Using an interleukin-6 challenge to evaluate neuropsychological performance in chronic fatigue syndrome

BACKGROUND: Individuals with acute infections experience a range of symptoms including fatigue, malaise, muscle aches, and difficulties with concentration and memory that are usually self-limited. This cluster of symptoms is otherwise, similar to those that characterize chronic fatigue syndrome (CFS). The goal of the present study was to evaluate the cognitive and psychological functioning of CFS patients and normal controls (NCs) when they both were experiencing acute influenza-like symptoms. To induce influenza-like symptoms, we administered interleukin-6 (IL-6), a cytokine that temporarily activates the acute phase immunological and endocrine responses. METHODS: Nineteen patients who met the 1994 International CFS Study Group Criteria and ten normal controls (NCs) completed routine clinical evaluations, neuropsychological tests of short-term memory, selective attention, and executive control, and self-ratings of somatic symptoms and psychological mood before, shortly following, and 1 day after IL-6 administration. RESULTS: CFS patients consistently reported more somatic symptoms, even when both groups perceived that they were ill. Both groups somatic symptoms increased during the IL-6 challenge, but the CFS patients symptoms increased more rapidly than controls. In general, the CFS patients performed similarly to NCs on the cognitive measures before, during, and after the IL-6. In contrast to predictions, IL-6 provocation did not impair the cognitive performance of either CFS patients or NCs. CONCLUSIONS: The IL-6 provocation exacerbated the patients self-reported symptoms but did not reveal notable cognitive impairments between patients and controls during cytokine-induced acute influenza-like symptoms.     

Distinguishing patients with chronic fatigue from those with chronic fatigue syndrome: a diagnostic study in UK primary care.

BACKGROUND: Chronic fatigue syndrome (CFS) has been defined, but many more patients consult in primary care with chronic fatigue that does not meet the criteria for CFS. General practitioners (GPs) do not generally use the CFS diagnosis, and have some doubt about the validity of CFS as an illness. AIM: To describe the proportion of patients consulting their GP for fatigue that met the criteria for CFS, and to describe the social, psychological, and physical differences between patients with CFS and those with non-CFS chronic fatigue in primary care. DESIGN OF STUDY: Baseline data from a trial of complex interventions for fatigue in primary care. SETTING: Twenty-two general practices located in London and the South Thames region of the United Kingdom recruited patients to the study between 1999 and 2001. METHOD: One hundred and forty-one patients who presented to their GP with unexplained fatigue lasting six months or more as a main symptom were recruited, and the Centers for Disease Control (CDC) case definition was applied to classify CFS. RESULTS: Approximately two-thirds (69%) of patients had chronic fatigue and not CFS. The duration of fatigue (32 months) and perceived control over fatigue were similar between groups; however, fatigue, functioning, associated symptoms, and psychological distress were more severe in the patients in the CFS group, who also consulted their GP significantly more frequently, were twice as likely to be depressed, and more than twice as likely to be unemployed. About half (CFS = 50%; chronic fatigue = 55%) in each group attributed their fatigue to mainly psychological causes. CONCLUSIONS: In primary care, CFS is a more severe illness than chronic fatigue, but non-CFS chronic fatigue is associated with significant fatigue and is reported at least twice as often. That half of patients, irrespective of CFS status, attribute their fatigue to psychological causes, more than is observed in secondary care, indicates an openness to the psychological therapies provided in that setting. More evidence on the natural history of chronic fatigue and CFS in primary care is required, as are trials of complex interventions. The results may help determine the usefulness of differentiating between chronic fatigue and CFS.     

A longitudinal study of the relationship between psychological distress and recurrence of upper respiratory tract infections in chronic fatigue syndrome

Objectives. Previous research has found that chronic fatigue syndrome (CFS) patients report increased susceptibility to upper respiratory tract illnesses (URTIs) when compared with healthy volunteers. This study aimed to replicate and extend this research by investigating the role of psychological distress (stress and negative mood) in the recurrence of URTIs in CFS patients as well as its role in the recurrence of CFS symptoms. Design. A 15‐week diary study. Methods. Measures of psychological stress, negative mood, recurrence of URTIs and symptoms were recorded each week for a 15‐week period. CFS patients (N = 21), who had been assessed and diagnosed according to the Oxford criteria, were recruited from the Cardiff Chronic Fatigue Clinic and compared with a matched group of healthy controls (N = 18). Frequency of occurrence of infectious illness and the relationship between psychological stress/negative mood and occurrence of illness were assessed. Results. CFS patients reported more URTIs than the controls. Stress scores (and negative mood) were significantly higher in the week prior to the occurrence of URTIs than in weeks when no subsequent illness occurred. High levels of psychological stress also preceded the severity of reported symptoms of fatigue in the CFS group. Conclusions. CFS patients reported more frequent URTIs than healthy controls and these recurrences were preceded by high levels of psychological stress. High levels of stress were also associated with greater subsequent fatigue. Possible explanations of these results are discussed.     

A Cross-Cultural Perspective on Psychological Determinants of Chronic Fatigue Syndrome: a Comparison Between a Portuguese and a Dutch Patient Sample

Background

Few studies focus on cross-cultural differences in Chronic fatigue syndrome (CFS).

Purpose

This study aimed to (1) compare fatigue severity and impairment, somatic complaints, psychological distress, and quality of life (QoL) in a population of Portuguese and Dutch patients; (2) explore the differential contribution of behavioral and cognitive determinants of fatigue severity; and (3) investigate the relation between fatigue severity and somatic complaints on one hand and QoL on the other in both populations.

Method

Eighty-five female patients from Portugal (Mean age?=?47.54) and 167 female CFS patients from The Netherlands (Mean age?=?44.93) participated in the study. All participants were surveyed for demographic and clinical characteristics, fatigue severity, somatic symptoms, psychological distress, (physical and psychological) QoL, physical activity, behavior regulation patterns, and illness representations.

Results

Cross-cultural differences were found in relation to working status, duration of fatigue symptoms, psychological distress, somatic complaints, and psychological QoL. Although behavioral characteristics and illness representations were significantly associated with fatigue severity in both Portuguese and Dutch patients, there were important differences in the determinants of CFS. Moreover, higher levels of fatigue and severity of other somatic complaints were related to poor QoL.

Conclusions

These findings show cross-cultural similarities and differences in clinical characteristics and psychological determinants of CFS that are important in view of diagnosis and treatment.     

Unconscious amygdalar fear conditioning in a subset of chronic fatigue syndrome patients

Here, a novel hypothesis for chronic fatigue syndrome (CFS) is proposed. CFS may be a neurophysiological disorder focussing on the amygdala. During a 'traumatic' neurological event often involving acute psychological stress combined with a viral infection or other chemical or physiological stressor, a conditioned network or 'cell assembly' may be created in the amygdala. The unconscious amygdala may become conditioned to be chronically sensitised to negative symptoms arising from the body. Negative signals from the viscera or physiological, chemical and dietary stressors, become conditioned stimuli and the conditioned response is a chronic sympathetic outpouring from the amygdala via various brain pathways including the hypothalamus. This cell assembly then produces the CFS vicious circle, where an unconscious negative reaction to symptoms causes immune reactivation/dysfunction, chronic sympathetic stimulation, leading to sympathetic dysfunction, mental and physical exhaustion, and a host of other distressing symptoms and secondary complications. And these are exactly the symptoms that the amygdala and associated limbic structures are trained to monitor and respond to, perpetuating a vicious circle. Recovery from CFS may involve projections from the medial prefrontal cortex to the amygdala, to control the amygdala's expressions. I shall firstly discuss predisposing, precipitating, and perpetuating factors involved in the possible etiology of chronic fatigue syndrome (CFS), followed by the patient's experience of the illness. Finally, I shall look at a suggested explanation for the symptoms of CFS.     

Hypothalamic-pituitary-adrenal axis reactivity in chronic fatigue syndrome and health under psychological,physiological, and pharmacological stimulation

OBJECTIVES: Subtle alterations of the hypothalamic-pituitary-adrenal (HPA) axis in chronic fatigue syndrome (CFS) have been proposed as a shared pathway linking numerous etiological and perpetuating processes with symptoms and observed physiological abnormalities. Because the HPA axis is involved in the adaptive responses to stress and CFS patients experience a worsening of symptoms after physical and psychological stress, we tested HPA axis functioning with three centrally acting stress tests. METHODS: We used two procedures mimicking real-life stressors and compared them with a standardized pharmacological neuroendocrine challenge test. CFS patients were compared with healthy control subjects regarding their cardiovascular and endocrine reactivity in a psychosocial stress test and a standardized exercise test, and their endocrine response in the insulin tolerance test (ITT). RESULTS: Controlling for possible confounding variables, we found significantly lower ACTH response levels in the psychosocial stress test and the exercise test, and significantly lower ACTH responses in the ITT, with no differences in plasma total cortisol responses. Also, salivary-free cortisol responses did not differ between the groups in the psychosocial stress test and the exercise test but were significantly higher for the CFS patients in the ITT. In all tests CFS patients had significantly reduced baseline ACTH levels. CONCLUSIONS: These results suggest that CFS patients are capable of mounting a sufficient cortisol response under different types of stress but that on a central level subtle dysregulations of the HPA axis exist.     

Sleep Quality and Psychological Adjustment in Chronic Fatigue Syndrome

Without specific etiology or effective treatment, chronic fatigue syndrome (CFS) remains a contentious diagnosis. Individuals with CFS complain of fatigue and poor sleep—symptoms that are often attributed to psychological disturbance. To assess the nature and prevalence of sleep disturbance in CFS and to investigate the widely presumed presence of psychological maladjustment we examined sleep quality, sleep disorders, physical health, daytime sleepiness, fatigue, and psychological adjustment in three samples: individuals with CFS; a healthy control group; and individuals with a definite medical diagnosis: narcolepsy. Outcome measures included physiological evaluation (polysomnography), medical diagnosis, structured interview, and self-report measures. Results indicate that the CFS sample had a very high incidence (58%) of previously undiagnosed primary sleep disorder such as sleep apnea/hypopnea syndrome and restless legs/periodic limb movement disorder. They also had very high rates of self-reported insomnia and nonrestorative sleep. Narcolepsy and CFS participants were very similar on psychological adjustment: both these groups had more psychological maladjustment than did control group participants. Our data suggest that primary sleep disorders in individuals with CFS are underdiagnosed in primary care settings and that the psychological disturbances seen in CFS may well be the result of living with a chronic illness that is poorly recognized or understood.     

Longitudinal change in chronic fatigue syndrome: what home-based assessments reveal

The purpose of this 2-year prospective study was to compare standard self-report and ecologically-based outcome measures in patients with chronic fatigue syndrome (CFS). Standard measures assessed physical function, fatigue impact, psychological variables, and global impression of change ratings. Ecological measures included actigraphy, a structured activity record, and an electronic fatigue/energy diary. Results for this high functioning sample (N = 75) revealed that self-report global improvement was significantly associated with lower momentary fatigue and fatigue impact, and a higher frequency of standing up (at home), but not with actigraphy or psychological variables. However, actigraphy change was significantly correlated with change in self-report physical function. At follow-up, only a small minority (<20%) scored in the healthy adult range for fatigue impact and physical function. The findings suggest that home-based measures of symptom severity and physical functioning may provide evidence of change (or lack of change) that is important for interpreting standard self-report outcomes in CFS.     

A real-time assessment of the effect of exercise in chronic fatigue syndrome

Patients with chronic fatigue syndrome (CFS) report substantial symptom worsening after exercise. However, the time course over which this develops has not been explored. Therefore, the objective of this study was to investigate the influence of exercise on subjective symptoms and on cognitive function in CFS patients in natural settings using a computerized ecological momentary assessment method, which allowed us to track the effects of exercise within and across days. Subjects were 9 female patients with CFS and 9 healthy women. A watch-type computer was used to collect real-time data on physical and psychological symptoms and cognitive function for 1week before and 2weeks after a maximal exercise test. For each variable, we investigated temporal changes after exercise using multilevel modeling. Following exercise, physical symptoms did get worse but not until a five-day delay in CFS patients. Despite this, there was no difference in the temporal pattern of changes in psychological symptoms or in cognitive function after exercise between CFS patients and controls. In conclusion, physical symptoms worsened after several days delay in patients with CFS following exercise while psychological symptoms or cognitive function did not change after exercise.     

Metacognitive factors in chronic fatigue syndrome

Chronic fatigue syndrome (CFS), which is characterized by fatigue and flu-like symptoms that are not alleviated by rest, is a poorly understood condition and an often controversial diagnosis. Earlier research has indicated that general metacognitions are associated with the severity of symptoms in patients with CFS. In the current study, we aimed to determine whether specific metacognitive factors are implicated in CFS. Using the metacognitive profiling interview template we investigated the following: (1) whether patients held positive or negative metacognitions about conceptual processes; (2) what their goals with respect to engaging in these processes were; and (3) what indicated that it was appropriate to stop. We also examined attention focus when experiencing CFS symptoms, and its advantages and disadvantages. Results showed that patients endorsed positive and negative metacognitions pertaining to conceptual processes. The goals of engaging in these processes were to identify the cause of, and devise strategies to cope with, symptoms. Patients were either unable to identify a stop signal for conceptual processing or identified an improvement in fatigue-related symptoms as representing the stop signal. Finally, patients reported that their attention focus when experiencing symptoms included distraction and monitoring of symptoms. Advantages to these strategies included symptom management, whereas disadvantages included an escalation of negative affect. The present findings provide preliminary evidence that specific metacognitive factors may be involved in CFS. Copyright ? 2011 John Wiley & Sons, Ltd. KEY PRACTITIONER MESSAGE: Metacognitive profiling that may aid assessment and conceptualisation of psychological distress in CFS.     

Psychiatric symptoms, personality and ways of coping in chronic fatigue syndrome

This study aimed to investigate the psychological characteristics of chronic fatigue syndrome (CFS: Holmes et al. 1988). A battery of psychometric instruments comprising the General Health Questionnaire (GHQ), the Beck Depression Inventory (BDI), the Minnesota Multiphasic Personality Inventory (MMPI) and the Lazarus Ways of Coping (WoC) inventory, was administered to a sample of clinically-defined CFS sufferers (N = 58), to a comparison group of chronic pain (CP) patients (N = 81) and to a group of healthy controls matched for sex and age with the CFS sample (N = 104). Considerable overlap was found between CFS and CP patients at the level of both physical and psychological symptoms. This raises the possibility that CFS sufferers are a sub-population of CP patients. However, while there was some commonality between CFS and CP patients in terms of personality traits, particularly the MMPI 'neurotic triad' (hypochondriasis, depression and hysteria), CFS patients showed more deviant personality traits reflecting raised levels on the first MMPI factor, emotionality. Moreover, results were not consistent with the raised emotionality being a reaction to the illness, but rather were consistent with the hypothesis that emotionality is a predisposing factor for CFS. The majority of CFS patients fell within four personality types, each characterized by the two highest MMPI scale scores. One type (N = 20) reported a lack of psychological symptoms or emotional disturbance contrary to the overall trend for the CFS sample. This group conformed to the ICD-10 classification of neurasthenia.     

Physical Activity, Emotional Stress, Sleep Disturbances, and Daily Fluctuations in Chronic Fatigue Symptomatology

The current study explored the relationships between physical and emotional stress and the symptomatology of chronic fatigue syndrome (CFS). Fifty-four CFS patients were studied using a longitudinal design. A self-report format was used to collect daily measures of major physical (sleep disturbance and physical activity) and emotional (subjective emotional stress level) stressors, as well as measures of levels of fatigue and secondary symptoms. The variables accounted for a moderate variance at the individual and occasion levels. Sleep disturbance and emotional stress were found to be positively associated with levels of fatigue and symptomatology, whereas physical activity was found to have a negative relationship with fatigue only. The severity of fatigue and symptoms were found to fluctuate daily in relation with the variables, indicating the complex nature of the associations.     

Psychological treatment of patients with chronic toxic encephalopathy: lessons from studies of chronic fatigue and whiplash

BACKGROUND: Chronic toxic encephalopathy (CTE), which can result from long-term exposure to organic solvents, is characterized by problems of attention and memory, fatigue and affective symptoms. There is little experience with (neuro)psychological treatment in this patient group. We reviewed treatment outcome studies of CTE and comparable syndromes, namely, chronic whiplash-associated disorder (WAD) and chronic fatigue syndrome (CFS), with a view to providing recommendations for the psychological treatment of patients with CTE. METHODS: PubMed and PsychLIT were systematically searched and reference lists of retrieved articles were studied. The articles were classified according to study design and level of evidence. RESULTS: The studies of CFS provided high-level evidence for the effectiveness of cognitive-behavior therapy (CBT) in challenging dysfunctional cognitions regarding the effectiveness of rest and in stimulating graded activity. The studies of WAD were methodologically weaker, and most evaluated a combination of CBT and graded activity training. There was some evidence that changing fatigue- or pain-related behaviors may result in cognitive improvement. Two uncontrolled studies of CTE evaluated cognitive rehabilitation techniques but yielded inconsistent findings. CONCLUSIONS: CBT techniques focusing on changing illness attributions and on stimulating graded activity might be useful for patients with CTE, diminishing fatigue-related problems of concentration and memory. Future studies should evaluate whether cognitive deficits of CTE patients as a result of neurotoxic effects of exposure should be treated by cognitive rehabilitation.     

Comorbid somatic symptoms and functional status in patients with fibromyalgia and chronic fatigue syndrome: sensory amplification as a common mechanism

BACKGROUND: Somatic symptoms are common in conditions such as fibromyalgia (FM) and chronic fatigue syndrome (CFS). OBJECTIVE: Authors investigated a potential shared pathologic mechanism: a generalized perceptual abnormality where there is heightened responsiveness to varied sensory stimulation, including pain. METHOD: A composite measure of sensory sensitivity was created and compared with measures of somatic symptoms, comorbid psychological disturbances, and self-reported physical functioning in 38 patients with FM and/or CFS. RESULTS: Sensory amplification influenced physical functioning indirectly through pain intensity, and physical symptoms and fatigue also independently contributed to physical functioning. CONCLUSION: Sensory amplification may be an underlying pathophysiologic mechanism in these disorders that is relatively independent of depression and depressive symptoms.     

Influence of Symptom Expectancies on Stair-Climbing Performance in Chronic Fatigue Syndrome: Effect of Study Context

Background

In 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.].

Purpose

We 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.

Method

In 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.

Results

Longer 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.

Conclusion

Symptom 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).     

Discriminating between chronic fatigue syndrome and depression: a cognitive analysis

BACKGROUND: Chronic fatigue syndrome (CFS) and depression share a number of common symptoms and the majority of CFS patients meet lifetime criteria for depression. While cognitive factors seem key to the maintenance of CFS and depression, little is known about how the cognitive characteristics differ in the two conditions. METHODS: Fifty-three CFS patients were compared with 20 depressed patients and 38 healthy controls on perceptions of their health, illness attributions, self-esteem, cognitive distortions of general and somatic events, symptoms of distress and coping. A 6 month follow-up was also conducted to determine the stability of these factors and to investigate whether CFS-related cognitions predict ongoing disability and fatigue in this disorder. RESULTS: Between-group analyses confirmed that the depressed group was distinguished by low self-esteem, the propensity to make cognitive distortions across all situations, and to attribute their illness to psychological factors. In contrast, the CFS patients were characterized by low ratings of their current health status, a strong illness identity, external attributions for their illness, and distortions in thinking that were specific to somatic experiences. They were also more likely than depressed patients to cope with their illness by limiting stress and activity levels. These CFS-related cognitions and behaviours were associated with disability and fatigue 6 months later. CONCLUSIONS: CFS and depression can be distinguished by unique cognitive styles characteristic of each condition. The documented cognitive profile of the CFS patients provides support for the current cognitive behavioural models of the illness.     

Are patients with chronic fatigue syndrome just ‘tired’ or also ‘sleepy’?

It is presently unclear whether chronic fatigue syndrome (CFS) patients exhibit daytime sleepiness in addition to fatigue. Both, fatigue, such as that seen in CFS patients, and excessive daytime sleepiness, such as in sleep apnea–hypopnea syndrome (SAHS), remain poorly understood. Both daytime conditions are generally related to unrefreshing sleep and show affective symptoms. This study’s objective was to contribute to the understanding of the relationship between fatigue and sleepiness in CFS patients not co‐morbid for primary sleep or psychiatric disorders. We compared 16 untreated CFS patients (mean age 32.8, all females) with 13 untreated SAHS (mean age 47.7, all females) patients and 12 healthy controls (mean age 32.2, all females). Objective sleepiness was measured using multiple sleep latency tests (MSLT). Subjective sleepiness and fatigue were assessed with the Epworth Sleepiness Scale and the Fatigue Severity Scale, respectively. Mean Sleep Latency (SL) on the MSLT was significantly shorter in SAHS patients than in CFS patients and CFS patients showed significantly shorter mean SL than matched controls but within normal range. Subjective sleepiness was greatest in SAHS patients and subjective fatigue was highest in CFS patients. Affective symptoms showed highest intensities in CFS patients. While higher than the control group on all measures, compared to SAHS, the CFS group had higher subjective fatigue and lower subjective and objective sleepiness. Despite possible overlap in symptoms and signs of both daytime conditions, our data indirectly support the clinical distinction between fatigue and sleepiness.     

Structure and Determinants of Illness Representations in Chronic Disease: A Comparison of Addison's Disease and Chronic Fatigue Syndrome

Although the clinical relevance of illness representations has been demonstrated in several studies, research on the structure and determinants of illness representations is rare. This article examines the illness representations of chronically ill patients, using a structured interview technique and taking chronic fatigue syndrome (CFS) and Addison's disease (AD) as examples. Considerable differences were found between the group of CFS patients (n = 98) and the group of AD patients (n = 63) with regard to their ideas about the identity, time line, control/cure , and consequences of their illness. Despite these differences, the pattern of correlations among these four dimensions of illness representation was found to be similar for the two groups. Moreover, the strength of the correlations points to the coherent nature of illness representations. The relations between the illness representations, personal variables, and disease- related variables were also explored. Regression analyses showed the dimensions of illness representation to be explained rather well by personal and disease-related variables. Disease-related variables were the most important predictors for the dimensions of identity and consequences; personal variables showed strong associations with time line and control/cure.     

Daily Fluctuation in Chronic Fatigue Syndrome Severity and Symptoms

The present study characterized 46 chronic fatigue syndrome (CFS) patients' experiences of CFS and compared these patients with 11 healthy control participants. Chronic fatigue syndrome patients reported more symptoms of CFS, distress, and functional impairment than the controls. These heightened symptoms remained relatively stable over time within the patient group. However, within individual patients, there were daily fluctuations in symptom reporting, indicating that some days were better than others. Additionally, there was a close association between CFS symptoms and reports of perceived stress and negative affect in the patient group. These results demonstrate the usefulness of the Daily Record Form for assessing symptom severity in CFS patients.     

The symptoms of chronic fatigue syndrome are related to abnormal ion channel function

The pathogenesis of chronic fatigue syndrome (CFS) is unknown but one of the most characteristic features of the illness is fluctuation in symptoms which can be induced by physical and/or mental stress. Other conditions in which fluctuating fatigue occurs are caused by abnormal ion channels in the cell membrane. These include genetically determined channelopathies, e.g. hypokalemic periodic paralysis, episodic ataxia type 2 and acquired conditions such as neuromyotonia, myasthenic syndromes, multiple sclerosis and inflammatory demyelinating polyneuropathies. Our hypothesis is that abnormal ion channel function underlies the symptoms of CFS and this is supported also by the finding of abnormal cardiac-thallium201 SPECT scans in CFS, similar to that found in syndrome X, another disorder of ion channels. CFS and syndrome X can have identical clinical symptoms. CFS may begin after exposure to specific toxins which are known to produce abnormal sodium ion channels. Finally, in CFS, increased resting energy expenditure (REE) occurs, a state influenced by transmembrane ion transport. The hypothesis that ion channels are abnormal in CFS may help to explain the fluctuating fatigue and other symptoms.