinguish gene expression subtypes of chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME)

Abstract:

AIMS: We have reported gene expression changes in patients with chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) and the fact that such gene expression data can be used to identify subtypes of CFS/ME with distinct clinical phenotypes. Due to the difficulties in using a comparative gene expression method as an aid to CFS/ME disease and subtype-specific diagnosis, we have attempted to develop such a method based on single-nucleotide polymorphism (SNP) analysis.

METHODS: To identify SNP allele associations with CFS/ME and CFS/ME subtypes, we tested genomic DNA of patients with CFS/ME (n=108), patients with endogenous depression (n=17) and normal blood donors (n=68) for 504 human SNP alleles located within 88 CFS-associated human genes using the SNP Genotyping GoldenGate Assay (Illumina, San Diego, California, USA). 360 ancestry informative markers (AIM) were also examined.

RESULTS: 21 SNPs were significantly associated with CFS/ME compared with depression and normal groups. 148 SNP alleles had a significant association with one or more CFS/ME subtypes. For each subtype, associated SNPs tended to be grouped together within particular genes. AIM SNPs indicated that 4 subjects were of Asian origin while the remainder were Caucasian. Hierarchical clustering of AIM data revealed the relatedness between 2 couples of patients with CFS only and confirmed the overall heterogeneity of all subjects.

CONCLUSIONS: This study provides evidence that human SNPs located within CFS/ME associated genes are associated with particular genomic subtypes of CFS/ME. Further work is required to develop this into a clinically useful subtype-specific diagnostic test.

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

 

Source: Shimosako N, Kerr JR. Use of single-nucleotide polymorphisms (SNPs) to distinguish gene expression subtypes of chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME). J Clin Pathol. 2014 Dec;67(12):1078-83. doi: 10.1136/jclinpath-2014-202597. Epub 2014 Sep 19. https://www.ncbi.nlm.nih.gov/pubmed/25240059

 

Multiple Sclerosis/Chronic Fatigue Syndrome overlap: When two common disorders collide

Abstract:

INTRODUCTION: Fatigue is a major cause of disability and handicap in Multiple Sclerosis (MS) patients. The management of this common problem is often difficult. Chronic Fatigue Syndrome (CFS/ME) is another common cause of fatigue which is prevalent in the same population of middle aged females commonly affected by MS.

AIM: This report aims at examining the potential coexistence of MS and CFS/ME in the same patients.

METHOD: This is a retrospective study examining a cohort of MS patients referred for rehabilitation. The subjects were screened for CFS/ME symptoms.

RESULTS: Sixty-four MS patients (43 females) were screened for CFS/ME. Nine patients (14%) with a mean age 52 (SD 9.7) who were all females fulfilled the Fukuda criteria for diagnosis of CFS/ME. Their symptoms, including muscular and joint pain, malaise and recurrent headaches, were not explained by the pattern of their MS.

DISCUSSION: MS and CFS/ME are two common conditions with increased prevalence in middle aged females. As the diagnosis of CFS/ME is clinical with no positive clinical signs or investigations; it can be made with difficulty in the presence of another clear explanation for the disabling fatigue. Our results suggest that the two conditions may co-exist. Considering CFS/ME as a potential co-morbidity may lead to more focused and appropriate management.

 

Source: Gaber TA, Oo WW, Ringrose H. Multiple Sclerosis/Chronic Fatigue Syndrome overlap: When two common disorders collide. NeuroRehabilitation. 2014;35(3):529-34. doi: 10.3233/NRE-141146. https://www.ncbi.nlm.nih.gov/pubmed/25238862

 

High-throughput sequencing of plasma microRNA in chronic fatigue syndrome/myalgic encephalomyelitis

Abstract:

BACKGROUND: MicroRNAs (miRNAs) are known to regulate many biological processes and their dysregulation has been associated with a variety of diseases including Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME). The recent discovery of stable and reproducible miRNA in plasma has raised the possibility that circulating miRNAs may serve as novel diagnostic markers. The objective of this study was to determine the role of plasma miRNA in CFS/ME.

RESULTS: Using Illumina high-throughput sequencing we identified 19 miRNAs that were differentially expressed in the plasma of CFS/ME patients in comparison to non-fatigued controls. Following RT-qPCR analysis, we were able to confirm the significant up-regulation of three miRNAs (hsa-miR-127-3p, hsa-miR-142-5p and hsa-miR-143-3p) in the CFS/ME patients.

CONCLUSION: Our study is the first to identify circulating miRNAs from CFS/ME patients and also to confirm three differentially expressed circulating miRNAs in CFS/ME patients, providing a basis for further study to find useful CFS/ME biomarkers.

 

Source: Brenu EW, Ashton KJ, Batovska J, Staines DR, Marshall-Gradisnik SM. High-throughput sequencing of plasma microRNA in chronic fatigue syndrome/myalgic encephalomyelitis. PLoS One. 2014 Sep 19;9(9):e102783. doi: 10.1371/journal.pone.0102783. ECollection 2014. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4169517/ (Full article)