Greta Moorkens

Hypothalamic-pituitary-adrenal axis function in chronic fatigue syndrome

There is evidence for a hypofunction of the hypothalamic-pituitary-adrenal (HPA) axis in a proportion of the patients with chronic fatigue syndrome (CFS), despite the negative studies and methodological difficulties. In this review, we focus on challenge studies and on the role of the HPA axis in the pathogenesis of CFS. Mild hypocortisolism, blunted adrenocorticotropin response to stressors and enhanced negative feedback sensitivity to glucocorticoids are the main findings. Several underlying mechanisms have been proposed. Currently, it is a matter of debate whether these disturbances have a primary role in the pathogenesis of CFS. However, even if the HPA axis dysfunctions are secondary to other factors, they are probably a relevant factor in symptom propagation in CFS.

Antioxidant status and lipoprotein peroxidation in chronic fatigue syndrome

The aetiology and pathogenesis of the Chronic Fatigue Syndrome (CFS) are still largely unresolved. Accompanying metabolic disorders such as selective n-6 fatty acid depletion suggest that oxidative stress and more specifically lipid peroxidation might play a role in its pathogenesis. In order to investigate this hypothesis, oxidant-antioxidant status and its impact on lipoprotein peroxidation in vitro was examined in 61 patients with unexplained fatigue lasting more than 1 month. They were subdivided into 2 groups: group CFS+ (33 subjects) fulfilled the 1988 Center of Disease Control criteria for CFS and group CFS- did not but was similar as regards age, sex distribution and clinical characteristics. Antioxidant status was similar in the 2 groups except for lower serum transferrin in the CFS + (mean (95 % CI) 2.41 (2.28-2.54) versus 2.73 (2.54-2.92) g/L in the CFS-, p = 0.009) and higher lipoprotein peroxidation in vitro: 6630 (5949-7312) versus 5581 (4852-6310) nmol MDA/mg LDL and VLDL cholesterol x minutes, p = 0.035). CFS intensified the influence of LDL cholesterol (p = 0.012) and of transferrin (p = 0.045) on peroxidation in vitro, suggesting additional pro-oxidant effects. These results indicate that patients with CFS have increased susceptibility of LDL and VLDL to copper-induced peroxidation and that this is related both to their lower levels of serum transferrin and to other unidentified pro-oxidising effects of CFS.

Magnesium Status and Parameters of the Oxidant-Antioxidant Balance in Patients with Chronic Fatigue: Effects of Supplementation with Magnesium

Objective: Magnesium deficiency and oxidative stress have both been identified as pathogenic factors in aging and in several age-related diseases. The link between these two factors is unclear in humans although, in experimental animals, severe Mg deficiency has been shown to lead to increased oxidative stress. Methods: The relationship between Mg body stores, dietary intakes and supplements on the one hand and parameters of the oxidant-antioxidant balance on the other was investigated in human subjects. Results: The study population consisted of 93 patients with unexplained chronic fatigue (median age 38 years, 25% male, 16% smokers and 54% with Chronic Fatigue Syndrome (CFS). Mg deficient patients (47%) had lower total antioxidant capacity in plasma (p=0.007) which was related to serum albumin. Mg deficient patients whose Mg body stores did not improve after oral supplementation with Mg (10 mg/kg/day) had persistently lower blood glutathione levels (p=0.003). In vitro production of thiobarbituric acid reactive substances (TBARS) by non-HDL lipoproteins incubated with copper was related to serum cholesterol (p<0.001) but not to Mg or antioxidants and did not improve after Mg supplementation. In contrast, velocity of formation of fluorescent products of peroxidation (slope) correlated with serum vitamin E (p<0.001), which was, in turn, related to Mg dietary intakes. Both slope and serum vitamin E improved after Mg supplementation (p<0.001). Conclusions: These results show that the lower antioxidant capacity found in moderate Mg deficiency was not due to a deficit in Mg dietary intakes and was not accompanied by increased lipid susceptibility to in vitro peroxidation. Nevertheless, Mg supplementation was followed by an improvement in Mg body stores, in serum vitamin E and its interrelated stage of lipid peroxidation.

In the mind or in the brain? Scientific evidence for central sensitisation in chronic fatigue syndrome

Eur J Clin Invest 2011

Combined dexamethasone/corticotropin-releasing factor test in chronic fatigue syndrome

BACKGROUND Studies of hypothalamic-pituitary-adrenal (HPA) axis function in chronic fatigue syndrome (CFS) point to hypofunction, although there are negative reports. Suggested mechanisms include a reduced hypothalamic or supra-hypothalamic stimulus to the HPA axis and enhanced sensitivity to the negative feedback of glucocorticoids. The aim of the current study was to investigate HPA axis function in CFS with the dexamethasone/corticotropin-releasing factor (Dex/CRF) test, in analogy with research in affective disorders. METHOD Thirty-four well-characterized female CFS patients and 25 healthy control subjects participated in the low-dose Dex/CRF test. Current major depressive episode was an exclusion criterion. History of early-life stress (ELS) was assessed with the Structured Trauma Interview. RESULTS Salivary cortisol responses after 0.5 mg Dex were lower in CFS patients than in controls (before 100 microg CRF, p=0.038; after 100 microg CRF, p=0.015). A secondary analysis revealed an influence of early-life stress and of oestrogen intake. After removal of the 10 participants who were taking an oral oestrogen, patients without a history of ELS showed lower cortisol responses than patients with ELS and controls (before CRF, p=0.005; after CRF, p=0.008). CONCLUSIONS CFS is globally associated with reduced cortisol responses in the combined low-dose Dex/CRF test, but this effect is only clearly present in CFS patients without a history of ELS. This study provides further support for an enhanced glucocorticoid negative feedback and/or a reduced central HPA axis drive in CFS. Furthermore, it demonstrates that ELS is an important variable to consider in CFS research.

Use of the Temperament and Character Inventory (TCI) for Assessment of Personality in Chronic Fatigue Syndrome

BACKGROUND Chronic fatigue syndrome (CFS) is characterized by severe and prolonged fatigue, along with a set of nonspecific symptoms and signs, such as sore throat, muscle pain, headaches, and difficulties with concentration or memory. OBJECTIVE The study examined whether CFS is associated with specific dimensions of Cloningers psychobiological model of personality. METHOD Personality profiles were compared between 38 CFS patients and 42 control subjects by means of the Temperament and Character Inventory (TCI). RESULTS The CFS group showed significantly higher scores on Harm-Avoidance and Persistence. CONCLUSION The current study shows a significant association between specific personality characteristics and CFS. These personality traits may be implicated in the onset and/or perpetuation of CFS and may be a productive focus for psychotherapy.

Chronic fatigue syndrome and DSM-IV personality disorders

OBJECTIVE Personality is an important factor in the research of the chronic fatigue syndrome (CFS). Although some studies report a high rate of personality disorders--around the 40% level--in samples of patients with CFS, the generalizability of these findings can be questioned. The present study evaluates the prevalence of Diagnostic and Statistical Manual for Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) personality disorders in a sample of female CFS patients and in two control groups. METHOD The ADP-IV questionnaire (Assessment of DSM Personality Disorders IV) was used to assess the DSM-IV-TR personality disorders at a dimensional and categorical level in a sample of 50 female CFS patients and in two matched control samples of Flemish civilians (n=50) and psychiatric patients (n=50). RESULTS The results indicate a striking lack of statistical significant differences between the CFS sample and the Flemish control group at the level of dimensional Trait scores, number of criteria, and prevalence rates of personality disorder diagnoses. Unsurprisingly, higher scores at these levels were obtained within the psychiatric sample. The prevalence of an Axis II disorder was 12% in the Flemish and CFS samples, whereas the psychiatric sample obtained a prevalence of 54%. CONCLUSION The prominent absence of any significant difference in personality disorder characteristics between the female Flemish general population and the CFS samples seems to suggest only a minor etiological role for personality pathology, as defined by the DSM-IV Axis II, within CFS.

Chronic Fatigue Syndrome and DNA Hypomethylation of the Glucocorticoid Receptor Gene Promoter 1F Region: Associations With Hypothalamic-Pituitary-Adrenal Axis Hypofunction and Childhood Trauma

Objectives Chronic fatigue syndrome (CFS) has been associated with hypothalamic-pituitary-adrenal axis hypofunction and enhanced glucocorticoid receptor (GR) sensitivity. In addition, childhood trauma is considered a major risk factor for the syndrome. This study examines DNA methylation of the GR gene (NR3C1) in CFS and associations with childhood sexual and physical trauma. Methods Quantification of DNA methylation within the 1F promoter region of NR3C1 was performed in 76 female patients (46 with no/mild and 30 with moderate/severe childhood trauma) and 19 healthy controls by using Sequenom EpiTYPER. Further, we examined the association of NR3C1-1F promoter methylation with the outcomes of the low-dose (0.5 mg) dexamethasone/corticotropin-releasing factor test in a subset of the study population. Mann-Whitney U tests and Spearman correlations were used for statistical analyses. Results Overall NR3C1-1F DNA methylation was lower in patients with CFS than in controls. After cytosine guanine dinucleotide (CpG)-specific analysis, CpG_1.5 remained significant after Bonferroni correction (adjusted p = .0014). Within the CFS group, overall methylation (&rgr; = 0.477, p = .016) and selective CpG units (CpG_1.5: &rgr; = 0.538, p = .007; CpG_12.13: &rgr; = 0.448, p = .025) were positively correlated with salivary cortisol after dexamethasone administration. There was no significant difference in NR3C1-1F methylation between traumatized and nontraumatized patients. Conclusions We found evidence of NR3C1 promoter hypomethylation in female patients with CFS and the functional relevance of these differences was consistent with the hypothalamic-pituitary-adrenalaxis hypofunction hypothesis (GR hypersuppression). However, we found no evidence of an additional effect of childhood trauma on CFS via alterations in NR3C1 methylation.

Kinesiophobia, catastrophizing and anticipated symptoms before stair climbing in chronic fatigue syndrome: an experimental study.

Purpose: Kinesiophobia and catastrophizing are frequent among people with chronic fatigue syndrome (CFS). This study was aimed at examining (1) whether kinesiophobia, anticipated symptoms and fatigue catastrophizing are related to stair climbing performance in people with CFS; and (2) whether kinesiophobia and fatigue catastrophizing are related to daily physical activity in CFS. Method: Patients with CFS filled in a set of questionnaires, performed a physical demanding task (two floors stair of climbing and descending) with pre-test and post-test heart rate monitoring and immediate post-stair climbing symptom assessment. Real-time activity monitoring was used between the baseline and second assessment day (7 days later). Results: Kinesiophobia and fatigue catastrophizing were strongly related (ρ = 0.62 and 0.67, respectively) to poorer stair climbing performance (i.e. more time required to complete the threatening activity). Kinesiophobia and fatigue catastrophizing were unrelated to the amount of physical activity on the first day following stair climbing or during the seven subsequent days. Conclusion: These findings underscore the importance of kinesiophobia and fatigue catastrophizing for performing physical demanding tasks in everyday life of people with CFS, but refute a cardinal role for kinesiophobia and fatigue catastrophizing in determining daily physical activity level in these patients. Implications for Rehabilitation People with chronic fatigue syndrome (CFS) can easily perform stair climbing, a daily physical activity perceived by themselves as threatening, without triggering symptom flares. This is important as it can be used clinically to convince people with CFS of undertaking such a threatening task during treatment programs such as graded activity or graded exposure. The finding that kinesiophobia and fatigue catastrophizing are strongly related to stair climbing performance in CFS underscores the importance of restructuring the beliefs of these patients about the relationship between activity and symptoms. This should be a key component of the early stages of rehabilitation for people with CFS. In rehabilitation practice, diminishing kinesiophobia and fatigue catastrophizing in patients with CFS appears only relevant for targeting physical activities that are perceived as threatening (e.g. stair climbing), and not for increasing work-related or social (physical) activities. Clinicians can use the Tampa Scale Kinesiophobia version CFS for assessing the fear of patients with CFS to exacerbate their symptoms (including pain, fatigue and brain fog) due to physical activities. Clinicians can use the Tampa Scale fatigue for assessing the fear of patients with CFS to exacerbate their fatigue level due to physical activities.

Influence of symptom expectancies on stair-climbing performance in chronic fatigue syndrome: effect of study context

BackgroundIn patients with chronic fatigue syndrome (CFS), performance of physical activities may be affected by an anticipated increase in symptoms after these activities. Nijs et al. previously studied the influence of symptom expectancies and related psychological processes on the performance of an isolated physical activity [Nijs J, Meeus M, Heins M, Knoop H, Moorkens G, Bleijenberg G. Kinesiophobia, catastrophizing and anticipated symptoms before stair climbing in chronic fatigue syndrome: an experimental study. Disabil Rehabil 2012. doi:10.3109/09638288.2011.641661.].PurposeWe aimed to validate the previous findings in a larger group of patients in a different setting. We also extended the possible underlying psychological processes studied.MethodIn 49 CFS patients, we measured performance (duration and increase in heart rate) during self-paced climbing and descending of two floors of stairs. Before this task, patients rated experienced fatigue and anticipated fatigue after stair climbing. In addition, kinesiophobia, catastrophising and focusing on bodily symptoms were measured. Using correlational and regression analyses, we tested whether performance during stair climbing could be explained by experienced and anticipated fatigue and psychological factors.ResultsLonger duration of stair climbing correlated with higher anticipated fatigue, independently of sex, age, body mass index and fatigue before stair climbing. Focusing on bodily symptoms and fatigue-related catastrophising were related to anticipated fatigue.ConclusionSymptom expectations affect the performance of physical activity in CFS patients, possibly through focusing on bodily symptoms and catastrophising. These findings partially contradict the findings of the previous study, which stresses the importance of study context in conducting this type of experiments (i.e., patient characteristics, instructions).