Reference List

1. Deale A, Husain K, Chalder T, Wessely S: Long-term outcome of cognitive behavior therapy versus relaxation therapy for chronic fatigue syndrome: a 5-year follow-up study. Am J Psychiatry 2001; 158: 2038-42.

Abstract: OBJECTIVE: This study evaluated the long-term outcome of cognitive behavior therapy versus relaxation therapy for patients with chronic fatigue syndrome. METHOD: Sixty patients who participated in a randomized controlled trial of cognitive behavior therapy versus relaxation therapy for chronic fatigue syndrome were invited to complete self-rated measures and participate in a 5-year follow-up interview with an assessor who was blind to treatment type. RESULTS: Fifty-three patients (88%) participated in the follow-up study: 25 received cognitive behavior therapy and 28 received relaxation therapy. A total of 68% of the patients who received cognitive behavior therapy and 36% who received relaxation therapy rated themselves as "much improved" or "very much improved" at the 5-year follow-up. Significantly more patients receiving cognitive behavior therapy, in relation to those in relaxation therapy, met criteria for complete recovery, were free of relapse, and experienced symptoms that had steadily improved or were consistently mild or absent since treatment ended. Similar proportions were employed, but patients in the cognitive behavior therapy group worked significantly more mean hours per week. Few patients crossed the threshold for "normal" fatigue, despite achieving a good outcome on other measures. Cognitive behavior therapy was positively evaluated and was still used by over 80% of the patients. CONCLUSIONS: Cognitive behavior therapy for chronic fatigue syndrome can produce some lasting benefits but is not a cure. Once therapy ends, some patients have difficulty making further improvements. In the future, attention should be directed toward ensuring that gains are maintained and extended after regular treatment ends.

2. Buchwald D, Herrell R, Ashton S, et al: A twin study of chronic fatigue. Psychosom Med 2001; 63: 936-43.

Abstract: OBJECTIVE: The etiology of chronic fatigue syndrome is unknown, but genetic influences may be important in its expression. Our objective was to assess the role of genetic and environmental factors in unexplained chronic fatigue. METHODS: A classic twin study was conducted using 146 female-female twin pairs, of whom at least one member reported greater than or equal to 6 months of fatigue. After completing questionnaires on symptoms, zygosity, physical health, and a psychiatric interview, twins were classified using three increasingly stringent definitions: 1) chronic fatigue for greater than or equal to 6 months, 2) chronic fatigue not explained by exclusionary medical conditions, and 3) idiopathic chronic fatigue not explained by medical or psychiatric exclusionary criteria of the chronic fatigue syndrome case definition. Concordance rates in monozygotic and dizygotic twins were calculated for each fatigue definition along with estimates of the relative magnitude of genetic and environmental influences on chronic fatigue. RESULTS: The concordance rate washigher in monozygotic than dizygotic twins for each definition of chronic fatigue. For idiopathic chronic fatigue, the concordance rates were 55% in monozygotic and 19% in dizygotic twins (p= .042). The estimated heritability in liability was 19% (95% confidence interval = 0-56) for chronic fatigue greater than or equal to6 months, 30% (95% confidence interval = 0-81) for chronic fatigue not explained by medical conditions, and 51% (95% confidence interval = 7-96) for idiopathic chronic fatigue. CONCLUSIONS: These results provide evidence supporting the familial aggregation of fatigue and suggest that genes may play a role in the etiology of chronic fatigue syndrome.

3. Parker AJ, Wessely S, Cleare AJ: The neuroendocrinology of chronic fatigue syndrome and fibromyalgia. Psychol Med 2001; 31: 1331-45.

Abstract: BACKGROUND: Disturbance of the HPA axis may be important in the pathophysiology of chronic fatigue syndrome (CFS) and fibromyalgia. Symptoms may be due to: (1) low circulating cortisol; (2) disturbance of central neurotransmitters; or (3) disturbance of the relationship between cortisol and central neurotransmitter function. Accumulating evidence of the complex relationship between cortisol and 5-HT function, make some form of hypothesis (3) most likely. We review the methodology and results of studies of the HPA and other neuroendocrine axes in CFS. METHOD: Medline, Embase and Psychlit were searched using the Cochrane Collaboration strategy. A search was also performed on the King's College CFS database, which includes over 3000 relevant references, and a citation analysis was run on the key paper (Demitrack et al. 1991). RESULTS: One-third of the studies reporting baseline cortisol found it to be significantly low, usually in one-third of patients. Methodological differences may account for some of the varying results. More consistent is the finding of reduced HPA function, and enhanced 5-HT function on neuroendocrine challenge tests. The opioid system, and arginine vasopressin (AVP) may also be abnormal, though the growth hormone (GH) axis appears to be intact, in CFS. CONCLUSIONS: The significance of these changes, remains unclear. We have little understanding of how neuroendocrine changes relate to the experience of symptoms, and it is unclear whether these changes are primary, or secondary to behavioural changes in sleep or exercise. Longitudinal studies of populations at risk for CFS will help to resolve these issues.

4. Cleare AJ, Miell J, Heap E, et al: Hypothalamo-pituitary-adrenal axis dysfunction in chronic fatigue syndrome, and the effects of low-dose hydrocortisone therapy. J Clin Endocrinol Metab 2001; 86: 3545-54.

Abstract: These neuroendocrine studies were part of a series of studies testing the hypotheses that 1) there may be reduced activity of the hypothalamic-pituitary-adrenal axis in chronic fatigue syndrome and 2) low-dose augmentation with hydrocortisone therapy would improve the core symptoms. We measured ACTH and cortisol responses to human CRH, the insulin stress test, and D-fenfluramine in 37 medication-free patients with CDC-defined chronic fatigue syndrome but no comorbid psychiatric disorders and 28 healthy controls. We also measured 24-h urinary free cortisol in both groups. All patients (n = 37) had a pituitary challenge test (human CRH) and a hypothalamic challenge test [either the insulin stress test (n = 16) or D-fenfluramine (n = 21)]. Baseline cortisol concentrations were significantly raised in the chronic fatigue syndrome group for the human CRH test only. Baseline ACTH concentrations did not differ between groups for any test. ACTH responses to human CRH, the insulin stress test, and D- fenfluramine were similar for patient and control groups. Cortisol responses to the insulin stress test did not differ between groups, but there was a trend for cortisol responses both to human CRH and D-fenfluramine to be lower in the chronic fatigue syndrome group. These differences were significant when ACTH responses were controlled. Urinary free cortisol levels were lower in the chronic fatigue syndrome group compared with the healthy group. These results indicate that ACTH responses to pituitary and hypothalamic challenges are intact in chronic fatigue syndrome and do not support previous findings of reduced central responses in hypothalamic-pituitary-adrenal axis function or the hypothesis of abnormal CRH secretion in chronic fatigue syndrome. These data further suggest that the hypocortisolism found in chronic fatigue syndrome may be secondary to reduced adrenal gland output. Thirty-two patients were treated with a low-dose hydrocortisone regime in a double- blind, placebo-controlled cross-over design, with 28 days on each treatment. They underwent repeated 24-h urinary free cortisol collections, a human CRH test, and an insulin stress test after both active and placebo arms of treatment. Looking at all subjects, 24-h urinary free cortisol was higher after active compared with placebo treatments, but 0900-h cortisol levels and the ACTH and cortisol responses to human CRH and the insulin stress test did not differ. However, a differential effect was seen in those patients who responded to active treatment (defined as a reduction in fatigue score to the median population level or less). In this group, there was a significant increase in the cortisol response to human CRH, which reversed the previously observed blunted responses seen in these patients. We conclude that the improvement in fatigue seen in some patients with chronic fatigue syndrome during hydrocortisone treatment is accompanied by a reversal of the blunted cortisol responses to human CRH. < /U >

5. Natelson BH: Chronic fatigue syndrome. JAMA 2001; 285: 2557-9.

Abstract: Chronic fatigue syndrome (CFS), like fibromyalgia and multiple chemical sensitivity, comprises a number of poorly understood signs and symptoms, and whether a patient receives the diagnosis for one or another of these symptom clusters may depend on the specialty of the physician making the diagnosis. Patients with CFS also often fulfill case definitions for these other illnesses. This overlap suggests that these "functional somatic illnesses" may be variants of one another. However, this does not necessarily mean that these syndromes share the same pathobiological processes or causes. For example, patients with fibromyalgia have been found to have elevated levels of substance P in spinal fluid and reduced pain thresholds, while patients with CFS have not. Similarly, the fatigue reported by patients with fibromyalgia may be secondary to chronic sleep disruption because of pain, while fatigue may be primary in CFS.

The case definitions for CFS reflect the observation that the severe fatigue and influenza-like symptoms, which often begin suddenly, were initially thought to represent an underlying viral infection. Thus, the diagnosis requires at least 6 months of new-onset symptoms of fatigue accompanied by infectious, rheumatological, and neuropsychiatric symptoms, and which cannot be explained by other medical diagnoses. In the United States, CFS has a prevalence of 0.52% in women and 0.29% in men. Patients with CFS may experience severe disability; one study reported that patients with CFS have lower self-reported functional status than a group of similar patients with congestive heart failure. In this article, I review the evidence for several proposed hypotheses about the etiology of CFS.

6. Hanson SJ, Gause W, Natelson B: Detection of immunologically significant factors for chronic fatigue syndrome using neural-network classifiers. Clin Diagn Lab Immunol 2001; 8: 658-62.

Abstract: Neural-network classifiers were used to detect immunological differences in groups of chronic fatigue syndrome (CFS) patients that heretofore had not shown significant differences from controls. In the past linear methods were unable to detect differences between CFS groups and non-CFS control groups in the nonveteran population. An examination of the cluster structure for 29 immunological factors revealed a complex, nonlinear decision surface. Multilayer neural networks showed an over 16% improvement in an n-fold resampling generalization test on unseen data. A sensitivity analysis of the network found differences between groups that are consistent with the hypothesis that CFS symptoms are a consequence of immune system dysregulation. Corresponding decreases in the CD19(+) B-cell compartment and the CD34(+) hematopoietic progenitor subpopulation were also detected by the neural network, consistent with the T-cell expansion. Of significant interest was the fact that, of all the cytokines evaluated, the only one to be in the final model was interleukin-4 (IL-4). Seeing an increase in IL-4 suggests a shift to a type 2 cytokine pattern. Such a shift has been hypothesized, but until now convincing evidence to support that hypothesis has been lacking.

7. Bell DS, Jordan K, Robinson M: Thirteen-year follow-up of children and adolescents with chronic fatigue syndrome. Pediatrics 2001; 107: 994-8.

Abstract: OBJECTIVE: To describe the educational, social, and symptomatic outcome of children and adolescents with chronic fatigue syndrome 13 years after illness onset. METHODS: Between January 1984 and December 1987, 46 children and adolescents developed an illness suggestive of chronic fatigue syndrome. Follow-up questionnaires were obtained from 35 participants an average of 13 years after illness onset. Data were obtained concerning subsequent medical diagnoses, amount of school missed, presence and severity of current symptoms, and subjective assessment of degree of illness resolution. RESULTS: Of the 35 participants, 24 were female (68.6%) and 11 were male (31.4%). Average age at illness onset was 12.1 years. Eight participants (22.9%) had an acute onset of symptoms, 27 (77.1%) had a gradual onset. No participant received an alternative medical diagnosis that could have explained the symptom complex between illness onset and follow-up. Thirteen participants (37.1%) considered themselves resolved of illness at follow-up; 15 participants (42.9%) considered themselves well but not resolved; 4 (11.4%) considered themselves chronically ill; and 3 (8.6%) considered themselves more ill than during the early years of illness. Correlation with the Medical Outcomes Study Short Form Health Survey was good for current level of symptoms and degree of recovery. Eight participants (22.9%) missed >2 years of school, and 5 of these were still ill at follow-up. Amount of school missed correlated with both illness severity at follow-up and perceived social impact of the illness. CONCLUSIONS: These data demonstrate the presence of an illness consistent with the current definition of chronic fatigue syndrome. Eighty percent of children and adolescents affected had a satisfactory outcome from their fatiguing illness, although the majority of these participants had mild to moderate persisting symptoms. Twenty percent of participants remain ill with significant symptoms and activity limitation 13 years after illness onset. Chronic fatigue syndrome in children and adolescents may result in persistent somatic symptoms and disability in a minority of those affected.

8. Friedberg F, Jason LA: Chronic fatigue syndrome and fibromyalgia: clinical assessment and treatment. J Clin Psychol 2001; 57: 433-55.

Abstract: Chronic fatigue syndrome (CFS) and fibromyalgia (FM) are closely related illnesses of uncertain etiology. This article reviews the research literature on these biobehavioral conditions, with an emphasis on explanatory models, clinical evaluation of comorbid psychiatric disorders, assessment of stress factors, pharmacologic and alternative therapies, and cognitive-behavioral treatment studies. Furthermore, clinical protocols suitable for professional practice are presented based on an integration of the authors' clinical observations with published data. The article concludes with the recognition that mental health professionals can offer substantial help to these patients. Copyright 2001 John Wiley & Sons, Inc.

9. Rowe PC, Calkins H, DeBusk K, et al: Fludrocortisone acetate to treat neurally mediated hypotension in chronic fatigue syndrome: a randomized controlled trial. JAMA 2001; 285: 52-9.

Abstract: CONTEXT: Patients with chronic fatigue syndrome (CFS) are more likely than healthy persons to develop neurally mediated hypotension (NMH) in response to prolonged orthostatic stress. OBJECTIVE: To examine the efficacy of fludrocortisone acetate as monotherapy for adults with both CFS and NMH. DESIGN: Randomized, double-blind, placebo-controlled trial conducted between March 1996 and February 1999. SETTING: Two tertiary referral centers in the United States. PATIENTS: One hundred individuals aged 18 to 50 years who satisfied Centers for Disease Control and Prevention criteria for CFS and had NMH provoked during a 2- stage tilt-table test. Eighty-three subjects had adequate outcome data to assess efficacy. INTERVENTION: Subjects were randomly assigned to receive fludrocortisone acetate, titrated to 0.1 mg/d (n = 50) or matching placebo (n = 50) for 9 weeks, followed by 2 weeks of observation after discontinuation of therapy. MAIN OUTCOME MEASURE: Proportion of subjects in each group with at least a 15-point improvement on a 100-point global wellness scale. RESULTS: Baseline demographic and illness characteristics between the groups were similar; CFS had been present for at least 3 years in 71%. Using an intention-to-treat analysis, 7 subjects (14%) treated with fludrocortisone experienced at least a 15-point improvement in their wellness scores compared with 5 (10%) among placebo recipients (P = .76). No differences were observed in several other symptom scores or in the proportion with normal follow-up tilt test results at the end of the treatment period. CONCLUSIONS: In our study of adults with CFS, fludrocortisone as monotherapy for NMH was no more efficacious than placebo for amelioration of symptoms. Failure to identify symptomatic improvement with fludrocortisone does not disprove the hypothesis that NMH could be contributing to some of the symptoms of CFS. Further studies are needed to determine whether other medications or combination therapy are more effective in treating orthostatic intolerance in patients with CFS. < /U >

10. Patarca-Montero R, Antoni M, Fletcher MA, Klimas NG: Cytokine and other immunologic markers in chronic fatigue syndrome and their relation to neuropsychological factors. Appl Neuropsychol 2001; 8: 51-64.

Abstract: The literature is reviewed and data are presented that relate to a model we have developed to account for the perpetuation of the perplexing disorder currently termed chronic fatigue syndrome (CFS). In patients with CFS there is chronic lymphocyte overactivation with cytokine abnormalities that include perturbations in plasma levels of proinflammatory cytokines and decrease in the ratio of Type 1 to Type 2 cytokines produced by lymphocytes in vitro following mitogen stimulation. The initiation of the syndrome is frequently sudden and often follows an acute viral illness. Our model for the subsequent chronicity of this disorder holds that the interaction of psychological factors (distress associated with either CFS-related symptoms or other stressful life events) and the immunologic dysfunction contribute to (a) CFS-related physical symptoms (e.g., perception of fatigue and cognitive difficulties, fever, muscle and joint pain) and increases in illness burden and (b) impaired immune surveillance associated with cytotoxic lymphocytes with resulting activation of latent herpes viruses.

11. Lange G, Holodny AI, DeLuca J, et al: Quantitative assessment of cerebral ventricular volumes in chronic fatigue syndrome. Appl Neuropsychol 2001; 8: 23-30.

Abstract: Previous qualitative volumetric assessment of lateral ventricular enlargement in chronic fatigue syndrome (CFS) has provided evidence for subtle structural changes in the brains of some individuals with CFS. The aim of this pilot study was to determine whether a more sensitive quantitative assessment of the lateral ventricular system would support the previous qualitative findings. In this study, we compared the total lateral ventricular volume, as well as the right and left hemisphere subcomponents in 28 participants with CFS and 15 controls. Ventricular volumes in the CFS group were larger than in control groups, a difference that approached statistical significance. Group differences in ventricular asymmetry were not observed. The results of this study provide further evidence of subtle pathophysiological changes in the brains of participants with CFS.

12. Daly E, Komaroff AL, Bloomingdale K, Wilson S, Albert MS: Neuropsychological function in patients with chronic fatigue syndrome, multiple sclerosis, and depression. Appl Neuropsychol 2001; 8: 12-22.

Abstract: Patients with chronic fatigue syndrome (CFS), multiple sclerosis (MS), and major depression were compared with controls and with each other on a neuropsychological battery that included standard neuropsychological tests and a computerized set of tasks that spanned the same areas of ability. A total of 101 participants were examined, including 29 participants with CFS, 24 with MS, 23 with major depressive disorder, and 25 healthy controls. There were significant differences among the groups in 3 out of 5 cognitive domains: memory, language, and spatial ability. Assessment of psychiatric symptoms indicated that all 3 patient groups had a higher prevalence of depression than the controls. A total measure of psychiatric symptomatology also differentiated the patients from the controls. After covarying the cognitive test scores by a measure of depression, the patient groups continued to differ from controls primarily in the area of memory. The findings support the view that the cognitive deficits found in CFS cannot be attributed solely to the presence of depressive symptomatology in the patients.

13. Stewart JM: Autonomic nervous system dysfunction in adolescents with postural orthostatic tachycardia syndrome and chronic fatigue syndrome is characterized by attenuated vagal baroreflex and potentiated sympathetic vasomotion. Pediatr Res 2000; 48: 218-26.

Abstract: The objective was to determine the nature of autonomic and vasomotor changes in adolescent patients with orthostatic tachycardia associated with the chronic fatigue syndrome (CFS) and the postural orthostatic tachycardia syndrome (POTS). Continuous electrocardiography and arterial tonometry was used to investigate the heart rate and blood pressure responses before and 3-5 min after head-up tilt in 22 adolescents with POTS and 14 adolescents with CFS, compared with control subjects comprising 10 healthy adolescents and 20 patients with simple faint. Heart rate and blood pressure variability, determined baroreceptor function using transfer function analysis, and measured cardiac vagal and adrenergic autonomic responses were calculated using timed breathing and the quantitative Valsalva maneuver. Two of 10 healthy controls and 14 of 20 simple faint patients experienced vasovagal syncope during head-up tilt. By design, all CFS and POTS patients experienced orthostatic tachycardia, often associated with hypotension. R-R interval and heart rate variability were decreased in CFS and POTS patients compared with control subjects and remained decreased with head-up tilt. Low-frequency (0.05-0.15 Hz) blood pressure variability reflecting vasomotion was increased in CFS and POTS patients compared with control subjects and increased further with head-up tilt. This was associated with depressed baroreflex transfer indicating baroreceptor attenuation through defective vagal efferent response. Only the sympathetic response remained. Heart rate variability declined progressively from normal healthy control subjects through syncope to POTS to CFS patients. Timed breathing and Valsalva maneuver were most often normal in CFS and POTS patients, although abnormalities in select individuals were found. Heart rate and blood pressure regulation in POTS and CFS patients are similar and indicate attenuated efferent vagal baroreflex associated with increased vasomotor tone. Loss of beat-to-beat heart rate control may contribute to a destabilized blood pressure resulting in orthostatic intolerance. The dysautonomia of orthostatic intolerance in POTS and in chronic fatigue are similar.

14. Klimas N, Wallace M: Toward optimal health: the experts discuss chronic fatigue syndrome: interview by Jodi Godfrey Meisler. J Womens Health Gend Based Med 2000; 9: 477-82.

15. Lloyd AR, Hickie IB, Loblay RH: Illness or disease? The case of chronic fatigue syndrome. Med J Aust 2000; 172: 471-2.

16. Komaroff AL: The biology of chronic fatigue syndrome. Am J Med 2000; 108: 169-71.

17. De Meirleir K, Bisbal C, Campine I, et al: A 37 kDa 2-5A binding protein as a potential biochemical marker for chronic fatigue syndrome. Am J Med 2000; 108: 99-105.

Abstract: PURPOSE: Recent studies have revealed abnormalities in the ribonuclease L pathway in peripheral blood mononuclear cells of patients with the chronic fatigue syndrome. We conducted a blinded study to detect possible differences in the distribution of 2-5A binding proteins in the cells of patients with chronic fatigue syndrome and controls. PATIENTS AND METHODS: We studied 57 patients with chronic fatigue syndrome and 53 control subjects (28 healthy subjects and 25 patients with depression or fibromyalgia). A radioactive probe was used to label 2-5A binding proteins in unfractionated peripheral blood mononuclear cell extracts and to compare their distribution in the three groups. RESULTS: A 37 kDa 2-5A binding polypeptide was found in 50 (88%) of the 57 patients with chronic fatigue syndrome compared with 15 (28%) of the 53 controls (P < 0.01). When present, the amount of 37 kDa protein was very low in the control groups. When expressed as the ratio of the 37 kDa protein to the 80 kDa protein, 41 (72%) of the 57 patients with chronic fatigue syndrome had a ratio > 0.05, compared with 3 (11%) of the 28 healthy subjects and none of the patients with fibromyalgia or depression. CONCLUSION: The presence of a 37 kDa 2-5A binding protein in extracts of peripheral blood mononuclear cells may distinguish patients with chronic fatigue syndrome from healthy subjects and those suffering from other diseases.

18. Schondorf R, Benoit J, Wein T, Phaneuf D: Orthostatic intolerance in the chronic fatigue syndrome. J Auton Nerv Syst 1999; 75: 192-201.

Abstract: This study aims to investigate the prevalence and pathophysiology of orthostatic intolerance (OI) and its potential contribution to symptoms of a group of unselected patients with chronic fatigue syndrome (CFS). Seventy five patients (65 women, 10 men) with CFS were evaluated. During an initial visit, a clinical suspicion as to the likelihood of observing laboratory evidence of OI was assigned. Laboratory investigation consisted of beat-to-beat recordings of heart rate, blood pressure (Finapres), and stroke volume (impedance cardiograph) while supine and during 80 degrees head-up tilt (HUT), during rhythmic deep breathing (6 breaths/min) and during the Valsalva maneuver. The responses of 48 age-matched healthy controls who had no history of OI were used to define the range of normal responses to these three maneuvers. Forty percent of patients with CFS had OI during head-up tilt. Sixteen exhibited neurally-mediated syncope alone, seven tachycardia (> 35 bpm averaged over the whole of the head-up tilt) and six a mixture of tachycardia and syncope. Eight of 48 controls exhibited neurally-mediated syncope. The responses to the Valsalva maneuver and to deep breathing were similar in controls and patients. On average, the duration of disease and patient age were significantly less and the onset of symptoms was more often subacute in patients with OI than in those without OI. We conclude that there exists a clinically identifiable subgroup of patients with CFS and OI that differs from control subjects and from those with CFS without OI for whom treatment specifically aimed at improving orthostatic tolerance may be indicated.

19. Schondorf R, Freeman R: The importance of orthostatic intolerance in the chronic fatigue syndrome. Am J Med Sci 1999; 317: 117-23.

Abstract: Chronic fatigue syndrome (CFS) or myalgic encephalomyelitis is a clinically defined syndrome characterized by persistent or relapsing debilitating fatigue for longer than 6 months in the absence of any definable medical diagnosis. The cause of this syndrome is unknown. Symptoms of orthostatic intolerance, such as disabling fatigue, dizziness, diminished concentration, tremulousness, and nausea, are often found in patients with CFS. In this review, we critically evaluate the relationship between orthostatic intolerance and CFS. Particular emphasis is placed on clinical diagnosis, laboratory testing, pathophysiology, and therapeutic management. It is hoped that this review will provide a stimulus for further study of this complex and disabling condition.

20. Scott LV, Dinan TG: The neuroendocrinology of chronic fatigue syndrome: focus on the hypothalamic-pituitary-adrenal axis. Funct Neurol 1999; 14: 3-11.