Undiagnosed and comorbid disorders in patients with presumed chronic fatigue syndrome

Objective

To assess undiagnosed and comorbid disorders in patients referred to a tertiary care center with a presumed diagnosis of chronic fatigue syndrome (CFS).

Methods

Patients referred for chronic unexplained fatigue entered an integrated diagnostic pathway, including internal medicine assessment, psychodiagnostic screening, physiotherapeutic assessment and polysomnography + multiple sleep latency testing. Final diagnosis resulted from a multidisciplinary team discussion. Fukuda criteria were used for the diagnosis of CFS, DSM-IV-TR criteria for psychiatric disorders, ICSD-2 criteria for sleep disorders.

Results

Out of 377 patients referred, 279 (74.0%) were included in the study [84.9% female; mean age 38.8 years (SD 10.3)].A diagnosis of unequivocal CFS was made in 23.3%. In 21.1%, CFS was associated with a sleep disorder and/or psychiatric disorder, not invalidating the diagnosis of CFS. A predominant sleep disorder was found in 9.7%, 19.0% had a psychiatric disorder and 20.8% a combination of both. Only 2.2% was diagnosed with a classical internal disease.In the total sample, a sleep disorder was found in 49.8%, especially obstructive sleep apnea syndrome, followed by psychophysiologic insomnia and periodic limb movement disorder. A psychiatric disorder was diagnosed in 45.2%; mostly mood and anxiety disorder.

Conclusions

A multidisciplinary approach to presumed CFS yields unequivocal CFS in only a minority of patients, and reveals a broad spectrum of exclusionary or comorbid conditions within the domains of sleep medicine and psychiatry. These findings favor a systematic diagnostic approach to CFS, suitable to identify a wide range of diagnostic categories that may be subject to dedicated care.     

Cognitive deficits in patients with chronic fatigue syndrome compared to those with major depressive disorder and healthy controls

Object

Chronic fatigue syndrome (CFS) patients report usually cognitive complaints. They also have frequently comorbid depression that can be considered a possible explanation for their cognitive dysfunction. We evaluated the cognitive performance of patients with CFS in comparison with a control group of healthy volunteers and a group of patients with MDD.

Patients and methods

Twenty-five patients with CFS, 25 patients with major depressive disorder (MDD), and 25 healthy control subjects were given standardized tests of attention, working memory, and verbal and visual episodic memory, and were also tested for effects related to lack of effort/simulation, suggestibility, and fatigue.

Results

Patients with CFS had slower phasic alertness, and also had impaired working, visual and verbal episodic memory compared to controls. They were, however, no more sensitive than the other groups to suggestibility or to fatigue induced during the cognitive session. Cognitive impairments in MDD patients were strongly associated with depression and subjective fatigue; in patients with CFS, there was a weaker correlation between cognition and depression (and no correlation with fatigue).

Conclusions

This study confirms the presence of an objective impairment in attention and memory in patients with CFS but with good mobilization of effort and without exaggerated suggestibility.     

Síndrome de fatiga crónica y los trastornos del sueño: relaciones clínicas y dificultades diagnósticas

Introduction

Chronic fatigue syndrome (CFS) is characterised by the presence of intractable fatigue and non-restorative sleep, symptoms which are also very prevalent in multiple diseases and appear as side effects of different drugs. Numerous studies have shown a high prevalence of sleep disorders in patients with CFS. However, non-restorative sleep and fatigue are frequently symptoms of the sleep disorders themselves, so primary sleep disorders have to be ruled out in many cases of CFS.

Chronic Fatigue and Personality: A Twin Study of Causal Pathways and Shared Liabilities

Background

The etiology of chronic fatigue syndrome (CFS) remains unknown. Personality traits influence well-being and may play a role in CFS and unexplained chronic fatigue.

Purpose

This study aimed to examine the association of emotional instability and extraversion with chronic fatigue and CFS in a genetically informative sample.

Methods

We evaluated 245 twin pairs for two definitions of chronic fatigue. They completed the Neuroticism and Extraversion subscales of the NEO Five Factor Inventory. Using a co-twin control design, we examined the association between personality and chronic fatigue.

Results

Higher emotional instability was associated with both definitions of chronic fatigue and was confounded by shared genetics. Lower extraversion was also associated with both definitions of fatigue, but was not confounded by familial factors.

Conclusions

Both emotional instability and extraversion are related to chronic fatigue and CFS. Whereas emotional instability and chronic fatigue are linked by shared genetic mechanisms, the relationship with extraversion may be causal and bidirectional.     

Does a decrease in avoidance behavior and focusing on fatigue mediate the effect of cognitive behavior therapy for chronic fatigue syndrome?

Objective

Cognitive behavior therapy (CBT) leads to a significant reduction in fatigue severity and impairment in patients with chronic fatigue syndrome (CFS). The purpose of the present study was to determine whether the effect of CBT for CFS on fatigue and impairment is mediated by a decrease in avoidance behavior and focusing on fatigue.

Methods

For this purpose, we reanalyzed a randomized controlled trial which was previously conducted to test the efficacy of CBT for CFS. Two hundred nineteen patients completed assessment prior and subsequent to treatment or a control group period.

Results

Mediation analysis revealed that a decrease in focusing on fatigue mediated the effect of CBT for CFS on fatigue and impairment. Avoidance of activity and avoidance of aversive stimuli were not significantly changed by treatment and were therefore excluded from mediation analysis.

Conclusion

A decrease in the focus on fatigue seems to contribute to the treatment effect of CBT for CFS.     

The Effects of Galantamine Hydrobromide Treatment on Dehydroepiandrosterone Sulfate and Cortisol Levels in Patients with Chronic Fatigue Syndrome

Objective

Mental fatigue, cognitive disorders, and sleep disturbances seen in chronic fatigue syndrome (CFS) may be attributed to cholinergic deficit. A functional deficiency of cholinergic neurotransmission may cause the hypothalamic-pituitary-adrenal axis hypoactivity seen in CFS. Therefore, we investigated the alterations in stress hormones such as cortisol and dehydroepiandrosterone sulfate (DHEAS) in CFS patients before and after 4-week administration of galantamine hydrobromide, a selective acetylcholinesterase inhibitor, and aimed to investigate whether there are any relationships between the probable hormonal changes and cholinergic treatment.

Methods

Basal levels of cortisol and DHEAS were measured in 29 untreated CFS patients who were diagnosed according to Centers for Disease Control (CDC) criteria and in 20 healthy controls. In the patient group, four weeks after 8 mg/d galantamine hydrobromide treatment, cortisol and DHEAS levels were measured again. After the treatment 22 patients who stayed in study were divided into two subgroups as responders and nonresponders according to the reduction in their Newcastle Research Group ME/CFS Score Card (NRG) scores.

Results

Important findings of this study are lower pre-and post-treatment cortisol levels and in all CFS patients compared to controls (F=4.129, p=0.049; F=4.803, p=0.035, respectively); higher basal DHEAS values and higher DHEAS/cortisol molar ratios which were normalized following four weeks'' treatment with 8 mg/d galantamine hydrobromide in the treatment-respondent group (F=5.382, p=0.029; F=5.722, p=0.025, respectively).

Conclusion

The findings of the decrease in basal DHEAS levels and DHEAS/cortisol molar ratios normalizing with galantamine treatment may give some support to the cholinergic deficit hypothesis in CFS.     

Childhood maltreatment and the response to cognitive behavior therapy for chronic fatigue syndrome

Objective

To examine the relationship between a history of childhood maltreatment and the treatment response to cognitive behavior therapy for chronic fatigue syndrome (CFS).

Methods

A cohort study in a tertiary care clinic with a referred sample of 216 adult patients meeting the Centers for Disease Control and Prevention criteria for CFS, and starting cognitive behavior therapy. Main outcome measures changes between pre- and post therapy in fatigue (Checklist Individual Strength fatigue subscale), disabilities (Sickness Impact Profile total score), physical functioning (short form 36 health survey subscale) and psychological distress (Symptom checklist 90 total score).

Results

At baseline, patients with a history of childhood maltreatment had significantly more limitations and a higher level of psychological distress, but were not more severely fatigued. Change scores on the outcome measures after cognitive behavior therapy did not differ significantly between patients with or without a history of childhood maltreatment, or between the different types of childhood maltreatment. However, patients with a history of childhood maltreatment still experienced more limitations and a higher level of psychological distress after CBT.

Conclusions

A history of childhood maltreatment was not related to the treatment response of cognitive behavior therapy for CFS. In patients with a history of childhood maltreatment CFS symptoms can be treated with CBT just as well as those without.     

The central role of cognitive processes in the perpetuation of chronic fatigue syndrome

Objective

Chronic fatigue syndrome (CFS) is considered to be one of the functional somatic syndromes (FSS). Cognitions and behavior are thought to perpetuate the symptoms of CFS. Behavioral interventions based on the existing models of perpetuating factors are quite successful in reducing fatigue and disabilities. The evidence is reviewed that cognitive processes, particularly those that determine the perception of fatigue and its effect on behavior, play a central role in the maintenance of symptoms.

Method

Narrative review.

Results

Findings from treatment studies suggest that cognitive factors mediate the positive effect of behavioral interventions on fatigue. Increased fitness or increased physical activity does not seem to mediate the treatment response. Additional evidence for the role of cognitive processes is found in studies comparing the subjective beliefs patients have of their functioning with their actual performance and in neurobiological research.

Conclusion

Three different cognitive processes may play a role in the perpetuation of CFS symptoms. The first is a general cognitive representation in which fatigue is perceived as something negative and aversive and CFS is seen as an illness that is difficult to influence. The second process involved is the focusing on fatigue. The third element is formed by specific dysfunctional beliefs about activity and fatigue.     

Evidence of inflammatory immune signaling in chronic fatigue syndrome: A pilot study of gene expression in peripheral blood

Background  

Genomic profiling of peripheral blood reveals altered immunity in chronic fatigue syndrome (CFS) however interpretation remains challenging without immune demographic context. The object of this work is to identify modulation of specific immune functional components and restructuring of co-expression networks characteristic of CFS using the quantitative genomics of peripheral blood.     

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.     

Premorbid personality in chronic fatigue syndrome as determined by the Temperament and Character Inventory

Background

Using the Temperament and Character Inventory (TCI), we examined personality characteristics in patients with chronic fatigue syndrome (CFS) compared with healthy control subjects, and CFS patients with and without psychiatric diseases. There have been no previous reports assessing personality in CFS patients using the TCI.

Methods

A total of 211 CFS patients and 90 control subjects completed the TCI and the Chalder Fatigue Scale questionnaires.

Results

Compared with control subjects, CFS patients demonstrated significantly lower premorbid Novelty Seeking, and higher Harm Avoidance and persistence. The fatigue score for CFS patients with psychiatric diseases was higher than that for CFS patients without psychiatric diseases. Patients with CFS with psychiatric diseases showed lower premorbid Self-Directedness when compared with CFS patients without psychiatric diseases. The fatigue score was negatively correlated with premorbid Self-Directedness and Cooperativeness, and positively correlated with Harm Avoidance among CFS patients.

Conclusion

This study supported the stereotyped image of CFS patients as perfectionists, which is similar to the Persistence score, and neurotics, which is similar to the Harm Avoidance score. Patients displaying greater neuroticisms and poorer social and communication skills, similar to the Self-Directedness and Cooperativeness scores, tend to have intercurrent psychiatry diseases and show more severe symptoms of CFS.     

Metacognitions and negative emotions as predictors of symptom severity in chronic fatigue syndrome

Objective

Chronic fatigue syndrome (CFS) describes a condition that is primarily characterized by fatigue and flu-like symptoms that are not alleviated by rest. This study investigated the relationship among metacognitions, negative emotions, and symptom severity in CFS.

Methods

A total of 96 patients who had received a diagnosis of CFS according to the Oxford Criteria completed a battery of self-report measures that consisted of the Depression Anxiety Stress Scales, the 30-Item Metacognitions Questionnaire, the Chalder Fatigue Questionnaire (CFQ), and the RAND 36-Item Short-Form Health Survey-Physical Functioning.

Results

Correlation analyses showed that negative emotions and metacognitions were positively correlated with measures of symptom severity and that metacognitions were a better predictor of symptom severity than anxiety and depression. Hierarchical regression analyses indicated that (1) lack of cognitive confidence predicted both mental and physical factors of the CFQ and physical functioning independently of negative emotions and (2) beliefs about the need to control thoughts predicted the mental factor of the CFQ independently of negative emotions and lack of cognitive confidence.

Conclusion

The data support the potential application of the metacognitive model of psychological disorder to understanding CFS.     

Non-REM sleep EEG power distribution in fatigue and sleepiness

Objectives

The aim of this study is to contribute to the sleep-related differentiation between daytime fatigue and sleepiness.

Methods

135 subjects presenting with sleep apnea–hypopnea syndrome (SAHS, n = 58) or chronic fatigue syndrome (CFS, n = 52) with respective sleepiness or fatigue complaints and a control group (n = 25) underwent polysomnography and psychometric assessments for fatigue, sleepiness, affective symptoms and perceived sleep quality. Sleep EEG spectral analysis for ultra slow, delta, theta, alpha, sigma and beta power bands was performed on frontal, central and occipital derivations.

Results

Patient groups presented with impaired subjective sleep quality and higher affective symptom intensity. CFS patients presented with highest fatigue and SAHS patients with highest sleepiness levels. All groups showed similar total sleep time. Subject groups mainly differed in sleep efficiency, wake after sleep onset, duration of light sleep (N1, N2) and slow wave sleep, as well as in sleep fragmentation and respiratory disturbance. Relative non-REM sleep power spectra distributions suggest a pattern of power exchange in higher frequency bands at the expense of central ultra slow power in CFS patients during all non-REM stages. In SAHS patients, however, we found an opposite pattern at occipital sites during N1 and N2.

Conclusions

Slow wave activity presents as a crossroad of fatigue and sleepiness with, however, different spectral power band distributions during non-REM sleep. The homeostatic function of sleep might be compromised in CFS patients and could explain why, in contrast to sleepiness, fatigue does not resolve with sleep in these patients. The present findings thus contribute to the differentiation of both phenomena.     

Identification of actin network proteins,talin-1 and filamin-A,in circulating extracellular vesicles as blood biomarkers for human myalgic encephalomyelitis/chronic fatigue syndrome

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a serious, debilitating disorder with a wide spectrum of symptoms, including pain, depression, and neurocognitive deterioration. Over 17 million people around the world have ME/CFS, predominantly women with peak onset at 30–50 years. Given the wide spectrum of symptoms and unclear etiology, specific biomarkers for diagnosis and stratification of ME/CFS are lacking. Here we show that actin network proteins in circulating extracellular vesicles (EVs) offer specific non-invasive biomarkers for ME/CFS. We found that circulating EVs were significantly increased in ME/CFS patients correlating to C-reactive protein, as well as biological antioxidant potential. Area under the receiver operating characteristic curve for circulating EVs was 0.80, allowing correct diagnosis in 90–94% of ME/CFS cases. From two independent proteomic analyses using circulating EVs from ME/CFS, healthy controls, idiopathic chronic fatigue, and depression, proteins identified from ME/CFS patients are involved in focal adhesion, actin skeletal regulation, PI3K-Akt signaling pathway, and Epstein-Barr virus infection. In particular, talin-1, filamin-A, and 14-3-3 family proteins were the most abundant proteins, representing highly specific ME/CFS biomarkers. Our results identified circulating EV number and EV-specific proteins as novel biomarkers for diagnosing ME/CFS, providing important information on the pathogenic mechanisms of ME/CFS.     

Deviations in daily physical activity patterns in patients with the chronic fatigue syndrome: a case control study

Objectives

Deviations in daily physical activity patterns may play an important role in the development and maintenance of fatigue in the chronic fatigue syndrome (CFS). The aim of this study is to gain insight into the objective daily physical activity pattern of patients with CFS in comparison with healthy controls. The secondary objective is studying the awareness in performing physical activities.

Methods

The objective daily physical activity pattern was measured with a tri-axial accelerometer in 35 patients with CFS and in 35 age- and gender-matched healthy controls. The objective daily physical activity level and distribution of physical activities at low, medium and high intensity levels during the day were measured. Moreover, variability in performing physical activities within and between subjects was computed. Subjective ratings of self-reported daily physical activity levels were assessed at a visual analog scale.

Results

CFS patients were significantly less physically active in the afternoon and evening, and spent fewer activities at high intensity levels and more at low intensity levels. Moreover, CFS patients showed more variability in their own physical activity pattern during the afternoon. The heterogeneity in the physical activity pattern between subjects within the CFS and control group did not differ. Finally, CFS patients were more aware about their daily physical activity level than healthy controls.

Conclusion

CFS patients showed deviations in the objectively measured daily physical activity pattern. Future research should elucidate the relation between impaired balances in daily physical activity patterns and fatigue severity in CFS.     

Chronic fatigue syndrome: Abnormally fast muscle fiber conduction in the membranes of motor units at low static force load

ObjectiveChronic fatigue syndrome (CFS) and fibromyalgia (FM) are disorders of unknown etiology and unclear pathophysiology, with overlapping symptoms of – especially muscular –fatigue and pain. Studies have shown increased muscle fiber conduction velocity (CV) in the non-painful muscles of FM patients. We investigated whether CFS patients also show CV abnormalities.MethodsFemales with CFS (n = 25), with FM (n = 22), and healthy controls (n = 21) underwent surface electromyography of the biceps brachii, loaded up to 20% of maximum strength, during short static contractions. The mean CV and motor unit potential (MUP) velocities with their statistical distribution were measured.ResultsThe CV changes with force differed between CFS-group and both FM-group and controls (P = 0.01). The CV of the CFS-group increased excessively with force (P < 0.001), whereas that of the controls increased only slightly and non-significantly, and that of the FM-group did not increase at all. In the CFS-group, the number of MUPs conveying very high conduction velocities increased abundantly with force and the MUPs narrowed.ConclusionOur results suggest disturbed muscle membrane function in CFS patients, in their motor units involved in low force generation. Central neural deregulation may contribute to this disturbance.SignificanceThese findings help to detangle the underlying mechanisms of CFS.     

The Beliefs about Emotions Scale: Validity, reliability and sensitivity to change

Objective

Beliefs about the unacceptability of experiencing or expressing negative emotions have been noted in individuals with a range of problems, including chronic fatigue syndrome (CFS), irritable bowel syndrome, somatization disorder, depression, eating disorders, social phobia, posttraumatic stress disorder, and borderline personality disorder. These beliefs are likely to have implications for emotion regulation and processing, and are addressed explicitly or implicitly within many therapies including cognitive behavior therapy (CBT), mindfulness-based cognitive therapy (MBCT), and Acceptance and Commitment Therapy (ACT). This article describes the development, validation, and internal reliability of the Beliefs about Emotions Scale (BES), a self-report questionnaire to assess such beliefs.

Methods

The new scale was completed by people with CFS (n=121) and healthy controls (n=73). Twenty-two individuals with CFS completed the scale before and after CBT.

Results

People with CFS had significantly higher scores on this new questionnaire than healthy controls. Principal components analysis identified one factor, and the scale had high internal consistency (0.91). Scores on the BES were most highly correlated with a measure of negative perfectionism (r=0.59) and also showed significant correlations with measures of dysfunctional attitudes, self-sacrifice, depression, anxiety, and fatigue. When completed before and after CBT for CFS, the questionnaire was sufficiently sensitive to detect a significant reduction in endorsement of unhelpful beliefs about emotions.

Conclusion

The new Beliefs about Emotions Scale showed good internal reliability, validity and sensitivity to change.     

The process of cognitive behaviour therapy for chronic fatigue syndrome: Which changes in perpetuating cognitions and behaviour are related to a reduction in fatigue?

Objective

Cognitive behaviour therapy (CBT) can significantly reduce fatigue in chronic fatigue syndrome (CFS), but little is known about the process of change taking place during CBT. Based on a recent treatment model (Wiborg et al. J Psych Res 2012), we examined how (changes in) cognitions and behaviour are related to the decrease in fatigue.

Methods

We included 183 patients meeting the US Centers for Disease Control criteria for CFS, aged 18 to 65 years, starting CBT. We measured fatigue and possible process variables before treatment; after 6, 12 and 18 weeks; and after treatment. Possible process variables were sense of control over fatigue, focusing on symptoms, self-reported physical functioning, perceived physical activity and objective (actigraphic) physical activity. We built multiple regression models, explaining levels of fatigue during therapy by (changes in) proposed process variables.

Results

We observed large individual variation in the patterns of change in fatigue and process variables during CBT for CFS. Increases in the sense of control over fatigue, perceived activity and self-reported physical functioning, and decreases in focusing on symptoms explained 20 to 46% of the variance in fatigue. An increase in objective activity was not a process variable.

Conclusion

A change in cognitive factors seems to be related to the decrease in fatigue during CBT for CFS. The pattern of change varies considerably between patients, but changes in process variables and fatigue occur mostly in the same period.     

The role of neuroticism,perfectionism and depression in chronic fatigue syndrome. A structural equation modeling approach

Objective

Previous studies have reported consistent associations between Neuroticism, maladaptive perfectionism and depression with severity of fatigue in Chronic Fatigue Syndrome (CFS). Depression has been considered a mediator factor between maladaptive perfectionism and fatigue severity, but no studies have explored the role of neuroticism in a comparable theoretical framework. This study aims to examine for the first time, the role of neuroticism, maladaptive perfectionism and depression on the severity of CFS, analyzing several explanation models.

Methods

A sample of 229 CFS patients were studied comparing four structural equation models, testing the role of mediation effect of depression severity in the association of Neuroticism and/or Maladaptive perfectionism on fatigue severity.

Results

The model considering depression severity as mediator factor between Neuroticism and fatigue severity is the only one of the explored models where all the structural modeling indexes have fitted satisfactorily (Chi square = 27.01, p = 0.079; RMSE = 0.047, CFI = 0.994; SRMR = 0.033). Neuroticism is associated with CFS by the mediation effect of depression severity. This personality variable constitutes a more consistent factor than maladaptive perfectionism in the conceptualization of CFS severity.