Does oral coenzyme Q10 plus NADH supplementation improve fatigue and biochemical parameters in chronic fatigue syndrome?

Abstract:

Chronic fatigue syndrome (CFS) is a chronic and extremely debilitating illness characterized by prolonged fatigue and multiple symptoms with unknown cause, diagnostic test, or universally effective treatment. Inflammation, oxidative stress, mitochondrial dysfunction, and CoQ10 deficiency have been well documented in CFS.

We conducted an 8-week, randomized, double-blind placebo-controlled trial to evaluate the benefits of oral CoQ10 (200 mg/day) plus NADH (20 mg/day) supplementation on fatigue and biochemical parameters in 73 Spanish CFS patients. This study was registered in ClinicalTrials.gov (NCT02063126).

A significant improvement of fatigue showing a reduction in fatigue impact scale total score (p<0.05) was reported in treated group versus placebo. In addition, a recovery of the biochemical parameters was also reported. NAD+/NADH (p<0.001), CoQ10 (p<0.05), ATP (p<0.05), and citrate synthase (p<0.05) were significantly higher, and lipoperoxides (p<0.05) were significantly lower in blood mononuclear cells of the treated group. These observations lead to the hypothesis that the oral CoQ10 plus NADH supplementation could confer potential therapeutic benefits on fatigue and biochemical parameters in CFS. Larger sample trials are warranted to confirm these findings.

 

Source: Castro-Marrero J, Cordero MD, Segundo MJ, Sáez-Francàs N, Calvo N, Román-Malo L, Aliste L, Fernández de Sevilla T, Alegre J. Does oral coenzyme Q10 plus NADH supplementation improve fatigue and biochemical parameters in chronic fatigue syndrome? Antioxid Redox Signal. 2015 Mar 10;22(8):679-85. doi: 10.1089/ars.2014.6181. Epub 2014 Dec 18. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4346380/ (Full article)

 

Assessment of activity limitations and participation restrictions with persons with chronic fatigue syndrome: a systematic review

Abstract:

PURPOSE: To summarize measurement instruments used to evaluate activity limitations and participation restrictions in patients with chronic fatigue syndrome (CFS) and review the psychometric properties of these instruments.

METHOD: General information of all included measurement instruments was extracted. The methodological quality was evaluated using the COSMIN checklist. Results of the measurement properties were rated based on the quality criteria of Terwee et al. Finally, overall quality was defined per psychometric property and measurement instrument by use of the quality criteria by Schellingerhout et al.

RESULTS: A total of 68 articles were identified of which eight evaluated the psychometric properties of a measurement instrument assessing activity limitations and participation restrictions. One disease-specific and 37 generic measurement instruments were found. Limited evidence was found for the psychometric properties and clinical usability of these instruments. However, the CFS-activities and participation questionnaire (APQ) is a disease-specific instrument with moderate content and construct validity.

CONCLUSION: The psychometric properties of the reviewed measurement instruments to evaluate activity limitations and participation restrictions are not sufficiently evaluated. Future research is needed to evaluate the psychometric properties of the measurement instruments, including the other properties of the CFS-APQ. If it is necessary to use a measurement instrument, the CFS-APQ is recommended.

IMPLICATIONS FOR REHABILITATION: Chronic fatigue syndrome (CFS). Chronic fatigue syndrome causes activity limitations and participation restrictions in one or more areas of life. Standardized, reliable and valid measurement instruments are necessary to identify these limitations and restrictions. Currently, no measurement instrument is sufficiently evaluated with persons with CFS. If a measurement instrument is needed to identify activity limitations and participation restrictions with persons with CFS, it is recommended to use the CFS-APQ in clinical practice and scientific research.

 

Source: Vergauwen K, Huijnen IP, Kos D, Van de Velde D, van Eupen I, Meeus M. Assessment of activity limitations and participation restrictions with persons with chronic fatigue syndrome: a systematic review. Disabil Rehabil. 2015;37(19):1706-16. doi: 10.3109/09638288.2014.978507. Epub 2014 Nov 3.https://www.ncbi.nlm.nih.gov/pubmed/25365699

 

Isoflavones inhibit poly(I:C)-induced serum, brain, and skin inflammatory mediators – relevance to chronic fatigue syndrome

Abstract:

BACKGROUND: Chronic Fatigue Syndrome (CFS) is a neuroimmunoendocrine disease affecting about 1% of the US population, mostly women. It is characterized by debilitating fatigue for six or more months in the absence of cancer or other systemic diseases. Many CFS patients also have fibromyalgia and skin hypersensitivity that worsen with stress. Corticotropin-releasing hormone (CRH) and neurotensin (NT), secreted under stress, activate mast cells (MC) necessary for allergic reactions to release inflammatory mediators that could contribute to CFS symptoms.

OBJECTIVE: To investigate the effect of isoflavones on the action of polyinosinic:polycytidylic acid (poly(I:C)), with or without swim stress, on mouse locomotor activity and inflammatory mediator expression, as well as on human MC activation.

METHODS: Female C57BL/6 mice were randomly divided into four groups: (a) control/no-swim, (b) control/swim, (c) polyinosinic:polycytidylic acid (poly(I:C))/no swim, and (d) polyinosinic:polycytidylic acid (poly(I:C))/swim. Mice were provided with chow low or high in isoflavones for 2 weeks prior to ip injection with 20 mg/kg poly(I:C) followed or not by swim stress for 15 minutes. Locomotor activity was monitored overnight and animals were sacrificed the following day. Brain and skin gene expression, as well as serum levels, of inflammatory mediators were measured. Data were analyzed using the non-parametric Mann-Whitney U-test.

RESULTS: Poly(I:C)-treated mice had decreased locomotor activity over 24 hours, and increased serum levels of TNF-α, IL-6, KC (IL-8/CXCL8 murine homolog), CCL2,3,4,5, CXCL10, as well as brain and skin gene expression of TNF, IL-6, KC (Cxcl1, IL8 murine homolog), CCL2, CCL4, CCL5 and CXCL10. Histidine decarboxylase (HDC) and NT expression were also increased, but only in the skin, over the same period. High isoflavone diet reversed these effects.

CONCLUSION: Poly(I:C) treatment decreased mouse locomotor activity and increased serum levels and brain and skin gene expression of inflammatory mediators. These effects were inhibited by isoflavones that may prove useful in CFS.

 

Source: Vasiadi M, Newman J, Theoharides TC. Isoflavones inhibit poly(I:C)-induced serum, brain, and skin inflammatory mediators – relevance to chronic fatigue syndrome. J Neuroinflammation. 2014 Oct 31;11:168. doi: 10.1186/s12974-014-0168-5. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4236420/ (Full article)

 

Right arcuate fasciculus abnormality in chronic fatigue syndrome

Abstract:

PURPOSE: To identify whether patients with chronic fatigue syndrome (CFS) have differences in gross brain structure, microscopic structure, or brain perfusion that may explain their symptoms.

MATERIALS AND METHODS: Fifteen patients with CFS were identified by means of retrospective review with an institutional review board-approved waiver of consent and waiver of authorization. Fourteen age- and sex-matched control subjects provided informed consent in accordance with the institutional review board and HIPAA. All subjects underwent 3.0-T volumetric T1-weighted magnetic resonance (MR) imaging, with two diffusion-tensor imaging (DTI) acquisitions and arterial spin labeling (ASL). Open source software was used to segment supratentorial gray and white matter and cerebrospinal fluid to compare gray and white matter volumes and cortical thickness. DTI data were processed with automated fiber quantification, which was used to compare piecewise fractional anisotropy (FA) along 20 tracks. For the volumetric analysis, a regression was performed to account for differences in age, handedness, and total intracranial volume, and for the DTI, FA was compared piecewise along tracks by using an unpaired t test. The open source software segmentation was used to compare cerebral blood flow as measured with ASL.

RESULTS: In the CFS population, FA was increased in the right arcuate fasciculus (P = .0015), and in right-handers, FA was also increased in the right inferior longitudinal fasciculus (ILF) (P = .0008). In patients with CFS, right anterior arcuate FA increased with disease severity (r = 0.649, P = .026). Bilateral white matter volumes were reduced in CFS (mean ± standard deviation, 467 581 mm(3) ± 47 610 for patients vs 504 864 mm(3) ± 68 126 for control subjects, P = .0026), and cortical thickness increased in both right arcuate end points, the middle temporal (T = 4.25) and precentral (T = 6.47) gyri, and one right ILF end point, the occipital lobe (T = 5.36). ASL showed no significant differences.

CONCLUSION: Bilateral white matter atrophy is present in CFS. No differences in perfusion were noted. Right hemispheric increased FA may reflect degeneration of crossing fibers or strengthening of short-range fibers. Right anterior arcuate FA may serve as a biomarker for CFS.

(©) RSNA, 2014.

 

Source: Zeineh MM, Kang J, Atlas SW, Raman MM, Reiss AL, Norris JL, Valencia I, Montoya JG. Right arcuate fasciculus abnormality in chronic fatigue syndrome. Radiology. 2015 Feb;274(2):517-26. doi: 10.1148/radiol.14141079. Epub 2014 Oct 29. https://www.ncbi.nlm.nih.gov/pubmed/25353054

 

Metabolism in chronic fatigue syndrome

Abstract:

Chronic fatigue syndrome (CFS) is a poorly understood condition that presents as long-term physical and mental fatigue with associated symptoms of pain and sensitivity across a broad range of systems in the body. The poor understanding of the disorder comes from the varying clinical diagnostic definitions as well as the broad array of body systems from which its symptoms present.

Studies on metabolism and CFS suggest irregularities in energy metabolism, amino acid metabolism, nucleotide metabolism, nitrogen metabolism, hormone metabolism, and oxidative stress metabolism. The overwhelming body of evidence suggests an oxidative environment with the minimal utilization of mitochondria for efficient energy production. This is coupled with a reduced excretion of amino acids and nitrogen in general.

Metabolomics is a developing field that studies metabolism within a living system under varying conditions of stimuli. Through its development, there has been the optimisation of techniques to do large-scale hypothesis-generating untargeted studies as well as hypothesis-testing targeted studies. These techniques are introduced and show an important future direction for research into complex illnesses such as CFS.

 

Source: Armstrong CW, McGregor NR, Butt HL, Gooley PR. Metabolism in chronic fatigue syndrome. Adv Clin Chem. 2014;66:121-72. https://www.ncbi.nlm.nih.gov/pubmed/25344988

 

Severity Scales for Use in Primary Health Care to Assess Chronic Fatigue Syndrome/Myalgic Encephalomyelitis

Abstract:

Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is a physical and cognitive disabling illness, characterized by severe fatigue and a range of physiological symptoms, that primarily affects women. The immense variation in clinical presentation suggests differences in severity based on symptomology and physical and cognitive functional capacities.

In this article, we examine a number of severity scales used in assessing severity of patients with CFS/ME and the clinical aspects of CFS/ME severity subgroups. The use of severity scales may be important in CFS/ME because it permits the establishment of subgroups that may improve accuracy in both clinical and research settings.

 

Source: Hardcastle SL, Brenu EW, Johnston S, Staines D, Marshall-Gradisnik S. Severity Scales for Use in Primary Health Care to Assess Chronic Fatigue Syndrome/Myalgic Encephalomyelitis. Health Care Women Int. 2016 Jun;37(6):671-86. doi: 10.1080/07399332.2014.962139. Epub 2014 Dec 20. https://www.ncbi.nlm.nih.gov/pubmed/25315708

 

What is in a name? Comparing diagnostic criteria for chronic fatigue syndrome with or without fibromyalgia

Abstract:

The current study had two objectives. (1) to compare objective and self-report measures in patients with chronic fatigue syndrome (CFS) according to the 1994 Center for Disease Control (CDC) criteria, patients with multiple sclerosis (MS), and healthy controls, and (2) to contrast CFS patients who only fulfill CDC criteria to those who also fulfill the criteria for myalgic encephalomyelitis (ME), the 2003 Canadian criteria for ME/CFS, or the comorbid diagnosis of fibromyalgia (FM).

One hundred six participants (48 CFS patients diagnosed following the 1994 CDC criteria, 19 MS patients, and 39 healthy controls) completed questionnaires assessing symptom severity, quality of life, daily functioning, and psychological factors. Objective measures consisted of activity monitoring, evaluation of maximal voluntary contraction and muscle recovery, and cognitive performance. CFS patients were screened whether they also fulfilled ME criteria, the Canadian criteria, and the diagnosis of FM.

CFS patients scored higher on symptom severity, lower on quality of life, and higher on depression and kinesiophobia and worse on MVC, muscle recovery, and cognitive performance compared to the MS patients and the healthy subjects. Daily activity levels were also lower compared to healthy subjects. Only one difference was found between those fulfilling the ME criteria and those who did not regarding the degree of kinesiophobia (lower in ME), while comorbidity for FM significantly increased the symptom burden.

CFS patients report more severe symptoms and are more disabled compared to MS patients and healthy controls. Based on the present study, fulfillment of the ME or Canadian criteria did not seem to give a clinically different picture, whereas a diagnosis of comorbid FM selected symptomatically worse and more disabled patients.

 

Source: Meeus M, Ickmans K, Struyf F, Kos D, Lambrecht L, Willekens B, Cras P, Nijs J. What is in a name? Comparing diagnostic criteria for chronic fatigue syndrome with or without fibromyalgia. Clin Rheumatol. 2016 Jan;35(1):191-203. doi: 10.1007/s10067-014-2793-x. Epub 2014 Oct 14. https://www.ncbi.nlm.nih.gov/pubmed/25308475

 

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)