A diagnostic biomarker profile for fibromyalgia syndrome based on an NMR metabolomics study of selected patients and controls

Abstract:

BACKGROUND: Fibromyalgia syndrome (FMS) is a chronic pain syndrome. A plausible pathogenesis of the disease is uncertain and the pursuit of measurable biomarkers for objective identification of affected individuals is a continuing endeavour in FMS research. Our objective was to perform an explorative metabolomics study (1) to elucidate the global urinary metabolite profile of patients suffering from FMS, and (2) to explore the potential of this metabolite information to augment existing medical practice in diagnosing the disease.

METHODS: We selected patients with a medical history of persistent FMS (n = 18), who described their recent state of the disease through the Fibromyalgia Impact Questionnaire (FIQR) and an in-house clinical questionnaire (IHCQ). Three control groups were used: first-generation family members of the patients (n = 11), age-related individuals without any indications of FMS or related conditions (n = 10), and healthy young (18-22 years) individuals (n = 20). All subjects were female and the biofluid under investigation was urine. Correlation analysis of the FIQR showed the FMS patients represented a well-defined disease group for this metabolomics study. Spectral analyses of urine were conducted using a 500 MHz 1H nuclear magnetic resonance (NMR) spectrometer; data processing and analyses were performed using Matlab, R, SPSS and SAS software.

RESULTS AND DISCUSSION: Unsupervised and supervised multivariate analyses distinguished all three control groups and the FMS patients, and significant increases in metabolites related to the gut microbiome (hippuric, succinic and lactic acids) were observed. We have developed an algorithm for the diagnosis of FMS consisting of three metabolites – succinic acid, taurine and creatine – that have a good level of diagnostic accuracy (Receiver Operating Characteristic (ROC) analysis – area under the curve 90%) and on the pain and fatigue symptoms for the selected FMS patient group.

CONCLUSION: Our data and comparative analyses indicated an altered metabolic profile of patients with FMS, analytically detectable within their urine. Validation studies may substantiate urinary metabolites to supplement information from medical assessment, tender-point measurements and FIQR questionnaires for an improved objective diagnosis of FMS.

Source: Malatji BG, Meyer H, Mason S, Engelke UFH, Wevers RA, van Reenen M, Reinecke CJ. A diagnostic biomarker profile for fibromyalgia syndrome based on an NMR metabolomics study of selected patients and controls. BMC Neurol. 2017 May 11;17(1):88. doi: 10.1186/s12883-017-0863-9. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5426044/ (Full article)

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Diagnosis and Management in Young People: A Primer

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex disease that affects children and adolescents as well as adults. The etiology has not been established. While many pediatricians and other health-care providers are aware of ME/CFS, they often lack essential knowledge that is necessary for diagnosis and treatment. Many young patients experience symptoms for years before receiving a diagnosis.

This primer, written by the International Writing Group for Pediatric ME/CFS, provides information necessary to understand, diagnose, and manage the symptoms of ME/CFS in children and adolescents. ME/CFS is characterized by overwhelming fatigue with a substantial loss of physical and mental stamina. Cardinal features are malaise and a worsening of symptoms following minimal physical or mental exertion. These post-exertional symptoms can persist for hours, days, or weeks and are not relieved by rest or sleep.

Other symptoms include cognitive problems, unrefreshing or disturbed sleep, generalized or localized pain, lightheadedness, and additional symptoms in multiple organ systems. While some young patients can attend school, on a full or part-time basis, many others are wheelchair dependent, housebound, or bedbound.

Prevalence estimates for pediatric ME/CFS vary from 0.1 to 0.5%. Because there is no diagnostic test for ME/CFS, diagnosis is purely clinical, based on the history and the exclusion of other fatiguing illnesses by physical examination and medical testing. Co-existing medical conditions including orthostatic intolerance (OI) are common.

Successful management is based on determining the optimum balance of rest and activity to help prevent post-exertional symptom worsening. Medications are helpful to treat pain, insomnia, OI and other symptoms. The published literature on ME/CFS and specifically that describing the diagnosis and management of pediatric ME/CFS is very limited. Where published studies are lacking, recommendations are based on the clinical observations and practices of the authors.

Source: Rowe PC, Underhill RA, Friedman KJ, Gurwitt A, Medow MS, Schwartz MS, Speight N, Stewart JM, Vallings R, Rowe KS. Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Diagnosis and Management in Young People: A Primer. Front Pediatr. 2017 Jun 19;5:121. doi: 10.3389/fped.2017.00121. eCollection 2017. http://journal.frontiersin.org/article/10.3389/fped.2017.00121/full

Medial prefrontal cortex deficits correlate with unrefreshing sleep in patients with chronic fatigue syndrome

Abstract:

Unrefreshing sleep is a hallmark of chronic fatigue syndrome/myalgic encephalomyelitis (CFS). This study examined brain structure variations associated with sleep quality in patients with CFS. 38 patients with CFS (34.8 ± 10.1 years old) and 14 normal controls (NCs) (34.7 ± 8.4 years old) were recruited. All subjects completed the Hospital Anxiety and Depression Scale, Pittsburgh Sleep Quality Index (PSQI), and Chalder Fatigue Scale (CFQ) questionnaires. Brain MRI measures included global and regional grey and white matter volumes, magnetization transfer T1 weighted (MT-T1w) intensities, and T1 weighted (T1w) and T2 weighted spin echo signal intensities.

We performed voxel based group comparisons of these regional brain MRI measures and regressions of these measures with the PSQI and CFQ scales adjusted for age, anxiety and depression, and the appropriate global measure. In CFS patients, negative correlations were observed in the medial prefrontal cortex (mPFC) between PSQI and MT-T1w intensities (family-wise error corrected cluster, PFWE < 0.05) and between PSQI and T1w intensities (PFWE < 0.05). In the same mPFC location, both MT and T1w intensities were lower in CFS patients compared with NCs (uncorrected voxel P < 0.001).

This study is the first to report that brain structural differences are associated with unrefreshing sleep in CFS. This result refutes the suggestion that unrefreshing sleep is a misperception in CFS patients and further investigation of this symptom is warranted.

Source: Shan ZY, Kwiatek R, Burnet R, Del Fante P, Staines DR, Marshall-Gradisnik SM, Barnden LR. Medial prefrontal cortex deficits correlate with unrefreshing sleep in patients with chronic fatigue syndrome. NMR Biomed. 2017 Jun 29. doi: 10.1002/nbm.3757. [Epub ahead of print] http://onlinelibrary.wiley.com/doi/10.1002/nbm.3757/full

Chronic fatigue syndrome patients have no reason to accept the PACE trial results: Response to Keith J Petrie and John Weinman

Abstract:

Petrie and Weinman urge chronic fatigue syndrome patients to move on from their beliefs about their illness and accept the findings of the PACE trial. This is unreasonable in view of the failure of PACE to achieve evidence of recovery through cognitive behaviour therapy and graded exercise therapy in either self-reports or the objective measure of the 6-minute walking test. Contrary to their suggestion, the Institute of Medicine describes chronic fatigue syndrome not as psychological but as a serious, chronic, systemic disease, with post-exertional malaise as its main feature which inhibits exercise. Linking debate about PACE with intimidation of researchers is unjustifiable and damaging to patients.

Source: Susanna Agardy. Chronic fatigue syndrome patients have no reason to accept the PACE trial results: Response to Keith J Petrie and John Weinman. Journal of Health Psychology. First Published June 27, 2017. http://journals.sagepub.com/doi/10.1177/1359105317715476 (Full article)

Neuroendocrine disorder in chronic fatigue syndrome

Abstract:

Background/aim: Neuroendocrine disorders are considered a possible pathogenetic mechanism in chronic fatigue syndrome (CFS). The aim of our study was to determine the function of the hypothalamic–pituitary–adrenal axis (HPA) and thyroid function in women of reproductive age suffering from CFS.

Materials and methods: The study included 40 women suffering from CFS and 40 healthy women (15–45 years old). Serum levels of cortisol (0800 and 1800 hours), ACTH, total T4, total T3, and TSH were measured in all subjects. The Fibro Fatigue Scale was used for determination of fatigue level.

Results: Cortisol serum levels were normal in both groups. The distinctively positive moderate correlation of morning and afternoon cortisol levels that was observed in healthy women was absent in the CFS group. This may indicate a disturbed physiological rhythm of cortisol secretion. Although basal serum T4, T3, and TSH levels were normal in all subjects, concentrations of T3 were significantly lower in the CFS group.

Conclusion: One-time hormone measurement is not sufficient to detect hormonal imbalance in women suffering from CFS. Absence of a correlation between afternoon and morning cortisol level could be a more representative factor for detecting HPA axis disturbance.

Source: Slavica TOMIC, Snezana BRKIC, Dajana LENDAK, Daniela MARIC, Milica MEDIC STOJANOSKA, Aleksandra NOVAKOV MIKIC. Neuroendocrine disorder in chronic fatigue syndrome. Turkish Journal of Medical Sciences.

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The UK ME/CFS Biobank for biomedical research on Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Multiple Sclerosis

Abstract:

The UK ME/CFS Biobank was launched in August 2011 following extensive consultation with professionals and patient representatives. The bioresource aims to enhance research on myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), related to pathophysiology, biomarkers and therapeutic approaches. The cohort includes 18–60 year olds, encompassing 284 clinically-confirmed ME/CFS cases, 60 neurologist-diagnosed multiple sclerosis (MS) cases, and 135 healthy individuals. The Biobank contains blood samples, aliquoted into serum, plasma, peripheral blood mononuclear cells (PBMC), red blood cells/granulocyte pellet, whole blood, and RNA (totalling 29,863 aliquots). Extensive dataset (700 clinical and socio-demographic variables/participant) enables comprehensive phenotyping. Potential reuse is conditional to ethical approval.

Source: Eliana M Lacerda , Erinna W Bowman, Jacqueline M Cliff, Caroline C Kingdon, Elizabeth C King, Ji-Sook Lee, Taane G Clark, Hazel M Dockrell, Eleanor M Riley, Hayley Curran, Luis Nacul. The UK ME/CFS Biobank for biomedical research on Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Multiple Sclerosis. Open Journal of Bioresources. 4(1), p.4. DOI: http://doi.org/10.5334/ojb.28 http://openbioresources.metajnl.com/articles/10.5334/ojb.28/ (Full article)

HPV vaccination and risk of chronic fatigue syndrome/myalgic encephalomyelitis: A nationwide register-based study from Norway

Abstract:

Background: Vaccination has been suggested to be involved in the aetiology of chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME). HPV vaccine was introduced in the Norwegian Childhood Immunisation Programme and offered 12 year old girls from 2009. We studied the association between HPV vaccination and risk of CFS/ME and also assessed medical history in relation to both risk of CFS/ME and HPV vaccine uptake.

Methods: Individual data from national registries, including the Norwegian Population Registry, the Norwegian Patient Registry and the Norwegian Immunisation Registry were linked using the unique personal identification number. Yearly incidence rates of CFS/ME for 2009–2014 were calculated among the 824,133 boys and girls, aged 10–17 living in Norway during these 6 years. A total of 176,453 girls born 1997–2002 were eligible for HPV vaccination and included in further analyses. Hazard ratios (HRs) of CFS/ME were estimated using Cox regression. Risk differences (RDs) of vaccine uptake were estimated with binomial regression.

Results: A similar yearly increase in incidence rate of CFS/ME was observed among girls and boys, IRR = 1.15 (95% confidence interval (CI) 1.10–1.19) and 1.15 (95% CI 1.09–1.22), respectively. HPV vaccination was not associated with CFS/ME, HR = 0.86 (95% CI 0.69–1.08) for the entire follow-up period and 0.96 (95% CI 0.64–1.43) for the first two years after vaccination. The risk of CFS/ME increased with increasing number of previous hospital contacts, HR = 5.23 (95% CI 3.66–7.49) for 7 or more contacts as compared to no contacts. Girls with 7 or more hospital contacts were less likely to be vaccinated than girls with no previous hospital contacts, RD = −5.5% (95% CI −6.7% to −4.2%).

Conclusions: No indication of increased risk of CFS/ME following HPV vaccination was observed among girls in the first 6 birth cohorts offered HPV vaccine through the national immunisation programme in Norway.

Source: Berit Feiring, Ida Laake, Inger Johanne Bakken, Margrethe Greve-Isdahl, Vegard Bruun Wyller, Siri E. Haberg, Per Magnus, Lill Trogstad. HPV vaccination and risk of chronic fatigue syndrome/myalgic encephalomyelitis: A nationwide register-based study from Norway. Vaccine, June 23, 2017. http://www.sciencedirect.com/science/article/pii/S0264410X17308083

Cognitive behaviour therapy and objective assessments in chronic fatigue syndrome

Abstract:

Most evaluations of cognitive behavioural therapy to treat people with chronic fatigue syndrome/myalgic encephalomyelitis rely exclusively on subjective self-report outcomes to evaluate whether treatment is effective. Few studies have used measures appropriate to assessing whether cognitive behavioural therapy changes in more objective measures. A review of studies incorporating objective measures suggests that there is a lack of evidence that cognitive behavioural therapy produces any improvement in a patient’s physical capabilities or other objective measures such as return to work. Future studies of chronic fatigue syndrome/myalgic encephalomyelitis should include some objective assessments as primary outcomes. If this is to include activity monitors, we first need a sound baseline dataset.

Source: Graham McPhee. Cognitive behaviour therapy and objective assessments in chronic fatigue syndrome. Journal of Health Psychology. First Published June 19, 2017. http://journals.sagepub.com/doi/abs/10.1177/1359105317707215 

Prevalence of and risk factors for severe cognitive and sleep symptoms in ME/CFS and MS

Abstract:

BACKGROUND: There are considerable phenotypic and neuroimmune overlaps between myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and multiple sclerosis (MS). While the precise aetiologies of both MS and ME/CFS are unclear, evidence suggests that deterioration in cognitive function is widely prevalent in patients with either condition. Little is known about differing risk factors or exposures, which may lead to severe cognitive or sleep symptoms. This study aims to gauge the extent of cognitive and sleep symptoms in ME/CFS and MS patients participating in the UK ME/CFS Biobank and identify the characteristics of those experiencing severe symptoms.

METHODS: This was a cross-sectional study of 395 UK ME/CFS Biobank participants, recruited from primary care and the community, using similar standardised protocols, and matched by age, sex and geographical area. Data were collected from participants using a standardized written questionnaire at clinical visits. Cognitive symptoms included problems with short-term memory, attention, and executive function. Sleep symptoms included unrefreshing sleep and poor quality or inadequate duration of sleep. All participants reported symptoms based on an ordinal severity scale. Multivariable logistic regression was carried out in the ME/CFS group to investigate socio-demographic factors associated with severe symptoms.

RESULTS: All cognitive and sleep symptoms were more prevalent in the ME/CFS group, with 'trouble concentrating' (98.3%) the most commonly reported symptom. Severe symptoms were also more commonly reported in the ME/CFS group, with 55% reporting 'severe, unrefreshing sleep'. Similarly, in the MS group, the most commonly reported severe symptoms were sleep-related. Logistic regression analysis revealed that ME/CFS patients aged over 50 years were more than three times as likely to experience severe symptoms than those younger than 30 (OR 3.23, p = 0.031). Current smoking was associated with severe symptoms, increasing the risk by approximately three times (OR 2.93, p = 0.003) and those with household incomes of more than £15,000 per year were less likely to experience severe symptoms compared to those earning less than this (OR 0.31, p = 0.017).

CONCLUSIONS:Cognitive and sleep symptoms are more common in ME/CFS patients than in MS patients and healthy controls, providing further support for existing evidence of central nervous system abnormalities in ME/CFS. Our findings suggest that people with ME/CFS who are smokers, or have a low income, are more likely to report severe cognitive and sleep symptoms. Future research should aim to develop strategies to prevent the progression of severe cognitive and sleep symptoms through early interventions that prioritise patients identified as being at highest risk.

Source: Jain V, Arunkumar A, Kingdon C, Lacerda E, Nacul L. Prevalence of and risk factors for severe cognitive and sleep symptoms in ME/CFS and MS. BMC Neurol. 2017 Jun 20;17(1):117. doi: 10.1186/s12883-017-0896-0. https://bmcneurol.biomedcentral.com/articles/10.1186/s12883-017-0896-0 (Full article)

Pharmacological treatment of patients with chronic fatigue syndrome

Abstract:

AIM: To evaluate the efficacy and safety of human placenta extract – laennec infusions in the treatment of patients with confirmed diagnosis of 'Chronic fatigue syndrome' (CFS).

MATERIAL AND METHODS: The study included 38 patients with CFS, randomized into 2 groups: patients of the experimental group (EG, n=24) were treated with 10 intravenous laennec infusions, 4 ml each, 2 times/week, for 5 weeks. The control group (CG) consisted of 14 patients. Treatment efficacy evaluated by the severity of chronic fatigue ('The degree of chronic fatigue' questionnaire), state anxiety, depression and anger (Spilberger test) and quality of life (SF-36v2), exercise tolerance (cardiopulmonary exercise test with gas analysis), blood parameters were assessed before, after, and 5 weeks of follow-up.

RESULTS AND CONCLUSION: The EG patients showed a significant reduction in the index of chronic fatigue, which was accompanied by the significant decrease in state depression, anxiety, improvements in subjective assessment of quality of life, as well as a significant increase in physical performance indices (maximal oxygen consumption, anaerobic threshold, load time to failure, normalization of the lipid 'profile' immediately after course of infusions and in 5 weeks follow-up). No changes in chronic fatigue index and other recorded indicators were identified in CG. Laennec did not cause side effects, was well tolerated by all patients.

Source: Glazachev OS, Dudnik ЕN, Zagaynaya EE. Pharmacological treatment of patients with chronic fatigue syndrome.Zh Nevrol Psikhiatr Im S S Korsakova. 2017;117(4):40-44. doi: 10.17116/jnevro20171174140-44. (Article in Russian; Abstract available in Russian from the publisher). https://www.ncbi.nlm.nih.gov/pubmed/2861737