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ME Research UK — Database of Research Publications 2005

Authors Author Address Title Publication Abstract

[No authors listed] Summaries for patients. The health of Gulf War veterans. Original report in: Ann Intern Med. 2005 Jun 7;142(11):881-90.

Ann Intern Med. 2005 Jun 7;142(11):I22.

[No authors listed] Increased activity OK for chronic pain.

Health News. 2005 May;11(5):6.

Armengaud D. Service de pediatrie-medecine neonatale, CHI Poissy-Saint-Germain, 78300 Poissy. [email protected]

[Chronic fatigue and sleep disorders in adolescents] [Article in French]

Rev Prat. 2005 May 31;55(10):1095-8.

To be, or to feel tired, is a frequent complaint at any age, and which does not seem in itself to be specific of the teenager. If it frequently lies within the scope of an organic pathology, acute or chronic, besides while being able to be a revealing element for it, it is often insulated and asks a rigorous step in the evaluation of its various possible components. It is then important to be in an active listening and patient, and not in a hasty regulation of a "cosmetic" treatment of this subjective allegation. It is all the work of the doctor whom to support the emergence of the subjacent complaint whose tensions and stakes of adolescence post there their singularity.

Aslangul E, Le Jeunne C.

Service de Medecine Interne, Hotel-Dieu, 75004 Paris. [email protected]

[Diagnosing asthenia and chronic fatigue syndrome] [Article in French]

Rev Prat. 2005 May 15;55(9):1029-33.

Axe EK, Satz P, Rasgon NL, Fawzy FI

ORIGINAL RESEARCHMajor Depressive Disorder in Chronic Fatigue Syndrome: A CDC Surveillance Study

Journal of Chronic Fatigue Syndrome 2005 12 (3): 7-23

Background: Controversy continues to exist as to whether Chronic Fatigue Syndrome is a psychological/psychiatric disorder. To further understand this condition the Centers for Disease Control (CDC) conducted a Surveillance Study. The CDC partitioned 565 subjects with fatiguing illnesses into four diagnostic groups, one of which met the 1988 CDC criteria for CFS. The non-CFS groups had either insufficient severity (idiopathic), medical exclusions or prior psychiatric disorders. Objectives: The present study reports on the psychiatric features in that study, estimates the time of onset of Major Depressive Disorder (MDD) and looks for possible relationships between 1988 CDC criteria for Chronic Fatigue Syndrome and psychiatric disorders. Methods: The study design is cross-sectional. The Diagnostic Interview Schedule (DIS) assessed for four Axis I psychiatric disorders. Time of onset ofMDDwas estimated from the DIS and validated by an examination of the medical records. Odds ratios and confidence intervals were calculated as tests of association between 1988 CDC criteria and psychiatric disorders. Results: Subjects classified as CFS and non-CFS had similar rates of psychiatric disorders. A minority of subjects had preexisting MDD. Three 1988 CDC criteria were associated with current MDD whilst no criteria were associated with prior MDD. Conclusions: CFS subjects did not demonstrate any unique patterns of psychiatric disorders. MDD may not be an important predisposing factor for CFS or the other fatiguing illnesses. Some 1988 CDC criteria may be preferentially endorsed by subjects with current MDD.


Badawy AA, Morgan CJ, Llewelyn MB, Albuquerque SR, Farmer A.

Cardiff & Vale NHS Trust, Biomedical Research Laboratory, Whitchurch Hospital, Cardiff, Wales, UK. [email protected]

Heterogeneity of serum tryptophan concentration and availability to the brain in patients with the chronic fatigue syndrome.

J Psychopharmacol. 2005 Jul;19(4):385-91.

We assessed the serotonin status of patients with the chronic fatigue syndrome (CFS). Tryptophan (Trp) availability to the brain, expressed as the ratio of concentration of serum Trp to the sum of those of its five competitors (CAA), and other parameters of Trp disposition were compared in 23 patients with the CFS and 42 healthy controls. The serum [free Trp]/[CAA] ratio was 43% higher in CFS patients, due to a 48% higher [free Trp]. [Total Trp] was also significantly higher (by 19%) in CFS patients, and, although the [total Trp]/[CAA] ratio did not differ significantly between the control and patient groups, the difference became significant when the results were co-varied with age and gender. [CAA] was not significantly different between groups, but was significantly lower in females, compared to males, of the CFS patient group. We have established normal ranges for Trp disposition parameters and propose criteria for defining the serotonin-biosynthetic status in humans. We have provisionally identified two subgroups of CFS patients, one with normal serotonin and the other with a high serotonin status. The relevance of our findings to, and their implications for, the pharmacological and other therapies of the chronic fatigue syndrome are discussed.

Baraniuk JN, Casado B, Maibach H, Clauw DJ, Pannell LK, Hess S S.

Georgetown University Proteomics Laboratory, Division of Rheumatology, Immunology & Allergy, Room B-105, Lower Level Kober-Cogan Building, Georgetown University, Washington, DC 20007-2197, USA. [email protected]

A Chronic Fatigue Syndrome - related proteome in human cerebrospinal fluid.

BMC Neurol. 2005 Dec 1;5:22.

BACKGROUND: Chronic Fatigue Syndrome (CFS), Persian Gulf War Illness (PGI), and fibromyalgia are overlapping symptom complexes without objective markers or known pathophysiology. Neurological dysfunction is common. We assessed cerebrospinal fluid to find proteins that were differentially expressed in this CFS-spectrum of illnesses compared to control subjects. METHODS: Cerebrospinal fluid specimens from 10 CFS, 10 PGI, and 10 control subjects (50 mul/subject) were pooled into one sample per group (cohort 1). Cohort 2 of 12 control and 9 CFS subjects had their fluids (200 mul/subject) assessed individually. After trypsin digestion, peptides were analyzed by capillary chromatography, quadrupole-time-of-flight mass spectrometry, peptide sequencing, bioinformatic protein identification, and statistical analysis. RESULTS: Pooled CFS and PGI samples shared 20 proteins that were not detectable in the pooled control sample (cohort 1 CFS-related proteome). Multilogistic regression analysis (GLM) of cohort 2 detected 10 proteins that were shared by CFS individuals and the cohort 1 CFS-related proteome, but were not detected in control samples. Detection of >or=1 of a select set of 5 CFS-related proteins predicted CFS status with 80% concordance (logistic model). The proteins were alpha-1-macroglobulin, amyloid precursor-like protein 1, keratin 16, orosomucoid 2 and pigment epithelium-derived factor. Overall, 62 of 115 proteins were newly described. CONCLUSION: This pilot study detected an identical set of central nervous system, innate immune and amyloidogenic proteins in cerebrospinal fluids from two independent cohorts of subjects with overlapping CFS, PGI and fibromyalgia. Although syndrome names and definitions were different, the proteome and presumed pathological mechanism(s) may be shared.

Baraniuk JN, Petrie KN, Le U, Tai CF, Park YJ, Yuta A, Ali M, Vandenbussche CJ, Nelson B.

Division of Rheumatology, Immunology and Allergy, Georgetown University, 3800 Reservoir Road, N.W., Washington, DC

Neuropathology in rhinosinusitis.

Am J Respir Crit Care Med. 2005 Jan 1;171(1):5-11. Epub 2004 Oct 11.

Pathophysiologic differences in neural responses to hypertonic saline (HTS) were investigated in subjects with acute sinusitis (n = 25), subjects with chronic fatigue syndrome (CFS) with nonallergic rhinitis (n = 14), subjects with active allergic rhinitis (AR; n = 17), and normal (n = 20) subjects. Increasing strengths of HTS were sprayed into their nostrils at 5-minute intervals. Sensations of nasal pain, blockage, and drip increased with concentration and were significantly elevated above normal. These parallels suggested activation of similar subsets of afferent neurons. Urea and lysozyme secretion were dose dependent in all groups, suggesting that serous cell exocytosis was one source of urea after neural stimulation. Only AR and normal groups had mucin dose responses and correlations between symptoms and lysozyme secretion (R(2) = 0.12-0.23). The lysozyme dose responses may

mailto:[email protected]



20007-2197, USA. [email protected]

represent axon responses in these groups. The neurogenic stimulus did not alter albumin (vascular) exudation in any group. Albumin and mucin concentrations were correlated in sinusitis, suggesting that nonneurogenic factors predominated in sinusitis mucous hypersecretion. CFS had neural hypersensitivity (pain) but reduced serous cell secretion. HTS nasal provocations identified significant, unique patterns of neural and mucosal dysregulation in each rhinosinusitis syndrome.

Baschetti R. Chronic fatigue syndrome, exercise, cortisol and lymphadenopathy.

J Intern Med. 2005 Sep;258(3):291-2.

Letter

Bazelmans E, Bleijenberg G, Voeten MJ, van der Meer JW, Folgering H.

Department of Medical Psychology, Radboud University Nijmegen Medical Centre, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands.

Impact of a maximal exercise test on symptoms and activity in chronic fatigue syndrome.

J Psychosom Res. 2005 Oct;59(4):201-8.

OBJECTIVE: This study examined the effects of exercise on symptoms and activity in chronic fatigue syndrome (CFS). METHODS: Twenty CFS patients and 20 neighborhood controls performed an incremental exercise test until exhaustion. Fatigue, muscle pain, minutes spent resting, and the level of physical activity were assessed with a self-observation list. Physical activity was assessed with an actometer as well. Data were obtained 3 days before the maximal exercise test (MET) up to 5 days thereafter. RESULTS: For CFS patients, daily observed fatigue was increased up to 2 days after the exercise test. For controls, self-observed fatigue returned to baseline after 2 h. Both CFS patients and controls spent more minutes resting on the day before and on the day after the MET. For CFS patients, self-observed minutes resting increased on the day of the exercise test. For neither group, a decrease of actometer recorded or self-observed physical activity after exercise was found. CONCLUSION: Fatigue in CFS patients increased after exercise, but the level of actual physical activity remained unchanged.

Bazelmans E, Bleijenberg G, Voeten MJ, van der Meer JW, Folgering H.

Department of Medical Psychology, Radboud University Nijmegen Medical Centre, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands. [email protected]

Impact of a maximal exercise test on symptoms and activity in chronic fatigue syndrome.

J Psychosom Res. 2005 Oct;59(4):201-8.

OBJECTIVE: This study examined the effects of exercise on symptoms and activity in chronic fatigue syndrome (CFS). METHODS: Twenty CFS patients and 20 neighborhood controls performed an incremental exercise test until exhaustion. Fatigue, muscle pain, minutes spent resting, and the level of physical activity were assessed with a self-observation list. Physical activity was assessed with an actometer as well. Data were obtained 3 days before the maximal exercise test (MET) up to 5 days thereafter. RESULTS: For CFS patients, daily observed fatigue was increased up to 2 days after the exercise test. For controls, self-observed fatigue returned to baseline after 2 h. Both CFS patients and controls spent more minutes resting on the day before and on the day after the MET. For CFS patients, self-observed minutes resting increased on the day of the exercise test. For neither group, a decrease of actometer recorded or self-observed physical activity after exercise was found. CONCLUSION: Fatigue in CFS patients increased after exercise, but the level of actual physical activity remained unchanged.

Bazelmans E, Prins JB, Lulofs R, van der Meer JW, Bleijenberg G; The Netherlands Fatigue Research Group Nijmegen.

Department of Medical Psychology, University Medical Centre Nijmegen, Nijmegen, The Netherlands. E.Bazelmans@cuk

Cognitive behaviour group therapy for chronic fatigue syndrome: a non-randomised waiting list controlled study.

Psychother Psychosom. 2005;74(4):218-24.

BACKGROUND: It has been demonstrated that individual cognitive behaviour therapy is an effective treatment for chronic fatigue syndrome (CFS). The aim of the present study was to investigate the effectiveness of cognitive behaviour group therapy (CBGT) in an unselected group of CFS patients. Additionally, pretreatment characteristics of CFS patients who improve after CBGT were explored. METHODS: In a non-randomised waiting list controlled design, 31 patients were allocated to CBGT and 36 to the waiting list condition. CBGT consisted of 12 two-hour sessions during 6 months. Main outcome measures were fatigue (Checklist Individual Strength) and functional impairment (Sickness Impact Profile). RESULTS: A moderate effect on fatigue in favour of CBGT




z.umcn.nl was found. For functional impairment, the effect was opposite to what was expected. Patients who improved after CBGT had less complaints at baseline compared to patients who did not improve. CONCLUSIONS: An explanation for the moderate effect might be that during CBGT, rest and relaxation were too much emphasised. Furthermore, an unselected group of CFS patients and therapists inexperienced in CB(G)T for CFS participated. Suggestions to improve CBGT for future research are given. Copyright (c) 2005 S. Karger AG, Basel.

Bell IR, Brooks AJ, Baldwin CM, Fernandez M, Figueredo AJ, Witten ML.

Research Service, Southern Arizona VA Health Care System, USA. [email protected]

JP-8 jet fuel exposure and divided attention test performance in 1991 Gulf War veterans.

Aviat Space Environ Med. 2005 Dec;76(12):1136-44.

INTRODUCTION: Previous research indicates that a large cohort of veterans from the 1991 Gulf War report polysymptomatic conditions. These syndromes often involve neurocognitive complaints, fatigue, and musculoskeletal symptoms, thus overlapping with civilian illnesses from low levels of environmental chemicals, chronic fatigue syndrome, and fibromyalgia. METHODS: To test for time-dependent changes over repeated intermittent exposures, we evaluated objective performance on a computerized visual divided attention test in chronically unhealthy Gulf War veterans (n = 22 ill with low-level chemical intolerance (CI); n = 24 ill without CI), healthy Gulf War veterans (n = 23), and healthy Gulf War era veterans (n = 20). Testing was done before and after each of three weekly, double blind, low-level JP-8 jet fuel or clean air sham exposure laboratory sessions, including acoustic startle stimuli. RESULTS: Unhealthy veterans receiving jet fuel had faster mean peripheral reaction times over sessions compared with unhealthy veterans receiving sham clean air exposures. Unhealthy Gulf veterans with CI exhibited faster post- vs. pre-session mean central reaction times compared with unhealthy Gulf veterans without CI. Findings were controlled for psychological distress variables. DISCUSSION: These data on unhealthy Gulf veterans show an acceleration of divided attention task performance over the course of repeated low-level JP-8 exposures. The present faster reaction times are consistent with rat neurobehavioral studies on environmental toxicant cross-sensitization and nonlinear dose-response patterns with stimulant drugs, as well as some previous civilian studies using other exposure agents. Together with previous research findings, the data suggest involvement of central nervous system dopaminergic pathways in affected Gulf veterans.

Bellanti JA, Sabra A, Castro HJ, Chavez JR, Malka-Rais J, de Inocencio JM.

Departments of Pediatrics , Georgetown University Medical Center, Washington, D.C. 20057, USA.

Are attention deficit hyperactivity disorder and chronic fatigue syndrome allergy related? what is fibromyalgia?

Allergy Asthma Proc. 2005 Jan-Feb;26(1):19-28.

Despite the progress made in the field of allergy-immunology in recent years, there are a group of diseases that the allergist-immunologist may be called on to manage in which their precise etiologies have not been identified but that appear to be initiated or exacerbated by allergic mechanisms. Attention deficit hyperactivity disorder (ADHD), chronic fatigue syndrome (CFS), and fibromyalgia (FM) fall into this category of disorders. Although the precise etiology of ADHD still remains unknown, the most prevalent theory is that it represents a neurobiologically based developmental disability leading to inadequate production of the neurotransmitter dopamine. In patients with CFS, there appears to be a fundamental dysfunction of the neuroendocrine-immunological system with deficiencies of immunological and neurological function, which, together with chronic viral infection, may lead to a sequence of events responsible for the symptoms of this disorder. FM appears to be a variant of CFS with a predominance of hypothalamic pituitary axis dysfunction. The disorder is characterized by chronic widespread pain and the finding of 11/18 tender points on examination. Now, there is emerging evidence to suggest that adverse reactions to foods or food components also may be associated with behavioral disturbances that may play a role in each of these disorders. An understanding of the interactive responses involved in the neuroendocrine-immunological network is essential for a comprehension of the pathophysiology of ADHD, CFS, and FM and the role of allergies appears to be an important triggering event in each of the disorders.




Bentler SE, Hartz AJ, Kuhn EM.

Department of Family Medicine, College of Medicine, University of Iowa, Iowa City, IA 52242-1097, USA.

Prospective observational study of treatments for unexplained chronic fatigue.

J Clin Psychiatry. 2005 May;66(5):625-32.

BACKGROUND: Unexplained chronic fatigue is a frequent complaint in primary care. A prospective observational study design was used to evaluate whether certain commonly used therapies for unexplained chronic fatigue may be effective. METHOD: Subjects with unexplained chronic fatigue of unknown etiology for at least 6 months were recruited from the Wisconsin Chronic Fatigue Syndrome Association, primary care clinics, and community chronic fatigue syndrome presentations. The primary outcome measure was change in a 5-question fatigue score from 6 months to 2 years. Self-reported interventions tested included prescribed medications, non-prescribed supplements and herbs, lifestyle changes, alternative therapies, and psychological support. Linear regression analysis was used to test the association of each therapy with the outcome measure after adjusting for statistically significant prognostic factors. RESULTS: 155 subjects provided information on fatigue and treatments at baseline and follow-up. Of these subjects, 87% were female and 79% were middle-aged. The median duration of fatigue was 6.7 years. The percentage of users who found a treatment helpful was greatest for coenzyme Q10 (69% of 13 subjects), dehydroepiandrosterone (DHEA) (65% of 17 subjects), and ginseng (56% of 18 subjects). Treatments at 6 months that predicted subsequent fatigue improvement were vitamins (p = .08), vigorous exercise (p = .09), and yoga (p = .002). Magnesium (p = .002) and support groups (p = .06) were strongly associated with fatigue worsening from 6 months to 2 years. Yoga appeared to be most effective for subjects who did not have unclear thinking associated with the fatigue. CONCLUSION: Certain alternative therapies for unexplained chronic fatigue, especially yoga, deserve testing in randomized controlled trials.

Black CD, McCully KK.

Department of Kinesiology, The University of Georgia, Athens, GA, USA. [email protected]

Time course of exercise induced alterations in daily activity in chronic fatigue syndrome.

Dyn Med. 2005 Oct 28;4:10.

In a previous study we demonstrated that while people with CFS had lower daily activity levels than control subjects, they were able to increase daily activity via a daily walking program. We reanalyzed our data to determine the time course of activity changes during the walking program. Daily activity assessed via an accelometer worn at the hip was divided into sleep, active, and walking periods. Over the first 4-10 days of walking the subjects with CFS were able to reach the prescribed activity goals each day. After this time, walking and total activity counts decreased. Sedentary controls subjects were able to maintain their daily walking and total activity goals throughout the 4 weeks. Unlike our previous interpretation of the data, we feel this new analysis suggests that CFS patients may develop exercise intolerance as demonstrated by reduced total activity after 4-10 days. The inability to sustain target activity levels, associated with pronounced worsening of symptomology, suggests the subjects with CFS had reached their activity limit.

Black CD, O'connor PJ, McCully KK.

Department of Exercise Science, The University of Georgia, Athens, GA, USA. [email protected].

Increased daily physical activity and fatigue symptoms in chronic fatigue syndrome.

Dyn Med. 2005 Mar 3;4(1):3.

Individuals with chronic fatigue syndrome (CFS) have been shown to have reduced activity levels associated with heightened feelings of fatigue. Previous research has demonstrated that exercise training has beneficial effects on fatigue-related symptoms in individuals with CFS. PURPOSE: The aim of this study was to sustain an increase in daily physical activity in CFS patients for 4 weeks and assess the effects on fatigue, muscle pain and overall mood. METHODS: Six CFS and seven sedentary controls were studied. Daily activity was assessed by a CSA accelerometer. Following a two week baseline period, CFS subjects were asked to increase their daily physical activity by 30% over baseline by walking a prescribed amount each day for a period of four weeks. Fatigue, muscle pain and overall mood were reported daily using a 0 to 100 visual analog scale and weekly using the Profile of Mood States (Bipolar) questionnaire. RESULTS: CFS patients had significantly lower daily activity counts than controls (162.5 +/- 51.7 x 103 counts/day vs. 267.2 +/- 79.5 x 103 counts/day) during a 2-week baseline period. At baseline, the CFS patients reported significantly (P < 0.01)



higher fatigue and muscle pain intensity compared to controls but the groups did not differ in overall mood. CFS subjects increased their daily activity by 28+/-19.7% over a 4 week period. Overall mood and muscle pain worsened in +the CFS patients with increased activity. CONCLUSION: CFS patients were able to increase their daily physical activity for a period of four weeks. In contrast to previous studies fatigue, muscle pain, and overall mood did not improve with increased activity. Increased activity was not presented as a treatment which may account for the differential findings between this and previous studies. The results suggest that a daily "activity limit" may exist in this population. Future studies on the impact of physical activity on the symptoms of CFS patients are needed.

Blotman F, Thomas E, Myon E, Andre E, Caubere JP, Taieb C.

Rheumatology Department, Lapeyronie Hospital, Montpellier, France. [email protected]

Awareness and knowledge of fibromyalgia among french rheumatologists and general practitioners.

Clin Exp Rheumatol. 2005 Sep-Oct;23(5):697-700.

OBJECTIVES: Fibromyalgia is a chronic disorder characterized by widespread musculoskeletal pain and fatigue. Its prevalence is estimated to be at 3.4% in women and 0.5% in men. It is a major cause of morbidity. Our objective was to evaluate, using a self-questionnaire sent by mail, the level of knowledge of French physicians, general practitioners, and rheumatologists on fibromyalgia and to analyse their therapeutic approach. METHODS: The demographic characteristics of a sample of general practitioners and rheumatologists were compared to those of the overall data available. This comparison demonstrated the good representativeness of our sample. RESULTS: Fibromyalgia was considered as a disease by 23% of rheumatologists and 33% of general practitioners. While on average, each rheumatologist followed 30 fibromyalgia patients, each general practitioner followed 6.1 patients (i.e., 2 to 5% of their practice's patient base). Among rheumatologists, 6.4% made no distinction between this disease and depression vs. 13.1% of general practitioners. The diagnosis of fibromyalgia was made based on tenderness that occurs in precise, localized areas of the body (trigger points) by 94% of rheumatologists and 79.1% of general practitioners. Of general practitioners and rheumatologists, 93.7% and 73.7% respectively, have not received any medical school training on fibromyalgia or chronic fatigue syndrome. CONCLUSION: Given the lack of medical school training and continuing professional education concerning fibromyalgia (rare use of pain rating scales, confusion in the classification of rheumatic diseases), there is an urgent need to initiate an explicit teaching effort on chronic pain, and on fibromyalgia in particular.

Bolk JH. Leids Universitair Medisch Centrum, afd Algemene Interne Geneeskunde, 2300 RC Leiden.

[Report from the Health Council of the Netherlands on the chronic fatigue syndrome: moving away from the body-mind dichotomy with a view to effective prevention and treatment] [Article in Dutch]

Ned Tijdschr Geneeskd. 2005 Apr 2;149(14):739-41.

The Health Council of the Netherlands has issued a report on the chronic fatigue syndrome (CFS). CFS is a real and seriously debilitating condition which imposes limitations on an individual's personal, occupational and social functioning. It is a syndrome of unknown aetiology without physical signs or biological markers. Although there is no disease, patients both feel ill and give the appearance of being ill. There is no consensus on whether CSF patients are able to work or whether they should be entitled to social security benefits. An imbalance between demand and coping is central in CFS, with stress as an important intermediary factor. It is little use concluding that unexplained signs are 'psychological' or that 'I cannot find anything wrong with you so you must be healthy'. The classical view that mind and body are separate systems is outmoded. The bio-psycho-social model of disease may be helpful in describing the interaction between body, mind and circumstance. Putting the CFS patient at ease and explaining the pathophysiology of the symptoms is a useful approach but many patients and patient associations are still very somatically orientated, thereby sustaining the condition. However, in patients who accept that their problems may be stress-induced and are prepared to participate in therapy, some therapies have been proven to be effective, notably cognitive behavioural therapy.


Bowen J, Pheby D, Charlett A, McNulty C.

Health Protection Agency Primary Care Unit, Gloucester, UK. [email protected]

Chronic Fatigue Syndrome: a survey of GPs' attitudes and knowledge.

Fam Pract. 2005 Aug;22(4):389-93. Epub 2005 Apr 1.

BACKGROUND: GPs need evidence and guidance to help them diagnose and manage Chronic Fatigue Syndrome (CFS)/ME appropriately. OBJECTIVES: The aim of this survey was to obtain baseline data and identify the factors associated with GPs' attitudes to and knowledge of CFS/ME. The attitude of GPs to the condition is an important indicator of likely prognosis. METHODS: A postal questionnaire was sent to 1054 GPs served by Taunton, Bristol and Gloucester laboratories. GPs' attitudes to nine statements about CFS/ME were assessed and the factors associated with positive or negative responses were determined. Knowledge of the clinical features was also assessed. RESULTS: 811 GPs (77%) returned the questionnaire. 48% of GPs did not feel confident with making a diagnosis of CFS/ME and 41% did not feel confident in treatment. 72% of GPs accepted CFS/ME as a recognisable clinical entity and those GPs had significantly more positive attitudes. Three other key factors that were significantly, positively associated with GPs' attitudes were knowing someone socially with CFS/ME, being male and seeing more patients with the condition in the last year. CONCLUSION: Despite the publication of guidance for GPs on CFS/ME, confidence with making a diagnosis and management was found to be low. Educational initiatives and guidance for GPs should stress the importance of accepting CFS/ME as a recognisable clinical entity, as this is linked to having a positive attitude and could lead to improved confidence to make a diagnosis and treat CFS/ME patients.

Brimacombe M, Lange G, Bisuchio K, Ciccone DS, Natelson B

ORIGINAL RESEARCH Cognitive Function Index for Patients with Chronic Fatigue Syndrome

Journal of Chronic Fatigue Syndrome 2005 12 (4): 3 - 23

Background: A comprehensive approach to assessing neuropsychological deficits in CFS patients is developed by assessing cognitive function across a number of domains using a battery of tests, rather than relying on any single instrument. Objective: A factor analytic approach was employed to examine the underlying dimensionality of 15 standard cognitive function related test variables in CFS patients. A cognitive function index (CFI) was then developed using appropriately weighted and interpreted factors. Methods: Factor analysis was applied to an initial sample of 65 CFS patients, identifying eight factors accounting for over 70% of total variation. This factor structure was then independently verified on a separate sample of 124 CFS patients. An overall combined CFS sample of 212 was then used to derive the CFI using an appropriately interpreted and weighted average of the derived factors. Results: After including age and education as separate factors, the CFI consists of nine factors accounting for 70% of total variation in the overall CFS group. The CFI was not affected by the presence of current psychiatric comorbidity. A cut-off score for cognitive dysfunction was established using the lower quartile value of a group of sedentary controls on the same index. Conclusions: The CFI will provide a useful summary measure for researchers investigating cognitive function performance in CFS patients. It does not replace existing individual specialized tests.

Buskila D, Neumann L, Press J.

Department of Internal Medicine, Faculty of Health Sciences, Ben Gurion University of the Negev, Beer Sheva 84101, Israel. [email protected]

Genetic factors in neuromuscular pain.

CNS Spectr. 2005 Apr;10(4):281-4.

Recent evidence suggests that fibromyalgia, a chronic widespread pain condition and related syndromes (chronic fatigue syndrome, irritable bowel syndrome, etc.) may share heritable pathophysiologic features. We review the recent literature on genetic and familial factors found to participate in the pathogenesis of these syndromes, specifically fibromyalgia, including evidence suggesting that serotonin- and dopamine-related genes may play a role in the pathogenesis of these illnesses. The importance of environmental factors triggering these conditions in predisposed individuals is also discussed.


Cairns R, Hotopf M.

Department of Psychological Medicine, Institute of Psychiatry, London, UK.

A systematic review describing the prognosis of chronic fatigue syndrome.

Occup Med (Lond). 2005 Jan;55(1):20-31.

AIM: To perform a systematic review of studies describing the prognosis of chronic fatigue (CF) and chronic fatigue syndrome (CFS) and to identify occupational outcomes from such studies. METHOD: A literature search was used to identify all studies describing the clinical follow-up of patients following a diagnosis of CF or CFS. The prognosis is described in terms of the proportion of individuals improved during the period of follow-up. Return to work, other medical illnesses and death as outcomes are also considered, as are variables which may influence prognosis. RESULTS: Twenty-eight articles met the inclusion criteria and, for the 14 studies of subjects meeting operational criteria for CFS, the median full recovery rate was 5% (range 0-31%) and the median proportion of patients who improved during follow-up was 39.5% (range 8-63%). Less fatigue severity at baseline, a sense of control over symptoms and not attributing illness to a physical cause were all associated with a good outcome. Return to work at follow-up ranged from 8 to 30% in the three studies that considered this outcome. CONCLUSIONS: Full recovery from untreated CFS is rare. The prognosis for an improvement in symptoms is less gloomy. This review looks at the course of CF/CFS without systematic intervention. However, there is increasing evidence for the effectiveness of cognitive behavioural and graded exercise therapies. Medical retirement should be postponed until a trial of such treatment has been given.

Cairns V, Godwin J.

Consultant Statistician, Am Rothlauf 9, 61476 Kronberg, Germany.

Post-Lyme borreliosis syndrome: a meta-analysis of reported symptoms.

Int J Epidemiol. 2005 Jul 22; [Epub ahead of print]

BACKGROUND: This meta-analysis compares the prevalence of fatigue, musculoskeletal pain, and neurocognitive difficulties in patients who have had Lyme borreliosis (LB) and control subjects without LB. METHODS: Titles and abstracts in PubMed were reviewed for studies with data on the symptoms listed above that compared patients who had had LB with controls from the general population. Five studies with 504 patients and 530 controls were included in the meta-analysis. RESULTS: The prevalence of symptoms was significantly higher in the LB patients, with P-values between <0.00001 and 0.007 for 8 of the 10 symptoms in the three categories listed above. The higher prevalence of certain neurocognitive symptoms but not others, in the same pattern as reported in the literature, is further confirmation of this syndrome. The pattern of symptoms appears to be different from that seen in fibromyalgia, depression, and chronic fatigue syndrome. CONCLUSIONS: This meta-analysis provides strong evidence that some patients with LB have fatigue, musculoskeletal pain, and neurocognitive difficulties that may last for years despite antibiotic treatment.

Cairns V, Godwin J.

Clinical Trial Service Unit, University of Oxford, UK. [email protected]

Post-Lyme borreliosis syndrome: a meta-analysis of reported symptoms.

Int J Epidemiol. 2005 Dec;34(6):1340-5. Epub 2005 Jul 22.

BACKGROUND: This meta-analysis compares the prevalence of fatigue, musculoskeletal pain, and neurocognitive difficulties in patients who have had Lyme borreliosis (LB) and control subjects without LB. METHODS: Titles and abstracts in PubMed were reviewed for studies with data on the symptoms listed above that compared patients who had had LB with controls from the general population. Five studies with 504 patients and 530 controls were included in the meta-analysis. RESULTS: The prevalence of symptoms was significantly higher in the LB patients, with P-values between <0.00001 and 0.007 for 8 of the 10 symptoms in the three categories listed above. The higher prevalence of certain neurocognitive symptoms but not others, in the same pattern as reported in the literature, is further confirmation of this syndrome. The pattern of symptoms appears to be different from that seen in fibromyalgia, depression, and chronic fatigue syndrome. CONCLUSIONS: This meta-analysis provides strong evidence that some patients with LB have fatigue, musculoskeletal pain, and neurocognitive difficulties that may last for years despite antibiotic treatment.



Casado B, Zanone C, Annovazzi L, Iadarola P, Whalen G, Baraniuk JN.

Department of Biochemistry A. Castellani, University of Pavia, V.le Taramelli 3/B, 27100 Pavia, Italy. [email protected]

Urinary electrophoretic profiles from chronic fatigue syndrome and chronic fatigue syndrome/fibromyalgia patients: a pilot study for achieving their normalization.

J Chromatogr B Analyt Technol Biomed Life Sci. 2005 Jan 5;814(1):43-51.

Aim of our study was to determine if there were distinct, disease-related patterns of urinary analytes in chronic fatigue syndrome (CFS) and chronic fatigue syndrome/fibromyalgia (CFS/FM) compared to normal controls (NC). Urine was collected from these subjects for two consecutive 24 h periods and aliquots were submitted to micellar electrokinetic chromatography (MEKC). To compensate for the differences in peak migration times, these were normalized from the 35 min duration of run to a 100-point scale, and each peak was assigned its normalized time measure. Peak heights were also normalized by dividing the mAU by that of the internal standard (creatinine) and multiplying by 100. MEKC with normalization for peak height and migration time generated comparable results within each of the patient groups. CFS/FM and CFS had significant differences in peaks compared to NC that may be of significance as biomarkers of illnesses.

Cervera C, Alegre J, Ruiz E, Vasquez A, Armadans L, Garcia-Quintana AM, Aleman C, de Sevilla TF

Employment Status and Financial Repercussions in 60 Patients with Chronic Fatigue Syndrome in Spain: Utility of the Fatigue Impact Scale


Chronic fatigue syndrome (CFS) is a disabling disorder with implications in employment status. We enrolled 60 patients who fulfilled the CDC diagnostic criteria of Holmes and those of Fukuda. All patients underwent a protocol involving a structured questionnaire to record diagnostic criteria items, clinical features of fatigue, social features and associated symptoms; application of the Fatigue Impact Scale (FIS); an employment repercussion questionnaire; and information on evolution of the symptoms. Statistical comparisons were performed with the Mann-Whitney U test and correlations with the Spearman test. A close correlation was found between work inactivity and higher scores in the FIS cognitive dimension. Patient age and duration of symptoms also correlated with high cognitive scores. Chronic fatigue syndrome patients report a considerable decrease in quality of life, and most of them have work limitations, particularly those with poor overall FIS scores and cognitive function scores.

Chalmers RA, Jones MG, Goodwin CS, Amjad S.

St George's Hospital Medical School, Cranmer Terrace, London SW17 0RE, UK.

CFSUM1 and CFSUM2 in urine from patients with chronic fatigue syndrome are methodological artefacts.

Clin Chim Acta. 2005 Aug 8; [Epub ahead of print]

McGregor et al. reported increased levels of an unidentified urinary compound (CFSUM1) in patients with chronic fatigue syndrome (CFS), with reduced excretion of another unidentified compound (CFSUM2), and suggested the possibility of chemical or metabolic 'markers' for CFS. The identity of CFSUM1 as reported was erroneous and the identities of these compounds have remained unknown until now. Urine samples were obtained from 30 patients with ME/CFS, 30 age- and sex-matched healthy controls, 20 control patients with depression and 22 control patients with rheumatoid arthritis. Samples were prepared using the published methods of McGregor et al. to produce heptafluorobutyryl-isobutyl derivatives of urinary metabolites. Alternative preparations utilised isopropyl, n-butyl and trifluoroacetyl derivatives. These were separated and identified using gas chromatography-mass spectrometry. CFSUM2 was identified as being partially derivatised [isobutyl ester-mono-heptafluorobutyryl (HFB)] serine. CFSUM1 was identified as partially derivatised pyroglutamic acid, being the isobutyl ester without formation of a HFB derivative. Both CFSUM1 and CFSUM2 are artefacts of the sample preparation procedure and previously reported quantitative abnormalities of CFSUM1 and CFSUM2 in urine from patients with ME/CFS are also artefactual. Pyroglutamic acid may be of primarily dietary origin. The methods used cannot provide reliable qualitative or quantitative data on urinary metabolites. No clinical or biochemical significance can be drawn between these compounds in ME/CFS or any other clinical conditions.

Chaudhuri A. Cognitive behaviour therapy for adolescents

BMJ. 2005 Apr 2;330(7494):789-90; author reply

Letter


with chronic fatigue syndrome: data are insufficient and conclusion inappropriate. Comment on: BMJ. 2005 Jan 1;330(7481):14.

790.

Chia JK. CEI Research Center, Torrance, CA 90505, USA. [email protected]

The role of enterovirus in chronic fatigue syndrome.

J Clin Pathol. 2005 Nov;58(11):1126-32.

Two and a half decades after coining of the term chronic fatigue syndrome (CFS), the diagnosis of this illness is still symptom based and the aetiology remains elusive. Enteroviruses are well known causes of acute respiratory and gastrointestinal infections, with tropism for the central nervous system, muscles, and heart. Initial reports of chronic enteroviral infections causing debilitating symptoms in patients with CFS were met with skeptism, and had been largely forgotten for the past decade. Observations from in vitro experiments and from animal models clearly established a state of chronic persistence through the formation of double stranded RNA, similar to findings reported in muscle biopsies of patients with CFS. Recent evidence not only confirmed the earlier studies, but also clarified the pathogenic role of viral RNA through antiviral treatment. This review summarises the available experimental and clinical evidence that supports the role of enterovirus in chronic fatigue syndrome.

Cho HJ, Hotopf M, Wessely S.

Section of General Hospital Psychiatry, Institute of Psychiatry, King's College London, United Kingdom. [email protected]

The placebo response in the treatment of chronic fatigue syndrome: a systematic review and meta-analysis.

Psychosom Med. 2005 Mar-Apr;67(2):301-13.

OBJECTIVE: The placebo response is conventionally asserted to be high in chronic fatigue syndrome (CFS) because of the latter's subjective nature and obscure pathogenesis, but no systematic review of placebo responses has been undertaken. We report such a study. Patient expectation is known to be important in the placebo response. It is also known that CFS patients attending specialist clinics often have strong physical attributions regarding causation and hence skepticism about psychological or psychiatric interventions. If so, the placebo response in CFS may be influenced by the type of intervention according to its perceived rationale. We aimed to estimate the summary placebo response in clinical trials of CFS and to determine whether intervention type influences the placebo response in CFS. METHODS: We searched Medline, Embase, Cochrane Library, PsychInfo, and the references of the identified articles, and contacted experts for controlled trials (randomized or nonrandomized) of any intervention on CFS patients reporting the placebo response as a clinical improvement in physical or general outcomes. Data were extracted from the articles and validity assessment conducted by one reviewer and checked by a second. Meta-analysis and metaregression were performed. RESULTS: The pooled placebo response was 19.6% (95% confidence interval, 15.4-23.7), lower than predicted and lower than in some other medical conditions. The meta-regression revealed that intervention type significantly contributed to the heterogeneity of placebo response (p = .03). CONCLUSION: In contrast with the conventional wisdom, the placebo response in CFS is low. Psychological-psychiatric interventions were shown to have a lower placebo response, perhaps linked to patient expectations.

Cho HJ, Wessely S.

Chronic fatigue syndrome: an overview.

Rev Bras Psiquiatr. 2005 Sep;27(3):174-5.

Editorial



Epub 2005 Oct 4. Cho HJ, Wessely S.

Chronic fatigue syndrome: an overview.

Rev Bras Psiquiatr. 2005 Sep;27(3):174-5. Epub 2005 Oct 4.

Editorial

Christie D, Wilson C.

University College and Middlesex Hopsitals, London, UK. [email protected]

CBT in paediatric and adolescent health settings: a review of practice-based evidence.

Pediatr Rehabil. 2005 Oct-Dec;8(4):241-7.

Cognitive Behavioural therapy (CBT) has strong theoretical underpinnings that facilitate the systematic evaluation of outcomes and process of change adults. CBT has been extensively adapted for use with children and young people with session content and method of delivery modified to acknowledge developmental stage and ability. Current approaches emphasise the psychological management of the impact of symptoms of particular types of physical health difficulties and prevention of the development of psychological difficulties, as well as in the alleviation of procedurally related stress. The need for collaboration with families and other parts of a child's network is particularly relevant in the paediatric setting. This review describes what we have found helpful in our work and provides a road map of where to go to find out more about how to do more. General CBT approaches are described as well as examples of how CBT has been used specifically for procedural distress, diabetes, sickle cell disease, chronic pain and chronic fatigue.

Chrousos GP, Kaltsas G.

Athens University, Athens, Greece and National Institutes of Health, Bethesda, MD, USA. [email protected]

Post-SARS sickness syndrome manifestations and endocrinopathy: how, why, and so what?

Clin Endocrinol (Oxf). 2005 Oct;63(4):363-5. Comment on: Clin Endocrinol (Oxf). 2005 Aug;63(2):197-202.

Comment

Cleare AJ, Messa C, Rabiner EA, Grasby PM.

Section of Neurobiology of Mood Disorders, Division of Psychological Medicine, Institute of Psychiatry and Guy-s, King-s and St. Thomas- School of Medicine, London, United Kingdom. [email protected]

Brain 5-HT1A receptor binding in chronic fatigue syndrome measured using positron emission tomography and [11C]WAY-100635.

Biol Psychiatry. 2005 Feb 1;57(3):239-46.

BACKGROUND: Research from neuroendocrine challenge and other indirect studies has suggested increased central 5-HT function in chronic fatigue syndrome (CFS) and increased 5-HT1A receptor sensitivity. We assessed brain 5-HT1A receptor binding potential directly using the specific radioligand [11C]WAY-100635 and positron emission tomography (PET). METHODS: We selected 10 patients from a tertiary referral clinic who fulfilled the CDC consensus criteria for CFS. To assemble a homogenous group and avoid confounding effects, we enrolled only subjects who were completely medication-free and did not have current comorbid psychiatric illness. We also scanned 10 healthy control subjects. RESULTS: There was a widespread reduction in 5-HT1A receptor binding potential in CFS relative to control subjects. This was particularly marked in the hippocampus bilaterally, where a 23% reduction was observed. CONCLUSIONS: There is evidence of decreased 5-HT1A receptor number or affinity in CFS. This may be a primary feature of CFS, related to the underlying pathophysiology, or a finding secondary to other processes, such as previous depression, other biological changes or the behavioral consequences of CFS.

Cook DB, Nagelkirk PR, Peckerman A,

University of Wisconsin-Madison,

Exercise and cognitive performance in

Med Sci Sports Exerc. 2005 Sep;37(9):1460-7.

PURPOSE: To determine the effect of submaximal steady-state exercise on cognitive performance in patients with chronic fatigue syndrome (CFS) alone, CFS with comorbid fibromyalgia FM (CFS + FM), and sedentary healthy controls (CON). METHODS: Twenty CFS-only patients, 19 CFS + FM,






Poluri A, Mores J, Natelson BH.

Department of Kinesiology, USA. [email protected]

chronic fatigue syndrome.

and 26 CON completed a battery of cognitive tests designed to assess speed of information processing, variability, and efficiency. Tests were performed at baseline, immediately before, and twice following 25 min of either cycle ergometry set at 40% of peak oxygen capacity or quiet rest. RESULTS: There were no group differences in average percentage of peak oxygen consumption during exercise (CFS = 45%; CFS + FM = 47%; Control = 43%: P = 0.2). There were no significant effects of acute exercise on cognitive performance for any group. At baseline, one-way ANOVA indicated that CFS patients displayed deficits in speed of processing, performance variability, and task efficiency during several cognitive tests compared with healthy controls. However, the CFS + FM patients were not different than controls. Repeated measures ANOVA indicated that across all tests (pre- and postexercise) CFS, but not CFS + FM, were significantly less consistent (F2,59 = 3.7, P = 0.03) and less efficient (F2,59 = 4.6, P = 0.01) than controls. CONCLUSION: CFS patients without comorbid FM exhibit subtle cognitive deficits in terms of speed, consistency, and efficiency that are not improved or exacerbated by light exercise. Importantly, our data suggest that CFS + FM patients do not exhibit cognitive deficits either pre- or postexercise. These results highlight the importance of disease heterogeneity in studies determining acute exercise and cognitive function in CFS.

Covelli V, Passeri ME, Leogrande D, Jirillo E, Amati L.

Division of Neurology, Polyclinic Hospital, Bari Italy.

Drug targets in stress-related disorders.

Curr Med Chem. 2005;12(15):1801-9.

Nervous and immune systems mutually cooperate via release of mediators of both neurological and immunological derivation. Adrenocorticotropin hormone (ACTH) is a product of the hypothalamus-pituitary adrenal axis (HPAA) which stimulates secretion of corticosteroids from adrenals. In turn, corticosteroids modulate the immune response in virtue of their anti-inflammatory activity. On the other hand, catecholamines, products of the sympathetic nervous system (SNS), regulate immune function by acting on specific beta-adrenergic receptors. Conversely, cytokines released by monocytes/macrophages and lymphocytes, upon antigenic stimulation, are able to cross the blood-brain-barrier, thus modulating nervous functions (e.g., thermoregulation, sleep, and appetite). However, cytokines are locally produced in the brain, especially in the hypothalamus, thus contributing to the development of anorexic, pyrogenic, somnogenic and behavioural effects. Besides pathogens and/or their products, the so-called stressors are able to activate both HPAA and SNS, thus influencing immune responses. In this respect, many studies conducted in medical students taking exams have evidenced an array of stress-induced immune alterations. Phobic disorders and migraine without aura (MWA) represent examples of stress-related disorders in which phagocytic immune deficits, endotoxemia and exaggerated levels of proinflammatory cytokines [Tumor Necrosis Factor-alpha (TNF- alpha), and interleukin- 1 beta] have been detected. Quite interestingly, administration of a thymic hormone could ameliorate clinical symptoms in phobic patients. In MWA patients, a beta-blocker, propranolol, could mitigate migraine, whose cessation coincided with a drop of TNF-alpha serum concentration. In phobic disorders and in MWA, benzodiazepines are very often administered and, in this respect, some of them, such as diazepam, inhibit immune functions, while others, e.g., alprazolam, enhance immune responses. Alprazolam could improve clinical symptoms in MWA patients. Chronic Fatigue Syndrome (CFS) is a disorder whose etiology and pathogenesis are still unknown. In this syndrome both abnormalities of nervous and immune systems have been reported. Despite many immune parameters evaluated in CFS no specific biomarkers of disease have been found. Our own data are in agreement with current literature in that we found decreased levels of serum (IFN)-gamma in these patients, thus indicating a predominance of T helper (h)1 response in


CFS. Also leptin, a hormone which regulates food intake, fluctuates within normal ranges in CFS individuals. Quite interestingly, in depressed patients, used as controls, leptinaemia was more elevated than in CFS. Finally, in a series of recent therapeutic trials several immunomodulating agents have been used, such as staphypan Berna, lactic acid bacteria, kuibitang and intravenous immunoglobulin. In conclusion, it seems that major drug targets in stress-related disorders are immune cells in terms of inhibition of proinflammatory cytokines and modulation of Th responses. In particular, according to recent evidences, antidepressants seem to exert beneficial effects in experimental autoimmune neuritis in rats by decreasing IFN- beta release or augmenting NK activity in depressed patients.

Crowhurst G. 25% Severe ME Group, Great Walsingham, Norfolk. [email protected]

Supporting people with severe myalgic encephalomyelitis.

Nurs Stand. 2005 Feb 2-8;19(21):38-43.

This article aims to raise nurses' awareness of myalgic encephalomyelitis (ME) also known as chronic fatigue syndrome (CFS). Key symptoms are presented along with possible service responses and treatment options. It emphasises that this condition is often misunderstood but that it can be serious and more research is needed to promote better understanding of the physical symptoms.

Darbishire L, Seed P, Ridsdale L.

Department of General Practice and Primary Care, Guy's, King's and St Thomas' School ol of Medicine, 5 Lambeth Walk, London, SE11 6SP, UK. [email protected]

Predictors of outcome following treatment for chronic fatigue.

Br J Psychiatry. 2005 Apr;186:350-1.

We explored the role of baseline characteristics of 105 patients who presented with fatigue in primary care in determining outcome following either graded exercise or cognitive-behavioural therapy. Meeting the criteria for chronic fatigue syndrome was the most powerful predictor of poor outcome and this negative effect was enhanced by greater functional impairment or greater perceived negative consequences, but was not further enhanced by both.

Davidson J. Department of Geography, Queen's University, Kingston, Ont., K7L 3N6, Canada. [email protected]

Contesting stigma and contested emotions: personal experience and public perception of specific phobias.

Soc Sci Med. 2005 Nov;61(10):2155-64.

This paper draws on interviews with members of the United Kingdom National Phobics Society to explore the implications of the contested nature of specific phobias for their experience and perception. In common with other chronic and contested conditions such as Chronic Fatigue Syndrome, phobias are stigmatised and subjected to widespread judgmental attitudes in both medical and lay populations. In contrast, however, phobic experience is rarely characterised by difficulty in describing symptoms and obtaining a diagnosis: core fearful reaction to and avoidance of particular objects is usually obvious and uncontested. The crucial difference is that phobias are constituted by emotions and behaviours considered irrational and inconsequential, and it is their (perceived absence of) significance that raises questions and eyebrows. In other words, what does it matter and who cares if you happen to be scared of snakes? Using phobics' own words as far as possible, the paper explores the processes through which phobic emotions are constructed as contested, and examines phobic means of managing experience and perception of these emotions. It reveals that many respondents are resourceful and resistant, continually renegotiating their positioning as irrational, incapable and emotionally weak.

de Lange FP, Kalkman JS,

F.C. Donders Centre for

Gray matter volume reduction

Neuroimage. 2005 Jul 1;26(3):777-81.

The chronic fatigue syndrome (CFS) is a disabling disorder of unknown etiology. The symptomatology of CFS (central fatigue, impaired concentration, attention and memory) suggests




Bleijenberg G, Hagoort P, van der Meer JW, Toni I.

Cognitive Neuroimaging, Radboud University Nijmegen, NL-6500 HB Nijmegen, The Netherlands. [email protected]

in the chronic fatigue syndrome.

Epub 2005 Apr 7. that this disorder could be related to alterations at the level of the central nervous system. In this study, we have used an automated and unbiased morphometric technique to test whether CFS patients display structural cerebral abnormalities. We mapped structural cerebral morphology and volume in two cohorts of CFS patients (in total 28 patients) and healthy controls (in total 28 controls) from high-resolution structural magnetic resonance images, using voxel-based morphometry. Additionally, we recorded physical activity levels to explore the relation between severity of CFS symptoms and cerebral abnormalities. We observed significant reductions in global gray matter volume in both cohorts of CFS patients, as compared to matched control participants. Moreover, the decline in gray matter volume was linked to the reduction in physical activity, a core aspect of CFS. These findings suggest that the central nervous system plays a key role in the pathophysiology of CFS and point to a new objective and quantitative tool for clinical diagnosis of this disabling disorder.

Di Giorgio A, Hudson M, Jerjes W, Cleare AJ.

Department of Neurological and Psychiatric Services, University of Bari, Bari, Italy

24-hour pituitary and adrenal hormone profiles in chronic fatigue syndrome.

Psychosom Med. 2005 May-Jun;67(3):433-40.

OBJECTIVES: Disturbances of neuroendocrine function, particularly the hypothalamo-pituitary-adrenal (HPA) axis, have been implicated in the pathophysiology of chronic fatigue syndrome (CFS). However, few studies have attempted to measure blood levels of pituitary or adrenal hormones across a whole 24-hour period in CFS, and those that did so have used infrequent sampling periods. Our aim was to assess 24-hour pituitary and adrenal function using frequent blood sampling. METHODS: We recruited 15 medication-free patients with CFS without comorbid psychiatric disorder and 10 healthy control subjects. Blood samples were collected over 24 hours and assayed for cortisol, corticotropin (ACTH), growth hormone (GH), and prolactin (PRL) levels on an hourly basis during daytime hours (10 am to 10 pm) and every 15 minutes thereafter (10 pm to 10 am). RESULTS: Repeated-measures analyses of variance were undertaken using hormone levels averaged over 2-hour blocks to smooth curves by reducing the influence of sample timing relative to secretory burst. For ACTH, there was both a main effect of group, suggesting reduced mean ACTH secretion in patients with CFS over the whole monitoring period, and a group-by-time interaction, suggesting a differential pattern of ACTH release. Post hoc analysis showed reduced ACTH levels in CFS during the 8 am to 10 am period. In contrast, there were no significant abnormalities in the levels of cortisol, GH, and PRL in patients with CFS over the full cycle compared with control subjects. Cosinor analysis found no differences in the cortisol circadian rhythm parameters, but the ACTH rhythm did differ, patients with CFS showing an earlier acrophase. CONCLUSIONS: Patients with CFS demonstrated subtle alterations in HPA axis activity characterized by reduced ACTH over a full circadian cycle and reduced levels during the usual morning physiological peak ACTH secretion. This provides further evidence of subtle dysregulation of the HPA axis in CFS. Whether this dysregulation is a primary feature of the illness or instead represents a biologic effect secondary to having the illness itself remains unclear.

Doljansky JT, Kannety H, Dagan Y.

The Institute for Sleep and Fatigue Medicine, Chaim Sheba Health Center, Tel-Hashomer, Israel. [email protected]

Working under daylight intensity lamp: an occupational risk for developing circadian rhythm sleep disorder?

Chronobiol Int. 2005;22(3):597-605.

A 47-yr-old male was admitted to the Institute for Fatigue and Sleep Medicine complaining of severe fatigue and daytime sleepiness. His medical history included diagnosis of depression and chronic fatigue syndrome. Antidepressant drugs failed to improve his condition. He described a gradual evolvement of an irregular sleep-wake pattern within the past 20 yrs, causing marked distress and severe impairment of daily functioning. He had to change to a part-time position 7 yrs ago, because he was unable to maintain a regular full-time job schedule. A 10-day actigraphic record revealed an irregular sleep-wake pattern with extensive day-to-day variability in sleep onset time and sleep duration, and a 36 h sampling of both melatonin level and oral temperature (12 samples, once every 3 h) showed abnormal patterns, with the melatonin peak around noon and oral temperature peak around


dawn. Thus, the patient was diagnosed as suffering from irregular sleep-wake pattern. Treatment with melatonin (5 mg, 2 h before bedtime) did not improve his condition. A further investigation of the patient's daily habits and environmental conditions revealed two important facts. First, his occupation required work under a daylight intensity lamp (professional diamond-grading equipment of more than 8000 lux), and second, since the patient tended to work late, the exposure to bright light occurred mostly at night. To recover his circadian rhythmicity and stabilize his sleep-wake pattern, we recommended combined treatment consisting of evening melatonin ingestion combined with morning (09:00 h) bright light therapy (0800 lux for 1 h) plus the avoidance of bright light in the evening. Another 10-day actigraphic study done only 1 wk after initiating the combined treatment protocol revealed stabilization of the sleep-wake pattern with advancement of sleep phase. In addition, the patient reported profound improvement in maintaining wakefulness during the day. This case study shows that chronic exposure to bright light at the wrong biological time, during the nighttime, may have serious effects on the circadian sleep-wake patterns and circadian time structure. Therefore, night bright light exposure must be considered to be a risk factor of previously unrecognized occupational diseases of altered circadian time structure manifested as irregularity of the 24 h sleep-wake cycle and melancholy.

Driver C. An under-active or over-active internal world? An exploration of parallel dynamics within psyche and soma, and the difficulty of internal regulation, in patients with Chronic Fatigue Syndrome and Myalgic Encephalomyelitis.

J Anal Psychol. 2005 Apr;50(2):155-73.

This paper explores the dynamics brought into analytic work when there is a symmetric fusion between psyche and soma within the patient. It will consider how such a fusion may emerge from reverberations between physical constitution and a lack of maternal attunement, containment and reflective function. I will describe the work with a patient, Jane, who was diagnosed with Myalgic Encephalomyelitis (ME) during the course of her analysis. The dynamic of her physical symptoms within the analytic work, and the impact of her internal affects and internal 'objects' within the transference and countertransference, indicated a difficulty in finding an homeostatic balance resulting in overactivity and underactivity at both somatic and psychological levels. Using the clinical work with Jane this paper will also examine the interrelationship between mother-infant attachment, an inadequate internalized maternal reflective function, affect dysregulation, unconscious fusion, the lack of psyche-soma differentiation and the impact of the latter in relation to internal regulation systems, or lack of, in patients with Chronic Fatigue Syndrome (CFS) and Myalgic Encephalomyelitis (ME). I will draw on similar work carried out by Holland (1997), Simpson (1997) and Simpson et al. (1997). The paper will also employ the concept of the reflective function (Fonagy 2001; Knox 2003), and consider Matte-Blanco's (1999) concepts of generalization and unconscious symmetry in relation to the patient's internal world. I go on to consider how analysis provides a point outside the 'fusion' that can enable the 'deadlock' to be broken.

Dumit J. Program in Science, Technology & Society, Massachusetts Institute of Technology, E51-296D MIT, Cambridge, MA

Illnesses you have to fight to get: Facts as forces in uncertain, emergent illnesses.

Soc Sci Med. 2005 Aug 5; [Epub ahead of print]

Chronic fatigue syndrome and multiple chemical sensitivity are two clusters of illnesses that are pervaded by medical, social and political uncertainty. This article examines how facts are talked about and experienced in struggles over these emergent, contested illnesses in the US. Based principally on a large archive of internet newsgroup postings, and also on fieldwork and on published debates, it finds that (1) sufferers describe their experiences of being denied healthcare and legitimacy through bureaucratic categories of exclusion as dependent upon their lack of biological facts; (2) institutions manage these exclusions rhetorically through exploiting the open-endedness of science to deny efficacy to new facts; (3) collective patient action responds by archiving the systematic nature of these exclusions and developing counter-tactics. The result is the maintenance of


02139-4307, USA. these very expensive struggles for all involved.Durlach J, Pages N, Bac P, Bara M, Guiet-Bara A.

SDRM, Universite Pierre et Marie Curie, 75252 Paris Cedex 05, France. [email protected]

Magnesium depletion with hypo- or hyperfunction of the biological clock may be involved in chronopathological forms of asthma.

Magnes Res. 2005 Mar;18(1):19-34.

Asthma is a chronic, inflammatory disorder of the airways leading to airflow limitation. Its worldwide rise, mainly in developed countries, is a matter of concern. Nocturnal asthma (NA) frequently occurs and concerns two thirds of asthmatics. But, it remains controversial whether NA is a distinct entity or is a manifestation of more severe asthma. Generally, it is considered as an exacerbation of the underlying pathology. The pathological mechanisms most likely involve endogenous circadian rhythms with pathological consequences on both respiratory inflammation and hyperresponsiveness. A decrease in blood and tissue magnesium levels is frequently reported in asthma and often testifies to a true magnesium depletion. The link with magnesium status and chronobiology are well established. The quality of magnesium status directly influences the Biological Clock (BC) function, represented by the suprachiasmatic nuclei and the pineal gland. Conversely, BC dysrythmias influence the magnesium status. Two types of magnesium deficits must be clearly distinguished: deficiency corresponding to an insufficient intake which can be corrected through mere nutritional Mg supplementation and depletion due to a dysregulation of the magnesium status which cannot be corrected through nutritional supplementation only, but requires the more or less specific correction of the dysregulation mechanisms. Both in clinical and in animal experiments, the dysregulation mechanisms of magnesium depletion associate a reduced magnesium intake with various types of stress including biological clock dysrhythmias. The differenciation between Mg depletion forms with hyperfunction of BC (HBC) and forms with hypofunction of BC (hBC) is seminal and the main biological marker is melatonin (MT) production alteration. We hypothesize that magnesium depletion with HBC or hBC may be involved in chronopathological forms of asthma. Nocturnal asthma would be linked to HBC, represented by an increase in MT levels. The corresponding clinical forms associate diverse expressions of nervous hypoexcitability such as depression, cluster headaches, dyssomnia, mainly advanced sleep phase syndrome, some clinical forms of chronic fatigue syndrome and of fibromyalgia. The main comorbidities are depression and/or asthenia. They take place during the night or the "bad" seasons (autumn and winter) when sunshine is at a minimum. The corresponding chronopathological therapy relies on bright light phototherapy sometimes with additional psychoanaleptics. Conversely, asthma forms linked to hBC are less frequently studied as a whole and present a decrease in MT levels. They associate various signs of nervous hyperexcitability such as anxiety, diurnal cephalalgia (mainly migraine), dyssomnia, mainly delayed sleep phase syndrome, and some clinical forms of chronic fatigue syndrome and of fibromyalgia. The treatment relies on diverse forms of "darkness therapy", possibly with the help of some psycholeptics. Finally, the treatment of asthma involves the maintenance of a standard dosing schedule of anti-asthma drugs, a balanced magnesium intake and the appropriate treatment of the chronopathological disorders.

Ehrlich GE. Silicone breast implants. Comment on: J Rheumatol. 2004 May;31(5):1015; author reply 1015-6.

J Rheumatol. 2005 Jun;32(6):1173-4; author reply 1174.

Letter


Eisen SA, Kang HK, Murphy FM, Blanchard MS, Reda DJ, Henderson WG, Toomey R, Jackson LW, Alpern R, Parks BJ, Klimas N, Hall C, Pak HS, Hunter J, Karlinsky J, Battistone MJ, Lyons MJ; Gulf War Study Participating Investigators.

Veterans Affairs Medical Center, Washington University School of Medicine, St. Louis, Missouri 63106, USA. [email protected]

Gulf War veterans' health: medical evaluation of a U.S. cohort.

Ann Intern Med. 2005 Jun 7;142(11):881-90.

BACKGROUND: United States military personnel reported various symptoms after deployment to the Persian Gulf during the 1991 Gulf War. However, the symptoms' long-term prevalence and association with deployment remain controversial. OBJECTIVE: To assess and compare the prevalence of selected medical conditions in a national cohort of deployed and nondeployed Gulf War veterans who were evaluated by direct medical and teledermatologic examinations. DESIGN: A cross-sectional prevalence study performed 10 years after the 1991 Gulf War. SETTING: Veterans were examined at 1 of 16 Veterans Affairs medical centers. PARTICIPANTS: Deployed (n = 1061) and nondeployed (n = 1128) veterans of the 1991 Gulf War. MEASUREMENTS: Primary outcome measures included fibromyalgia, the chronic fatigue syndrome, dermatologic conditions, dyspepsia, physical health-related quality of life (Short Form-36 [SF-36]), hypertension, obstructive lung disease, arthralgias, and peripheral neuropathy. RESULTS: Of 12 conditions, only 4 conditions were more prevalent among deployed than nondeployed veterans: fibromyalgia (deployed, 2.0%; nondeployed, 1.2%; odds ratio, 2.32 [95% CI, 1.02 to 5.27]); the chronic fatigue syndrome (deployed, 1.6%; nondeployed 0.1%; odds ratio, 40.6 [CI, 10.2 to 161]); dermatologic conditions (deployed, 34.6%; nondeployed, 26.8%; odds ratio, 1.38 [CI, 1.06 to 1.80]), and dyspepsia (deployed, 9.1%; nondeployed, 6.0%; odds ratio, 1.87 [CI, 1.16 to 2.99]). The mean physical component summary score of the SF-36 for deployed and nondeployed veterans was 49.3 and 50.8, respectively. LIMITATIONS: Relatively low participation rates introduce potential participation bias, and deployment-related illnesses that resolved before the research examination could not, by design, be detected. CONCLUSIONS: Ten years after the Gulf War, the physical health of deployed and nondeployed veterans is similar. However, Gulf War deployment is associated with an increased risk for fibromyalgia, the chronic fatigue syndrome, skin conditions, dyspepsia, and a clinically insignificant decrease in the SF-36 physical component score.

Elena Garralda M, Chalder T.

Imperial College, London, UK. [email protected]

Practitioner review: chronic fatigue syndrome in childhood.

J Child Psychol Psychiatry. 2005 Nov;46(11):1143-51.

BACKGROUND: Chronic fatigue syndrome (CFS) is being increasingly recognized in children and adolescents. Yet comparatively little attention has been given in the literature to management. METHODS: Description of the main features of the disorder, precipitating and maintaining factors and diagnostic assessment. Outline of different views on the nature and treatment of CFS in childhood. Description of a rehabilitation program based on cognitive behavior therapy and graded activity. RESULTS: Using adult research criteria, CFS can be diagnosed in children and adolescents. In its severe form it is often triggered by infectious illness episodes. It is commonly associated with mood disorders in the child and with mental distress and high levels of emotional involvement in parents. A number of patient support groups hold the view that CFS is a medical disorder, contest a psychiatric contribution and advocate 'pacing' as an approach to rehabilitation which includes avoiding activities. To date there is no empirical evidence for the efficacy of this approach. Research in adults, open and clinical reports in children support the use of graded activity and family cognitive behavior therapy. The main aim is to enable children, with the help of their family, to carry out their own rehabilitation with some support and guidance from a health professional. Engaging the child and family in treatment and forming a therapeutic alliance is a continual process and a crucial aspect of management, as many families view the condition as a medical disorder and are initially ambivalent towards this approach. CONCLUSIONS: There is controversy about the nature and management of CFS in childhood but a rehabilitation program based on family cognitive behavior therapy can be implemented and seems to hold most promise in the management of children with




CFS. Family engagement is a crucial aspect of management. Evengard B, Jacks A, Pedersen NL, Sullivan PF.

Department of Laboratory Medicine, Karolinska Institutet at Karolinska University Hospital Huddinge, Stockholm, Sweden.

The epidemiology of chronic fatigue in the Swedish Twin Registry.

Psychol Med. 2005 Sep;35(9):1317-26.

BACKGROUND: Chronic fatigue syndrome (CFS) remains an idiopathic and controversial entity. METHOD: We screened 31405 individual members of the Swedish Twin Registry (aged 42-64 years) for the symptoms of fatiguing illness via a telephone questionnaire. We refined self-reported symptoms via data from several national registries and from physician review of all available medical records in order to approximate closely the dominant case definition of CFS. FINDINGS: The 6-month prevalence of CFS-like illness was 2.36% (95% CI 2.19-2.53) and was markedly higher in women than men, odds ratio 3.92 (95% CI 3.24-4.72) with no significant association with age or years of education. There was a highly significant association with occupation that disappeared after accounting for gender. INTERPRETATION: CFS-like illness may be more common that previously acknowledged. There is a marked increase in risk by gender. Previous reports that CFS is more prevalent in individuals in certain occupational categories were not confirmed and may have been due to confounding by gender.

Fernandez-Sola J, Lluis Padierna M, Nogue Xarau S, Munne Mas P.

Servicio de Medicina Interna. Unidad Multidisciplinar de Fatiga Cronica. Hospital Clinic de Barcelona. IDIBAPS. Universitat de Barcelona. Barcelona. Spain.

[Chronic fatigue syndrome and multiple chemical hypersensitivity after insecticide exposition.] [Article in Spanish]

Med Clin (Barc). 2005 Apr 2;124(12):451-3.

Background and objective: Chronic Fatigue Syndrome (CFS) and Multiple Chemical Sensitivity (MCS) are well-defined illnesses that may appear after some toxic exposures. Patients and method: We report a consecutive series of 26 patients who developed CFS after exposure to insecticide products. It was associated with MCS in a third of cases. RESULTS: Toxic exposure was of labour origin after returning to usual work place after a process of fumigation. In 42% of cases there was no fulfilment of fumigation safety rules. The majority of patients were mean-aged women who developed an acute upper airway inflammatory syndrome, without muscarinic or nicotinic manifestations, followed by digestive syndrome, neurocognitive, fibromyalgic and chronic fatigue manifestations. The course of disease was shorter than 1 year in 5 cases (19%), longer than 1 year in 15(58%), and disabling in 6 cases (23%). CONCLUSIONS: Due to the possible prevention of this toxic exposure, it is very important to carefully follow measures of environment isolation and ventilation after insecticide use in order to avoid the development of these diseases.

Ferre Ybarz L, Cardona Dahl V, Cadahia Garcia A, Ruiz E, Vazquez A, Fernandez de Sevilla T, Alegre Martin J.

Hospital Vall d'Hebron, Barcelona, Spain. [email protected]

[Prevalence of atopy in chronic fatigue syndrome] [Article in Spanish]

Allergol Immunopathol (Madr). 2005 Jan-Feb;33(1):42-7.

BACKGROUND: Several hypotheses have been postulated to explain the etiopathogenesis of chronic fatigue syndrome (CFS). Among these, immunologic dysfunction has been proposed. Up to 30 % of these patients have a history of allergic disease. The aim of this study was to investigate whether allergic sensitization is higher in patients with CFS than in the general population. METHODS: Twenty-five patients with CFS and 20 controls were evaluated. A clinical history for allergy was taken and immediate hypersensitivity tests were performed. RESULTS: Twelve patients (48 %) and eight controls (40 %) had a family history of atopy. Personal histories of atopy were as follows: rhinoconjunctivitis: 12 patients (48 %), seven controls (35 %); asthma: five patients (20 %), two controls (10 %); food allergy: three patients (12 %); atopic dermatitis: two patients; contact dermatitis: two patients. No statistically significant differences were found between the groups in any of the variables (p > 0.05). In the CSF group, 3.4 % (15/441) of the inhalant prick tests were positive, and in the control group 3.8 % (16/420) were positive. None of the tests for hypersensitivity to food or latex were positive. CONCLUSIONS: In our study atopy was not more prevalent in patients with CFS than in healthy controls, although the CSF group tended to report more respiratory symptoms and drug allergies.

Fowler T, Duthie P, Thapar A,

Department of Psychological

The definition of disabling fatigue in

BMC Fam Pract. 2005 Aug 9;6:33.

BACKGROUND: Disabling fatigue is the main illness related reason for prolonged absence from school. Although there are accepted criteria for diagnosing chronic fatigue in adults, it remains


Farmer A. Medicine, Wales College of Medicine, Cardiff University, UK. [email protected]

children and adolescents.

uncertain as to how best to define disabling fatigue and Chronic Fatigue Syndrome (CFS) in children and adolescents. In this population-based study, the aim was to identify children who had experienced an episode of disabling fatigue and examine the clinical and demographic differences between those individuals who fulfilled a narrow definition of disabling fatigue and those who fulfilled broader definitions of disabling fatigue. METHODS: Participants (aged 8-17 years) were identified from a population-based twin register. Parent report was used to identify children who had ever experienced a period of disabling fatigue. Standardised telephone interviews were then conducted with the parents of these affected children. Data on clinical and demographic characteristics, including age of onset, gender, days per week affected, hours per day spent resting, absence from school, comorbidity with depression and a global measure of impairment due to the fatigue, were examined. A narrow definition was defined as a minimum of 6 months disabling fatigue plus at least 4 associated symptoms, which is comparable to the operational criteria for CFS in adults. Broader definitions included those with at least 3 months of disabling fatigue and 4 or more of the associated symptoms and those with simply a minimum of 3 months of disabling fatigue. Groups were mutually exclusive. RESULTS: Questionnaires were returned by 1468 families (65% response rate) and telephone interviews were completed on 99 of the 129 participants (77%) who had experienced fatigue. There were no significant differences in demographic and clinical characteristics or levels of impairment between those who fulfilled the narrower definition and those who fulfilled the broader definitions. The only exception was the reported number of days per week that the child was affected by the fatigue. All groups demonstrated evidence of substantial impairment associated with the fatigue. CONCLUSION: Children and adolescents who do not fulfil the current narrow definition of CFS but do suffer from disabling fatigue show comparable and substantial impairment. In primary care settings, a broader definition of disabling fatigue would improve the identification of impaired children and adolescents who require support.

Fremont M, El Bakkouri K, Vaeyens F, Herst CV, De Meirleir K, Englebienne P.

RED Laboratories, Pontbeek 61, B-1731 Zellik, Belgium.

2',5'-Oligoadenylate size is critical to protect RNase L against proteolytic cleavage in chronic fatigue syndrome.

Exp Mol Pathol. 2005 Jun;78(3):239-46. Epub 2005 Mar 2.

A dysregulation in the 2',5'-oligoadenylate (2-5A)-dependent RNase L antiviral pathway has been detected in peripheral blood mononuclear cells (PBMC) of chronic fatigue syndrome (CFS) patients, which is characterized by upregulated 2-5A synthetase and RNase L activities, as well as by the presence of a low molecular weight (LMW) 2-5A-binding protein of 37-kDa related to RNase L. This truncated protein has been shown to originate from proteolytic cleavage of the native 83-kDa RNase L by m-calpain and human leukocyte elastase (HLE). We investigated the possible role of 2-5A oligomers in the proteolytic action toward the endonuclease and show that incubation of CFS PBMC extracts with 2-5A trimer and tetramer, but not with the dimer, results in a significant protection of the native 83-kDa RNase L against cleavage by endogenous and purified proteases. Similar results are obtained with a purified recombinant RNase L. An analysis of the size of 2-5A oligomers produced by the catalytic activity of the 2-5A synthetase present in PBMC extracts further shows that samples containing the 37-kDa RNase L preferentially produce 2-5A dimers instead of higher oligomers. Taken together, our results indicate that homodimerization of RNase L by 2-5A oligomers higher than the dimer prevents its cleavage by proteolytic enzymes. The presence of the truncated 37-kDa RNase L in PBMC extracts is therefore likely to result, not only from the abnormal activation of inflammatory proteases, but also from a dysregulation in 2-5A synthetase induction or activation towards the preferential production of 2-5A dimers.

Fremont M, 37-Kilodalton/83- Clin Diagn Lab


Vaeyens F, Herst CV, De Meirleir K, Englebienne P, Tiev KP, Cabane J, Lebleu B. [email protected].

Kilodalton RNase L Isoform Ratio in Peripheral Blood Mononuclear Cells: Analytical Performance and Relevance for Chronic Fatigue Syndrome.

Immunol. 2005 Oct;12(10):1259-60.

Fremont M, Vaeyens F, Herst CV, De Meirleir K, Englebienne P.

37-Kilodalton/83-kilodalton RNase L isoform ratio in peripheral blood mononuclear cells: analytical performance and relevance for chronic fatigue syndrome.

Clin Diagn Lab Immunol. 2005 Oct;12(10):1259-60; author reply 1260. Comment on: Clin Diagn Lab Immunol. 2003 Mar;10(2):315-6.

Comment Letter

Friedberg F, Leung DW, Quick J.

Department of Psychiatry, Stony Brook University, Stony Brook, New York 11794-8790, USA. [email protected]

Do support groups help people with chronic fatigue syndrome and fibromyalgia? A comparison of active and inactive members.

J Rheumatol. 2005 Dec;32(12):2416-20.

OBJECTIVE: To examine the benefits and problems of a chronic fatigue syndrome (CFS) and fibromyalgia (FM) support organization as reported by its participants. METHODS: Active members (n = 32) and inactive members or dropouts (n = 135) of a regional support organization for people with CFS and FM completed a 26 item questionnaire by telephone interview or by self-completion and postal return. RESULTS: The most frequently endorsed benefits of membership were illness legitimization (67.8%), finding out helpful new information (66.4%), and feeling understood by others (62.2%). Lower frequency endorsements were given to: helped to find (35.0%) or deal with (38.5%) doctors, and helped to improve my illness (36.4%). The most frequently reported reasons for dropping out were inconvenient location (37.8%) or time (37.0%), too much negative talk or complaining (33.3%), too sick to attend (28.8%), and illness or coping improvement (29.6% each). The active-member group showed significantly higher (p < 0.04) symptom severity scores and less illness improvement (p < 0.01) in comparison to the inactive/dropout group. CONCLUSION: This cross-sectional study suggests that support groups for CFS are viewed as helpful by participants on a number of illness related issues. On the other hand, active members reported greater symptom severity and less illness improvement than inactive members or dropouts.

Fries E, Hesse J, Hellhammer J, Hellhammer DH.

Department for Psychobiology, University of Trier, Johanniterufer 15, 54290 Trier, Germany.

A new view on hypocortisolism.

Psychoneuroendocrinology. 2005 Nov;30(10):1010-6.

Low cortisol levels have been observed in patients with different stress-related disorders such as chronic fatigue syndrome, fibromyalgia, and post-traumatic stress disorder. Data suggest that these disorders are characterized by a symptom triad of enhanced stress sensitivity, pain, and fatigue. This overview will present data on the development, mechanisms and consequences of hypocortisolism on different bodily systems. We propose that the phenomenon of hypocortisolism may occur after a prolonged period of hyperactivity of the hypothalamic-pituitary-adrenal axis due to chronic stress as illustrated in an animal model. Further evidence suggests that despite symptoms such as pain, fatigue and high stress sensitivity, hypocortisolism may also have beneficial effects on the organism. This






assumption will be underlined by some studies suggesting protective effects of hypocortisolism for the individual.

Frissora CL, Koch KL.

Department of Medicine, The Weill Medical College of Cornell University, 520 E. 70th Street, Suite J-314, New York, NY 10021, USA. [email protected]

Symptom overlap and comorbidity of irritable bowel syndrome with other conditions.

Curr Gastroenterol Rep. 2005 Aug;7(4):264-71.

Irritable bowel syndrome (IBS) is one of several highly prevalent, multi-symptom gastrointestinal motility disorders that have a wide clinical spectrum and are associated with symptoms of gastrointestinal dysmotility and visceral hypersensitivity. Symptom overlap and comorbidity between IBS and other gastrointestinal motility disorders (eg, chronic constipation, functional dyspepsia, gastroesophageal reflux disease), with gastrointestinal disorders that are not related to motility (eg, celiac disease, lactose intolerance), and with somatic conditions (eg, fibromyalgia, chronic fatigue syndrome), are frequent. The clinical associations and pathophysiologic links between IBS and these disorders continue to be explored. This review discusses overlapping symptoms and comorbidity of IBS with select gastrointestinal and non-gastrointestinal disorders and attempts to identify commonalities among these conditions.

Furberg H, Olarte M, Afari N, Goldberg J, Buchwald D, Sullivan PF.

Department of Genetics, University of North Carolina, Chapel Hill, NC, USA.

The prevalence of self-reported chronic fatigue in a U.S. twin registry.

J Psychosom Res. 2005 Nov;59(5):283-90.

OBJECTIVE: To investigate the prevalence and correlates of various definitions of self-reported lifetime fatiguing illness in a U.S. twin registry. METHODS: Data from 4591 female and male twins from the population-based Mid-Atlantic Twin Registry were available for this study. Variables representing different definitions of lifetime fatiguing illness and personal characteristics were obtained through questionnaires. Odds ratios and 95% confidence intervals were calculated as measures of association between fatigue and gender. Kaplan-Meier curves were produced to examine the age at onset for lifetime fatiguing illnesses. RESULTS: Prevalences for different definitions of self-reported lifetime fatigue ranged from 36.7% for any fatigue to 2.7% for chronic fatigue syndrome-like illness. Females were two to three times more likely to report fatigue than males. Gender differences increased as fatigue definitions grew more restrictive. Ages at onset of chronic fatiguing illness were significantly earlier and the number of ancillary symptoms was greater for females than males. People with lifetime fatigue had significantly more compromised functional status than people without lifetime fatigue. CONCLUSION: The prevalence of self-reported lifetime fatiguing illness varied widely depending upon how it was defined. Given the debilitating consequences of fatiguing illnesses, the reasons for the female predominance and the earlier onset in women should receive increased research priority.

Gaab J, Rohleder N, Heitz V, Engert V, Schad T, Schurmeyer TH, Ehlert U.

Center for Psychobiological and Psychosomatic Research, University of Trier, Trier, Germany. [email protected]

Stress-induced changes in LPS-induced pro-inflammatory cytokine production in chronic fatigue syndrome.

Psychoneuroendocrinology. 2005 Feb;30(2):188-98.

OBJECTIVE: It has been suggested that a hypofunctional hypothalamic-pituitary-adrenal (HPA) axis in chronic fatigue syndrome could result in an exaggerated release of pro-inflammatory cytokines during stress. As pro-inflammatory cytokines are involved in the induction of sickness behavior and thus constitute a potential physiological correlate of stress-induced symptom exacerbation in chronic fatigue syndrome, we set out to evaluate the LPS-induced production of pro-inflammatory cytokines during psychosocial stress in CFS and healthy controls. METHOD: Twenty-one CFS patients and 20 healthy controls matched for age and gender underwent a standardized psychosocial stress test (Trier social stress test, TSST). Adrenocorticotropine hormone (ACTH), salivary cortisol and plasma cortisol levels were measured before and repeatedly following exposure to the stressor. Lipopolysaccharide-stimulated production of interleukin-6 and tumor necrosis factor-alpha were assessed at baseline as well as 10 and 60 min after the stress test. RESULTS: CFS patients showed an inverse stress-induced response pattern of LPS-stimulated cytokines responses in comparison to healthy controls, i.e. stimulated cytokine production decreased shortly after stress in CFS patients, while it increased in controls. Fatigue scores and basal LPS-induced cytokine levels were


significantly associated for TNF-alpha in controls and for both cytokines in CFS patients. Stress-induced changes in stimulated cytokine production were not associated with general fatigue scores in the control group, whereas in the CFS group, fatigue scores were significantly correlated with integrated levels of LPS-induced cytokines. However, partial correlations revealed that these results were due to the high correlations with basal LPS-induced cytokine levels. CONCLUSION: CFS patients do not show an exaggerated secretion of LPS-induced cytokines. Although cortisol responses to stress were normal, pro-inflammatory cytokine levels in CFS patients were significantly attenuated. Possible intracellular mechanisms, such as for example an enhanced sensitivity to inhibitory effects of glucocorticoids, a diminished responsivity to catecholaminergic stimulation, and a disruption of intracellular activation are discussed. Basal levels of stimulated pro-inflammatory Il-6 levels are generally related to fatigue scores. However, in CFS patients this association is of greater magnitude and can also be observed for TNF-alpha.

Gallagher AM, Coldrick AR, Hedge B, Weir WR, White PD.

Centre for Psychiatry, Institute of Community Health Sciences, Queen Mary School of Medicine and Dentistry, St. Bartholomew's Hospital, EC1A 7BE London, UK.

Is the chronic fatigue syndrome an exercise phobia? A case control study.

J Psychosom Res. 2005 Apr;58(4):367-73.

OBJECTIVE: The aim of this study was to test whether patients with chronic fatigue syndrome (CFS) have an exercise phobia, by measuring anxiety-related physiological and psychological reactions to ordinary activity and exercise. METHODS: Patients and healthy but sedentary controls were assessed over 8 h of an ordinary day, and before, during and after an incremental exercise test on a motorised treadmill. To avoid confounding effects, those with a comorbid psychiatric disorder were excluded. Heart rate, galvanic skin resistance (GSR) and the amount of activity undertaken were measured, along with state and trait measures of anxiety. RESULTS: Patients with CFS were more fatigued and sleep disturbed than were the controls and noted greater effort during the exercise test. No statistically significant differences were found in either heart rate or GSR both during a normal day and before, during and after the exercise test. Patients with CFS were more symptomatically anxious at all times, but this did not increase with exercise. CONCLUSION: The data suggest that CFS patients without a comorbid psychiatric disorder do not have an exercise phobia.

Garralda ME, Rangel L.

Academic Unit of Child and Adolescent Psychiatry, Faculty of Medicine, Imperial College London, St Mary's Campus, Norfolk Place, London W2 1PG, UK. [email protected]

Chronic fatigue syndrome of childhood. Comparative study with emotional disorders.

Eur Child Adolesc Psychiatry. 2005 Dec;14(8):424-30.

OBJECTIVE: To examine clinical specificity in chronic fatigue syndrome (CFS) of childhood, by comparing clinical features in childhood CFS and in emotional disorders (ED). METHOD SAMPLE: 28 children with CFS; 27 with ED. MEASURES: History of disorder; K-SADS psychiatric interviews; self-esteem and physical symptoms questionnaires; premorbid history, behavioural and personality assessments. RESULTS: There were high levels of comorbid emotional disorders in children with CFS, and the two groups were comparable on self-esteem, but CFS children endorsed more fatigue and other somatic symptoms. The two groups were comparable on age at illness onset, but parents of children with CSF reported more biological illness precipitants, more pre-morbid recurrent medical problems and infections. The CFS group had fewer pre-morbid psychological problems and less psychiatric comorbidity than the ED group. CONCLUSION: There is considerable clinical overlap between CFS and ED of childhood, but there are also differences in clinical presentation between these disorders.

Glaser R, Padgett DA, Litsky ML, Baiocchi RA, Yang EV, Chen M, Yeh PE, Klimas NG, Marshall GD,

Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State

Stress-associated changes in the steady-state expression of latent Epstein-Barr virus: implications

Brain Behav Immun. 2005 Mar;19(2):91-103.

Antibodies to several Epstein-Barr virus (EBV)-encoded enzymes are observed in patients with different EBV-associated diseases. The reason for these antibody patterns and the role these proteins might play in the pathophysiology of disease, separate from their role in virus replication, is unknown. In this series of studies, we found that purified EBV deoxyuridine triphosphate nucleotidohydrolase (dUTPase) can inhibit the replication of human peripheral blood mononuclear cells in vitro and upregulate the production of TNF-alpha, IL-1beta, IL-6, IL-8, and IL-10. It also




Whiteside T, Herberman R, Kiecolt-Glaser J, Williams MV.

University Medical Center, 333 W. 10th Avenue, Columbus, OH 43210, USA. [email protected]

for chronic fatigue syndrome and cancer.

enhanced the ability of natural killer cells to lyse target cells. The EBV dUTPase also significantly inhibited the replication of mitogen-stimulated lymphocytes and the synthesis of IFN-gamma by cells isolated from lymph nodes and spleens obtained from mice inoculated with the protein. It also produced sickness behaviors known to be induced by some of the cytokines that were studied in the in vitro experiments. These symptoms include an increase in body temperature, a decrease in body mass and in physical activity. The data provide a new perspective on how an early nonstructural EBV-encoded protein can cause immune dysregulation and produce clinical symptoms observed in patients with chronic fatigue syndrome (CFS) separate from its role in virus replication and may serve as a new approach to help identify one of the etiological agents for CFS. The data also provide additional insight into the pathophysiology of EBV infection, inflammation, and cancer.

Glozier N. Department of Occupational Health and Safety, Kings College Hospital, Denmark Hill, London SE5 9RS, UK. [email protected]

Chronic fatigue syndrome: it's tiring not knowing much--an in-depth review for occupational health professionals.


Godas Sieso T, Gomez-Gil E, Fernandez-Sola J, Fernandez-Huertas JM.

[Significant increase of functional status and decrease of fatigue in patients with chronic fatigue syndrome after completing cognitive behavioural group therapy] [Article in Spanish]

Med Clin (Barc). 2005 Oct 22;125(14):556.

Letter

Gottschalk M, Kumpfel T, Flachenecker P, Uhr M, Trenkwalder C, Holsboer F, Weber F.

Max Planck Institute of Psychiatry, Munich, Germany.

Fatigue and regulation of the hypothalamo-pituitary-adrenal axis in multiple sclerosis.

Arch Neurol. 2005 Feb;62(2):277-80.

BACKGROUND: Fatigue is a common and disabling symptom in patients with multiple sclerosis (MS). Underlying mechanisms postulated so far have involved localization of brain lesions and abnormalities of the neuroendocrine system and cytokine regulation. OBJECTIVE: To investigate the relationship between fatigue and the hypothalamo-pituitary-adrenal (HPA) axis in patients with MS. DESIGN: A prospective survey. SETTING: Outpatient and inpatient study at the Max Planck Institute of Psychiatry, Munich, Germany. PATIENTS: Thirty-one patients with clinically definite MS, a relapsing-remitting disease course, and without MS-specific treatment. INTERVENTIONS: Assessment of fatigue with 3 questionnaires: the Fatigue Severity Scale (FSS), the Modified Fatigue Impact Scale (MFIS), and the Visual Analog Scale. Assessment of HPA axis regulation with the combined dexamethasone-corticotropin releasing hormone (Dex-CRH) test. RESULTS: The FSS score was significantly correlated with the MFIS score. Patients with fatigue had significantly


elevated adrenocorticotropin (ACTH) levels in the combined Dex-CRH test. CONCLUSIONS: In contrast to results for chronic fatigue syndrome, where a hyporeactivity of the HPA axis has been shown, MS patients with fatigue exhibited a higher activity of the HPA axis than those without fatigue, as evidenced by significantly increased ACTH concentrations. Proinflammatory cytokines, known to be elevated in patients with MS, may cause both HPA axis alterations and fatigue.

Goudsmit E, Stouten B

Chronic Fatigue Syndrome: Editorial Bias in the British Medical Journal


A literature search identified all papers published on chronic fatigue syndrome (CFS) and myalgic encephalomyelitis (ME) in the British Medical Journal between 1995 and 2000. Analysis of the findings revealed a bias towards the views of one school of thought and a lack of papers on the immunological or virological aspects of CFS. This contrasts with the mainstream American journals, which generally covered a much wider range of subjects and views. We examine the arguments for and against covert editorial policies, and summarise the results of discussions with the relevant individuals and organisations.

Grans H, Nilsson P, Evengard B.

Gene expression profiling in the chronic fatigue syndrome.

J Intern Med. 2005 Oct;258(4):388-90.

Letter

Grans H, Nilsson P, Evengard B.

Gene expression profiling in the chronic fatigue syndrome.

J Intern Med. 2005 Oct;258(4):388-90.

Letter

Gutenbrunner C, Linden M, Gerdes N, Ehlebracht-Konig I, Grosch E.

Klinik fur Physikalische Medizin und Rehabilitation der Medizinischen Hochschule Hannover, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany. [email protected]

[Significance of the chronic fatigue syndrome in rehabilitation medicine--status and perspectives] [Article in German]

Rehabilitation (Stuttg). 2005 Jun;44(3):176-85.

It appears that from a clinical point of view chronic exhaustion or fatigue is an important factor in rehabilitation. This is, however, first of all a phenomenon that can be described as a function in accordance with the International Classification of Functioning, Disability and Health (JCF), caused by chronic illnesses or chronic excessive stress. The clinical and sociomedical ranking of chronic fatigue or exhaustion in respect of rehabilitation was discussed in the framework of a Workshop at the 12th Rehabilitation Science Colloquium, 2003 from the viewpoints of psychiatric rehabilitation, methodology, sociology and practical rehabilitation, and conclusions for future research were drawn. The definition of chronic fatigue is first of all mainly based on the feeling of chronic tiredness but also on phenomena of disturbed concentration, physical discomfort, headache and disorders of "drive" and mood. A psychiatric diagnosis linked with symptoms of chronic fatigue is neurasthenia, which is arrived at according to precisely defined criteria. Depressive disorder is one of the most important differential diagnoses in this sphere. Examinations by general practitioners revealed that about 90 % of the patients who had been diagnosed as suffering from psychovegetative disorders completely agreed with the diagnosis of neurasthenia. Neurasthenia resulted more often in work disability periods than disorders of somatisation and other psychosomatic diagnoses. Basing on the "IRES" scale "vital exhaustion", singular of even serious changes become evident in about 50 % to 90 % of the patients undergoing rehabilitation, depending on their individual range of indications. As was to be expected, the majority of pathologic findings concerns patients undergoing psychosomatic rehabilitation, since in such cases there is an overlapping with symptoms of psychosomatic diseases. It is, however, remarkable that also in somatically oriented orthopaedic rehabilitation symptoms of fatigue are seen in up to 50 % of the patients. Preliminary studies have shown that these symptoms can be definitely ameliorated within the rehabilitation framework, although pathological signs are


still abundantly apparent in follow-up examinations. Markedly severe degrees of "vital exhaustion" and "vocational exhaustion" are also seen in rheumatology patients undergoing somatic rehabilitation. This agrees with case history details related by many female and male patients. Hence, it appears necessary to adapt rehabilitative intervention to both the psychovegetative and the medical behavioural aspects of this symptom. Scientific classification of the entire sphere of chronic fatigue in respect of rehabilitation requires classification of the relevant functions within the ICF framework. To this end it would be necessary to conduct patient inquiries within cross-sectional studies on the one hand and, on the other, a systematic consensus process among experts would have to be used for allocation to the relevant functions. This is the basis for development of suitable assessment tools for use in prospective studies in order to systematically evaluate the impact on functions and especially their effects on activities and participation.

Haines LC, Saidi G, Cooke RW.

Royal College of Paediatrics and Child Health, 50 Hallam Street, London W1W 6DE, UK. [email protected]

Prevalence of severe fatigue in primary care.

Arch Dis Child. 2005 Apr;90(4):367-8.

A postal survey of 1024 UK GP practices showed the prevalence of medically unexplained severe fatigue over three months in 5-19 year olds to be 62/100,000. Cases were predominantly adolescent girls and were more likely to come from practices in less deprived areas, which could reflect consulting behaviours.

Hamilton WT, Gallagher AM, Thomas JM, White PD.

The Grange, Bristol BS8 1AU, UK. [email protected]

The prognosis of different fatigue diagnostic labels: a longitudinal survey.

Fam Pract. 2005 Aug;22(4):383-8. Epub 2005 Apr 1.

BACKGROUND: Several different diagnostic labels exist for the fatigue syndromes, including chronic fatigue syndrome (CFS), myalgic encephalomyelitis (ME) and postviral fatigue syndrome (PVFS). An allied condition is fibromyalgia. No study has examined prognostic differences across these different labels. OBJECTIVE: To compare the prognoses of patients labelled with different fatigue syndromes in primary care. METHODS: We performed a longitudinal survey, using electronic records from the General Practice Research Database. All 18,122 patients diagnosed by their GP with a fatigue syndrome from 1988-2001 with a minimum of one year of records after diagnosis were collated into four groups: CFS, ME, PVFS and fibromyalgia. CFS and ME were combined for the main analysis as no code for CFS was available until 1995. The length of illness was calculated as the interval between the diagnosis and the last recorded fatigue symptom, expressed as days per year, to account for differing lengths of record after diagnosis. RESULTS: Patients with CFS/ME combined had a worse prognosis (median length of illness 80 days per year; interquartile range 0-242) than fibromyalgia (51;0-244) or PVFS 0 (0-108), a significant difference, P < 0.001. In a subgroup analysis, ME had a worse prognosis (median length of illness in days per year 106; interquartile range 0-259) than CFS (33; 0-170), P < 0.001, in spite of a better course before diagnosis. Secondary outcome measures were consistent with these results. CONCLUSION: There were important differences in outcome between the various fatigue labels, with ME having the worst prognosis and PVFS the best. This could be an adverse effect of the label ME itself. Alternatively, patients who are destined to have a worse prognosis may preferentially attract the ME label. Our data support the first interpretation.

Henderson M, Tannock C.

Academic Department of Psychological

Use of depression rating scales in chronic fatigue

J Psychosom Res. 2005 Sep;59(3):181-4.

OBJECTIVE: The aim of this study was to examine the performance of three commonly used depression rating scales in a hospital sample of patients with chronic fatigue syndrome (CFS). METHODS: Sixty-one patients with CDC criteria for CFS completed the General Health


Medicine, GKT School of Medicine and Institute of Psychiatry, Weston Education Centre, Cutcombe Road, London SE5 9RJ, United Kingdom.

syndrome. Questionnaire (GHQ), the Hamilton Depression Scale (HAM-D) and the depression subscale of the Hospital Anxiety and Depression Scale (HADS-D). Current psychiatric status was assessed using the Structured Clinical Interview for DSM-III-R. DISORDERS: Patient version (SCID-P). Receiver operating curves were drawn for each of the depression rating scales. RESULTS: Thirty-one percent of the patients were depressed according to the SCID-P. Using the standard cut-offs, both GHQ and HAM-D overestimated the number of depressed patients, whilst the HADS-D underestimated the number. The receiver operating curves suggest that the optimum cut-offs for GHQ, HAM-D and HADS-D in this population are 7/8, 13/14 and 8/9, respectively. CONCLUSIONS: Standard cutoffs may not be appropriate when using depression rating scales in CFS patients in a tertiary care setting.

Hershfield NB. Division of Gastroenterology, Department of Medicine, University of Calgary, Calgary, Alberta. [email protected]

Nongastrointestinal symptoms of irritable bowel syndrome: an office-based clinical survey.

Can J Gastroenterol. 2005 Apr;19(4):231-4.

Irritable bowel syndrome (IBS) is the most prevalent gastrointestinal problem faced by practicing gastroenterologists. For many years, nongastrointestinal symptoms have been documented in IBS patients, but the medical literature does not emphasize them. The present study explored how IBS and inflammatory bowel disease patients differ in their reporting of nongastrointestinal symptoms. Information from 200 consecutive patients with IBS and a similar number of patients with Crohn's disease (in a single gastroenterology practice) was obtained at the initial visit using a simple questionnaire. Comparison of the data revealed that IBS patients describe certain nongastrointestinal symptoms far more frequently than do those with inflammatory bowel disease. It is recommended that these symptoms be considered along with the generally accepted criteria for making a positive diagnosis of IBS.

Hutchings A, Raine R, Sanderson C, Black N.

Health Services Research Unit, London School of Hygiene and Tropical Medicine, London WC1E 7HT, UK. [email protected]

An experimental study of determinants of the extent of disagreement within clinical guideline development groups.

Qual Saf Health Care. 2005 Aug;14(4):240-5.

OBJECTIVE: To assess the effect of design features and clinical and social cues on the extent of disagreement among participants in a formal consensus development process. METHODS: Factorial design involving 16 groups consisting of 135 general practitioners (GPs) and 42 mental health professionals from England. The groups rated the appropriateness of four mental health interventions for three conditions (chronic back pain, irritable bowel syndrome, and chronic fatigue syndrome) in the context of various clinical and social cues. The groups differed in three design features: provision of a systematic literature review (versus not provided), group composition (mixed versus GP only), and assumptions about the healthcare resources available (realistic versus idealistic). Disagreement was measured using the mean absolute deviation from a group's median rating for a scenario. RESULTS: None of the design features significantly affected the extent of disagreement within groups (all p>0.3). Disagreement did differ between treatments (closer consensus for cognitive behavioural therapy and behavioural therapy than for brief psychodynamic intervention therapy and antidepressants) and cues (closer consensus for depressed patients and patients willing to try any treatment). CONCLUSION: In terms of the extent of disagreement in the groups in this study, formal consensus development was a robust technique in that the results were not dependent on the way it was conducted.

Hvenegaard V. [Chronic fatigue syndrome, an acknowledged neurologic diagnosis] [Article in Danish]

Ugeskr Laeger. 2005 Feb 14;167(7):784-5.

Letter


Inder WJ, Prickett TC, Mulder RT.

Department of Endocrinology, Christchurch Hospital, and Department of Psychological Medicine, Christchurch School of Medicine, Christchurch, New Zealand. [email protected]

Normal opioid tone and hypothalamic-pituitary-adrenal axis function in chronic fatigue syndrome despite marked functional impairment.

Clin Endocrinol (Oxf). 2005 Mar;62(3):343-8.

OBJECTIVE: To determine whether the functional impairment seen in chronic fatigue syndrome (CFS) is associated with reduced levels of central opioids and/or deficiency of the hypothalamic-pituitary-adrenal (HPA) axis. DESIGN: Single-blinded case-control study measuring functional and psychological status, basal hormonal parameters and ACTH/cortisol response to naloxone and ovine corticotrophin-releasing hormone (oCRH) vs. placebo in people with CFS and healthy controls. PATIENTS: Twelve people with CFS and 11 age-matched controls. MEASUREMENTS: Hormonal parameters: basal levels of 09:00 h plasma cortisol, dehydroepiandrosterone sulfate (DHEAS) and IGF-1. 24-h urinary free cortisol. Plasma ACTH and cortisol response to naloxone 125 microg/kg, oCRH 1 microg/kg and placebo (normal saline). Psychological parameters: SF-36, Hamilton Depression Score, Hospital Anxiety and Depression Scale and Fatigue Scale. RESULTS: There were highly significant differences between the CFS subjects and the controls with respect to the measures of fatigue and physical functioning. However, there were no differences in basal levels of 09:00 h cortisol (367 +/- 37 vs. 331 +/- 39 nmol/l, P = 0.51), DHEAS (4.2 +/- 0.6 vs. 4.0 +/- 0.5 micromol/l, P = 0.81), 24-h urinary free cortisol (182 +/- 27 vs. 178 +/- 21 nmol/24 h, P = 0.91) or IGF-1 (145 +/- 19 vs. 130 +/- 11 microg/l, P = 0.52) between the CFS group and controls, respectively. There was also no difference between the groups with respect to the ACTH and cortisol response to either oCRH or naloxone. CONCLUSIONS: Our data do not support an aetiological role for deficiency in central opioids or the HPA axis in the symptoms of CFS.

Iwakami E, Arashima Y, Kato K, Komiya T, Matsukawa Y, Ikeda T, Arakawa Y, Oshida S.

Department of Legal Medicine, Nihon University School of Medicine, Tokyo, Japan.

Treatment of chronic fatigue syndrome with antibiotics: pilot study assessing the involvement of Coxiella burnetii infection.

Intern Med. 2005 Dec;44(12):1258-63.

OBJECTIVE: To examine whether Coxiella burnetii (C. burnetii) is involved in chronic fatigue syndrome (CFS), we administered tetracycline antibiotics to subjects with CFS, and followed changes in clinical symptoms, PCR findings, and C. burnetii antibody titers. PATIENTS AND METHODS: The subjects were 8 patients with CFS and 213 with nonspecific complaints such as chronic fatigue and low-grade fever for several months or longer but not meeting the diagnostic criteria for CFS. All were examined for C. burnetii infection by nested PCR and the indirect immunofluorescence test (IF). RESULTS: Four CFS patients (the CFS group) and 54 controls [the post-Q fever fatigue syndrome (QFS) group] positive for C. burnetii were treated mainly with minocycline or doxycycline (100 mg/day) for 3 months. After treatment, all 58 patients tested negative for C. burnetii infection. In the CFS group, no significant difference was noted between the mean pre- and post-treatment temperatures or headache scores. Similarly, there was no significant improvement in performance status (PS) scores. In the QFS group, however, mean temperatures and headache scores were significantly decreased after treatment (p<0.001). PS scores were also improved. CONCLUSION: These results suggest the possibility of direct involvement of C. burnetii in the pathological state of CFS to be low, despite the C. burnetii infection rate being high in CFS patients. This is a pilot study and further larger investigations are necessary to confirm our preliminary results.

J R Soc Med. 2004 Dec;97(12):571-5.

Berger E. Brain imaging in fatigue syndromes. Comment on:

J R Soc Med. 2005 Mar;98(3):135.

Letter

Jammes Y, Steinberg JG, Mambrini O, Bregeon F, Delliaux S.

Laboratoire de Physiopathologie Respiratoire (UPRES EA 2201), Faculte de

Chronic fatigue syndrome: assessment of increased oxidative stress

J Intern Med. 2005 Mar;257(3):299-310.

OBJECTIVES: Because the muscle response to incremental exercise is not well documented in patients suffering from chronic fatigue syndrome (CFS), we combined electrophysiological (compound-evoked muscle action potential, M wave), and biochemical (lactic acid production, oxidative stress) measurements to assess any muscle dysfunction in response to a routine cycling exercise. DESIGN: This case-control study compared 15 CFS patients to a gender-, age- and weight-


Medecine, Institut Federatif de Recherche Jean Roche, Marseille, France. [email protected]

and altered muscle excitability in response to incremental exercise.

matched control group (n=11) of healthy subjects. INTERVENTIONS: All subjects performed an incremental cycling exercise continued until exhaustion. MAIN OUTCOME MEASURES: We measured the oxygen uptake (VO2), heart rate (HR), systemic blood pressure, percutaneous O2 saturation (SpO2), M-wave recording from vastus lateralis, and venous blood sampling allowing measurements of pH (pHv), PO2 (PvO2), lactic acid (LA), and three markers of the oxidative stress (thiobarbituric acid-reactive substances, TBARS, reduced glutathione, GSH, and ascorbic acid, RAA). RESULTS: Compared with control, in CFS patients (i) the slope of VO2 versus work load relationship did not differ from control subjects and there was a tendency for an accentuated PvO2 fall at the same exercise intensity, indicating an increased oxygen uptake by the exercising muscles; (ii) the HR and blood pressure responses to exercise did not vary; (iii) the anaerobic pathways were not accentuated; (iv) the exercise-induced oxidative stress was enhanced with early changes in TBARS and RAA and enhanced maximal RAA consumption; and (v) the M-wave duration markedly increased during the recovery period. CONCLUSIONS: The response of CFS patients to incremental exercise associates a lengthened and accentuated oxidative stress together with marked alterations of the muscle membrane excitability. These two objective signs of muscle dysfunction are sufficient to explain muscle pain and postexertional malaise reported by our patients.

Jason LA, Corradi K, Torres-Harding S, Taylor RR, King C.

DePaul University, Chicago, Illinois 60614, USA. [email protected]

Chronic fatigue syndrome: the need for subtypes.

Neuropsychol Rev. 2005 Mar;15(1):29-58.

Chronic fatigue syndrome (CFS) is an important condition confronting patients, clinicians, and researchers. This article provides information concerning the need for appropriate diagnosis of CFS subtypes. We first review findings suggesting that CFS is best conceptualized as a separate diagnostic entity rather than as part of a unitary model of functional somatic distress. Next, research involving the case definitions of CFS is reviewed. Findings suggest that whether a broad or more conservative case definition is employed, and whether clinic or community samples are recruited, these decisions will have a major influence in the types of patients selected. Review of further findings suggests that subtyping individuals with CFS on sociodemographic, functional disability, viral, immune, neuroendocrine, neurology, autonomic, and genetic biomarkers can provide clarification for researchers and clinicians who encounter CFS' characteristically confusing heterogeneous symptom profiles. Treatment studies that incorporate subtypes might be particularly helpful in better understanding the pathophysiology of CFS. This review suggests that there is a need for greater diagnostic clarity, and this might be accomplished by subgroups that integrate multiple variables including those in cognitive, emotional, and biological domains.

Jerjes WK, Cleare AJ, Wessely S, Wood PJ, Taylor NF.

Department of Clinical Biochemistry, King's College Hospital, Denmark Hill, London SE5 9RX, United Kingdom. [email protected]

Diurnal patterns of salivary cortisol and cortisone output in chronic fatigue syndrome.

J Affect Disord. 2005 Aug;87(2-3):299-304.

BACKGROUND: The aim of the present study was to obtain a naturalistic measure of diurnal hypothalamic-pituitary-adrenal (HPA) axis output in CFS patients unaffected by medication or comorbid psychiatric disorder likely to influence the axis. METHOD: Cortisol and cortisone levels were measured in saliva samples collected from 0600 h to 2100 h at 3-h intervals in CFS patients and healthy controls. RESULTS: Mean cortisol and cortisone concentrations were significantly lower in patients than controls across the whole day, as were levels at each individual time point except 2100 h. Cosinor analysis showed a significant diurnal rhythm of cortisol and cortisone that was not phase-shifted in CFS compared to controls. However, there was a lower rhythm-adjusted mean and a lower amplitude in CFS patients. The cortisol/cortisone ratio showed no diurnal rhythm and did not differ between CFS subjects and controls. LIMITATIONS: The sample size was relatively small, and drawn from specialist referral patients who had been ill for some time; generalisation of these results to other populations is therefore unwarranted. CONCLUSION: The main findings of this study are to


provide further evidence for reduced basal HPA axis function in at least some patients with CFS and to show for the first time that salivary cortisone is also reduced in CFS and has a diurnal rhythm similar to that of cortisol. We have also demonstrated that the cortisol/cortisone ratio remains unchanged in CFS, suggesting that increased conversion of cortisol to cortisone cannot account for the observed lowering of salivary cortisol.

Jones JF, Kulkarni PS, Butera ST, Reeves WC.

Division of Viral and Rickettsial Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia 30333, USA. [email protected]

GB virus-C--a virus without a disease: we cannot give it chronic fatigue syndrome.

BMC Infect Dis. 2005 Sep 28;5:78.

BACKGROUND: Chronic fatigue syndrome (CFS) is an illness in search of an infectious etiology. GB virus-C (GBV-C) virus is a flavivirus with cell tropism and host defense induction qualities compatible with a role in producing the syndrome. The GBV-C genome is detectable in 4% of the population and 12% of the population is seropositive. The present study evaluated the association between infection with GBV and CFS. METHODS: We used a commercial EIA to detect antibodies against the GBV-C E2 protein and a quantitative real-time RT-PCR assay to detect active GBV-C infection. Sera were from a case control study of CFS in Atlanta, Georgia. The Fisher's exact two-tailed test was used for statistical analysis. RESULTS: Two of 12 CFS patients and one of 21 controls were seropositive for prior GBV-C infection and one control had viral RNA detected, indicating active infection. The results are not statistically different. CONCLUSION: We found no evidence that active or past infection with GBV is associated with CFS.

Jones JF, Nicholson A, Nisenbaum R, Papanicolaou DA, Solomon L, Boneva R, Heim C, Reeves WC.

Division of Viral and Rickettsial Diseases, National Center for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, Ga 30333, USA. [email protected]

Orthostatic instability in a population-based study of chronic fatigue syndrome.

Am J Med. 2005 Dec;118(12):1415.

PURPOSE: Autonomic nervous system dysfunction has been suggested as involved in the pathophysiology of chronic fatigue syndrome. This population-based case control study addressed the potential association between orthostatic instability (one sign of dysautonomia) and chronic fatigue syndrome. SUBJECTS AND METHODS: Fifty-eight subjects who fulfilled criteria of the 1994 chronic fatigue syndrome research case definition and 55 healthy controls participated in a 2-day inpatient evaluation. Subjects had been identified during a 4-year population-based chronic fatigue syndrome surveillance study in Wichita, Kan. The present study evaluated subjects' current medical and psychiatric status, reviewed past medical/psychiatric history and medication use, used a stand-up test to screen for orthostatic instability, and conducted a head-up tilt table test to diagnose orthostatic instability. RESULTS: No one manifested orthostatic instability in the stand-up test. The head-up tilt test elicited orthostatic instability in 30% of eligible chronic fatigue syndrome subjects (all with postural orthostatic tachycardia) and 48% of controls (50% with neurally mediated hypotension); intolerance was present in only nonfatigued (n=7) subjects. Neither fatigue nor illness severity were associated with outcome. CONCLUSIONS: Orthostatic instability was similar in persons with chronic fatigue syndrome and nonfatigued controls subjects recruited from the general Wichita population. Delayed responses to head-up tilt tests were common and may reflect hydration status. These findings suggest reappraisal of primary dysautonomia as a factor in the pathogenesis of chronic fatigue syndrome.

Jones MG, Cooper E, Amjad S, Goodwin CS, Barron JL, Chalmers RA.

St George's Hospital Medical School, Cranmer Terrace, London, SW17 0RE, UK.

Urinary and plasma organic acids and amino acids in chronic fatigue syndrome.

Clin Chim Acta. 2005 Nov;361(1-2):150-8.

Previous work by others have suggested the occurrence of one or more chemical or metabolic 'markers' for ME/CFS including specific amino acids and organic acids and a number of unidentified compounds (CFSUM1, CFSUM2). We have shown elsewhere that CFSUM1 is partially derivatised pyroglutamic acid and CFSUM2 partially derivatised serine and have suggested and demonstrated that the analytical methods used were unsuitable to identify or to accurately quantify urinary metabolites. We have now made a detailed analysis of plasma and urinary amino acids and of urinary organic acids from patients with ME/CFS and from three control groups. Fasting blood plasma and timed urine samples were obtained from 31 patients with CFS, 31 age and sex-matched healthy



controls, 15 patients with depression and 22 patients with rheumatoid arthritis. Plasma and urinary amino acids and urinary organic acids were determined using established and validated methods and data compared by statistical analysis. None of the previously reported abnormalities in urinary amino acids or of organic acids could be confirmed. Results however provide some evidence in patients with ME/CFS for underlying inflammatory disease and for reduced intramuscular collagen with a lowered threshold for muscle micro-injury. These factors in combination may provide a basis for the fatigue and muscle pain that are the major symptoms in these patients.

Jones MG, Goodwin CS, Amjad S, Chalmers RA.

St. George's Hospital Medical School, Cranmer Terrace, London, SW17 0RE, UK.

Plasma and urinary carnitine and acylcarnitines in chronic fatigue syndrome.

Clin Chim Acta. 2005 Oct;360(1-2):173-7.

Contradictory reports have suggested that serum free carnitine and acylcarnitine concentrations are decreased in patients with chronic fatigue syndrome (CFS) and that this is a cause of the muscle fatigue observed in these patients. Others have shown normal serum free carnitine and acylcarnitines in similar patients. We report here studies on free, total and esterified (acyl) carnitines in urine and blood plasma from UK patients with CFS and three control groups. Plasma and timed urine samples were obtained from 31 patients with CFS, 31 healthy controls, 15 patients with depression and 22 patients with rheumatoid arthritis. Samples were analysed using an established radioenzymatic procedure for total, free and esterified (acyl) carnitine. There were no significant differences in plasma or urinary total, free or esterified (acyl) carnitine between UK patients with CFS and the control groups or in renal excretion rates of these compounds. The data presented here show that, in the CFS patients studied, there are no significant abnormalities of free or esterified (acyl) carnitine. It is thus unlikely that abnormalities in carnitine homeostasis have any significant role in the aetiology of their chronic fatigue.

Jones MG, Goodwin CS, Amjad S, Chalmers RA.

St. George's Hospital Medical School, Cranmer Terrace, London, SW17 0RE, UK.

Plasma and urinary carnitine and acylcarnitines in chronic fatigue syndrome.

Clin Chim Acta. 2005 Oct;360(1-2):173-7.

Contradictory reports have suggested that serum free carnitine and acylcarnitine concentrations are decreased in patients with chronic fatigue syndrome (CFS) and that this is a cause of the muscle fatigue observed in these patients. Others have shown normal serum free carnitine and acylcarnitines in similar patients. We report here studies on free, total and esterified (acyl) carnitines in urine and blood plasma from UK patients with CFS and three control groups. Plasma and timed urine samples were obtained from 31 patients with CFS, 31 healthy controls, 15 patients with depression and 22 patients with rheumatoid arthritis. Samples were analysed using an established radioenzymatic procedure for total, free and esterified (acyl) carnitine. There were no significant differences in plasma or urinary total, free or esterified (acyl) carnitine between UK patients with CFS and the control groups or in renal excretion rates of these compounds. The data presented here show that, in the CFS patients studied, there are no significant abnormalities of free or esterified (acyl) carnitine. It is thus unlikely that abnormalities in carnitine homeostasis have any significant role in the aetiology of their chronic fatigue.

Karmisholt K, Gotzsche PC.

Nordic Cochrane Centre, H:S Rigshospitalet, DK-2100 Kobenhavn O, Denmark.

Physical activity for secondary prevention of disease. Systematic reviews of randomised clinical trials.

Dan Med Bull. 2005 May;52(2):90-4.

BACKGROUND: Physical activity is recommended for secondary prevention of several diseases but it is not always clear how reliable the evidence is. METHODS: We searched MEDLINE and The Cochrane Library for systematic reviews of randomised clinical trials published 1998-2004. RESULTS: We identified 30 eligible systematic reviews and excluded 13 that contained trials covered in larger reviews or were older than other reviews on the same subject. Physical activity decreased all-cause mortality in patients with coronary heart disease, odds ratio 0.73 (95% confidence interval 0.54 to 0.98), increased maximum walking time in patients with intermittent claudication by 6.5 min (4.4 to 8.7), and decreased pain in patients with osteoarthritis of the knee, standardised mean difference 0.34 (0.24 to 0.44). There were positive effects also in heart failure,


chronic obstructive lung disease, type 2 diabetes and fibromyalgia, but they need confirmation in high-quality trials. Exercise improved quality of life in several conditions and generally led to improved physical performance. An effect was not shown in stroke, asthma, rheumatoid arthritis, acute or chronic low back pain, chronic fatigue syndrome, depression, cystic fibrosis or HIV/AIDS. The occurrence of harms was generally not reported. CONCLUSION: Physical activity can have important, and even life-saving, effects as secondary prevention of disease, but more and better trials are needed to fully assess its benefits and harms, in particular trials that compare exercise with drugs.

Kaushik N, Fear D, Richards SC, McDermott CR, Nuwaysir EF, Kellam P, Harrison TJ, Wilkinson RJ, Tyrrell DA, Holgate ST, Kerr JR.

Department of Paediatric Infectious Diseases, St Marys Campus, Imperial College, Norfolk Place, London W2 1PG, UK.

Gene expression in peripheral blood mononuclear cells from patients with chronic fatigue syndrome.

J Clin Pathol. 2005 Aug;58(8):826-32.

BACKGROUND: Chronic fatigue syndrome (CFS) is a multisystem disease, the pathogenesis of which remains undetermined. AIMS: To test the hypothesis that there are reproducible abnormalities of gene expression in patients with CFS compared with normal healthy persons. METHODS: To gain further insight into the pathogenesis of this disease, gene expression was analysed in peripheral blood mononuclear cells from 25 patients with CFS diagnosed according to the Centers for Disease Control criteria and 25 normal blood donors matched for age, sex, and geographical location, using a single colour microarray representing 9522 human genes. After normalisation, average difference values for each gene were compared between test and control groups using a cutoff fold difference of expression > or = 1.5 and a p value of 0.001. Genes showing differential expression were further analysed using Taqman real time polymerase chain reaction (PCR) in fresh samples. RESULTS: Analysis of microarray data revealed differential expression of 35 genes. Real time PCR confirmed differential expression in the same direction as array results for 16 of these genes, 15 of which were upregulated (ABCD4, PRKCL1, MRPL23, CD2BP2, GSN, NTE, POLR2G, PEX16, EIF2B4, EIF4G1, ANAPC11, PDCD2, KHSRP, BRMS1, and GABARAPL1) and one of which was downregulated (IL-10RA). This profile suggests T cell activation and perturbation of neuronal and mitochondrial function. Upregulation of neuropathy target esterase and eukaryotic translation initiation factor 4G1 may suggest links with organophosphate exposure and virus infection, respectively. CONCLUSION: These results suggest that patients with CFS have reproducible alterations in gene regulation.

Kazar J. Research Base of the Slovak Medical University, Bratislava, Slovak Republic. [email protected].

Coxiella burnetii Infection.

Ann N Y Acad Sci. 2005 Dec;1063:105-14.

Coxiella burnetii is an obligate intracellular bacterium that causes a worldwide zoonosis, Q fever, and can be misused as a biological warfare agent. Infection in animals (coxiellosis) is mostly persistent. Infection in humans is often asymptomatic, but it can manifest as an acute disease (usually a self-limited flu-like illness, pneumonia, or hepatitis) or as a chronic form (mainly endocarditis, but also hepatitis and chronic fatigue syndrome). C. burnetii infection in pregnant women may result in abortions, premature deliveries, and stillbirths. Infection in nature is maintained and transmitted by ticks as the principal vector and reservoir. Cattle, sheep, and goats are the most important source of human infections. Humans contract C. burnetii infection mostly by aerosol in contact with contaminated environs, wind playing an important factor in spreading the infection. The wide distribution of C. burnetii contributes to a high resistance of its extracellular small cell variant to environmental conditions. Its intracellular large cell variant, adapted to survive under harsh conditions of phagolysosomes, enables long-term survival and persistence of C. burnetii, namely in monocytes/macrophages. Host factors such as underlying disease and cell-mediated immunity play a decisive role in the clinical expression of C. burnetii infection. Complete genome analysis of C. burnetii will certainly contribute to better understanding of the pathogenesis of C. burnetii infection and will improve Q fever diagnosis and immunoprophylaxis.



Kennedy G, Spence VA, McLaren M, Hill A, Underwood C, Belch JJ.

Vascular Diseases Research Unit, The Institute of Cardiovascular Research, Ninewells Hospital and Medical School, Dundee, Scotland DD1 9SY, UK. [email protected]

Oxidative stress levels are raised in chronic fatigue syndrome and are associated with clinical symptoms.

Free Radic Biol Med. 2005 Sep 1;39(5):584-9.

The aetiology of chronic fatigue syndrome (CFS) is unknown; however, recent evidence suggests excessive free radical (FR) generation may be involved. This study investigated for the first time levels of 8-iso-prostaglandin-F(2 alpha)-isoprostanes alongside other plasma markers of oxidative stress in CFS patients and control subjects. Forty-seven patients (18 males, 29 females, mean age 48 [19--63] years) who fulfilled the Centres for Disease Control classification for CFS and 34 healthy volunteers (13 males, 21 females, 46 [19--63] years) were enrolled in the study. The CFS patients were divided into two groups; one group had previously defined cardiovascular (CV) risk factors of obesity and hypertension (group 1) and the second were normotensive and nonobese (group 2). Patients had significantly increased levels of isoprostanes (group 1, P=0.007; group 2, P=0.03, unpaired t test compared to controls) and oxidised low-density lipoproteins (group 2, P=0.02) indicative of a FR attack on lipids. CFS patients also had significantly lower high-density lipoproteins (group 1, P=0.011; group 2, P=0.005). CFS symptoms correlated with isoprostane levels, but only in group 2 low CV risk CFS patients (isoprostanes correlated with; total symptom score P=0.005; joint pain P=0.002; postexertional malaise P=0.027, Pearson). This is the first time that raised levels of the gold standard measure of in vivo oxidative stress (isoprostanes) and their association with CFS symptoms have been reported.

Kim CH, Shin HC, Won CW.

Department of Family Medicine, Sungkyunkwan University School of Medicine, Korea. [email protected]

Prevalence of chronic fatigue and chronic fatigue syndrome in Korea: community-based primary care study.

J Korean Med Sci. 2005 Aug;20(4):529-34.

There have been many epidemiological and clinical researches on chronic fatigue (CF) and chronic fatigue syndrome (CFS) since the 1990s, but such studies have been quite limited in Korea. The aim of this study was to investigate the point prevalence of CF and CFS in patients who visited community-based eight primary care clinics in Korea. The study subjects were 1,648 patients aged 18 yr and over who visited one of eight primary care clinics in Korea between the 7th and 17th of May 2001. The physicians determined the status of the subjects through fatigue-related questionnaires, medical history, physical examination, and laboratory tests. The subjects were categorized into no fatigue, prolonged fatigue, CF and then CF were further classified to medically explained CF (Physical CF and Psychological CF) and medically unexplained CF (CFS and idiopathic chronic fatigue). The point prevalence of CF and CFS were 8.4% (95% CI 7.1-9.7%) and 0.6% (95% CI 0.2-1.0%). Medically explained CF was 80.5% of CF, of which 57.1% had psychological causes. The clinical characteristics of CFS were distinguished from explained CF. CF was common but CFS was rare in community-based primary care settings in Korea.

King C, Jason LA. Spinal Cord Injury Service (128), Hines VA Hospital, P.O. Box 5000, Hines, IL 60141-5128, USA. [email protected]

Improving the diagnostic criteria and procedures for chronic fatigue syndrome.

Biol Psychol. 2005 Feb;68(2):87-106.

Since the publication of the case definition for chronic fatigue syndrome (CFS) in 1988 the diagnostic criteria have been revised twice in the U.S. None of the case definitions were derived empirically. As a result, there is concern regarding the sensitivity, specificity, and reliability of the criteria. The goal of the present study was to identify methods for improving the diagnostic criteria for CFS. Three groups of 15 participants each were recruited: participants with (1) CFS, (2) major depressive disorder (MDD), and (3) healthy controls. Using statistical procedures, three methods for improving the diagnostic criteria were explored: identification of new diagnostic symptoms, the use of severity ratings for symptomatology, and the identification of standardized measures that differentiate cases of CFS from other conditions. Results of the present study suggest that these three methods hold promise for improving the sensitivity, specificity, and reliability of the diagnostic criteria for CFS.

Kodama M, Kodama T.

Kodama Research Institute of

The clinical course of interstitial

Int J Mol Med. 2005

The year 1995 marked the onset of interstitial pneumonia spread in Nagoya, Japan. For the last 9 years, we have been accumulating clinical experience with the disease control using the combination


Preventive Medicine, 50-5 Chikusaku, Chikusaku, Nagoya 464-0005, Japan.

pneumonia alias chronic fatigue syndrome under the control of megadose vitamin C infusion system with dehydroepiandrosterone-cortisol annex.

Jan;15(1):109-16. of prophylactic use of anti-biotics and regular practice of megadose vitamin C infusion with either dehydroepiandrosterone-annex or dehydroepiandrosterone-cortisol annex. The purpose of this study is to assess the usefulness of our new treatment system for the control of interstitial pneumonia alias chronic fatigue syndrome. The results obtained are given as follows: i) The long-term maintenance of the above treatment system was effective not only for decreasing the risk for recurrence of active form pneumonia, but also for prevention of malignancy emergence in aged patients with interstitial pneumonia. ii) Evidence is presented to indicate that interstitial pneumonia was associated with increased risk for depression of which the emergence is a candidate subject causally related to the long-term use of glucocorticoid. iii) A patient with both interstitial pneumonia and depression was found to be less responsive to our treatment system. It is suggested that the use of more dehydroepiandrosterone at the sacrifice of cortisol in the infusion annex may be a choice for the control of both interstitial pneumonia and depression. iv) The description of chronic fatigue syndrome as regards the endocrinological, epidemiological and psychiatric characteristics are in good agreement with our experience on patients having interstitial pneumonia, evidence in support of our proposal that there is no convincing reasoning to separate chronic fatigue syndrome from interstitial pneumonia. v) The long-term practice of our treatment system for the control of interstitial pneumonia (an autoimmune disease) was found to suppress the inflammatory process but not the fibrotic process in the long run. vi) A few innovations were made in our treatment system to reduce the risk of bleeding or thrombosis--vascular complications of pneumonia. vii) The merit of our treatment system is to create a new hormonal environment to improve the state of immunodeficiency by use of a non-steroid substance--vitamin C which encounters little resistance from the feedback mechanism of steroid metabolism in the in vivo system.

Kop WJ, Lyden A, Berlin AA, Ambrose K, Olsen C, Gracely RH, Williams DA, Clauw DJ.

Department of Medical and Clinical Psychology, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814, USA. [email protected]

Ambulatory monitoring of physical activity and symptoms in fibromyalgia and chronic fatigue syndrome.

Arthritis Rheum. 2005 Jan;52(1):296-303.

OBJECTIVE: Fibromyalgia (FM) and chronic fatigue syndrome (CFS) are associated with substantial physical disability. Determinants of self-reported physical disability are poorly understood. This investigation uses objective ambulatory activity monitoring to compare patients with FM and/or CFS with controls, and examines associations of ambulatory activity levels with both physical function and symptoms during activities of daily life. METHODS: Patients with FM and/or CFS (n = 38, mean +/- SD age 41.5 +/- 8.2 years, 74% women) completed a 5-day program of ambulatory monitoring of physical activity and symptoms (pain, fatigue, and distress) and results were compared with those in age-matched controls (n = 27, mean +/- SD age 38.0 +/- 8.6 years, 44% women). Activity levels were assessed continuously, ambulatory symptoms were determined using electronically time-stamped recordings at 5 time points during each day, and physical function was measured with the 36-item Short Form health survey at the end of the 5-day monitoring period. RESULTS: Patients had significantly lower peak activity levels than controls (mean +/- SEM 8,654 +/- 527 versus 12,913 +/- 1,462 units; P = 0.003) and spent less time in high-level activities when compared with controls (P = 0.001). In contrast, patients had similar average activity levels as those of controls (mean +/- SEM 1,525 +/- 63 versus 1,602 +/- 89; P = 0.47). Among patients, low activity levels were associated with worse self-reported physical function over the preceding month. Activity levels were inversely related to concurrent ambulatory pain (P = 0.031) and fatigue (P < 0.001). Pain and fatigue were associated with reduced subsequent ambulatory activity levels, whereas activity levels were not predictive of subsequent symptoms. CONCLUSION: Patients with FM and/or CFS engaged in less high-intensity physical activities than that recorded for sedentary control subjects. This reduced peak


activity was correlated with measures of poor physical function. The observed associations may be relevant to the design of behavioral activation programs, because activity levels appear to be contingent on, rather than predictive of, symptoms.

Lange G, Steffener J, Cook DB, Bly BM, Christodoulou C, Liu WC, Deluca J, Natelson BH.

Department of Radiology, University of Medicine and Dentistry of New Jersey-New Jersey Medical School, Newark, 07103, USA. [email protected]

Objective evidence of cognitive complaints in Chronic Fatigue Syndrome: a BOLD fMRI study of verbal working memory.

Neuroimage. 2005 Jun;26(2):513-24. Epub 2005 Apr 7.

Individuals with Chronic Fatigue Syndrome (CFS) often have difficulties with complex auditory information processing. In a series of two Blood Oxygen Level Dependent (BOLD) functional Magnetic Resonance Imaging (fMRI) studies, we compared BOLD signal changes between Controls and individuals with CFS who had documented difficulties in complex auditory information processing (Study 1) and those who did not (Study 2) in response to performance on a simple auditory monitoring and a complex auditory information processing task (mPASAT). We hypothesized that under conditions of cognitive challenge: (1) individuals with CFS who have auditory information processing difficulties will utilize frontal and parietal brain regions to a greater extent than Controls and (2) these differences will be maintained even when objective difficulties in this domain are controlled for. Using blocked design fMRI paradigms in both studies, we first presented the auditory monitoring task followed by the mPASAT. Within and between regions of interest (ROI), group analyses were performed for both studies with statistical parametric mapping (SPM99). Findings showed that individuals with CFS are able to process challenging auditory information as accurately as Controls but utilize more extensive regions of the network associated with the verbal WM system. Individuals with CFS appear to have to exert greater effort to process auditory information as effectively as demographically similar healthy adults. Our findings provide objective evidence for the subjective experience of cognitive difficulties in individuals with CFS.

Li YJ, Gao XG, Wang DX, Lin T, Bai XL, Yang FZ.

Department of Neurology, People's Hospital, Peking University, Beijing 100044, China.

[Cognitive function and psychological characteristics of patients with chronic fatigue syndrome] [Article in Chinese]

Zhonghua Yi Xue Za Zhi. 2005 Nov 2;85(41):2926-9.

OBJECTIVE: To investigate the cognitive function and psychological characteristics of the patients with chronic fatigue syndrome (CFS) in China and analyze its relation with primary psychological diseases. METHODS: Ninety-one patients with CFS who visited the People's Hospital, Peking University, in Beijing from Beijing, Shanghai, Tianjin, Heilongjiang, Jilin, Hebei, Inner Mongolia, Shanxi, Shandong, Sichuan, Gansu, Fujian, and Guangdong, 42 males and 49 females, aged 37 +/- 7, 43% of which had the record of formal schooling of regular college course or over and 21 of which had the record of formal schooling of college for professional training, and 58% of which showed clear causes, diagnosed by the CDC criteria 1994, underwent case history collection, physical examination, necessary laboratory test, memory test, and SCL-90, Hamilton depression rating scale (HAMD), and Hamilton anxiety rating scale (HAMA) testing. Thirty healthy persons, 14 males and 16 females, aged 37 +/- 7, were used as controls., A table of case file was established based on the CDC criteria 1994 for each patient to record the relevant data. Independent-Samples T Test was used to compare the memory quotient, the total score and general mean score of SCL-90, the score of HAMD and HAMA. Analyzed the impairment of cognitive function and psychological characteristics of patients with CFS. RESULTS: The most common symptoms was descent of remembrance and/or attention (82/91, 90%). The memory quotient of the CFS patients was 85 +/- 14, significantly lower than that of the healthy controls (98 +/- 12, t = 4.627, P = 0.000). The total score of SCL-90 of the CFS patients was 192 +/- 47, significantly higher than that of the healthy controls (140 +/- 46, t = 5.297, P = 0.000). The symptoms with a factor score > or = 2.0 in SCL-90 included obsessive-compulsive symptoms (61/91, 67%), somatization (61/91, 67 %), depression (57/91, 63%), and anxiety (49/91, 54%). The HAMD score of the CFS patients was 9.9 +/- 6.1, significantly higher than that of the healthy controls (6.5 +/- 2.5, t = 2.948, P = 0.004). The HAMA score of the CFS patients


was 9.9 +/- 7.0, significantly higher than that of the healthy controls (5.9 +/- 2.9, t = 3.015, P = 0.003). CONCLUSION: The CFS patients in China have an obvious impairment of remembrance and show different psychological abnormalities that are different from those of the patients with primary psychological diseases.

Li YJ, Wang DX, Bai XL, Chen J, Liu ZD, Feng ZJ, Zhao YM.

Department of Neurology, People's Hospital, Beijing University, Beijing 100044, China.

[Clinical characteristics of patients with chronic fatigue syndrome: analysis of 82 cases] [Article in Chinese]

Zhonghua Yi Xue Za Zhi. 2005 Mar 16;85(10):701-4.

OBJECTIVE: To analyze the clinical characteristics of Chinese patients suffering from chronic fatigue syndrome (CFS) and provide clinical and laboratory evidence for the study of its etiology and treatment. METHODS: 82 patients with CFS diagnosed based on the CDC criteria 1994 were recruited. History was collected, and physical examination was made. SCL-90 and memory test were used, and Hamilton Anxiety Rating Scale was used to those showing depression and/or anxiety. Laboratory examination, including examination of electrolytes, blood sugar, creatinine, bilirubin, alkaline phosphatase, alanine trasaminase, etc, was conducted. Western blotting was used to detect the protein-24 of Borna disease virus (BDV) in the plasma of 61 patients and 73 healthy controls. High-pressure chromatography was conducted to detect n-6 fatty acids on the membrane of erythrocytes of 42 patients and 37 healthy controls. Plasma L-carnitine in 61 patients and 73 healthy controls was detected by zymological analysis. In different examinations sex and age-matched controls were used. RESULTS: Most of the patients were 21 approximately 50 years old (74/82, 90.24%). No gender difference was found. The patients usually had 4 approximately 6 symptoms besides distinctive fatigue. Descent of remembrance and/or attention was the most conspicuous accompanying symptoms (69/82, 84.15%). Abnormalities in SCL-90 scores were present in 57 patients (69.51%), e.g, somatization existed most commonly (32/82, 39.02%), and anxiety and depression were 20.73% (17/82) and 18.29% (15/82) respectively. The prevalence of anti-BDV-p24 antibody was 20.73% (17/82), significantly higher than that of the controls (0%, chi(2) = 6.673, P = 0.010). The arachidonic acid level was significantly lower in the CFS group than in the controls (P > 0.05) and there were no differences in linoleic acid and ETA (both P > 0.05). The level of L-carnitine was 6.4336 +/- 3.4225, significantly lower than that of the control group (7.6666 +/- 3.5819, t = 2.025, P = 0.045) and the L-carnitine level was increased 2 weeks after supplementary treatment, together with improvement of symptoms. CONCLUSION: Most of the CFS patients are young and middle-aged. Descent of reorganization is common in these patients. Psychological abnormalities exist in most patients. Some patients are infected with BDV, some with deficiency of nutrition and/or abnormality of energy metabolism.

Lijue Z. Affiliated Hospital of Guiyang Medical College, Guiyang, Guizhou 550001, China.

Acupuncture and Chinese patent drugs for treatment of chronic fatigue syndrome.

J Tradit Chin Med. 2005 Jun;25(2):99-101.

Lo YL, Leong HN, Hsu LY, Tan TT, Kurup A, Fook-Chong S, Tan BH.

Autonomic dysfunction in recovered severe acute respiratory syndrome patients.

Can J Neurol Sci. 2005 May;32(2):264.

Letter

Maes M, Mihaylova I, De

M-Care4U outpatient Clinics,

Decreased dehydroepiandrost

Neuro Endocrinol Lett. 2005

There are a few reports that chronic fatigue syndrome (CFS) may be accompanied by changes in hormones, such as dehydroepiandrosterone (DHEA) and insulin-like growth factor (IGF1). This study


Ruyter M. and the Clinical Research Center for Mental Health, Olmenlaan 9, 2610 Antwerp, Belgium.

erone sulfate but normal insulin-like growth factor in chronic fatigue syndrome (CFS): relevance for the inflammatory response in CFS.

Oct;26(5):487-92. examines the serum concentrations of DHEA-sulfate (DHEAS), IGF1 and IGF1 binding protein-3 (IGFBP3) in 20 patients with CFS and in 12 normal controls. The IGFBP3/IGF1 ratio was computed as an index for IGF1 availability. We found significantly lower serum DHEAS concentrations in CFS, but no significant differences either in IGF1 or the IGFBP3/IGF1 ratio between CFS patients and normal controls. The decrease in serum DHEAS was highly sensitive and specific for CFS. There were significant and positive correlations between serum DHEAS and serum zinc and the mitogen-induced expression of the CD69 molecule on CD3+CD8+ T cells (an indicator of early T cell activation). There was a significant and negative correlation between serum DHEAS and the increase in the serum alpha-2 protein fraction (an inflammatory marker). Serum IGF1, but not DHEAS, was significantly and inversely correlated to age. The results show that CFS is accompanied by lowered levels of DHEAS and that the latter may play a role in the immune (defect in the early activation of T cells) and the inflammatory pathophysiology of CFS.

Maes M, Mihaylova I, Leunis JC.

M-Care4U Outpatient Clinics, and the Clinical Research Center for Mental Health, Belgium.

In chronic fatigue syndrome, the decreased levels of omega-3 poly-unsaturated fatty acids are related to lowered serum zinc and defects in T cell activation.

Neuro Endocrinol Lett. 2005 Dec 28;26(6):745-751 [Epub ahead of print]

There is now evidence that major depression is accompanied by decreased levels of omega3 poly-unsaturated fatty acids (PUFA), such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). There is a strong comorbidity between major depression and chronic fatigue syndrome (CFS). The present study has been carried out in order to examine PUFA levels in CFS. In twenty-two CFS patients and 12 normal controls we measured serum PUFA levels using gas chromatography and mass spectrometry. We found that CFS was accompanied by increased levels of omega6 PUFAs, i.e. linoleic acid and arachidonic acid (AA), and mono-unsaturated fatty acids (MUFAs), i.e. oleic acid. The EPA/AA and total omega3/omega6 ratios were significantly lower in CFS patients than in normal controls. The omega3/omega6 ratio was significantly and negatively correlated to the severity of illness and some items of the FibroFatigue scale, i.e. aches and pain, fatigue and failing memory. The severity of illness was significantly and positively correlated to linoleic and arachidonic acid, oleic acid, omega9 fatty acids and one of the saturated fatty acids, i.e. palmitic acid. In CFS subjects, we found significant positive correlations between the omega3/omega6 ratio and lowered serum zinc levels and the lowered mitogen-stimulated CD69 expression on CD3+, CD3+CD4+, and CD3+CD8+ T cells, which indicate defects in early T cell activation. The results of this study show that a decreased availability of omega3 PUFAs plays a role in the pathophysiology of CFS and is related to the immune pathophysiology of CFS. The results suggest that patients with CFS should respond favourably to treatment with - amongst other things - omega3 PUFAs, such as EPA and DHA.

Maher KJ, Klimas NG, Fletcher MA.

Department of Medicine, University of Miami Miller School of Medicine, Miami, FL 33176, USA.

Chronic fatigue syndrome is associated with diminished intracellular perforin.

Clin Exp Immunol. 2005 Dec;142(3):505-11.

Chronic fatigue syndrome (CFS) is an illness characterized by unexplained and prolonged fatigue that is often accompanied by abnormalities of immune, endocrine and cognitive functions. Diminished natural killer cell cytotoxicity (NKCC) is a frequently reported finding. However, the molecular basis of this defect of in vitro cytotoxicy has not been described. Perforin is a protein found within intracellular granules of NK and cytotoxic T cells and is a key factor in the lytic processes mediated by these cells. Quantitative fluorescence flow cytometry was used to the intracellular perforin content in CFS subjects and healthy controls. A significant reduction in the NK cell associated perforin levels in samples from CFS patients, compared to healthy controls, was observed. There was also an indication of a reduced perforin level within the cytotoxic T cells of CFS subjects, providing the first evidence, to our knowledge, to suggest a T cell associated cytotoxic deficit in CFS. Because perforin is important in immune surveillance and homeostasis of the immune system, its deficiency may prove to be an important factor in the pathogenesis of CFS and its analysis


may prove useful as a biomarker in the study of CFS. Masuda A, Kihara T, Fukudome T, Shinsato T, Minagoe S, Tei C.

Respiratory and Stress Care Center, Kagoshima University Hospital, 8-35-1 Sakuragaoka, Kagoshima 890-8520, Japan. [email protected]

The effects of repeated thermal therapy for two patients with chronic fatigue syndrome.

J Psychosom Res. 2005 Apr;58(4):383-7.

OBJECTIVE: This paper describes the successful treatment of two patients with chronic fatigue syndrome (CFS) using repeated thermal therapy. METHODS: Two patients with CFS underwent treatment with prednisolone (PSL), with no satisfactory effect. They were subjected to thermal therapy that consisted of a far-infrared ray dry sauna at 60 degrees C and postsauna warming. The therapy was performed once a day, for a total of 35 sessions. After discharge, these subjects continued the therapy once or twice a week on an outpatient basis for 1 year. RESULTS: Symptoms such as fatigue, pain, sleep disturbance, and low-grade fever were dramatically improved after 15 to 25 sessions of thermal therapy. Although PSL administration was discontinued, the subjects showed no relapse or exacerbation of symptoms during the first year after discharge. The patients became socially rehabilitated 6 months after discharge. CONCLUSIONS: These results suggest that repeated thermal therapy might be a promising method for the treatment of CFS.

McGhee SA, Kaska B, Liebhaber M, Stiehm ER.

Department of Pediatrics, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA. [email protected]

Persistent parvovirus-associated chronic fatigue treated with high dose intravenous immunoglobulin.

Pediatr Infect Dis J. 2005 Mar;24(3):272-4.

We report a 16-year-old boy with no evidence of immunodeficiency who had a 2-year history of chronic fatigue, low grade fever and slapped-cheek rash associated with chronic parvovirus B19 viremia. Prolonged intravenous immunoglobulin therapy resulted in resolution of his symptoms and viremia. Intravenous immunoglobulin may be useful in the resolution of parvovirus viremia regardless of immune status.

Metcalf LN, McGregor NR, Roberts TK

Membrane Damaging Toxins from Coagulase-Negative Staphylococcus Are Associated with Self-Reported Temporomandibular Disorder (TMD) in Patients with Chronic Fatigue Syndrome


Aim: To assess whether there is any association between membrane damaging toxin production by Staphylococcus spp. and self-reported TMD symptom expression in a group of patients selected to have CFS. Methods: Thirty-three defined Chronic Fatigue Syndrome (CFS) patients and 33 ageand sex-matched controls were assessed to evaluate the relationship between carriage of membrane damaging toxin producing staphylococcus, CFS and temporomandibular dysfunction (TMD) symptoms. Results: The CFS patients had an increased prevalence of face pain (Odds Ratio = 21.0, 95% CL 4.2-106, P < .001) and temporomandibular joint (TMJ) clicking/locking (OR = 5.7, 95% CL 1.423.5, P < .007), and the coagulase-negative staphylococcus maximum% B*-toxin haemolysis per patient. Both multivariate and univariate analyses revealed an association between the membrane damaging o*-toxin producing CoNS (MDT-CoNS) species per subject and face pain prevalence and intensity within both the CFS patients and the control subjects. No association was found between CoNS toxin production and TMJ clicking/locking. Importantly, áand B*-toxin production by CoNS was associated with patient reporting of arthritis. Conclusions: These data confirm the original observations of the association between MDTCoNS and facial muscle pain (Butt et al, 1998; McGregor et al, 2003). These data also suggest that MDT-CoNS associated facial muscle pain expression represents a distinct clinical entity, which has an increased prevalence in CFS patients.

Michielsen HJ, Van Houdenhove B, Leirs I, Vandenbroeck A, Onghena P.

Department of Psychology and Health, Tilburg University, Tilburg, The

Depression, attribution style and self-esteem in chronic fatigue syndrome and

Clin Rheumatol. 2005 Jul 12; [Epub ahead of print]

The aims of the present study were to compare a single diagnosis (chronic fatigue syndrome, CFS) and a double diagnosis (CFS + fibromyalgia, CFS+FM) group regarding depression, attribution style and self-esteem as well as to examine whether attribution style is a mediator in the relationship between self-esteem and depression. Eighty-five patients (CFS: 47, CFS+FM: 38) completed questionnaires on attribution style, self-esteem and depression. The single and double diagnosis


Netherlands. fibromyalgia patients: is there a link?

groups tended to differ slightly, but the differences were never statistically significant. In addition, only one condition was met of the four conditions mentioned by Baron and Kenny to establish that mediation exists between two variables. In conclusion, an external attribution style does not protect the CFS or CFS+FM patients with a low self-esteem from depression. The prevalence rate of depression was high in both patient samples, of which clinicians should be aware.

Mihrshahi R, Beirman R.

Department of Biological Sciences, Macquarie University, Sydney, NSW, Australia. [email protected]

Aetiology and pathogenesis of chronic fatigue syndrome: a review.

N Z Med J. 2005 Dec 16;118(1227):U1780.

Chronic fatigue syndrome (CFS) is a debilitating disease of uncertain aetiology that is characterised by unexplained, severe fatigue associated with a number of typical symptoms. This paper reviews the scientific literature related to current theories about the aetiology and pathogenesis of CFS by focussing on what appear to be the four most significant aspects in the development and perpetuation of this disease: the role of infectious agents as well as immunological, neuroendocrine, and psychiatric factors. A multifactorial model for the aetiology of CFS, which includes and draws together these four aspects, is proposed; and suggestions are offered regarding approaches to the diagnosis and treatment of this disease.

Miller R. Thimerosal, micromercurialism and chronic fatigue syndrome.

Med Hypotheses. 2005;64(5):1063-4.

Letter

Mommersteeg PM, Heijnen CJ, Verbraak MJ, van Doornen LJ.

Department of Health Psychology, Utrecht University, P.O. Box 80.140, 3508 TC Utrecht, The Netherlands.

Clinical burnout is not reflected in the cortisol awakening response, the day-curve or the response to a low-dose dexamethasone suppression test.

Psychoneuroendocrinology. 2005 Sep 5; [Epub ahead of print]

Burnout is presumed to be the result of chronic stress, and chronic stress is known to affect the HPA-axis. To date, studies on HPA-axis functioning in burnout have showed inconsistent results. In the present study, a large sample (n=74) of clinically diagnosed burnout individuals, mostly on sick-leave, were included and compared with 35 healthy controls. Salivary cortisol was sampled on 2 days to determine the cortisol awakening response (CAR) and the day-curve. In addition, the dexamethasone suppression test (DST) was applied to assess the feedback efficacy of the HPA-axis. There were no differences observed in the CAR, day-curve or CAR after DST in the burnout group as compared to a healthy control group. Burnout shows overlap in symptoms with chronic fatigue syndrome (CFS) and depression. Therefore, differential changes in HPA-axis functioning that resemble the hypo-functioning of the HPA-axis in CFS, or rather the hyper-functioning of the HPA-axis in depression, might have obscured the findings. However, no effect of fatigue or depressive mood on HPA-axis functioning was found in the burnout group. We concluded that HPA-axis functioning in clinically diagnosed burnout participants as tested in the present study, seems to be normal.

Moss J. Association of Young People with ME, Milton Keynes MK2 2XD, UK. [email protected]

Development of a functional ability scale for children and young people with myalgic encephalopathy (ME)/chronic fatigue syndrome (CFS).

J Child Health Care. 2005 Mar;9(1):20-30.

The numerous symptoms and unpredictable pattern of myalgic encephalopathy (ME) make it difficult to describe, especially for children. It was left to carers to guess what the child could achieve each day, often leading to over/underestimates. A functional ability scale was needed, which measured from 0 to 100 percent able and that children and young people themselves designed. A new scale was developed from the Moss Ability Scale using the critique of 251 children and young people from the Association of Young People with ME (AYME). Responding to the shift in emphasis towards patients taking an active role in their own care, it was felt these young people would know whether the scale measured what it had set out to measure, and were asked questions on the face and content validity of the scale. There was a 99 percent agreement between the young people that the final scale was 'workable' or better.




Moss-Morris R, Sharon C, Tobin R, Baldi JC.

Health Psychology, The Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92 019, Auckland, New Zealand. [email protected]

A randomized controlled graded exercise trial for chronic fatigue syndrome: outcomes and mechanisms of change.

J Health Psychol. 2005 Mar;10(2):245-59.

The aim of this study was to investigate the potential mechanisms underlying the efficacy of graded exercise therapy for chronic fatigue syndrome (CFS). Forty-nine CFS patients were randomized to a 12-week graded exercise programme or to standard medical care. At the end of treatment the exercise group rated themselves as significantly more improved and less fatigued than the control group. A decrease in symptom focusing rather than an increase in fitness mediated the treatment effect. Graded exercise appears to be an effective treatment for CFS and it operates in part by reducing the degree to which patients focus on their symptoms.

Naschitz JE, Mussafia-Priselac R, Peck ER, Peck S, Naftali N, Storch S, Slobodin G, Elias N, Rosner I.

Department of Internal Medicine A, Bnai-Zion Medical Center, Haifa, Israel. [email protected]

Hyperventilation and amplified blood pressure response: is there a link?

J Hum Hypertens. 2005 May;19(5):381-7.

Based on prior studies, the hypothesis that hyperventilation (HV) may have a pressor effect and play a causal role in hypertension has been suggested. The objective of this study was to correlate HV with blood pressure (BP)-change during a postural challenge. Consecutive subjects referred for evaluation of syncope, dizziness, chronic fatigue syndrome (CFS), fibromyalgia, or non-CFS fatigue were assessed with a 10-min supine 30-min head-up tilt test combined with capnography. We selected for analysis the records of patients aged 17-70 years, not taking vasoactive medications, having sitting systolic BP (SBP) < 140 mmHg, sitting diastolic BP (DBP) < 90 mmHg, and who completed 30 min of tilt. HV was diagnosed when end-tidal pressure of CO2 < 30 mmHg was recorded consecutively for > or = 10 min. Postural hypertension (PHT) was diagnosed when DBP on tilt > or = 90 mmHg was recorded consecutively for > or = 10 min. DBP-change was computed as (median DBP on tilt) -(median DBP supine). PHT and DBP-change were correlated with HV. A total of 320 patient charts were reviewed. PHT was present in 30 cases. The mean DBP-change in patients with PHT was +9.9 mmHg (s.d. 5.8), with three patients manifesting HV. Of the remaining 290 patients, 56 had HV, their mean DBP-change was -0.3 mmHg (s.d. 7.2). The other 234 patients without HV had a mean DBP-change +0.95 mmHg (s.d. 5.7), comparable to the DBP-change in patients with HV. In, conclusion, posturally induced HV was not associated with an increase in BP, nor was PHT associated with HV, except in a small minority of cases.

Naschitz JE, Rozenbaum M, Fields M, Isseroff H, Enis S, Babich JP, Peck S, Peck ER, Gaitini L, Naschitz S, Sabo E, Rosner I.

Department of Internal Medicine A, Bnai Zion Medical Center and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel. [email protected]

Search for disease-specific cardiovascular reactivity patterns: developing the methodology.

Clin Sci (Lond). 2005 Jan;108(1):37-46.

Aberrations of CVR (cardiovascular reactivity), an expression of autonomic function, lack specificity for a particular disorder. Recently, a CVR pattern particular to chronic fatigue syndrome has been observed. In the present study, we aimed to develop methodologies for assessing disease-specific CVR patterns. As a prototype, a population of 50 consecutive patients with FMF (familial Mediterranean fever) was studied and compared with control populations. A 10 min supine/30 min head-up tilt test with recording of the heart rate and blood pressure or the pulse transit time was performed. Five studies were conducted applying different methods. In each study, statistical analysis identified independent predictors of CVR in FMF. Based on regression coefficients of these predictors, a linear DS (discriminant score) was computed for every subject. Each study established an equation to assess CVR, calculate DS for FMF and determine the sensitivity and specificity of the DS cut-off. In each of the five studies, abnormal CVR was observed in FMF patients. The best accuracy (88% sensitivity and 90.1% specificity for FMF) was obtained by a method based on beat-to-beat heart rate and pulse transit time recordings. Data was processed by fractal and recurrence


quantitative analysis with recordings in FMF patients compared with a mixed control population. Identification of disease-specific CVR patterns was possible with the methodologies described in the present study. In FMF, disease-specific CVR may be explained by the interplay between neuroendocrine loops specific to FMF with cardiovascular homoeostatic mechanisms. Recognition of disease-specific CVR patterns may advance the understanding of homoeostatic mechanisms and have implications in clinical practice.

Naschitz JE, Rozenbaum M, Fields MC, Enis S, Manor H, Dreyfuss D, Peck S, Peck ER, Babich JP, Mintz EP, Sabo E, Slobodin G, Rosner I.

Department of Internal Medicine A and Rheumatology, Bnai Zion Medical Center and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel. [email protected]

Cardiovascular reactivity in fibromyalgia: evidence for pathogenic heterogeneity.

J Rheumatol. 2005 Feb;32(2):335-9.

OBJECTIVE: To evaluate disease-specific cardiovascular reactivity patterns in patients with fibromyalgia (FM) using a recently described method called fractal and recurrence analysis score (FRAS). METHODS: The study group included 30 women with FM, average age 46.7 years (SD 7.03). An age matched group of 30 women with other rheumatic disorders or having a dysautonomic background [chronic fatigue syndrome (CFS), non-CFS fatigue, neurally mediated syncope, and psoriatic arthritis (PsA)] served as controls. Subjects were evaluated with a head-up tilt test with beat-to-beat recording of the heart rate (HR) and pulse transit time. A 10-minute supine phase was followed by 600 cardiac cycles recorded on tilt. Data were processed by recurrence plot and fractal analysis. Variables acting as independent predictors of the cardiovascular reactivity were identified in FM patients versus controls. RESULTS: No statistically significant differences were found between the groups by univariate analysis comparing 92 variables of cardiovascular reactivity in FM patients compared to controls. CONCLUSION: Study of cardiovascular reactivity utilizing a head-up tilt test and processing the data using the FRAS method did not reveal a specific FM-associated abnormality. Our data confirm studies that utilized other methodologies and reached similar conclusions. Patients with FM represent a heterogenous group with respect to their pattern of cardiovascular reactivity.

Natelson BH, Weaver SA, Tseng CL, Ottenweller JE.

CFS Cooperative Research Center and Department of Neurosciences, University of Medicine and Dentistry of New Jersey-New Jersey Medical School, Newark, New Jersey, USA. [email protected]

Spinal fluid abnormalities in patients with chronic fatigue syndrome.

Clin Diagn Lab Immunol. 2005 Jan;12(1):52-5.

Arguments exist as to the cause of chronic fatigue syndrome (CFS). Some think that it is an example of symptom amplification indicative of functional or psychogenic illness, while our group thinks that some CFS patients may have brain dysfunction. To further pursue our encephalopathy hypothesis, we did spinal taps on 31 women and 13 men fulfilling the 1994 case definition for CFS and on 8 women and 5 men serving as healthy controls. Our outcome measures were white blood cell count, protein concentration in spinal fluid, and cytokines detectable in spinal fluid. We found that significantly more CFS patients had elevations in either protein levels or number of cells than healthy controls (30 versus 0%), and 13 CFS patients had protein levels and cell numbers that were higher than laboratory norms; patients with abnormal fluid had a lower rate of having comorbid depression than those with normal fluid. In addition, of the 11 cytokines detectable in spinal fluid, (i) levels of granulocyte-macrophage colony-stimulating factor were lower in patients than controls, (ii) levels of interleukin-8 (IL-8) were higher in patients with sudden, influenza-like onset than in patients with gradual onset or in controls, and (iii) IL-10 levels were higher in the patients with abnormal spinal fluids than in those with normal fluid or controls. The results support two hypotheses: that some CFS patients have a neurological abnormality that may contribute to the clinical picture of the illness and that immune dysregulation within the central nervous system may be involved in this process.

Nicolson GL, Gan R, Haier J.

ORIGINAL RESEARCHEvidence for Brucella spp. and Mycoplasmaspp.


We examined the blood of 94 North American Chronic Fatigue Syndrome (CFS) patients using forensic polymerase chain reaction and found that a subset (10.6%) of CFS patients show evidence of Brucella spp. infections compared to one of 70 control subjects (Odds Ratio = 8.2; 95% Confidence Limits (CL) 1-66; P < .01). Rural patients showed a higher incidence of Brucella spp. infections over urban patients (OR = 5.5, 95% CL 1.3-23.5, P < .02). Since CFS patients also have a high prevalence


Co-Infections in Blood of Chronic Fatigue Syndrome Patients

of one of four Mycoplasma species and sometimes show evidence of infections with Chlamydia pneumoniae, we examined Brucella-positive patients for other bacterial infections. Previously we found that 8% of the CFS patients showed evidence of C. pneumoniae and about 50% show evidence of Mycoplasma spp. infections. Since the presence of one or more chronic systemic infections may predispose patients to other infections, we examined the prevalence of C. pneumoniae and Mycoplasma spp. infections in Brucella-positive patients. We found only one Brucella-positive patient with C. pneumoniae and four other patients with evidence of Mycoplasma spp., suggesting that such bacterial infections occur independently in CFS patients. Control subjects (N = 70) had low rates of Brucella spp. (1.4%), Mycoplasma spp. (7.2%) or C. pneumoniae (1.4%) infections, and there were no co-infections in control subjects. The results indicate that a subset of CFS patients show evidence of infection with Brucella spp., and some of these patients also have other bacterial infections.

Nijs J, De Meirleir K

CRITICAL REVIEWS AND COMMENTS ON CURRENT RESEARCHEnterovirus Related Myopathy in a Subset of Chronic Fatigue Syndrome?


Nijs J, De Meirleir K.

Department of Human Physiology, Faculty of Physical Education and Physiotherapy, Vrije University Brussel, Belgium; Division of Musculoskeletal Physiotherapy, Higher Institute of Physiotherapy, Department of Health Sciences, Hogeschool Antwerpen, Belgium.

Nitric oxide and chronic fatigue syndrome: Are we caring for our patients or are we practicing selfcare?

Med Hypotheses. 2005 Oct 7; [Epub ahead of print]

LETTER

Nijs J, De Meirleir Department of Impairments of In Vivo. 2005 This paper provides an overview of the evidence addressing the impairments of the 2'-5'


K. Human Physiology, Faculty of Physical Education and Physiotherapy, Vrije Universiteit Brussel, Brussels, Belgium. [email protected]

the 2-5A synthetase/RNase L pathway in chronic fatigue syndrome.

Nov-Dec;19(6):1013-21.

oligoadenylate (2-5 A) synthetase/RNase L pathway in Chronic Fatigue Syndrome (CFS) patients. The 2-5A synthetase/RNase L pathway in CFS patients appears to be both up-regulated (i.e. increased levels of bioactive 2-5A synthetase and increased activity of the RNase L enzyme) and deregulated (elastase and calpain initiate 83 kDa RNase L proteolysis, generating two major fragments with molecular masses of 37 and 30 kDa, respectively). The deregulation of the 2-5A synthetase/RNase L pathway in CFS accompanies decreased NK-function and deregulation of apoptotic pathways. Since various components of the pathway appear to be related to performance during a graded exercise stress test, some evidence supportive of the clinical importance of the impaired pathway in CFS patients has been provided. Studies addressing the treatment of the deregulation of the 2-5A synthetase/RNase L pathway in CFS are warranted.

Nijs J, Meeus M, McGregor NR, Meeusen R, de Schutter G, van Hoof E, de Meirleir K.

Department of Human Physiology, Faculty of Physical Education and Physiotherapy, Vrije Universiteit Brussel, Brussels, Belgium.

Chronic fatigue syndrome: exercise performance related to immune dysfunction.

Med Sci Sports Exerc. 2005 Oct;37(10):1647-54.

PURPOSE: To date, the exact cause of abnormal exercise response in chronic fatigue syndrome (CFS) remains to be revealed, but evidence addressing intracellular immune deregulation in CFS is growing. Therefore, the aim of this cross-sectional study was to examine the interactions between several intracellular immune variables and exercise performance in CFS patients. METHODS: After venous blood sampling, subjects (16 CFS patients) performed a maximal exercise stress test on a bicycle ergometer with continuous monitoring of cardiorespiratory variables. The following immune variables were assessed: the ratio of 37 kDa Ribonuclease (RNase) L to the 83 kDa native RNase L (using a radiolabeled ligand/receptor assay), RNase L enzymatic activity (enzymatic assay), protein kinase R activity assay (comparison Western blot), elastase activity (enzymatic-colorimetric assay), the percent of monocytes, and nitric oxide determination (for monocytes and lymphocytes; flow cytometry, live cell assay). RESULTS: Forward stepwise multiple regression analysis revealed 1) that elastase activity was the only factor related to the reduction in oxygen uptake at a respiratory exchange ratio (RER) of 1.0 (regression model: R = 0.53, F (1,14) = 15.5, P < 0.002; elastase activity P < 0.002); 2) that the protein kinase R activity was the principle factor related to the reduction in workload at RER = 1.0; and 3) that elastase activity was the principle factor related to the reduction in percent of target heart rate achieved. CONCLUSION: These data provide evidence for an association between intracellular immune deregulation and exercise performance in patients with CFS. To establish a causal relationship, further study of these interactions using a prospective longitudinal design is required.

Nijs J, Vaes P, De Meirleir K.

Department of Physiology, Faculty of Physical Education and Physiotherapy, Vrije Universiteit Brussel (VUB), Brussels, Belgium. [email protected]

The Chronic Fatigue Syndrome Activities and Participation Questionnaire (CFS-APQ): an overview.

Occup Ther Int. 2005;12(2):107-21.

Chronic fatigue syndrome (CFS) is characterized by severe fatigue and a reduction in activity levels. The purpose of this study was to provide an overview of design, reliability, and validity of the CFS Activities and Participation Questionnaire (CFS-APQ). The CFS-APQ was constructed based on a retrospective analysis of the Karnofsky Performance Status Questionnaire and the Activities of Daily Living Questionnaire (n = 141). In a reliability study of 34 participants the test-retest reliability coefficient of the CFS-APQ was 0.95. In two different studies, the Cronbach alpha coefficient for internal consistency varied between 0.87 (n = 88) and 0.94 (n = 47). The CFS-APQ was administered to 47 patients who listed 183 activities that had become difficult due to their chronic symptoms, and 157 (85.8%) answers matched the content of the CFS-APQ. The outcome of a cross-sectional study (n = 88) studying the correlations between the Medical Outcomes Short Form 36 Health Status Survey subscale scores and the CFS-APQ supported the validity of the CFS-APQ. The CFS-APQ scores correlated with a behavioural assessment of the patients' performance of activities encompassed by the questionnaire (r = 0.29-0.55; n = 63), and correlated with exercise capacity



parameters (r = 0.26-0.39; n = 77) obtained during a maximal exercise capacity stress test. Finally, the CFS-APQ correlated with visual analogue scales for pain (r = 0.51) and fatigue (r = 0.50; n = 47). It is concluded that the CFS-APQ generates reliable and valid data, and can be used as a clinical measure of disease severity in patients with CFS. Future studies should aim at examining the sensitivity of the CFS-APQ.

Nijs J, Van de Putte K, Louckx F, De Meirleir K.

Department of Human Physiology, Faculty of Physical Education and Physiotherapy, Vrije Universiteit Brussel, Belgium. [email protected]

Employment status in chronic fatigue syndrome. A cross-sectional study examining the value of exercise testing and self-reported measures for the assessment of employment status.

Clin Rehabil. 2005 Dec;19(8):895-9.

OBJECTIVE: To examine the value of exercise testing and self-reported disability for the assessment of employment status in patients with chronic fatigue syndrome. DESIGN: Cross-sectional observational study. SETTING: A university-based chronic fatigue clinic. SUBJECTS: Fifty-four consecutive, Flemish, employed (not self-employed) chronic fatigue syndrome patients (49/54 female). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Participants were questioned about their current and premorbid employment status, filled in the Chronic Fatigue Syndrome Activities and Participation Questionnaire (CFS-APQ), the Medical Outcomes Short Form 36 Health Status Survey (SF-36), and performed a maximal exercise test on a bicycle ergometer with continuous monitoring of cardiorespiratory variables. RESULTS: A significant association was observed between the current employment rate and two SF-36 subscales (i.e., role limitations due to physical functioning and social functioning; rho = 0.39 and 0.35 respectively) (n = 54). Analysing only the female chronic fatigue syndrome patients (n = 49), the current employment rate correlated significantly with the peak workload (rho = 0.38). CONCLUSIONS: The associations between either exercise testing or self-reported disability and employment status are too weak to predict employment status.

Nijs J, Van de Velde B, De Meirleir K.

Department of Human Physiology, Faculty of Physical Education and Physical Therapy, Vrije Universiteit Brussel (VUB), Belgium. [email protected]

Pain in patients with chronic fatigue syndrome: does nitric oxide trigger central sensitisation?

Med Hypotheses. 2005;64(3):558-62.

Previous studies have provided evidence supportive of the clinical importance of widespread pain in patients with chronic fatigue syndrome (CFS): pain severity may account for 26-34% of the variability in the CFS patient's activity limitations and participation restrictions. The etiology of widespread pain in CFS remains to be elucidated, but sensitisation of the central nervous system has been suggested to take part of CFS pathophysiology. It is hypothesised that a nitric oxide (NO)-dependent reduction in inhibitory activity of the central nervous system and consequent central sensitisation accounts for chronic widespread pain in CFS patients. In CFS patients, deregulation of the 2',5'-oligoadenylate synthetase/RNase L pathway is accompanied by activation of the protein kinase R enzyme. Activation of the protein kinase R and subsequent nuclear factor-kappaB activation might account for the increased production of NO, while infectious agents frequently associated with CFS (Coxsackie B virus, Epstein-Barr Virus, Mycoplasma) might initiate or accelerate this process. In addition, the evidence addressing behavioural changes in CFS patients fits the central sensitisation-hypothesis: catastrophizing, avoidance behaviour, and somatization may result in, or are initiated by sensitisation of the central nervous system.

Nijs J, Van Parijs M

CRITICAL REVIEWS AND COMMENTS ON CURRENT RESEARCH Long-Term Effectiveness of Pool Exercise




Therapy and Education in Patients with Fibromyalgia

Njoku MG, Jason LA, Torres-Harding SR.

Center for Community Research, Chronic Fatigue Research Study, Chicago, IL 60614, USA. [email protected]

The relationships among coping styles and fatigue in an ethnically diverse sample.

Ethn Health. 2005 Nov;10(4):263-78.

The present study focused on coping strategies among African Americans, Latinos, and European Americans with chronic fatigue syndrome (CFS) and idiopathic chronic fatigue (ICF). The coping strategies examined were measured by using the COPE Scales, which assess Seeking Emotional Social Support, Positive Reinterpretation and Growth, Acceptance, Denial, Turning to Religion, Behavioral Disengagement, and Focusing on and Venting Emotions. In addition, the four coping strategies specifically designed for people with CFS, including maintaining activity, accommodating to the illness, focusing on symptoms, and information-seeking, were used in this study. It was hypothesized that African Americans and Latinos in comparison to European Americans would be more likely to use religious coping, behavioral disengagement, and denial. As predicted, African Americans were significantly more likely to turn to religion than European Americans, and Latinos and African Americans used denial significantly more often than European Americans. An additional finding was that focusing on symptoms was associated with greater fatigue and more physical disability among African Americans. Within the Latino sample, acceptance was related to greater fatigue and less physical disability, and greater optimism predicted less mental disability. Among European American participants, maintaining activity was related to less mental disability, whereas accommodating to the illness predicted more physical disability. These results indicate that coping varies among various ethnic groups with CFS and ICF; however, denial is consistently related to less adaptive outcomes. Therefore, healthcare professionals should find ways to reduce patient use of denial and promote alternative strategies for managing life events.

Ohayon MM. Stanford Sleep Epidemiology Research Center, Stanford University School of Medicine, Stanford, Calif., USA. [email protected]

Prevalence and correlates of nonrestorative sleep complaints.

Arch Intern Med. 2005 Jan 10;165(1):35-41.

BACKGROUND: Nonrestorative sleep (NRS) has been little studied in the general population, even though this symptom has an important role in several medical conditions such as heart disease, fibromyalgia, and chronic fatigue syndrome, as well as various sleep disorders. METHODS: A total of 25,580 individuals (age range, 15-100 years) from the noninstitutionalized general population representative of 7 European countries (France, the United Kingdom, Germany, Italy, Portugal, Spain, and Finland) were interviewed by telephone using the Sleep-EVAL system. Nonrestorative sleep was analyzed in relationship to sociodemographic determinants, environmental factors, life habits, health, sleep-wake schedule, and psychological factors. RESULTS: The prevalence of NRS was 10.8% (95% confidence interval, 10.4%-11.2%) in the sample, was higher in women than in men (12.5% vs 9.0%; P<.001), and decreased with age. The United Kingdom (16.1%) and Germany (15.5%) had the highest prevalence of NRS and Spain (2.4%), the lowest. In multivariate analyses, several factors were positively associated with NRS. The most important were younger age, dissatisfaction with sleep, difficulty getting started in the morning, stressful life, presence of anxiety, bipolar or a depressive disorder, and having a physical disease. When compared with subjects who have difficulty initiating or maintaining sleep (without NRS), subjects with NRS reported more frequently a variety of daytime impairment (irritability, physical, and mental fatigue) and consulted a physician twice as frequently for their sleeping difficulties than did other subjects with insomnia. CONCLUSIONS: Nonrestorative sleep is a frequent symptom in the general population, but its prevalence largely varies between countries. It is often associated with mental disorders and




characteristics of sleep deprivation (such as extra sleep time on weekends). Nonrestorative sleep affected more frequently the active classes of the population and caused greater daytime impairment than difficulty initiating or maintaining sleep.

Ong BN, Evans D, Bartlam A.

Health Services Research, Primary Care Sciences Research Centre, Keele University, Keele ST5 5BG. [email protected]

A patient's journey with myalgic encephalomyelitis.

BMJ. 2005 Mar 19;330(7492):648-50.

Pall ML. Nitric oxide and the etiology of chronic fatigue syndrome: giving credit where credit is due.

Med Hypotheses. 2005;65(3):631-3.

Letter

Patten SB, Beck CA, Kassam A, Williams JV, Barbui C, Metz LM.

Department of Community Health Sciences, University of Calgary, Alberta. [email protected]

Long-term medical conditions and major depression: strength of association for specific conditions in the general population.

Can J Psychiatry. 2005 Mar;50(4):195-202.

BACKGROUND: The prevalence of major depression (MD) in persons with nonpsychiatric medical conditions is an indicator of clinical need in those groups, an indicator of the feasibility of screening and case-finding efforts, and a source of etiologic hypotheses. This analysis explores the prevalence of MD in the general population in relation to various long-term medical conditions. METHODS: We used a dataset from a large-scale Canadian national health survey, the Canadian Community Health Survey (CCHS). The sample consisted of 115 071 subjects aged 18 years and over, randomly sampled from the Canadian population. The survey interview recorded self-reported diagnoses of various long-term medical conditions and employed a brief predictive interview for MD, the Composite International Diagnostic Interview Short Form for Major Depression. Logistic regression was used to adjust estimates of association for age and sex. RESULTS: The conditions most strongly associated with MD were chronic fatigue syndrome (adjusted odds ratio [AOR] 7.2) and fibromyalgia (AOR 3.4). The conditions least strongly associated were hypertension (AOR 1.2), diabetes, heart disease, and thyroid disease (AOR 1.4 in each case). We found associations with various gastrointestinal, neurologic, and respiratory conditions. CONCLUSIONS: A diverse set of long-term medical conditions are associated with MD, although previous studies might have lacked power to detect some of these associations. The strength of association in prevalence data, however, varies across specific conditions.

Piche T, Vanbiervliet G, Cherikh F, Antoun Z, Huet PM, Gelsi E, Demarquay JF, Caroli-Bosc FX, Benzaken S, Rigault MC,

Department of Hepatogastroenterology, Chu de Nice, France. [email protected]

Effect of ondansetron, a 5-HT3 receptor antagonist, on fatigue in chronic hepatitis C: a randomised, double blind,

Gut. 2005 Aug;54(8):1169-73.

BACKGROUND AND AIMS: There are no available effective therapies for fatigue associated with chronic hepatitis C (CHC). The serotonin antagonist ondansetron has been shown to be effective in the chronic fatigue syndrome. In this randomised, placebo controlled, double blind trial, we investigated the effect of orally administered ondansetron on fatigue in CHC. METHODS: Thirty six patients with CHC were included if fatigue was their predominant symptom and they scored more than 4 on a visual analogue scale (0-10). During the study, fatigue and depression were measured on days 0, 15, 30, and 60 using a validated self report questionnaire (fatigue impact scale and Beck depression inventory). Patients were randomised to receive ondansetron tablets 4 mg twice daily or




Renou C, Rampal P, Tran A.

placebo controlled study.

placebo for one month followed by an additional four weeks of observation. RESULTS: Fatigue score was 85.4 (28.2) and 98.2 (26.9) in the ondansetron and placebo groups, respectively (NS). Ondansetron significantly reduced the fatigue score with more than 30% improvement on day 15 (57.1 (38.9); p<0.01), day 30 (54.5 (37.6); p<0.01), and day 60 (60.8 (37.3); p<0.01) whereas placebo did not. Overall, the reduction in fatigue was significantly higher with ondansetron compared with placebo (ANOVA for repeated measurements) for the whole follow up period (p = 0.03) or for the treatment period only (p = 0.04). Ondansetron also significantly reduced depression scores. CONCLUSIONS: The 5-hydroxytryptamine receptor type 3 antagonist ondansetron had a significant positive effect on fatigue in CHC. These observations support the concept that fatigue involves serotoninergic pathways and may encourage further evaluations of the efficacy of ondansetron on fatigue in chronic liver diseases.

Prins J, Bleijenberg G, Rouweler EK, van der Meer J.

Department of Psychology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. [email protected]

Effect of psychiatric disorders on outcome of cognitive-behavioural therapy for chronic fatigue syndrome.

Br J Psychiatry. 2005 Aug;187:184-5.

Psychiatric disorders have been associated with poor outcome in individuals with chronic fatigue syndrome (CFS). This study examines the impact of psychiatric disorders on outcome of cognitive-behavioural therapy (CBT). Psychiatric diagnoses were assessed with a structured psychiatric interview in a CBT trial of 270 people with CFS. Lifetime and current psychiatric disorders were found in 50 and 32% respectively. No significant differences in fatigue severity and functional impairment following treatment were found between participants with and without psychiatric diagnoses.

Rakib A, White PD, Pinching AJ, Hedge B, Newbery N, Fakhoury WK, Priebe S.

Queen Mary's School of Medicine and Dentistry, Newham Centre for Mental Health, London, UK.

Subjective quality of life in patients with chronic fatigue syndrome.

Qual Life Res. 2005 Feb;14(1):11-9.

The aim of this study was to (1) assess Subjective Quality of Life (SQOL) of patients with Chronic Fatigue Syndrome (CFS) using a generic concept and to compare the findings with those in groups with mental disorders and healthy subjects, and (2) investigate whether and, if so, to what extent socio-demographic and clinical variables predict SQOL in CFS patients. Seventy-three patients diagnosed with CFS were randomly selected and interviewed from two specialised clinics. CFS was diagnosed using the Oxford Criteria. SQOL was assessed on the Manchester Short Assessment of Quality of Life (MANSA) and Health-Related Quality of Life (HRQOL) on the Medical Outcome Study Short-Form 36 (MOS) SF-36. A battery of mood and symptom questionnaires, including the Symptom Checklist Questionnaire (SCL-90-R), was administered to assess various aspects of symptomatology as potential predictor variables. Multiple regression analyses were conducted to identify predictors of SQOL. Overall, SQOL was low in CFS patients and less favourable than in groups with mental disorders and healthy subjects. Satisfaction was particularly low with life as a whole, leisure activities and financial situation. Whilst SQOL was only moderately correlated with HRQOL, the SCL-90-R score, especially SCL-90-R Depression scale score, was the best predictor of SQOL explaining 35% of the variance. HRQOL and generic SQOL appear distinct despite some overlap. The findings underline that SQOL is significantly disrupted in CFS patients. Depressive symptoms are statistically the strongest 'predictor' of SQOL, although the direction of the relationship is not established. These data suggest that treatment of depression associated with CFS, regardless of causation, could help to improve SQOL in CFS patients.

Randall DC, Cafferty FH, Shneerson JM,

Psychopharmacology Research Unit,

Chronic treatment with modafinil may not be

J Psychopharmacol. 2005

Fourteen patients (7 male, 7 female, 22-63 years), classified as having chronic fatigue syndrome (CFS), but without concurrent major depression, significant sleepiness or use of psychoactive medication, completed a double-blind, placebo-controlled, crossover study of the effects of the


Smith IE, Llewelyn MB, File SE.

Centre for Neuroscience Research, King's College London, London, UK.

beneficial in patients with chronic fatigue syndrome.

Nov;19(6):647-60. selective wakefulness-promoting agent, modafinil (200 and 400mg/day). The treatment periods were each 20 days, with washout periods of 2 weeks. The primary aim was to determine effects on cognition and the secondary aim was to determine effects on self-ratings of fatigue, quality of life and mood. Modafinil had mixed effects in two cognitive tasks. In a test of sustained attention, treatment with 200mg reduced the latency to correctly detect sequences, but 400mg increased the number of missed targets. In a test of spatial planning, the 200mg dose resulted in a slower initial thinking time for the easiest part of the task, whereas 400mg reduced the initial thinking time for the hardest part of the test. Lastly, in a test of mental flexibility and one of motor speed, patients performed worse whilst on modafinil (400mg), compared with the placebo period. No effects were observed on the performance of other psychometric tests or on self-ratings of fatigue, quality of life or mood, but this may have been due to insufficient statistical power. It is discussed whether the limited and mixed cognitive effects that we observed could have occurred by chance, or whether a subgroup of CFS patients with daytime sleepiness would have shown greater benefits.

Rangel L, Garralda ME, Jeffs J, Rose G.

Academic Unit of Child and Adolescent Psychiatry, Imperial College, London, UK.

Family health and characteristics in chronic fatigue syndrome, juvenile rheumatoid arthritis, and emotional disorders of childhood.

J Am Acad Child Adolesc Psychiatry. 2005 Feb;44(2):150-8.

OBJECTIVE: To compare family health and characteristics in children with chronic fatigue syndrome (CFS), in juvenile rheumatoid arthritis (JRA), and emotional disorders. METHOD: Parents of 28 children and adolescents aged 11 to 18 years with CFS, 30 with JRA, and 27 with emotional disorders (i.e., anxiety and/or depressive disorders) were recruited from specialty clinical settings and completed interviews and questionnaires assessing family health problems, parental mental distress, illness attitudes, and family burden of illness. RESULTS: Parents of children with CFS were significantly more likely than those of children with JRA to report a history of CFS-like illness, high levels of mental distress, and a tendency to experience functional impairment in response to physical symptoms. Families of children with CFS were characterized by significantly greater emotional involvement and reported greater family burden related to the child's illness in comparison with families of children with JRA. CONCLUSIONS: CFS in childhood and adolescence is associated with higher levels of parental CFS-like illness, mental distress, emotional involvement, and family illness burden than those observed in association with JRA, a chronic pediatric physical illness.

Ranjith G. Department of Psychological Medicine, King's College Hospital, London, UK. [email protected]

Epidemiology of chronic fatigue syndrome.


BACKGROUND: Chronic fatigue syndrome (CFS) is a controversial disorder with different case definitions, aetiological models and proposed treatments. An epidemiological approach is likely to bring some clarity to the field. AIM: The aim of this article is to review the literature on the epidemiology of fatigue, chronic fatigue and CFS. METHOD: A literature search was conducted using the databases Medline and Pubmed as well as the reference lists of recent reviews to identify the relevant studies. The aim was not to do a systematic review but to review the key studies in the area to highlight the methodological issues. RESULTS: The review is organized according to the following areas: the prevalence of fatigue and chronic fatigue, the prevalence and incidence of CFS, epidemiological associations such as gender, social class and psychiatric co-morbidity and CFS in special groups such as those recovering from a viral infection, specific occupational groups and Gulf War veterans. CONCLUSION: While fatigue as a symptom is very common, CFS is relatively rare. Many of the epidemiological associations seen in specialist clinics are not found in community samples. It is unlikely that one specific causal factor can explain CFS. Future studies should go beyond estimating the prevalence to testing more complex aetiological models.

Reeves WC, Wagner D,

Division of Viral and Rickettsial

Chronic fatigue syndrome--a

BMC Med. 2005 Dec 15;3:19.

BACKGROUND: The lack of standardized criteria for defining chronic fatigue syndrome (CFS) has constrained research. The objective of this study was to apply the 1994 CFS criteria by standardized


Nisenbaum R, Jones JF, Gurbaxani B, Solomon L, Papanicolaou DA, Unger ER, Vernon SD, Heim C.

Diseases, Centers for Disease Control and Prevention, Atlanta, GA, USA. [email protected]

clinically empirical approach to its definition and study.

reproducible criteria. METHODS: This population-based case control study enrolled 227 adults identified from the population of Wichita with: (1) CFS (n = 58); (2) non-fatigued controls matched to CFS on sex, race, age and body mass index (n = 55); (3) persons with medically unexplained fatigue not CFS, which we term ISF (n = 59); (4) CFS accompanied by melancholic depression (n = 27); and (5) ISF plus melancholic depression (n = 28). Participants were admitted to a hospital for two days and underwent medical history and physical examination, the Diagnostic Interview Schedule, and laboratory testing to identify medical and psychiatric conditions exclusionary for CFS. Illness classification at the time of the clinical study utilized two algorithms: (1) the same criteria as in the surveillance study; (2) a standardized clinically empirical algorithm based on quantitative assessment of the major domains of CFS (impairment, fatigue, and accompanying symptoms). RESULTS: One hundred and sixty-four participants had no exclusionary conditions at the time of this study. Clinically empirical classification identified 43 subjects as CFS, 57 as ISF, and 64 as not ill. There was minimal association between the empirical classification and classification by the surveillance criteria. Subjects empirically classified as CFS had significantly worse impairment (evaluated by the SF-36), more severe fatigue (documented by the multidimensional fatigue inventory), more frequent and severe accompanying symptoms than those with ISF, who in turn had significantly worse scores than the not ill; this was not true for classification by the surveillance algorithm. CONCLUSION: The empirical definition includes all aspects of CFS specified in the 1994 case definition and identifies persons with CFS in a precise manner that can be readily reproduced by both investigators and clinicians.

Richards J, Turk J, White S.

Child and Family Clinic, Unit 5 Des Roches Square, Witan Way, Witney, OX28 4BE, Oxfordshire, UK.

Children and adolescents with Chronic Fatigue Syndrome in non-specialist settings Beliefs, functional impairment and psychiatric disturbance.

Eur Child Adolesc Psychiatry. 2005 Sep;14(6):310-8.

BACKGROUND: Adolescents with Chronic Fatigue Syndrome (CFS) seen in specialist centres have substantial psychological and functional impairment. Beliefs about activity levels may be important in the development of CFS. METHOD: The aim was to investigate psychological and functional impairment, and beliefs in children and adolescents with CFS recruited from non-specialist services. A total of 30 such individuals participated, and 30 young people with Inflammatory Bowel Disease (IBD) formed the comparison group. RESULTS: Emotional symptoms and disorder were high in both groups. In all, 50% of those with CFS and 30% with IBD reached the threshold for emotional disorder according to the Strengths and Difficulties Questionnaire (SDQ) parent report, although this difference did not reach statistical significance. Participants with CFS scored statistically significantly higher on measures of functional impairment, including school non-attendance, compared to those with IBD. According to questionnaire responses, those with CFS were statistically significantly more likely to favour rest rather than exercise compared to those with IBD. Comparison of parental beliefs did not show such a difference. CONCLUSIONS: These young people with CFS were at high risk of psychiatric disorder. They were substantially disabled when compared to individuals with a known chronic illness. Also, as a group, they were characterised by a preference for rest rather than exercise.

Richards RS, McGregor NR, Roberts TK

Association Between Oxidative Damage Markers and Self-Reported Temporomandibular Dysfunction


Full blood counts, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), haematinics and markers for oxidative stress were measured on thirty-three patients diagnosed with chronic fatigue syndrome (CFS) and twenty-seven age and sex matched controls. The CFS patients had increased prevalence of symptoms of temporomandibular dysfunction (TMD). Jaw muscle pain was associated with increases in methaemoglobin (P < .002), ferritin (P < .02) and malondialdehyde (P < .007) whilst temporomandibular joint (tmj) clicking and/or locking was associated with increases in



Symptoms in Patients with Chronic Fatigue Syndrome

methaemoglobin (P < .001), malondialdehyde (P < .05) and vitamin B12 (P < .02) levels. Multiple regression analysis found methaemoglobin to be the principle component associated with TMD symptoms in the CFS patients. Increases in scalar severity responses to jaw muscle pain and TMJ clicking and/or locking were positively correlated with methaemoglobin by multiple regression. These data indicate that oxidative stress due to excess free radical formation was associated with jaw muscle pain in CFS patients and suggest that these symptoms were likely to be associated with a pathogen-associated aetiology.

Rimes KA, Chalder T.

Department of Psychological Medicine, Institute of Psychiatry, London, UK. [email protected]

Treatments for chronic fatigue syndrome.


AIMS: To review studies evaluating the treatment of chronic fatigue and chronic fatigue syndrome, to describe predictors of response to treatment and to discuss the role of the occupational health physician. METHODS: A literature search was carried out using Medline and PsychInfo. RESULTS: Studies evaluating cognitive behaviour therapy, graded exercise therapy, pharmacological interventions (e.g. antidepressants and corticosteroids), immunological interventions and nutritional supplements were reviewed. The most promising results have been found with cognitive behaviour therapy and graded exercise therapy, and some predictors of outcome have been identified. Most of the other interventions were evaluated in just one or two studies and therefore evidence is insufficient to draw firm conclusions. CONCLUSIONS: By applying the models of fatigue that form the bases for cognitive behaviour therapy and graded exercise therapy, occupational health physicians may play an important role in helping the patients with chronic fatigue syndrome to reduce their symptoms, improve their functioning and return to work.

Robertson MJ, Schacterle RS, Mackin GA, Wilson SN, Bloomingdale KL, Ritz J, Komaroff AL.

Division of Hematologic Malignancies, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA. [email protected]

Lymphocyte subset differences in patients with chronic fatigue syndrome, multiple sclerosis and major depression.

Clin Exp Immunol. 2005 Aug;141(2):326-32.

Chronic fatigue syndrome (CFS) is a heterogeneous disorder of unknown aetiology characterized by debilitating fatigue, along with other symptoms, for at least 6 months. Many studies demonstrate probable involvement of the central and autonomic nervous system, as well as a state of generalized immune activation and selective immune dysfunction in patients with CFS. The aim of this study was to compare the lymphocyte subsets of patients with chronic fatigue syndrome to those of patients with major depression and multiple sclerosis as well as those of healthy control subjects. No differences were found in total numbers of T cells, B cells or natural killer (NK) cells. However, differences were found in T, B and NK cell subsets. Patients with major depression had significantly fewer resting T (CD3(+)/CD25(-)) cells than the other groups. Patients with major depression also had significantly more CD20(+)/CD5(+) B cells, a subset associated with the production of autoantibodies. Compared to patients with multiple sclerosis, patients with CFS had greater numbers of CD16(+)/CD3(-) NK cells. Further study will be required to determine whether these alterations in lymphocyte subsets are directly involved in the pathophysiology of these disorders, or are secondary effects of the causal agent(s).

Rubin GJ, Hotopf M, Papadopoulos A, Cleare A.

Division of Psychological Medicine, Institute of Psychiatry and Guy's, King's and St. Thomas' School of Medicine, King's College London,

Salivary cortisol as a predictor of postoperative fatigue.

Psychosom Med. 2005 May-Jun;67(3):441-7.

OBJECTIVE: Some patients with chronic fatigue syndrome (CFS) exhibit low basal cortisol levels, but it is not known whether low cortisol is a cause of CFS, predates the onset of CFS symptoms, or is an epiphenomenon caused by the behavioral changes typical of CFS. Because elective surgery is one of the few predictable risk factors for chronic fatigue, in this study, we followed a cohort of surgery patients from before to 6 months after their operation to test these theories. METHOD: One hundred sixty-one patients completed fatigue questionnaires and provided salivary cortisol samples before undergoing an elective inpatient surgical procedure, and then 2 days, 3 weeks, and 6 months afterward. RESULTS: Controlling for relevant demographic and surgical variables and for preoperative fatigue, low preoperative cortisol did not predict postoperative fatigue severity on any


London, UK. [email protected]

occasion (p > .05). Similarly, there was no correlation between low postoperative cortisol and postoperative fatigue severity at 3 weeks or 6 months (p > .05). Although 16 patients met our case definition for "chronic fatigue" at the 6-month follow up, low preoperative and low postoperative cortisol did not significantly predict fatigue caseness (p > .05). CONCLUSIONS: Any association between chronic fatigue and low cortisol would seem to develop after the onset of fatigue symptoms. Low cortisol is therefore unlikely to be the primary cause of chronic fatigue states.

Sanchez Rodriguez A, Gonzalez Marono C, Sanchez Ledesma M.

Servicio de Medicina Interna 1, Hospital Universitario de Salamanca, Salamanca.

[Chronic fatigue syndrome: a syndrome in search of definition] [Article in Spanish]

Rev Clin Esp. 2005 Feb;205(2):70-4.

Segal TY, Hindmarsh PC, Viner RM.

University College London Hospitals, UK.

Disturbed adrenal function in adolescents with chronic fatigue syndrome.

J Pediatr Endocrinol Metab. 2005 Mar;18(3):295-301.

OBJECTIVE: To investigate adrenal function in children and adolescents with chronic fatigue syndrome (CFS) compared with age-matched controls. METHODS: Case-control study of low dose (500 ng/m2) synacthen tests (LDST) in 23 adolescents with CFS and 17 age-matched controls. Serum cortisol concentrations were measured at 5-min intervals from 10 to 45 minutes. Peak serum cortisol concentration, time to peak, rise in cortisol and area under the curve (AUC) were derived. RESULTS: Patients with CFS had significantly lower mean cortisol levels during the LDST (p <0.001), lower peak cortisol (p <0.025), reduced cortisol AUC (p <0.005) and longer time to peak cortisol (p <0.05). Abnormalities were seen in both sexes but were more pronounced in females. Unstimulated adrenal androgen and 17-hydroxyprogesterone concentrations were normal. CONCLUSIONS: Adolescents with CFS have subtle alterations in adrenal function suggesting a reduction in central stimulation of the adrenal glands. The more pronounced effects in females may reflect differential central effects of stress on hypothalamic-pituitary-adrenal axis regulation between the sexes.

Shephard RJ. Faculty of Physical Education and Health and , Department of Public Health Sciences, Faculty of Medicine , University of Toronto, Toronto, ON, Canada.

Chronic fatigue syndrome. A brief review of functional disturbances and potential therapy.

J Sports Med Phys Fitness. 2005 Sep;45(3):381-92.

The chronic fatigue syndrome (CFS) is debilitating for both athletes and the general population. A review of etiology and mechanisms underlying functional disturbances is undertaken to provide a valid basis for therapeutic options. The review focuses on CFS as characterized by standard diagnostic criteria, building on previous reviews through use of articles identified by Medline search. Overtraining, a negative energy balance, excessive physical or environmental stress, disorders of personality and affect, dysfunction of the hypophyseal-pituitary adrenal axis, hormonal imbalance, nutritional deficits, immune suppression or activation and chronic infection have all been proposed as factors precipitating CFS, but none of these precipitants are observed consistently. Impairments of peak aerobic power and muscle strength, together with many functional disturbances, seem related to patient- or physician-imposed inactivity. Once CFS is established, treatment should aim at breaking the vicious cycle of effort avoidance, deterioration in physical condition and increasing fatigue through a combination of psychotherapy, general encouragement and a progressive exercise regimen.

Shin YI, Lee MS. Department of Physical Medicine and Rehabilitation, Wonkwang University School

Qi therapy (external qigong) for chronic fatigue syndrome: case studies.

Am J Chin Med. 2005;33(1):139-41.

The aim of this study was to examine the effects of Qi therapy (QT) on the symptoms of chronic fatigue syndrome (CFS), including fatigue and complications. QT affected the experience of mental and emotional relaxation in the subjects of these case studies, who also gained strength to overcome their pain and fatigue. Although the results of these two case studies may not constitute conclusive evidence, they provide a foundation for the exploration of QT as a complementary therapy in the


of Medicine, Institute of Medical Science, Wonkwang University, Iksan 570-749, Republic of Korea.

reduction of negative symptoms of chronic fatigue syndrome.

Singal A, Kaur S, Tirkey N, Chopra K.

Pharmacology Division, University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh, India.

Green tea extract and catechin ameliorate chronic fatigue-induced oxidative stress in mice.

J Med Food. 2005 Spring;8(1):47-52.

Chronic fatigue syndrome (CFS) is an illness characterized by persistent and relapsing fatigue, often accompanied by numerous symptoms involving various body systems. The etiology of CFS remains unclear, but a number of studies have shown that oxidative stress may be involved in its pathogenesis. The present study was designed to investigate the protective effect of green tea extract (GTE) and catechin in the mouse model of CFS. Animals were subjected to a forced swimming test session of 6 minutes every day for 7 days; a significant increase in immobility time on successive days represented the CFS in mice. Biochemical analysis revealed that the chronic swim test significantly increased lipid peroxidation levels and decreased glutathione levels in mouse whole-brain homogenate. Treatment with GTE (25 or 50 mg/kg, i.p.) and catechin (50 or 100 mg/kg, i.p.) for 7 days reversed the increase in immobility time. Protection was correlated with the lowered levels of lipid peroxidation and restoration of reduced glutathione levels in the brains of fatigued mice. These findings strongly suggest the pivotal role of oxidative stress in the pathophysiology of CFS and that GTE and catechin could be used as potential agents in the management of CFS and warrant the inclusion of GTE and catechin in the treatment regimen of CFS patients.

Siniscalchi M, Iovino P, Tortora R, Forestiero S, Somma A, Capuano L, Franzese MD, Sabbatini F, Ciacci C.

Gastrointestinal Unit, Department of Clinical and Experimental Medicine, Federico II University of Naples, Italy.

Fatigue in adult coeliac disease.

Aliment Pharmacol Ther. 2005 Sep 1;22(5):489-94.

BACKGROUND: Fatigue is reported by many adults at the moment of diagnosis of coeliac disease and during follow-up. AIM: To evaluate the prevalence, characteristics and associations of fatigue in adult coeliac disease patients. METHODS: The investigated sample comprised adults from Campania, Italy. A total of 130 coeliac disease patients were consecutively recruited in both treated (59 on gluten-free diet) and untreated conditions (71 on normal diet). The control group was made up of 80 healthy controls. Coeliac disease patients and healthy controls underwent laboratory tests, a set of questionnaires for studying fatigue: visual analogue scale for fatigue, chronic fatigue syndrome questionnaire, fatigue severity scale and a modified version of the Zung self-rating depression scale. RESULTS: Coeliac disease patients showed a significantly lower body mass index than controls (P = 0.0001), lower serum iron (P = 0.04). The entire cohort of coeliac disease patients reported greater modified version of the Zung self-rating depression scale score (P = 0.001), greater visual analogue scale for fatigue score (P = 0.0001) and greater chronic fatigue syndrome questionnaire score (P = 0.0001) compared with healthy controls. Coeliac disease patients on a gluten-free diet had a significantly higher modified version of the Zung self-rating depression scale score than coeliacs on a normal diet (P = 0.001). The prevalence of pathological modified version of the Zung self-rating depression scale score was 17% in all coeliac disease patients and 0% in healthy controls. A significant correlation was found between modified version of the Zung self-rating depression scale score and fatigue scale scores in coeliacs on a normal diet. Presence/absence of gastrointestinal symptoms did not show any significant correlation with modified version of the Zung self-rating depression scale score and fatigue scale scores. In coeliacs on a gluten-free diet, modified version of the Zung self-rating depression scale and fatigue scales scores did not significantly differ from


coeliacs on a normal diet and were not related to dietetic compliance. CONCLUSION: In coeliacs, fatigue is a common finding, which ameliorates with the gluten-free diet and is strictly correlated to depression although coeliacs on a gluten-free diet showed more frequent and more severe depression symptoms than coeliacs on a normal diet.

Smith J, Fritz EL, Kerr JR, Cleare AJ, Wessely S, Mattey DL.

Tissue Typing Laboratory, Harefield Hospital, Middlesex UB9 6JH, UK.

Association of chronic fatigue syndrome with human leucocyte antigen class II alleles.

J Clin Pathol. 2005 Aug;58(8):860-3.

BACKGROUND: A genetic component to the development of chronic fatigue syndrome (CFS) has been proposed, and a possible association between human leucocyte antigen (HLA) class II antigens and chronic fatigue immune dysfunction has been shown in some, but not all, studies. AIMS: To investigate the role of HLA class II antigens in CFS. METHODS: Forty nine patients with CFS were genotyped for the HLA-DRB1, HLA-DQA1, and HLA-DQB1 alleles and the frequency of these alleles was compared with a control group comprising 102 normal individuals from the UK. All patients and controls were from the same region of England and, apart from two patients, were white. RESULTS: Analysis by 2 x 2 contingency tables revealed an increased frequency of HLA-DQA1*01 alleles in patients with CFS (51.0% v 35%; odds ratio (OR), 1.93; p = 0.008). HLA-DQB1*06 was also increased in the patients with CFS (30.2% v 20.0%; OR, 1.73, p = 0.052). Only the association between HLA-DQA1*01 and CFS was significant in logistic regression models containing HLA-DQA1*01 and HLA-DRQB1*06, and this was independent of HLA-DRB1 alleles. There was a decreased expression of HLA-DRB1*11 in CFS, although this association disappeared after correction for multiple comparisons. CONCLUSIONS: CFS may be associated with HLA-DQA1*01, although a role for other genes in linkage disequilibrium cannot be ruled out.

Snell CR, Vanness JM, Strayer DR, Stevens SR.

University of the Pacific, Department of Sport Sciences, Stockton, CA 95211-0197, USA. [email protected]

Exercise capacity and immune function in male and female patients with chronic fatigue syndrome (CFS).

In Vivo. 2005 Mar-Apr;19(2):387-90.

Hyperactivition of an unwanted cellular cascade by the immune-related protein RNase L has been linked to reduced exercise capacity in persons with chronic fatigue syndrome (CFS). This investigation compares exercise capacities of CFS patients with deregulation of the RNase L pathway and CFS patients with normal regulation, while controlling for potentially confounding gender effects. Thirty-five male and seventy-one female CFS patients performed graded exercise tests to voluntary exhaustion. Measures of peak VO2, peak heart rate, body mass index, perceived exertion, and respiratory quotient were entered into a two-way factorial analysis with gender and immune status as independent variables. A significant multivariate main effect was found for immune status (p < 0.01), with no gender effect or interaction. Follow-up analyses identified VO2(peak) as contributing most to the difference. These results implicate abnormal immune activity in the pathology of exercise intolerance in CFS and are consistent with a channelopathy involving oxidative stress and nitric oxide-related toxicity.

Soderlund A, Malterud K.

Section for General Practice, Department of Public Health and Primary Health Care, University of Bergen, Norway. [email protected]

Why did I get chronic fatigue syndrome? A qualitative interview study of causal attributions in women patients.

Scand J Prim Health Care. 2005 Dec;23(4):242-7.

OBJECTIVES: To explore causal attributions among women with chronic fatigue syndrome (CFS). DESIGN: Qualitative study where data from individual semi-structured interviews were analysed according to Malterud's systematic text condensation. SETTING: Bergen, Norway. SUBJECTS: A purposeful sample of eight women aged 25-55, recruited among members of a self-help organization. MAIN OUTCOME MEASURES: Accounts of causal attribution for CFS among the informants, focusing on gender. RESULTS: The participants agreed that their way of living could have increased the vulnerability of their resistance resources. Pressure they put upon themselves, workload burdens without subsequent relaxation, emotional conflicts, or preparing for assumed problem-solving were mentioned as gendered dimensions. They presented different explanations regarding potential triggers encountering their fragile immune systems, most often a virus infection. The participants thought women might have a weaker immune system than men, or that CFS was caused by a virus that



women are more likely to catch. In their experience, their symptoms were activated when people put pressure on them, such that they might be nervous as to whether they could live up to the demands of their surroundings, and in the case of emotional strain related to family and work. CONCLUSION: More studies are needed exploring hypotheses concerning the complex interplay between molecular predispositions and more or less gendered lifestyle issues in CFS. Doctors need to challenge their strong beliefs regarding medically unexplained conditions, where facts still remain unresolved. Recognizing this, the doctor may provide realistic support and advice, and contribute to the establishment of common ground for understanding and managing the condition.

Staevska M, Baraniuk JN.

Division of Rheumatology, Immunology and Allergy, Room B105, Georgetown University, Lower Level Kober-Cogan Building, 3800 Reservoir Road, NW, Washington, DC 20007-2197, USA.

Persistent nonallergic rhinosinusitis.

Curr Allergy Asthma Rep. 2005 May;5(3):233-42.

Nonallergic rhinitis is a complex of syndromes that are united by the absence of atopic, T(H)2 lymphocyte, immunoglobulin E (IgE)-mediated mechanisms. We propose a classification system based on the presence or absence of inflammatory granulocytes. Eosinophilic nonallergic rhinosinusitis may also be called chronic eosinophilic sinusitis syndromes (CESS) to help classify these disorders in which diverse mechanisms of eosinophil chemoattraction and survival predominate. Allergic fungal sinusitis, eosinophilic nasal polyps, aspirin sensitivity, and related disorders would fit in this category. Accumulation of neutrophils occurs in chronic infectious rhinosinusitis, foreign body reactions, and immunodeficiencies. More complex and variable combinations of leukocytes are found in Wegner's granulomatosis and related syndromes, and during the evolution of viral infections. The noninflammatory disorders can be divided by mechanism into hormonal; sympathetic dysfunction (including antihypertensive adrenergic drug therapy); cholinergic rhinitis; and nociceptive syndromes with hyperalgesia and other features (eg, the nonallergic rhinitis of chronic fatigue syndrome). Therapy based on the most likely pathophysiologic mechanism is anticipated to have the most success, but requires acceptance of the wide differential diagnosis of nonallergic rhinitis and rejection of the obsolete term of "vasomotor rhinitis."

Staines D. Gold Coast Public Health Unit, 10-12 Young Street, Southport 4215, Queensland, Australia. [email protected]

Do vasoactive neuropeptide autoimmune disorders explain pyridostigmine's association with Gulf War syndrome?

Med Hypotheses. 2005;65(3):591-4.

Gulf War syndrome (GWS) is a perplexing multi-symptom condition comprising a constellation of signs and symptoms consistently described in the literature. These include muscle fatigue and tiredness, malaise, myalgia, impaired cognition, ataxia, diarrhoea, bladder dysfunction, sweating disturbances, headaches, fever, arthralgia, skin rashes, and gastrointestinal and sleep disturbances. Excessive chemical sensitivity and odour intolerance is reported. Epidemiological analysis suggests association with pyridostigmine bromide (PB) use as nerve gas prophylaxis, insect repellent, certain vaccination regimes, a variety of possible chemical exposures and physical and psychological stress. Pituitary adenylate cyclase-activating polypeptide (PACAP), calcitonin gene-related peptide (CGRP) and vasoactive intestinal peptide (VIP) are potent vasoactive (vasodilatory) neuropeptides (VNs) having pleiotropic functions as immunomodulators, neuroregulators and hormones. VNs also have neurotrophic and anti-apoptotic roles. VNs act on G protein-coupled receptors (GPCRs) to activate adenylate cyclase, an important step in cyclic AMP metabolism. Autoimmune dysfunction of these VNs or their receptors is postulated to give rise to fatigue-related conditions such as chronic fatigue syndrome (CFS). Complex mechanisms involving heat shock proteins (hsps) and cytosine-guanine dinucleotide (CpG) DNA fragments may also be associated with autoimmunity to VNs or their GPCRs in contributing to fatigue-related conditions. Dysfunction of certain VNs may be the missing link in explaining the nebulous nexus between PB and GWS. This paper explores a possible link between exposures to PB and other chemical, physical and psychological stressors in producing a fatigue-related illness possibly related to autoimmune dysfunction of certain VNs. Treatment options


involving restoration of VN function are considered in the context of analogues with other neurotransmitter fatigue-related conditions such as myasthenia gravis (MG). While evidence associating these conditions is thin, vasoactive neuropeptide neurotransmitters of the VIP/PACAP family have acetylcholine co-transmission functions via specific GPCRs. Autoimmune reactions to these receptors may have parallels with muscarinic (e.g., Sjogren's syndrome) and nicotinic (e.g., MG) acetylcholine neurotransmission. Hence theoretically, treatment options such as thymectomy, corticosteroids, plasma exchange, anti-idiotype antibodies and receptor genomic expression reactivation/suppression may be considered. Paradoxically pyridostigmine may prove to have a role in therapy although VN treatment/replacement may be associated with tachyphylaxis.

Staines D. Gold Coast Public Health Unit, 10-12 Young Street, Southport 4215, Qld., Australia. [email protected]

Are vasoactive neuropeptide autoimmune fatigue-related disorders mediated via G protein-coupled receptors?

Med Hypotheses. 2005;65(1):29-31.

Vasoactive neuropeptides such as pituitary adenylate cyclase activating polypeptide (PACAP), calcitonin gene related peptide (CGRP) and vasoactive intestinal peptide (VIP) have been implicated in a number of fatigue-related conditions. Associations of these vasoactive neuropeptides with heat shock proteins (hsps) and cytosine-guanosine dinucleotide (CpG) DNA fragments in autoimmune phenomena have been postulated to interfere with receptor signal activation for adenylate cyclase and other vital cellular processes. However, a specific mechanism for receptor dysfunction has not been explored to date. G protein-coupled receptors (GPCRs) constitute a high proportion of biological receptor mechanisms and serve a wide range of substances including nucleosides, nucleotides, catecholamines, calcium, histamine, serotonin and prostaglandins. They are complex transmembrane hepta-helical serpentine structures with specific binding capabilities resulting in conformational changes that activate cognate cyclic GMP (G proteins). GPCRs adapt to certain stimuli through desensitisation and changes in phosphorylation and are subject to distortions of signalling processes. Hence, these vital signalling structures are susceptible to impairment of function through a range of mechanisms. One of their vital functions is signalling through adenylate cyclase, a vital step in cyclic AMP metabolism. This step involves ATP metabolism and therefore is a crucial mediator of cellular energy pathways. Some GPCRs act to inhibit adenylate cyclase (Gi proteins). Also vasoactive neuropeptides, such as PACAP display a number of receptor isotypes including null variants. Overexpression of Gi proteins and null variant receptors may account for major disruptions of signal transduction and ATP/cAMP metabolism. This paper examines the possible role of GPCR dysfunction in contributing to fatigue-related vasoactive neuropeptide autoimmune disorders which may include chronic fatigue syndrome (CFS), Gulf War syndrome (GWS) and even sudden infant death syndrome (SIDS).

Staines DR. Gold Coast Public Health Unit, 10-12 Young Street, Southport 4215, Queensland, Australia. [email protected]

Therapeutic and preventive interventions for postulated vasoactive neuropeptide autoimmune fatigue-related disorders.

Med Hypotheses. 2005;65(4):797-803.

Major advances have been made in understanding the relatively novel group of vasoactive (vasodilatory) neuropeptides (VNs) in humans. VNs comprise a novel but expanding group of substances having immunoregulation, inflammation modulation, neurotransmitter, neurotrophic, hormonal and metabolic functions. These substances may control gene expression for mRNA for themselves and their receptors. They have complex relationships with gaseous and other neurotransmitters and xenobiotic substances. Theoretical arguments have implicated these substances in autoimmune phenomena resulting in fatigue-related conditions such as chronic fatigue syndrome (CFS), sudden infant death syndrome (SIDS), fibromyalgia (FM) and Gulf War syndrome (GWS) but remain unproven. As well as possibly spontaneous onset, the precipitating causes of VN autoimmune dysfunction are likely to be a combination of genetic predisposition, infection and xenobiotic substances. Therapeutic and preventive possibilities for postulated VN autoimmune conditions will


be influenced by the complex patholophysiology underpinning them. Some speculative possibilities are VN substitution/replacement, preservation of biological effect, epigenetic DNA modifications, plasma exchange, anti-cholinesterases, e.g., pyridostigmine, corticosteroids and other drug treatments, thymectomy, intravenous immunoglobulin and anti-idiotype antibodies, and CpG/DNA vaccines. Prevention and treatment of possible VN autoimmune fatigue-related disorders may prove to be important areas for future research and development.

Staines DR. Gold Coast Public Health Unit, 10-12 Young Street, Southport 4215, Queensland, Australia.

Does dysregulation of key epigenetic and biochemical pathways occur in postulated vasoactive neuropeptide autoimmune disorders?

Med Hypotheses. 2005;65(6):1154-60. Epub 2005 Jul 18.

Autoimmune dysfunction of certain vasoactive neuropeptides (VNs) has been postulated as a contributing cause of sudden infant death syndrome (SIDS), chronic fatigue syndrome (CFS), Gulf War syndrome (GWS) and other fatigue-related disorders. This family of VNs includes pituitary adenylate cyclase activating polypeptide (PACAP), vasoactive intestinal peptide (VIP) and calcitonin gene related peptide (CGRP). The postulated mechanism is compromise of adenylate cyclase activation, a vital and unique step in cyclic AMP production from ATP, through autoimmune dysfunction of VNs, their receptors or their genes possibly involving cytosine-phosphate-guanine (CpG) fragments. CpG fragments are immunomodulatory dinucleotides serving as 'friend or foe' recognition systems to differentiate bacterial and viral (hypomethylated CpG) from mammalian (methylated CpG) DNA. However hypomethylation disorders affecting these fragments in mammals may convert them to dysfunctional states by promoting autoimmune inflammatory reactions. Epigenetic mechanisms acting on gene promoter regions may contribute to the development of VN autoimmune fatigue-related disorders through CpG fragments located in vital segments of VN/receptor genes by causing signalling defects with profound implications for VN function. Neurotransmitter dysfunction particularly glutamatergic transmission could also result with disruption of neuronal cellular biochemical functions such as ammonia regulation. Endosomal acidity and mitochondrial membrane potential modifiers such as chloroquine, together with immunoregulatory therapies, may have therapeutic implications in protecting against these apparent autoimmune disorders. This paper examines specific epigenetic and biochemical mechanisms possibly mediated by VN or receptor genes resulting in postulated VN autoimmune fatigue-related disorders. These mechanisms may have implications for treatment and prevention options for VN autoimmune disorders. VN autoimmune processes have implications for military medicine where radiological, chemical and biological agents may play an important role in pathogenesis.

Staines DR. Gold Coast Public Health Unit, 10-12 Young Street, Southport 4215, Qld., Australia. [email protected]

Do cytosine guanine dinucleotide (CpG) fragments induce vasoactive neuropeptide mediated fatigue-related autoimmune disorders?

Med Hypotheses. 2005;65(2):370-3.

Autoimmune dysfunction of certain vasoactive neuropeptides (e.g., vasoactive intestinal peptide, pituitary adenylate cyclase activating polypeptide) may be implicated in a range of disorders associated with fatigue-like states (chronic fatigue syndrome, Gulf War syndrome) and even sudden infant death syndrome (SIDS). The important roles of these vasoactive neuropeptides make them a vulnerable target for autoimmune dysfunction. They are known to be associated with heat shock proteins for intracellular functioning with which they may form immunostimulating complexes. Cytosine guanine dinucleotide (CpG) fragments are potently immunogenic DNA fragments which serve as friend or foe recognition systems between bacterial (hypomethylated) and mammalian (methylated) DNA and are being assessed for suitability for use in human vaccines as adjuvants. Interactions between CpG fragments, heat shock proteins and vasoactive neuropeptides may be associated with fatigue-related autoimmune conditions.

Staines DR. Gold Coast Public Health Unit, 10-12

Do vasoactive neuropeptides and

Med Hypotheses. 2005;64(3):539-

Autoimmune dysfunction of certain vasoactive neuropeptides may be implicated in a range of disorders associated with fatigue like states (chronic fatigue syndrome, Gulf War syndrome) and even


Young Street, Southport 4215, Qld, Australia. [email protected]

heat shock proteins mediate fatigue-related autoimmune disorders?

42. sudden infant death syndrome. These substances have neurotrophic, neuroregulatory, and neurotransmission functions, as well as that of immune modulators and hormones. They exert significant control over carbohydrate and lipid metabolism. The hypothesis is that because these substances have vital and indispensable roles in cellular processes, loss or compromise of these roles would lead to predictable and severe cellular and systemic effects. The important roles of certain VNs make them a vulnerable target for autoimmune dysfunction. They are known to be associated with heat shock proteins for intracellular functioning with which they may form immunostimulating complexes. While peptide-HSP complexes are a relatively new area for research, this paper asserts that attention could be focused on these substances and complexes in an effort to elucidate a number of perplexing fatigue-associated disorders.

Stang A, Korn K, Wildner O, Uberla K.

Department of Molecular and Medical Virology, Ruhr University Bochum, D-44780 Bochum, Germany.

Characterization of virus isolates by particle-associated nucleic acid PCR.

J Clin Microbiol. 2005 Feb;43(2):716-20.

Diagnostic virus isolation is still frequently used, particularly from respiratory tract secretions. Testing positive virus cultures for all possible viruses is time-consuming, and unexpected or unknown viruses may escape detection. Therefore, a novel random PCR approach was developed that allows sequence-independent amplification of viral nucleic acids from virus isolation-positive cultures. Selectivity for viral sequences is obtained by preferential isolation of nucleic acids that are particle associated and resistant to nucleases. Using primers with a degenerated 3' end, the isolated nucleic acids are amplified and the randomly amplified PCR products are cloned and sequenced. As proof of the concept, the PAN-PCR approach was applied to supernatants of coxsackievirus B3 and murine adenovirus type 1-infected cells. Enterovirus and adenovirus sequences were obtained, demonstrating that the random PCR approach allows detection of RNA and DNA viruses. As a first application of this PAN-PCR approach, we characterized a virus isolate from mouth-washing material of a patient with chronic fatigue syndrome and high antibody titers to coxsackievirus B2. The virus isolate had tested negative for enteroviruses and respiratory viruses (influenza viruses A and B, parainfluenza virus types 1 to 3, respiratory syncytial virus, and adenovirus) by immunofluorescence and PCR. Particle-associated, nuclease-resistant RNA and DNA were prepared from the supernatant of infected cells. The DNA and the reverse-transcribed RNA were randomly amplified, and PCR products were cloned and sequenced. Of 25 sequences obtained from the DNA preparation, 24 contained herpes simplex virus type 1 (HSV-1) sequences from 14 different loci spread over the HSV-1 genome. This result was confirmed by using a standard diagnostic HSV-PCR, demonstrating that the PAN-PCR correctly identified the virus isolate. Although the identification of HSV-1 in mouth-washing material is not surprising in retrospect, it clearly demonstrates the applicability of the PAN-PCR approach. This method should be particularly useful for characterizing virus isolates that have tested negative for all expected viruses and for identifying unknown viruses.

Stouten B. Identification of ambiguities in the 1994 chronic fatigue syndrome research case definition and recommendations for resolution.

BMC Health Serv Res. 2005 May 13;5(1):37.

BACKGROUND: A recent article by Reeves et al. on the identification and resolution of ambiguities in the 1994 chronic fatigue syndrome (CFS) research case definition recommended the Checklist Individual Strength, the Chalder Fatigue Scale, and the Krupp Fatigue Severity Scale for evaluating fatigue in CFS studies. To be able to discriminate between various levels of severe fatigue, extreme scoring on the individual items of these questionnaires must not occur too often. METHODS: We derived an expression that allows us to compute a lower bound for the number of items with the maximum item score for a given study from the reported mean scale score, the number of reported subjects, and the properties of the fatigue rating scale. Several CFS studies that used the recommended fatigue rating scales were selected from literature and analyzed to verify whether


abundant extreme scoring had occurred. RESULTS: Extreme scoring occurred on a large number of the items for all three recommended fatigue rating scales across several studies. The percentage of items with the maximum score exceeded 40% in several cases. The amount of extreme scoring for a certain scale varied from one study to another, which suggests heterogeneity in the selected subjects across studies. CONCLUSION: Because all three instruments easily reach the extreme ends of their scales on a large number of the individual items, they do not accurately represent the severe fatigue that is characteristic for CFS. This should lead to serious questions about the validity and suitability of the Checklist Individual Strength, the Chalder Fatigue Scale, and the Krupp Fatigue Severity Scale for evaluating fatigue in CFS research.

Stulemeijer M, de Jong LW, Fiselier TJ, Hoogveld SW, Bleijenberg G.

Expert Centre Chronic Fatigue, University Medical Centre Nijmegen, PO Box 9101, 6500 HB, Netherlands.

Cognitive behaviour therapy for adolescents with chronic fatigue syndrome: randomised controlled trial.

BMJ. 2005 Jan 1;330(7481):14. Epub 2004 Dec 7.

OBJECTIVE: To evaluate the efficacy of cognitive behaviour therapy for adolescents aged 10-17 years with chronic fatigue syndrome. DESIGN: Randomised controlled trial. SETTING: Department of child psychology. PARTICIPANTS: 71 consecutively referred patients with chronic fatigue syndrome; 36 were randomly assigned to immediate cognitive behaviour therapy and 35 to the waiting list for therapy. INTERVENTION: 10 sessions of therapy over five months. Treatment protocols depended on the type of activity pattern (relatively active or passive). All participants were assessed again after five months. MAIN OUTCOME MEASURES: Fatigue severity (checklist individual strength), functional impairment (SF-36 physical functioning), and school attendance. RESULTS: 62 patients had complete data at five months (29 in the immediate therapy group and 33 on the waiting list). Patients in the therapy group reported significantly greater decrease in fatigue severity (difference in decrease on checklist individual strength was 14.5, 95% confidence interval 7.4 to 21.6) and functional impairment (difference in increase on SF-36 physical functioning was 17.3, 6.2 to 28.4) and their attendance at school increased significantly (difference in increase in percentage school attendance was 18.2, 0.8 to 35.5). They also reported a significant reduction in several accompanying symptoms. Self reported improvement was largest in the therapy group. CONCLUSION: Cognitive behaviour therapy is an effective treatment for chronic fatigue syndrome in adolescents.

Sullivan PF, Pedersen NL, Jacks A, Evengard B.

Department of Genetics, University of North Carolina at Chapel Hill, NC 27599-7264, USA. [email protected]

Chronic fatigue in a population sample: definitions and heterogeneity.

Psychol Med. 2005 Sep;35(9):1337-48.

BACKGROUND: Numerous nosological decisions are made when moving from the common human symptom of unusual fatigue to the rare chronic fatigue syndrome (CFS). These decisions have infrequently been subjected to rigorous evaluation. METHOD: We obtained telephone interview data on fatiguing symptoms from 31406 individuals twins in the Swedish Twin Registry aged 42-64 years; 5330 subjects who endorsed fatigue and possessed no exclusionary condition formed the analytic group. We evaluated the definition and classification of CFS-like illness using graphical methods, regression models, and latent class analysis. RESULTS: Our results raise fundamental questions about the 1994 Centers for Disease Control criteria as (1) there was no empirical support for the requirement of four of eight cardinal CFS symptoms; (2) these eight symptoms were not equivalent in their capacity to predict fatigue; and (3) no combination of symptoms was markedly more heritable. Critically, latent class analysis identified a syndrome strongly resembling CFS-like illness. CONCLUSIONS: Our data are consistent with the 'existence' of CFS-like illness although the dominant nosological approach captures population-level variation poorly. We suggest that studying a more parsimonious case definition - impairing chronic fatigue not due to a known cause - would represent a way forward.

Swain NF, The Children's Tender point Arthritis Rheum.


Kashikar-Zuck S, Brent Graham T, Prahalad S.

Hospital, Denver, CO 80218, USA. [email protected]

assessment in juvenile primary fibromyalgia syndrome.

2005 Oct 15;53(5):785-7.

Theoharides TC, Papaliodis D, Tagen M, Konstantinidou A, Kempuraj D, Clemons A.

Chronic fatigue syndrome, mast cells, and tricyclic antidepressants.

J Clin Psychopharmacol. 2005 Dec;25(6):515-20.

Editorial

Thomas MA, Smith AP.

Centre for Occupational and Health Psychology, School of Psychology, Cardiff University, 63 Park Place, Cardiff, UK. [email protected]

Primary healthcare provision and Chronic Fatigue Syndrome: a survey of patients' and General Practitioners' beliefs.

BMC Fam Pract. 2005 Dec 13;6:49.

BACKGROUND: The current study was conducted as part of a research project into the evaluation and assessment of healthcare provision and education in Chronic Fatigue Syndrome (CFS). One aim of the study was the development of informative and educational literature for both General Practitioners (GP) and sufferers. Issues such as diagnosis, management and treatment of the syndrome should be included in information booklets written by healthcare professionals. It was important to begin the process by assessing the level of specialist knowledge that existed in typical GP surgeries. This data would then be compared to data from CFS patients. METHOD: 197 survey booklets were sent to CFS sufferers from an existing research panel. The patients approached for the purpose of the study had been recruited onto the panel following diagnosis of their illness at a specialised CFS outpatient clinic in South Wales. A further 120 booklets were sent to GP surgeries in the Gwent Health Authority region in Wales. RESULTS: Results from the study indicate that the level of specialist knowledge of CFS in primary care remains low. Only half the GP respondents believed that the condition actually exists. CONCLUSION: Steps are recommended to increase the knowledge base by compiling helpful and informative material for GPs and patient groups.

Tiev KP, Briant M, Ziani M, Cabane J, Demettre E, Lebleu B.

Variability of the RNase L isoform ratio (37 kiloDaltons/83 kiloDaltons) in diagnosis of chronic fatigue syndrome.

Clin Diagn Lab Immunol. 2005 Feb;12(2):366.

Letter

Tomoda A, Joudoi T, Rabab el-M, Matsumoto T, Park TH, Miike T.

Department of Child Development, School of Medicine, Kumamoto University, Kumamoto, Japan. [email protected]

Cytokine production and modulation: comparison of patients with chronic fatigue syndrome and normal controls.

Psychiatry Res. 2005 Mar 30;134(1):101-4.

We studied cytokine production in 15 patients with chronic fatigue syndrome (CFS) and 23 controls. CFS patients' peripheral blood mononuclear cells were cultured with lipopolysaccharide or phytohemagglutinin. Enzymatic immunoassay indicated cytokine concentration in culture supernatants. CFS patients showed significantly lower mRNA levels and transforming growth factor-beta1 (TGF-beta1) production. Cytokine dysregulation affects CFS pathogenesis. TGF-beta1 may aid treatment because it affects CFS inflammatory characteristics.






Torres-Harding SR, Jason LA, Dicle Turkoglu O

Family Medical History of Persons with Chronic Fatigue Syndrome


Background: Little research has examined the family history of persons with CFS, although a few studies have found people with CFS may be more likely to have family members with fatigue or CFS-like conditions, cancers, autoimmune illness, and early parental death. Research into the family history of fatigue, chronic fatigue syndrome, and other medical or psychiatric illness may help inform the etiology of this illness. Objectives: The present investigation examined the occurrence of medical and psychiatric illness in the family history of persons with CFS, and then compared these results with the family history of medical illness reported by a control group of persons without fatigue. Methods: Family medical history data was obtained from questionnaire responses, a medical assessment, and medical records, and were then classified into specific illness categories, using the International Classification of Diseases, Tenth Revision (ICD-10). Family history data was compared among three groups using logistic regression analyses. Results: Results indicated that persons with chronic fatigue syndrome were significantly more likely to report a family history of endocrine/ metabolic disorders when compared to the control group. Conclusions: Findings suggest an underlying familial predisposition toward the development of both CFS and endocrine/metabolic disorders. This finding is consistent with the hypothesis that CFS represents a deregulation of the endocrine system.

Vallings R Hypnosis in the Management of Chronic Fatigue Syndrome


During the past 30 years hypnosis has become recognised as a useful adjunct to traditional medical therapies, and has become part of mainstream medicine. Hypnosis societies provide training for health professionals to obtain registrable qualifications. The modality has been incorporated in the management of many medical conditions and diseases, with opportunities for symptom control, building confidence and enhancing the benefits of regular therapies. There are many opportunities for using hypnosis as an adjunctive therapy in the management of Chronic Fatigue Syndrome, despite some early difficulties. Problems likely to be encountered are discussed and the structure of the hypnosis session is outlined. Suggestions are given for practitioners to construct useful scripts, which can be used to teach self-hypnosis.

Vallings R CONFERENCE REPORTS Report on the AACFS 7th International Conference


van de Putte EM, Engelbert RH, Kuis W, Sinnema G, Kimpen JL, Uiterwaal CS.

Department of Paediatrics, Wilhelmina Children's Hospital, University Medical Center, Utrecht, Netherlands. [email protected]

Chronic fatigue syndrome and health control in adolescents and parents.

Arch Dis Child. 2005 Oct;90(10):1020-4. Epub 2005 Jul 27.

AIMS: To explore the locus of health control in adolescents with chronic fatigue syndrome (CFS) and their parents in comparison with healthy adolescents and their parents. METHODS: In this cross-sectional study 32 adolescents with CFS were compared with 167 healthy controls and their respective parents. The Multidimensional Health Locus of Control (MHLC) questionnaire was applied to all participants. RESULTS: There was significantly less internal health control in adolescents with CFS than in healthy controls. An increase of internal health control of one standard deviation was associated with a 61% reduced risk for CFS (OR = 0.39, 95% CI 0.25 to 0.61). Internal health control of the parents was also protective (OR fathers: 0.57 (95% CI 0.38 to 0.87); OR mothers: 0.74 (95% CI 0.50 to 1.09)). The external loci of health control were higher in adolescents with CFS and in their parents. Increased levels of fatigue (56%) were found in the mothers of the adolescents with CFS, in contrast with the fathers who reported a normal percentage of 13. CONCLUSIONS: In comparison with healthy adolescents, adolescents with CFS and their parents


show less internal health control. They attribute their health more to external factors, such as chance and physicians. This outcome is of relevance for treatment strategies such as cognitive behaviour therapy, for which health behaviour is the main focus.

van de Putte EM, Engelbert RH, Kuis W, Sinnema G, Kimpen JL, Uiterwaal CS.

Department of Paediatrics, Wilhelmina Children's Hospital, University Medical Center, Utrecht, Netherlands. [email protected]

Chronic fatigue syndrome and health control in adolescents and parents.

Arch Dis Child. 2005 Oct;90(10):1020-4. Epub 2005 Jul 27.

AIMS: To explore the locus of health control in adolescents with chronic fatigue syndrome (CFS) and their parents in comparison with healthy adolescents and their parents. METHODS: In this cross-sectional study 32 adolescents with CFS were compared with 167 healthy controls and their respective parents. The Multidimensional Health Locus of Control (MHLC) questionnaire was applied to all participants. RESULTS: There was significantly less internal health control in adolescents with CFS than in healthy controls. An increase of internal health control of one standard deviation was associated with a 61% reduced risk for CFS (OR = 0.39, 95% CI 0.25 to 0.61). Internal health control of the parents was also protective (OR fathers: 0.57 (95% CI 0.38 to 0.87); OR mothers: 0.74 (95% CI 0.50 to 1.09)). The external loci of health control were higher in adolescents with CFS and in their parents. Increased levels of fatigue (56%) were found in the mothers of the adolescents with CFS, in contrast with the fathers who reported a normal percentage of 13. CONCLUSIONS: In comparison with healthy adolescents, adolescents with CFS and their parents show less internal health control. They attribute their health more to external factors, such as chance and physicians. This outcome is of relevance for treatment strategies such as cognitive behaviour therapy, for which health behaviour is the main focus.

van de Putte EM, Uiterwaal CS, Bots ML, Kuis W, Kimpen JL, Engelbert RH.

Department of Pediatric, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, Netherlands. [email protected]

Is chronic fatigue syndrome a connective tissue disorder? A cross-sectional study in adolescents.

Pediatrics. 2005 Apr;115(4):e415-22.

OBJECTIVES: To investigate whether constitutional laxity of the connective tissues is more frequently present in adolescents with chronic fatigue syndrome (CFS) than in healthy controls. Increased joint hypermobility in patients with CFS has been previously described, as has lower blood pressure in fatigued individuals, which raises the question of whether constitutional laxity is a possible biological predisposing factor for CFS. DESIGN: Cross-sectional study. PARTICIPANTS: Thirty-two adolescents with CFS (according to the criteria of the Centers for Disease Control and Prevention) referred to a tertiary hospital and 167 healthy controls. METHODS: The 32 adolescents with CFS were examined extensively regarding collagen-related parameters: joint mobility, blood pressure, arterial stiffness and arterial wall thickness, skin extensibility, and degradation products of collagen metabolism. Possible confounding factors (age, gender, height, weight, physical activity, muscle strength, diet, alcohol consumption, and cigarette smoking) were also measured. The results were compared with findings in 167 healthy adolescents who underwent the same examinations. RESULTS: Joint mobility, Beighton score, and collagen biochemistry, all indicators of connective tissue abnormality, were equal for both groups. Systolic blood pressure, however, was remarkably lower in patients with CFS (117.3 vs. 129.7 mm Hg; adjusted difference: -13.5 mm Hg; 95% confidence interval [CI]: -19.1, -7.0). Skin extensibility was higher in adolescents with CFS (mean z score: 0.5 vs. 0.1 SD; adjusted difference: 0.3 SD; 95% CI: 0.1, 0.5). Arterial stiffness, expressed as common carotid distension, was lower in adolescents with CFS, indicating stiffer arteries (670 vs 820 mum; adjusted difference: -110 mum; 95% CI: -220, -10). All analyses were adjusted for age, gender, body mass index, and physical activity. Additionally, arterial stiffness was adjusted for lumen diameter and pulse pressure. CONCLUSIONS: These findings do not consistently point in the same direction of an abnormality in connective tissue. Patients with CFS did have lower blood pressure and more extensible skin but lacked the most important parameter indicating constitutional laxity, ie,




joint hypermobility. Moreover, the collagen metabolism measured by crosslinks and hydroxyproline in urine, mainly reflecting bone resorption, was not different. The unexpected finding of stiffer arteries in patients with CFS warrants additional investigation.

Van Hoof E, Coomans D, Cluydts R, De Meirleir K

Association Between Fennel Phase Inventory Scores and Immune and RNase-L Parameters in Chronic Fatigue Syndrome


All patients suffering from a chronic condition, are challenged to manage the reality of their disease, the accompanying anxiety, the problems of daily living, and the effect on relationships. Therefore, when confronted with debilitating complaints, patients suffering from chronic fatigue syndrome (CFS) need to adapt to a new way of living during the course of their illness. Fennell developed an integrated model to manage CFS. This article is a follow-up of a study by Jason et al. (9, 10) to verify the existence of the different phases. Although not all differences are statistically significant, a clear distinction is made according to the conclusions drawn by Jason et al. (9, 10). Relationships between these distinctions and measures of symptoms, disability, psychological distress, coping, and immune parameters were revealed using non-parametric statistical tests.

Van Hoof E, De Meirleir K

The Influence of Chronic Fatigue Syndrome on the Personality Profile: A Case Report


Objective: Chronic fatigue syndrome (CFS) functionally impairs many patients. Despite numerous studies and reviews in CFS, little is known about the behavioral consequences. Several researchers have already suggested the influential role of personality as a possible predisposing or perpetuating factor. Method: Acase study is presented of a 34-year-old man with a history of CFS. Psychological profiling using the MMPI-2 was performed during the course of his condition. Results: His passive-aggressive manner during the medical encounter was underscored by his personality profile (code type 3-2). After his recovery, however, a spike 3 profile emerged indicating a fulfilled individual. Somatic items included in the inventory, created a secondary increase of the clinical scales. Physical complaints diminished as his condition improved and subsequently, decreased the clinical scales. Conclusion: The relevance of classifying personality characteristics in CFS patients as traits could not be supported by this case report.

Vernon SD, Reeves WC.

Division of Viral and Rickettsial Diseases, National Center for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia 30333, USA. [email protected]

Evaluation of autoantibodies to common and neuronal cell antigens in Chronic Fatigue Syndrome.

J Autoimmune Dis. 2005 May 25;2:5.

People with chronic fatigue syndrome (CFS) suffer from multiple symptoms including fatigue, impaired memory and concentration, unrefreshing sleep and musculoskeletal pain. The exact causes of CFS are not known, but the symptom complex resembles that of several diseases that affect the immune system and autoantibodies may provide clues to the various etiologies of CFS. We used ELISA, immunoblot and commercially available assays to test serum from subjects enrolled in a physician-based surveillance study conducted in Atlanta, Georgia and a population-based study in Wichita, Kansas for a number of common autoantibodies and antibodies to neuron specific antigens. Subsets of those with CFS had higher rates of antibodies to microtubule-associated protein 2 (MAP2) (p = 0.03) and ssDNA (p = 0.04). There was no evidence of higher rates for several common nuclear and cellular antigens in people with CFS. Autoantibodies to specific host cell antigens may be a useful approach for identifying subsets of people with CFS, identify biomarkers, and provide clues to CFS etiologies.

Viner R, Christie D.

Middlesex Adolescent Unit, University College London Hospitals NHS Foundation Trust, London. [email protected].

Fatigue and somatic symptoms.

BMJ. 2005 Apr 30;330(7498):1012-5.



ukVinjamury SP, Singh BB.

Southern California University of Health Sciences, Whittier, USA.

Ayurvedic treatment of chronic fatigue syndrome--a case report.

Altern Ther Health Med. 2005 Sep-Oct;11(5):76-8.

Wagner D, Nisenbaum R, Heim C, Jones JF, Unger ER, Reeves WC.

Division of Viral and Rickettsial Diseases, National Center for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, GA, USA. [email protected]

Psychometric properties of the CDC Symptom Inventory for assessment of chronic fatigue syndrome.

Popul Health Metr. 2005 Jul 22;3:8.

OBJECTIVES: Validated or standardized self-report questionnaires used in research studies and clinical evaluation of chronic fatigue syndrome (CFS) generally focus on the assessment of fatigue. There are relatively few published questionnaires that evaluate case defining and other accompanying symptoms in CFS. This paper introduces the self-report CDC CFS Symptom Inventory and analyzes its psychometric properties. METHODS: One hundred sixty-four subjects (with CFS, other fatiguing illnesses and non fatigued controls) identified from the general population of Wichita, Kansas were enrolled. Evaluation included a physical examination, a standardized psychiatric interview, three previously validated self-report questionnaires measuring fatigue and illness impact (Medical Outcomes Survey Short-Form-36 [MOS SF-36], Multidimensional Fatigue Inventory [MFI], Chalder Fatigue Scale), and the CDC CFS Symptom Inventory. Based on theoretical assumptions and statistical analyses, we developed several different Symptom Inventory scores and evaluated them on their ability to differentiate between participants with CFS and non-fatigued controls. RESULTS: The Symptom Inventory had good internal consistency and excellent convergent validity. A Total score (all symptoms), Case Definition score (CFS case defining symptoms) and Short Form score (6 symptoms with minimal correlation) differentiated CFS cases from controls. Furthermore, both the Case Definition and Short Form scores distinguished people with CFS from fatigued subjects who did not meet criteria for CFS. CONCLUSION: The Symptom Inventory appears to be a reliable and valid instrument to assess symptoms that accompany CFS. It is a positive addition to existing instruments measuring fatigue because it allows other dimensions of the illness to be assessed. Further research is needed to confirm and replicate the current findings in a normative population.

Wallman KE, Morton AR, Goodman C, Grove R.

Human Movement and Exercise Science, University of Western Australia, 35 Stirling Highway, Crawley, WA 6009. [email protected]

Exercise prescription for individuals with chronic fatigue syndrome.

Med J Aust. 2005 Aug 1;183(3):142-3.

Wang Q, Xiong JX.

The First Affiliated Hospital of Guangzhou University of TCM, Guangdong

[Clinical observation on electroacupuncture for treatment of chronic fatigue

Zhongguo Zhen Jiu. 2005 Oct;25(10):691-2.

OBJECTIVE: To observe clinical therapeutic effect of acupuncture at Back-shu acupoints of five zang-organs on chronic fatigue syndrome (CFS). METHODS: Forty cases of CFS were treated with electroacupuncture at main acupoints Back-shu, and Fatigue Assessment Instrument (FAI) and Mental State Self-rating Scale (SCL-90) were used for assessment of therapeutic effect. RESULTS: After electroacupuncture treatment, clinical symptoms improved. The cumulative scores of FAI



510405, China. [email protected]

syndrome] [Article in Chinese]

decreased from 148.36 +/- 26.53 before treatment to 98.63 +/- 28.36 after treatment (P < 0.01). And the scores of somatization, depression, anxiety and interpersonal relationship in SCL-90 reduced significantly (P < 0.01). CONCLUSION: Electroacupuncture has a definite therapeutic effect on chronic fatigue syndrome.

Wernham W, Pheby D, Saffron L.

SHORT COMMUNICATION/PILOT STUDIESRisk Factors for the Development of Severe ME/CFS–: A Pilot Study


The pilot phase is reported of a case-control study to determine risk factors for severe CFS/ME. One hundred fifty-seven members of the ME Association, selected at random, were sent postal questionnaires, with a 56% response. The Barthel index was used as a validated proxy measure to distinguish severe disease (cases) and those less severe. Thirteen of 88 respondents had severe disease, and 44 mild disease. Two matched controls from the 'mild' group were selected per case. Of possible risk factors, odds ratios greater than 2 were found for comorbidities, damaging initial treatment and occupational chemical exposure, although in this study they were not statistically significant. These data suggest that additional studies are warranted.

Wheatland R. The Endocrine Research Project, 574 Sims Road, Santa Cruz, CA 95060, USA. [email protected]

Chronic ACTH autoantibodies are a significant pathological factor in the disruption of the hypothalamic-pituitary-adrenal axis in chronic fatigue syndrome, anorexia nervosa and major depression.

Med Hypotheses. 2005;65(2):287-95.

Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis is a commonly recognized feature of many pathological conditions. Abnormal adrenal responses to experimental manipulation have been well documented in patients suffering from chronic fatigue syndrome, anorexia nervosa and major depression. Yet no defect of any single organ, gland or brain region has been identified as a cause of these abnormalities. The disruption of the HPA axis that occurs in these conditions can be understood if an interfering factor is present in these patients. Evidence indicates that this interfering factor is adrenocorticotropin hormone (ACTH) autoantibodies. Chronic high levels of ACTH autoantibodies will significantly disrupt the HPA axis and force the body to compensate for an impaired cortisol response. The resulting effect of chronic ACTH autoantibody interference is the manifestation of adrenocortical insufficient symptoms and psychological disturbances. Some symptoms of chronic fatigue syndrome, anorexia nervosa and major depression, such as anxiety, are the adverse effects of mechanisms compensating for less effective ACTH due to autoantibodies. Furthermore, these patients engage in extraordinary behaviors, such as self-injury, to increase their cortisol levels. When this compensation is inadequate, symptoms of adrenocortical insufficiency appear. Corticosteroid supplements have been demonstrated to be an effective treatment for chronic fatigue syndrome, anorexia nervosa and major depression. It allows the patients to have the corticosteroids they require for daily functioning and daily stressors. This therapy will relieve the patients of their symptoms of adrenocortical insufficiency and permit their cortisol-stimulating mechanisms to operate at levels that will not cause pathological problems.

Whistler T, Jones JF, Unger ER, Vernon SD.

Viral Exanthems and Herpesvirus Branch, Centers for Disease Control and Prevention, Atlanta, GA 30333, USA. [email protected]

Exercise responsive genes measured in peripheral blood of women with chronic fatigue syndrome and matched control subjects.

BMC Physiol. 2005 Mar 24;5(1):5.

BACKGROUND: Chronic fatigue syndrome (CFS) is defined by debilitating fatigue that is exacerbated by physical or mental exertion. To search for markers of CFS-associated post-exertional fatigue, we measured peripheral blood gene expression profiles of women with CFS and matched controls before and after exercise challenge. RESULTS: Women with CFS and healthy, age-matched, sedentary controls were exercised on a stationary bicycle at 70% of their predicted maximum workload. Blood was obtained before and after the challenge, total RNA was extracted from mononuclear cells, and signal intensity of the labeled cDNA hybridized to a 3800-gene oligonucleotide microarray was measured. We identified differences in gene expression among and between subject groups before and after exercise challenge and evaluated differences in terms of Gene Ontology categories. Exercise-responsive genes differed between CFS patients and controls.




These were in genes classified in chromatin and nucleosome assembly, cytoplasmic vesicles, membrane transport, and G protein-coupled receptor ontologies. Differences in ion transport and ion channel activity were evident at baseline and were exaggerated after exercise, as evidenced by greater numbers of differentially expressed genes in these molecular functions. CONCLUSION: These results highlight the potential use of an exercise challenge combined with microarray gene expression analysis in identifying gene ontologies associated with CFS.

White PD, Nye KE, Pinching AJ, Yap TM, Power N, Vleck V, Bentley DJ, Thomas JM, Buckland M, Parkin JM

Immunological Changes After Both Exercise and Activity in Chronic Fatigue Syndrome: A Pilot Study


Background: The chronic fatigue syndrome (CFS) is characterized by post-exertional malaise and fatigue. We designed this pilot study to explore whether the illness was associated with alterations in immunological markers following exercise. Methods: We measured immunological markers before and up to three days after either a sub-maximal or maximal bicycle exercise test.We studied nine patients with CFS and nine ageand sex-matched healthy but sedentary controls. We also studied the same patients with CFS at home after a night's sleep and then after traveling to the study center. Results: There were no significant differences in any of the cell markers after a sub-maximal exercise test compared to a maximal test. However, we found elevated concentrations of plasma transforming growth factor beta (TGF-ß), even before exercise, in subjects with CFS (median (IQR) of 904 (182-1072) pg/ml) versus controls (median (IQR) of 50 (45-68) pg/ml) (P < .001). Traveling from home to the hospital significantly elevated TGF-ß concentrations from a resting median (IQR) concentration of 1161 (130-1246) pg/ml to a median (IQR) concentration of 1364 (1155-1768) pg/ml (P < .02). There was also a sustained increase in plasma tumor necrosis factor alpha (TNF-α) after exercise in CFS patients, but not in controls (P = .004 for the area under the curve), although traveling had no such effect. CD3, CD4 and HLA DR-expressing lymphocyte counts were lower in CFS patients, but exercise had the same effect in both groups, causing an immediate increase in circulating cell numbers that lasted less than three hours. Conclusions: These results suggest that the relationship between physical activity and both pro-inflammatory and anti-inflammatory cytokines merits further investigation in patients with CFS. The results also emphasize the importance of defining a truly resting baseline condition in such studies.

Whitehead LC. University of Stirling Stornoway, UK.

Quest, chaos and restitution: Living with chronic fatigue syndrome/myalgic encephalomyelitis.

Soc Sci Med. 2005 Oct 15; [Epub ahead of print]

Chronic illness is disruptive, threatening people's sense of identity and taken for granted assumptions. Transformations in values, expectations and life priorities are likely to be experienced and in order to regain a coherent sense of self, people must interpret their experiences. People with difficult to diagnose illnesses can find themselves living with greater uncertainty and stigma. This paper explores how people with chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) describe and interpret their illness experience by applying Arthur Frank's narrative typologies to analyse interviews with 17 British people with CFS/ME. The analysis proposes that a trajectory of narrative typologies is experienced, starting with a restitution narrative, moving to a chaos narrative and, for most, back to a restitution narrative and on to a quest narrative. The presentation of narrative types put forward by people living with CFS/ME differ to those presented by people who are HIV positive and have been treated for breast cancer.

Whitehead LC. University of Stirling Stornoway, UK.

Quest, chaos and restitution: Living with chronic fatigue syndrome/myalgic

Soc Sci Med. 2005 Oct 15; [Epub ahead of print]

Chronic illness is disruptive, threatening people's sense of identity and taken for granted assumptions. Transformations in values, expectations and life priorities are likely to be experienced and in order to regain a coherent sense of self, people must interpret their experiences. People with difficult to diagnose illnesses can find themselves living with greater uncertainty and stigma. This paper explores how people with chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME)


encephalomyelitis. describe and interpret their illness experience by applying Arthur Frank's narrative typologies to analyse interviews with 17 British people with CFS/ME. The analysis proposes that a trajectory of narrative typologies is experienced, starting with a restitution narrative, moving to a chaos narrative and, for most, back to a restitution narrative and on to a quest narrative. The presentation of narrative types put forward by people living with CFS/ME differ to those presented by people who are HIV positive and have been treated for breast cancer.

Wright B, Ashby B, Beverley D, Calvert E, Jordan J, Miles J, Russell I, Williams C.

Lime Trees, Shipton Road, York, UK. [email protected]

A feasibility study comparing two treatment approaches for chronic fatigue syndrome in adolescents.

Arch Dis Child. 2005 Apr;90(4):369-72.

Yiu YM, Qiu MY. School of Chinese Medicine, University of Hong Kong, Hong Kong, China. [email protected]

[A preliminary epidemiological study and discussion on traditional Chinese medicine pathogenesis of chronic fatigue syndrome in Hong Kong] [Article in Chinese]

Zhong Xi Yi Jie He Xue Bao. 2005 Sep;3(5):359-62.

OBJECTIVE: Our purpose is to conduct an epidemiological study of chronic fatigue syndrome (CFS) and its syndrome types and symptoms of traditional Chinese medicine (TCM) among adults (20-50 years old) in Hong Kong, and to discuss the TCM pathogenesis. METHODS: Design: Cross-sectional questionnaire survey. Measures: Demographic data, CDC (1994) CFS diagnostic criteria, Trudie Chalder fatigue scale, and China national standard for TCM syndrome types criteria. Subjects: Twenty to fifty years old adults by convenient sampling. RESULTS: One thousand and thirteen subjects were successfully interviewed. Five hundred and eighty-five subjects (57.8%) had different levels of fatigue. Sixty-five subjects (6.4%) met CFS diagnostic criteria. In terms of TCM syndrome types, blood stasis due to qi deficiency had the highest prevalence (35.7%) among CFS. In the 54 symptoms investigated in total, the first eight symptoms in order of appearing rates were soreness of loins and weakness in knees, poor spirit, lassitude, pain, insomnia, forgetting, vessels blood stasis, vertigo and dazzle. The mostly appeared tongue figures were pale and corpulent or pale dim tongue proper, white and white greasy tongue coating, and the mostly appeared pulse figure was sunken-thin. CONCLUSION: The point prevalence of CFS among adults of 20 to 50 years old was found to be 6.4%. The most prevalent TCM syndrome type was blood stasis due to qi deficiency. The TCM pathogenesis of CFS was deficiency of origin, mainly deficiency of qi and kidney, with excess of superficiality.

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