Chronic Fatigue Syndrome and Chronic Widespread Pain in Adolescence: Population Birth Cohort Study

Abstract:

Although many studies have investigated the overlap between pain phenotypes and chronic fatigue syndrome (CFS) in adults, little is known about the relationship between these conditions in adolescents. The study’s aim was therefore to identify whether a relationship exists between chronic widespread pain (CWP) and CFS in adolescents and investigate whether the two share common associations with a set of covariates.

A questionnaire was administered to offspring of the Avon Longitudinal Study of Parents and Children (ALSPAC) at age 17, asking about site, duration, and pain intensity, from which participants with CWP were identified. At the same research clinic, a computer-based Revised Clinical Interview Schedule was filled out, from which a classification of CFS was obtained. The relationship between selected covariates and CFS and CWP was investigated using a variety of logistic, ordinal logistic, and multinomial regressions.

We identified 3,214 adolescents with complete data for all outcomes and covariates. There were 82 (2.6%) individuals classified as CFS and 145 (4.5%) as CWP. A classification of CFS resulted in an increased likelihood of having CWP (odds ratio = 3.87; 95% confidence interval, 2.05-7.31). Female adolescents were approximately twice as likely to have CFS or CWP, with multinomial regression revealing a greater sex effect for CWP compared with CFS.

Those with exclusive CFS were more likely to report higher levels of pain and greater effect of pain compared with those without CFS, although associations attenuated to the null after adjustment for covariates, which did not occur in those with exclusive CWP. Multinomial regression revealed that relative to having neither CFS nor CWP, a 1-unit increase in the depression and anxiety scales increased the risk of having exclusive CFS and, to a greater extent, the risk of having comorbid CFS and CWP, but not exclusive CWP, which was only related to anxiety.

PERSPECTIVE: In this cohort, 14.6% of adolescents with CFS have comorbid CWP. The likely greater proportion of more mild cases observed in this epidemiological study means that prevalence of overlap may be underestimated compared with those attending specialist services. Clinicians should be aware of the overlap between the 2 conditions and carefully consider treatment options offered.

Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

 

Source: Norris T, Deere K, Tobias JH, Crawley E. Chronic Fatigue Syndrome and Chronic Widespread Pain in Adolescence: Population Birth Cohort Study. J Pain. 2016 Nov 12. pii: S1526-5900(16)30308-X. doi: 10.1016/j.jpain.2016.10.016. [Epub ahead of print] http://www.jpain.org/article/S1526-5900(16)30308-X/fulltext (Full article)

 

Prefrontal Structure Varies as a Function of Pain Symptoms in Chronic Fatigue Syndrome

Abstract:

BACKGROUND: Chronic fatigue syndrome (CFS) is characterized by severe fatigue persisting for ≥6 months and leading to considerable impairment in daily functioning. Neuroimaging studies of patients with CFS have revealed alterations in prefrontal brain morphology. However, it remains to be determined whether these alterations are specific for fatigue or whether they relate to other common CFS symptoms (e.g., chronic pain, lower psychomotor speed, and reduced physical activity).

METHODS: We used magnetic resonance imaging to quantify gray matter volume (GMV) and the N-acetylaspartate and N-acetylaspartylglutamate/creatine ratio (NAA/Cr) in a group of 89 women with CFS. Building on previous reports, we tested whether GMV and NAA/Cr in the dorsolateral prefrontal cortex are associated with fatigue severity, pain, psychomotor speed, and physical activity, while controlling for depressive symptoms. We also considered GMV and NAA/Cr differences between patients with CFS and 26 sex-, age-, and education-matched healthy controls.

RESULTS: The presence of pain symptoms was the main predictor of both GMV and NAA/Cr in the left dorsolateral prefrontal cortex of patients with CFS. More pain was associated with reduced GMVs and NAA/Cr, over and above the effects of fatigue, depressive symptoms, physical activity, and psychomotor speed. In contrast to previous reports and despite a large representative sample, global GMV did not differ between the CFS and healthy control groups.

CONCLUSIONS: CFS, as diagnosed by Centers for Disease Control and Prevention criteria, is not a clinical entity reliably associated with reduced GMV. Individual variation in the presence of pain, rather than fatigue, is associated with neuronal alterations in the dorsolateral prefrontal cortex of patients with CFS.

Copyright © 2016 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

 

Source: van der Schaaf ME, De Lange FP, Schmits IC, Geurts DE, Roelofs K, van der Meer JW, Toni I, Knoop H. Prefrontal Structure Varies as a Function of Pain Symptoms in Chronic Fatigue Syndrome. Biol Psychiatry. 2017 Feb 15;81(4):358-365. doi: 10.1016/j.biopsych.2016.07.016. Epub 2016 Aug 31. https://www.ncbi.nlm.nih.gov/pubmed/27817843

 

Association of biomarkers with health-related quality of life and history of stressors in myalgic encephalomyelitis/chronic fatigue syndrome patients

Abstract:

BACKGROUND: Myalgic encephalomyelitis chronic fatigue syndrome (ME/CFS) is a common debilitating disorder associated with an intense fatigue, a reduced physical activity, and an impaired quality of life. There are no established biological markerof the syndrome. The etiology is unknown and its pathogenesis appears to be multifactorial. Various stressors, including intense physical activity, severe infection, and emotional stress are reported in the medical history of ME/CFS patients which raises the question whether any physiological and biological abnormalities usually found in these patients could be indicative of the etiology and/or the quality-of-life impairment.

METHODS: Thirty-six patients and 11 age-matched healthy controls were recruited. The following variables that appear to address common symptoms of ME/CFS were studied here: (1) muscle fatigue during exercise has been investigated by monitoring the compound muscle action potential (M-wave); (2) the excessive oxidative stress response to exercise was measured via two plasma markers (thiobarbituric acid reactive substances: TBARS; reduced ascorbic-acid: RAA); (3) a potential inflammatory component was addressed via expression of CD26 on peripheral blood mononuclear cells; (4) quality-of-life impairment was assessed using the London Handicap Scale (LHS) and the Medical Outcome Study Short Form-36 (SF-36). The medical history of each patient, including the presence of stressors such as intense sports practice, severe acute infection and/or severe emotional stress was documented.

RESULTS: We observed that: (1) there were striking differences between cases and controls with regard to three biological variables: post-exercise M-wave, TBARS variations and CD26-expression at rest; (2) each of these three variables correlated with the other two; (3) abnormalities in the biomarkers associated with health-related quality of life: the LHS score was negatively correlated with the exercise-induced TBARS increase and positively correlated with CD26-expression while the pain component of SF-36 was negatively correlated with CD26-expression; (4) the TBARS increase and the M-wave decrease were the highest, and the CD26-expression level the lowest in patients who had been submitted to infectious stressors.

CONCLUSION: In ME/CFS patients, severe alterations of the muscle excitability, the redox status, as well as the CD26-expression level are correlated with a marked impairment of the quality-of-life. They are particularly significant when infectious stressors are reported in the medical history.

 

Source: Fenouillet E, Vigouroux A, Steinberg JG, Chagvardieff A, Retornaz F, Guieu R, Jammes Y. Association of biomarkers with health-related quality of life and history of stressors in myalgic encephalomyelitis/chronic fatigue syndrome patients. J Transl Med. 2016 Aug 31;14:251. doi: 10.1186/s12967-016-1010-x. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5006431/ (Full article)

 

Aberrant Resting-State Functional Connectivity in the Salience Network of Adolescent Chronic Fatigue Syndrome

Abstract:

Neural network investigations are currently absent in adolescent chronic fatigue syndrome (CFS). In this study, we examine whether the core intrinsic connectivity networks (ICNs) are altered in adolescent CFS patients.

Eighteen adolescent patients with CFS and 18 aged matched healthy adolescent control subjects underwent resting-state functional magnetic resonance imaging (rfMRI). Data was analyzed using dual-regression independent components analysis, which is a data-driven approach for the identification of independent brain networks. Intrinsic connectivity was evaluated in the default mode network (DMN), salience network (SN), and central executive network (CEN). Associations between network characteristics and symptoms of CFS were also explored.

Adolescent CFS patients displayed a significant decrease in SN functional connectivity to the right posterior insula compared to healthy comparison participants, which was related to fatigue symptoms. Additionally, there was an association between pain intensity and SN functional connectivity to the left middle insula and caudate that differed between adolescent patients and healthy comparison participants.

Our findings of insula dysfunction and its association with fatigue severity and pain intensity in adolescent CFS demonstrate an aberration of the salience network which might play a role in CFS pathophysiology.

 

Source: Wortinger LA, Endestad T, Melinder AM, Øie MG, Sevenius A, Bruun Wyller V. Aberrant Resting-State Functional Connectivity in the Salience Network of Adolescent Chronic Fatigue Syndrome. PLoS One. 2016 Jul 14;11(7):e0159351. doi: 10.1371/journal.pone.0159351. ECollection 2016. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4944916/ (Full article)

 

Neurocognitive complaints and functional status among patients with chronic fatigue syndrome and fibromyalgia

Abstract:

PURPOSE: The purpose of this study was to conduct a longitudinal examination of cognitive complaints and functional status in patients with chronic fatigue syndrome (CFS) alone and those who also had fibromyalgia (CFS/FM).

METHODS: A total of 93 patients from a tertiary care fatigue clinic were evaluated on four occasions, each 6 months apart. Each evaluation included a tender point assessment, and self-reported functional status and cognitive complaints.

RESULTS: Patients with CFS/FM reported significantly worse physical functioning, more bodily pain, and more cognitive difficulties (visuo-perceptual ability and verbal memory) than patients with CFS alone. Over time, bodily pain decreased only for participants with CFS alone. Verbal memory problems were associated with more bodily pain for both patient groups, whereas visuo-perceptual problems were associated with worse functional status for patients with CFS alone.

CONCLUSIONS: This study adds to the literature on functional status, longitudinal course, and cognitive difficulties among patients with CFS and those with CFS and FM. The results suggest that patients with CFS/FM are more disabled, have more cognitive complaints, and improve more slowly over time than patients with CFS alone. Specific cognitive difficulties are related to worse functional status, which supports the addition of cognitive difficulties to the FM case criteria.

 

Source: Schmaling KB, Betterton KL. Neurocognitive complaints and functional status among patients with chronic fatigue syndrome and fibromyalgia. Qual Life Res. 2016 May;25(5):1257-63. doi: 10.1007/s11136-015-1160-y. Epub 2015 Oct 15. https://www.ncbi.nlm.nih.gov/pubmed/26471263

 

Associations Between Cognitive Performance and Pain in Chronic Fatigue Syndrome: Comorbidity with Fibromyalgia Does Matter

Abstract:

BACKGROUND: In addition to the frequently reported pain complaints, performance-based cognitive capabilities in patients with chronic fatigue syndrome (CFS) with and without comorbid fibromyalgia (FM) are significantly worse than those of healthy controls. In various chronic pain populations, cognitive impairments are known to be related to pain severity. However, to the best of our knowledge, the association between cognitive performance and experimental pain measurements has never been examined in CFS patients.

OBJECTIVES: This study aimed to examine the association between cognitive performance and self-reported as well as experimental pain measurements in CFS patients with and without FM.

STUDY DESIGN: Observational study.

SETTING: The present study took place at the Vrije Universiteit Brussel and the University of Antwerp.

METHODS: Forty-eight (18 CFS-only and 30 CFS+FM) patients and 30 healthy controls were studied. Participants first completed 3 performance-based cognitive tests designed to assess selective and sustained attention, cognitive inhibition, and working memory capacity. Seven days later, experimental pain measurements (pressure pain thresholds [PPT], temporal summation [TS], and conditioned pain modulation [CPM]) took place and participants were asked to fill out 3 questionnaires to assess self-reported pain, fatigue, and depressive symptoms.

RESULTS: In the CFS+FM group, the capacity of pain inhibition was significantly associated with cognitive inhibition. Self-reported pain was significantly associated with simple reaction time in CFS-only patients. The CFS+FM but not the CFS-only group showed a significantly lower PPT and enhanced TS compared with controls.

LIMITATIONS: The cross-sectional nature of this study does not allow for inferences of causation.

CONCLUSIONS: The results underline disease heterogeneity in CFS by indicating that a measure of endogenous pain inhibition might be a significant predictor of cognitive functioning in CFS patients with FM, while self-reported pain appears more appropriate to predict cognitive functioning in CFS patients without FM.

 

Source: Ickmans K, Meeus M, De Kooning M, Lambrecht L, Pattyn N, Nijs J. Associations Between Cognitive Performance and Pain in Chronic Fatigue Syndrome: Comorbidity with Fibromyalgia Does Matter. Pain Physician. 2015 Sep-Oct;18(5):E841-52. http://www.painphysicianjournal.com/current/pdf?article=MjQxOA%3D%3D&journal=91 (Full article as PDF file)

 

Effect of Milnacipran Treatment on Ventricular Lactate in Fibromyalgia: A Randomized, Double-Blind, Placebo-Controlled Trial

Abstract:

Milnacipran, a serotonin/norepinephrine reuptake inhibitor, has been approved by the US Food and Drug Administration for the treatment of fibromyalgia (FM). This report presents the results of a randomized, double-blind, placebo-controlled trial of milnacipran conducted to test the hypotheses that a) similar to patients with chronic fatigue syndrome, patients with FM have increased ventricular lactate levels at baseline; b) 8 weeks of treatment with milnacipran will lower ventricular lactate levels compared with baseline levels and with ventricular lactate levels after placebo; and c) treatment with milnacipran will improve attention and executive function in the Attention Network Test compared with placebo. In addition, we examined the results for potential associations between ventricular lactate and pain. Baseline ventricular lactate measured by proton magnetic resonance spectroscopic imaging was found to be higher in patients with FM than in healthy controls (F1,37 = 22.11, P < .0001, partial η(2) = .37). Milnacipran reduced pain in patients with FM relative to placebo but had no effect on cognitive processing.

At the end of the study, ventricular lactate levels in the milnacipran-treated group had decreased significantly compared with baseline and after placebo (F1,18 = 8.18, P = .01, partial η(2) = .31). A significantly larger proportion of patients treated with milnacipran showed decreases in both ventricular lactate and pain than those treated with placebo (P = .03). These results suggest that proton magnetic resonance spectroscopic imaging measurements of lactate may serve as a potential biomarker for a therapeutic response in FM and that milnacipran may act, at least in part, by targeting the brain response to glial activation and neuroinflammation.

PERSPECTIVE: Patients treated with milnacipran showed decreases in both pain and ventricular lactate levels compared with those treated with placebo, but, even after treatment, levels of ventricular lactate remained higher than in controls. The hypothesized mechanism for these decreases is via drug-induced reductions of a central inflammatory state.

TRIAL REGISTRATION: ClinicalTrials.gov NCT01108731.

Copyright © 2015 American Pain Society. Published by Elsevier Inc. All rights reserved.

 

Source: Natelson BH, Vu D, Mao X, Weiduschat N, Togo F, Lange G, Blate M, Kang G, Coplan JD, Shungu DC. Effect of Milnacipran Treatment on Ventricular Lactate in Fibromyalgia: A Randomized, Double-Blind, Placebo-Controlled Trial. J Pain. 2015 Nov;16(11):1211-9. doi: 10.1016/j.jpain.2015.08.004. Epub 2015 Aug 31. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4630071/ (Full article)

 

Isometric yoga improves the fatigue and pain of patients with chronic fatigue syndrome who are resistant to conventional therapy: a randomized, controlled trial

Abstract:

BACKGROUND: Patients with chronic fatigue syndrome (CFS) often complain of persistent fatigue even after conventional therapies such as pharmacotherapy, cognitive behavioral therapy, or graded exercise therapy. The aim of this study was to investigate in a randomized, controlled trial the feasibility and efficacy of isometric yoga in patients with CFS who are resistant to conventional treatments.

METHODS: This trial enrolled 30 patients with CFS who did not have satisfactory improvement after receiving conventional therapy for at least six months. They were randomly divided into two groups and were treated with either conventional pharmacotherapy (control group, n = 15) or conventional therapy together with isometric yoga practice that consisted of biweekly, 20-minute sessions with a yoga instructor and daily in-home sessions (yoga group, n = 15) for approximately two months. The short-term effect of isometric yoga on fatigue was assessed by administration of the Profile of Mood Status (POMS) questionnaire immediately before and after the final 20-minute session with the instructor. The long-term effect of isometric yoga on fatigue was assessed by administration of the Chalder’s Fatigue Scale (FS) questionnaire to both groups before and after the intervention. Adverse events and changes in subjective symptoms were recorded for subjects in the yoga group.

RESULTS: All subjects completed the intervention. The mean POMS fatigue score decreased significantly (from 21.9 ± 7.7 to 13.8 ± 6.7, P < 0.001) after a yoga session. The Chalder’s FS score decreased significantly (from 25.9 ± 6.1 to 19.2 ± 7.5, P = 0.002) in the yoga group, but not in the control group. In addition to the improvement of fatigue, two patients with CFS and fibromyalgia syndrome in the yoga group also reported pain relief. Furthermore, many subjects reported that their bodies became warmer and lighter after practicing isometric yoga. Although there were no serious adverse events in the yoga group, two patients complained of tiredness and one of dizziness after the first yoga session with the instructor.

CONCLUSIONS: Isometric yoga as an add-on therapy is both feasible and successful at relieving the fatigue and pain of a subset of therapy-resistant patients with CFS.

TRIAL REGISTRATION: University Hospital Medical Information Network (UMIN CTR) UMIN000009646.

 

Source: Oka T, Tanahashi T, Chijiwa T, Lkhagvasuren B, Sudo N, Oka K. Isometric yoga improves the fatigue and pain of patients with chronic fatigue syndrome who are resistant to conventional therapy: a randomized, controlled trial. Biopsychosoc Med. 2014 Dec 11;8(1):27. doi: 10.1186/s13030-014-0027-8. ECollection 2014. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4269854/ (Full article)

 

The Process of Change in Pain During Cognitive-Behavior Therapy for Chronic Fatigue Syndrome

Abstract:

BACKGROUND: Cognitive-behavior therapy (CBT) leads to a reduction of fatigue and pain in chronic fatigue syndrome. The processes underlying the reduction in pain have not been investigated. Recently, it was shown that increased self-efficacy, decreased focusing on symptoms, increased physical functioning, and a change in beliefs about activity contribute to the decrease in fatigue.

OBJECTIVES: The present study has 2 objectives: (1) to determine the relationship between the reduction of fatigue and pain during CBT; (2) test to what extent the model for change in fatigue is applicable to the reduction in pain.

MATERIALS AND METHODS: One hundred forty-two patients meeting United States centers for Disease Control and Prevention criteria for chronic fatigue syndrome, currently reporting pain, and starting CBT were included. A cross-lagged analysis was performed to study the causal direction of change between pain and fatigue. Pain and process variables were assessed before therapy, 3 times during CBT, and after therapy. Actual physical activity was also assessed. The model was tested with multiple regression analyses.

RESULTS: The direction of change between pain and fatigue could not be determined. An increase in physical functioning and decrease in focusing on symptoms explained 4% to 14% of the change in pain.

CONCLUSIONS: Pain and fatigue most probably decrease simultaneously during CBT. Pain reduction can partly be explained by a reduction of symptom focusing and increased physical functioning. Additional, yet unknown cognitive-behavioral factors also play a role in the reduction of pain.

 

Source: Bloot L, Heins MJ, Donders R, Bleijenberg G, Knoop H. The Process of Change in Pain During Cognitive-Behavior Therapy for Chronic Fatigue Syndrome. Clin J Pain. 2015 Oct;31(10):914-21. doi: 10.1097/AJP.0000000000000191. https://www.ncbi.nlm.nih.gov/pubmed/25503595

 

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)