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CO-CURE Medical & Research Posts Only Digest - 2 Oct 2006 to 9 Oct 2006 (#2006-46)

There are 25 messages totalling 4750 lines in this issue. Topics of the week:

[Return to digest index] --------------------------------------------- This is a special digest of Co-Cure Research & Medical posts only Problems? Write to mailto:mods@co-cure.org --------------------------------------------- ---------------------------------------------------------------------- Date: Tue, 3 Oct 2006 14:52:56 -0400 From: "Jan van Roijen <j.van.roijen@xxxxx.xx> (via Co-Cure Moderators) Subject: NOT,RES: The Trouble with Medical Journals Send an Email for free membership ~:~:~:~:~:~:~:~:~:~:~:~:~:~:~:~:~:~:~:~ >>>> Help ME Circle <<<< >>>> 3 October 2006 <<<< Editorship : j.van.roijen@chello.nl Outgoing mail scanned by Norton AV ~:~:~:~:~:~:~:~:~:~:~:~:~:~:~:~:~:~:~:~ http://www.ireland.com/newspaper/health/2006/0919/1158590761760.html Sun Oct 1, 2006 7:51 pm (PST) Special Reports Health Tue, Sep 19, 06 Add a pinch of salt to medical findings ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ Good debate: Don't believe all you read in a medical journal, a former editor tells Claire O'Connell Every day, doctors thumb through medical journals looking for the latest information on treatments. Meanwhile, journalists relate the findings of published studies to millions of people. And the underlying belief is that if it is in a prestigious medical journal, then it must be true. Right? Not always, according to Dr Richard Smith, whose book, The Trouble with Medical Journals, is published today. Smith, a medical doctor and editor with the BMJ (British Medical Journal) for more than 20 years, lifts the lid on shady ethical practices in large medical journals. These include dodgy courtships with the mass media leading to public scares, as well as unsavoury links with the pharmaceutical industry, which he claims uses medical journals to promote its drugs. He also recommends ditching the time-honoured practice of expert peers reviewing papers before they are published. But why should we care about how medical journals work? "The ways that medical journals behave have an important influence on people," Smith says. "They can create a lot of havoc," he adds, citing examples where studies in medical journals sparked media-fuelled scares about emotive issues such as vaccination, alternative treatments for cancer and the contraceptive pill. His book raises the awkward question of whether journals, in their passion for publicity, might be tempted to publish weak but controversial studies to grab media headlines on "things that are likely to appeal to the public's interest [quite a different thing from the public interest]." For example, a dubious study published in The Lancet in 1998 sparked media hype that led to public fears about links between the MMR vaccine and autism. The study was later withdrawn, its author was discredited and numerous larger and more rigorous studies have since shown no link between the MMR jab and autism. But the mud stuck, and uptake of the triple vaccine was substantially reduced. "All medical journals publish rubbish, and quite a lot of it," says Smith, who openly admits transgressions by his own journal. "But luckily, most of it doesn't have the kind of impact that the MMR paper did." However, medical journals have more worrying bedfellows than the media, according to Smith, who left the BMJ in 2004. Top of his list of gripes is how "medical journals have become an extension of the marketing arm of the pharmaceutical industry". Pharmaceutical companies sponsor most of the large clinical drug trials that are published in major medical journals, and the outcomes of such studies are generally good for the sponsor, he says. "When you look at how often those trials come up with anything that's really bad news for the drug companies, the answer is almost never," says Smith. "It's not because the drug companies are fiddling the results, it's just that they are rather clever at the kinds of questions that they ask and the way they analyse the data. So they very rarely come up with anything that's bad news," he says. A favourable clinical trial published in a prestigious journal can have a major impact on drug sales, says Smith. And there is also a pay-off for the journal: if the pharmaceutical company orders reprints of the paper to send to prospective clients, the journal can make hundreds of thousands of dollars in profit, he adds. Such cosy arrangements benefit neither the doctor nor the patient, and Smith believes a more open and accountable approach would be to publish full details of trials on regulated websites and have journals critique them. Smith also dismisses peer review, a vetting system where journal editors choose experts in a particular field (peers) to review submitted papers and recommend whether or not to publish them. Getting a study into a peer-reviewed journal is generally seen as a mark of quality, but Smith disagrees. "I think it would be good for the world at large to realise just what a dodgy process peer review is," he says. "It just doesn't work very well and it's a bit of a lottery." Instead, he believes that new studies should be published online where everyone can access them and spark a public discourse. "I'm all for sticking it up on the web with a big sign saying don't believe this just because it's here, wait and see what response there is." In fact, Smith believes that printed medical journals are generally not the place for original research data, because they offer little of value for doctors. He suggests that journals instead convey the important information in print and put the full research reports on the web for those who are interested. "The whole model of sending a lot of original research to ordinary doctors is bonkers," says Smith. "Most of the scientific articles [in medical journals] are not relevant to the average doctor. "He or she hasn't got time to read them anyway. And most doctors are not equipped to critically appraise the evidence, so there's a tendency to say 'it's in the New England Journal of Medicine so it must be true'." The extensive list of ills in Smith's book, which he wrote during a two-month stay in Venice, came as something of a surprise, even to himself. "I had no idea the book was going to turn out like that - I've become a grumpy old man," he says. "But probably the closer you get to any institution, the more you see the human defects," he adds. Dr Richard Smith will give a public interview hosted by Dick Ahlstrom, science editor of The Irish Times, on Thursday, September 21st at 6pm in the Royal Irish Academy, 19 Dawson Street, Dublin 2. The event is co-organised by the British Council. Places are free but must be reserved in advance by phoning Laura on 01 6090635 or Maura on 01 6090633 (10am-5pm). © The Irish Times [Return to top] ------------------------------ Date: Tue, 3 Oct 2006 15:23:39 -0400 From: Fred Springfield <fredspringfield@xxxxx.xxx> Subject: RES: Brief Report: The Accuracy of Parents for the Thoughts and Feelings of Their Adolescent Suffering from Chronic Fatigue: A Preliminary Study of Empathy Brief Report: The Accuracy of Parents for the Thoughts and Feelings of Their Adolescent Suffering from Chronic Fatigue: A Preliminary Study of Empathy Journal: Journal of Pediatric Psychology Advance Access published online on September 29, 2006, doi:10.1093/jpepsy/jsl032 Authors: Tine Vervoort MSc [1,2,*], Geert Crombez PhD [1], Ann Buysse PhD [2], Liesbet Goubert PhD [1], Tine De Backer MSc [3], and William Ickes PhD[4] Affiliations: [1] Department of Experimental-Clinical and Health Psychology, Ghent University, Belgium; Research Institute for Psychology and Health, The Netherlands [2] Department of Experimental-Clinical and Health Psychology, Ghent University, Belgium [3] Zeepreventorium, De Haan, Belgium [4] Department of Psychology, University of Texas at Arlington, USA [*] To whom correspondence should be addressed. Tine Vervoort, E-mail: Tine.Vervoort@Ugent.be NLM Citation: PMID: 17012438 Objective: This study examined the actual and estimated empathic accuracy (EA) of the parents of adolescents with chronic fatigue syndrome (CFS). Methods: The actual EA of both parents (n = 24) was assessed in relation to the thoughts and feelings of their child (n = 14) about CFS and about other life events. Adolescents were also asked to estimate the parents' EA. Results: For the actual EA, both parents were significantly less accurate regarding the adolescent's thoughts and feelings about CFS than about other life events. Fathers were just as empathically accurate as mothers. For the estimated EA, however, results indicated that adolescents perceived their mother to be more empathically accurate than their father. Actual EA and estimated EA about CFS were negatively correlated for fathers, not for mothers. Conclusions: Results are discussed in terms of the importance of assessing EA in relation to other dimensions of empathic understanding and distress in the observer. Keywords: adolescents; chronic fatigue syndrome; empathy; parents. [Return to top] ------------------------------ Date: Tue, 3 Oct 2006 15:54:04 -0400 From: "Bernice A. Melsky" <bernicemelsky@xxxxx.xxx> Subject: RES: Pain thresholds and tender point counts as predictors of new chronic widespread pain in psychologically distressed subjects Pain thresholds and tender point counts as predictors of new chronic widespread pain in psychologically distressed subjects. Ann Rheum Dis. 2006 Sep 29; [Epub ahead of print] Gupta A, McBeth J, Macfarlane GJ, Morriss RK, Dickens C, Ray D, Chiu YH, Silman AJ. University of Manchester, United Kingdom. PMID: 17012291 OBJECTIVE: Tender points are a general measure of distress both in community and clinic subjects. It has been suggested that multiple tender points should be regarded as the early stages of somatization of distress. Similarly, there is recent evidence to suggest that chronic widespread pain is one manifestation of the somatization of distress. Given that a high tender point count and chronic widespread pain are clinical hallmarks of the fibromyalgia syndrome, we hypothesized that in psychologically distressed subjects, a high tender point count, or a low pain threshold would predict the development of chronic widespread pain in the future. METHODS: In this population based prospective study, 245 psychologically distressed adults between 25- 65 years, free of chronic widespread pain, were identified, based on a detailed pain questionnaire, and a psychosocial questionnaire comprising the Somatic Symptom Checklist and the Illness Behaviour subscale of the Illness Attitude Scales. These subjects took part in a pain threshold examination with a Fischer pressure algometer. Tender point counts were computed by including all areas with a pain threshold below 4kg/cm2. Individuals were followed up at 15 months, at which time 231 (97% of subjects still living at their baseline address) provided data on pain status, using the same instruments. RESULTS: At follow-up, 26 subjects (11%) developed new chronic widespread pain. Neither baseline pain threshold, nor tender point count, adjusted for age, gender and baseline pain status, predicted the development of new chronic widespread pain. CONCLUSION: Psychologically distressed subjects free of chronic widespread pain are not at an increased risk of its development if they have high tender points or low pain thresholds. Data from this population based prospective study suggest that a low pain-threshold in subjects with chronic widespread pain is likely to be a secondary phenomenon as a result of pain or associated distress rather than being the antecedent of symptoms. [Return to top] ------------------------------ Date: Wed, 4 Oct 2006 17:08:28 -0400 From: Co-Cure Moderator <ray@xxxxx.xxx> Subject: RES: Conceptual issues in undifferentiated somatoform disorder and chronic fatigue syndrome Conceptual issues in undifferentiated somatoform disorder and chronic fatigue syndrome. Journal: Curr Opin Psychiatry. 2006 Nov;19(6):613-8. Author: van Staden WC. Affiliation: Department of Psychiatry, University of Pretoria, Pretoria, South Africa. NLM Citation: PMID: 17012941 PURPOSE OF REVIEW: To review the conceptual problems in distinguishing between undifferentiated somatoform disorder and chronic fatigue syndrome, for both may present with fatigue as the main symptom. RECENT FINDINGS: The differences and/or similarities between undifferentiated somatoform disorder and chronic fatigue syndrome have not been studied, conceptually or empirically. The literature fails to present discriminant validity of chronic fatigue syndrome in relation to undifferentiated somatoform disorder. A critical feature is implied in the definition of undifferentiated somatoform disorder but absent from the definitions of chronic fatigue syndrome: some patients experience their fatigue as being exclusively physical and not as mental, which is prima facie peculiar, for fatigue is necessarily a mental experience. One is not able to experience fatigue without a mind (or a brain). This experience is characterized as a 'mindless' fatigue, underpinned by pathological reductionist thinking. By not recognizing this critical feature, diagnostic endeavours may perpetuate the problem as a function of the patient's difficulty. SUMMARY: Proponents of chronic fatigue syndrome should distinguish chronic fatigue syndrome from undifferentiated somatoform disorder, if chronic fatigue syndrome is a distinct entity at all. Further, the 'mindless' quality is a critical feature that needs consideration in refining the concept of undifferentiated somatoform disorder. [Return to top] ------------------------------ Date: Wed, 4 Oct 2006 17:18:56 -0400 From: Fred Springfield <fredspringfield@xxxxx.xxx> Subject: RES: Cognitive behavioural therapy in chronic fatigue syndrome: a randomised controlled trial of an outpatient group programme Cognitive behavioural therapy in chronic fatigue syndrome: a randomised controlled trial of an outpatient group programme. Journal: Health Technol Assess. 2006 Oct;10(37):1-140. Authors: O'Dowd H, Gladwell P, Rogers CA, Hollinghurst S, Gregory A. Affiliation: Pain Management Centre, Frenchay Hospital, Bristol, UK. NLM Citation: PMID: 17014748 OBJECTIVES: To test the hypothesis that group cognitive behavioural therapy (CBT) will produce an effective and cost-effective management strategy for patients in primary care with chronic fatigue syndrome/myalgic encephalopathy (CFS/ME). DESIGN: A double-blind, randomised controlled trial was adopted with three arms. Outcomes were assessed at baseline and 6 and 12 months after first assessment and results were analysed on an intention-to-treat basis. SETTING: A health psychology department for the management of chronic illness in a general hospital in Bristol, UK. PARTICIPANTS: Adults with a diagnosis of CFS/ME referred by their GP. INTERVENTIONS: The three interventions were group CBT incorporating graded activity scheduling, education and support group (EAS) and standard medical care (SMC). OUTCOME MEASURES: The primary outcome measure was the Short Form with 36 Items (SF-36) physical and mental health summary scales. Other outcome measures included the Chalder fatigue scale, Hospital Anxiety and Depression Scale, General Health Questionnaire, physical function (shuttles walked, walking speed and perceived fatigue), health utilities index and cognitive function (mood, recall and reaction times). RESULTS: A total of 153 patients were recruited to the trial and 52 were randomised to receive CBT, 50 to EAS and 51 to SMC. Twelve patients failed to attend for the 12-month follow-up and 19 patients attended one follow-up, but not both. The sample was found to be representative of the patient group and the characteristics of the three groups were similar at baseline. Three outcome measures, SF-36 mental health score, Chalder fatigue scale and walking speed, showed statistically significant differences between the groups. Patients in the CBT group had significantly higher mental health scores [difference +4.35, 95% confidence interval (CI) +0.72 to +7.97, p = 0.019], less fatigue (difference -2.61, 95% CI -4.92 to -0.30, p = 0.027) and were able to walk faster (difference +2.83 shuttles, 95% CI +1.12 to +5.53, p = 0.0013) than patients in the SMC group. CBT patients also walked faster and were less fatigued than those randomised to EAS (walking speed: difference +1.77, 95% CI +0.025 to +3.51, p = 0.047; fatigue: difference -3.16, 95% CI -5.59 to -0.74, p = 0.011). Overall, no other statistically significant difference across the groups was found, although for many measures a trend towards an improved outcome with CBT was seen. Except for walking speed, which, on average, increased by +0.87 shuttles (95% CI +0.09 to +1.65, p = 0.029) between the 6- and 12-month follow-ups, the scores were similar at 6 and 12 months. At baseline, 30% of patients had an SF-36 physical score within the normal range and 52% had an SF-36 mental health score in the normal range. At 12 months, the physical score was in the normal range for 46% of the CBT group, 26% of the EAS group and 44% of SMC patients. For mental health score the percentages were CBT 74%, EAS 67% and SMC 70%. Of the CBT group, 32% showed at least a 15% increase in physical function and 64% achieved a similar improvement in their mental health. For the EAS and SMC groups, this improvement in physical and mental health was achieved for 40 and 60% (EAS) and 49 and 53% (SMC), respectively. The cost-effectiveness of the intervention proved very difficult to assess and did not yield reliable conclusions. CONCLUSIONS: Group CBT did not achieve the expected change in the primary outcome measure as a significant number did not achieve scores within the normal range post-intervention. The treatment did not return a significant number of subjects to within the normal range on this domain; however, significant improvements were evident in some areas. Group CBT was effective in treating symptoms of fatigue, mood and physical fitness in CFS/ME. It was found to be as effective as trials using individual therapy in these domains. However, it did not bring about improvement in cognitive function or quality of life. There was also evidence of improvement in the EAS group, which indicates that there is limited value in the non-specific effects of therapy. Further research is needed to develop better outcome measures, assessments of the broader costs of the illness and a clearer picture of the characteristics best fitted to this type of intervention. [Return to top] ------------------------------ Date: Thu, 5 Oct 2006 12:55:00 -0400 From: Fred Springfield <fredspringfield@xxxxx.xxx> Subject: RES: Potential Polygenic Influences on Chronic Fatigue Syndrome [Note: See http://listserv.nodak.edu/cgi-bin/wa.exe?A2=ind0606A&L=CO-CURE&P=R2320 for the original article that this letter comments on.] LETTER TO THE EDITOR Potential Polygenic Influences on Chronic Fatigue Syndrome Journal: PEDIATRICS Vol. 118 No. 4 October 2006, pp. 1799-1800 (doi:10.1542/peds.2006-1664) Author: Kenneth N. Schikler, MD, FAAP, FACR Affiliation: Section of Pediatric Rheumatology and Adolescent Medicine Department of Pediatrics University of Louisville School of Medicine Louisville, KY 40202 Center for Pediatric Fatiguing and Painful Conditions Frazier Rehab Institute Louisville, KY 40202 To the Editor. I found the article by van de Putte et al1 to be most interesting and insightful in construct design and in the conclusions drawn from their study of 40 adolescents with chronic fatigue syndrome (CFS), one of the many syndromes that fit into the category of central pain-processing disorders (along with other disturbing conditions such as fibromyalgia, irritable bowel syndrome, and complex regional pain syndrome type I). Their study results led them to conclude that the shared symptom complex of mother and child suggested an interplay between genetic variability and environmental factors. They, in fact, suggested the potential for a polygenic rather than monogenic inheritance pattern and made reference to an article by Torpy et al2 regarding an association of CFS and the serine allele of the CBG gene. This article was obviously prepared and accepted for publication long before the recently published findings of Goertzel et al,3 who found that combinations of single-gene polymorphisms had a 76.3% predictive accuracy for CFS in studying 43 adults and 58 control subjects. The 3 genes with the highest accumulated importance were neuronal tryptophan hydroxylase (TPH2, involved in serotonin metabolism), catechol-O-methyltransferase (COMT, involved in methylation of norepinephrine), and nuclear receptor subfamily 3, group C member 1 glucocorticoid receptor (NR3C1, involved in corticosteroid sensitivity via signal transduction and transcription of RNA polymerase II promoter). This adds supportive evidence to the concept of a polygenic predisposition to the development of CFS and possibly other central pain-perception processes,4 such as fibromyalgia, that have been felt to have alterations in serotonin,5 norepinephrine,6 and response to stress or allostasis.7 REFERENCES 1. van de Putte EM, van Doornen LJ, Engelbert RH, Kuis W, Kimpen JL, Uiterwaal CS. Mirrored symptoms in mother and child with chronic fatigue syndrome. Pediatrics. 2006;117 :2074 2079[Abstract/Free Full Text] 2. Torpy DF, Bachmann AW, Gartside M, et al. Association between chronic fatigue syndrome and the corticosteroid-binding globulin gene ALA SER224 polymorphism. Endocr Res. 2004;30 :417 429[CrossRef][ISI][Medline] 3. Goertzel BN, Pennachin C, de Souza Coehlo L, Gurbaxani B, Maloney EM, Jones JF. Combinations of single nucleotide polymorphisms in neuroendocrine effector and receptor genes predict chronic fatigue syndrome. Pharmacogenomics. 2006;7 :475 483[CrossRef][ISI][Medline] 4. Diatchenko L, Slade GD, Nackley AG, et al. Genetic basis for individual variation in pain perception and the development of a chronic pain condition. Hum Mol Genet. 2005;14 :135 143[Abstract/Free Full Text] 5. Russell IJ. Advances in fibromyalgia: possible role for central neurochemicals. Am J Med Sci. 1998;315 :377 384[CrossRef][ISI][Medline] 6. Legangneux E, Mora JJ, Spreux-Varoquaux O, et al. Cerebrospinal fluid biogenic amine metabolites, plasma-rich platelet serotonin and [3H]imipramine reuptake in the primary fibromyalgia syndrome. Rheumatology (Oxford). 2001;40 :290 296 7. Maloney EM, Gurbaxani BM, Jones JF, de Souza Coelho L, Pennachin C, Goertzel BN. Chronic fatigue syndrome and high allostatic load. Pharmacogenomics. 2006;7 :467 473[CrossRef][ISI][Medline] ©2006 by the American Academy of Pediatrics [Return to top] ------------------------------ Date: Thu, 5 Oct 2006 13:12:40 -0400 From: "Bernice A. Melsky" <bernicemelsky@xxxxx.xxx> Subject: RES: Efficacy of duloxetine in painful symptoms: an analgesic or antidepressant effect? Efficacy of duloxetine in painful symptoms: an analgesic or antidepressant effect? Int Clin Psychopharmacol. 2006 Nov;21(6):311-7. Perahia DG, Pritchett YL, Desaiah D, Raskin J. [a]Lilly Research Centre, Windlesham, Surrey, UK [b]The Gordon Hospital, London, UK [c]Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, USA [d]Lilly Research Laboratorios, Eli Lilly Canada, Toronto, Ontario, Canada. PMID: 17012978 The evidence that the effects of the antidepressant duloxetine on painful physical symptoms in depression and chronic pain disorders are a direct analgesic effect rather than an indirect antidepressant effect is reviewed. Data from placebo-controlled acute studies of duloxetine in major depressive disorder, diabetic peripheral neuropathic pain and fibromyalgia syndrome are included in this review. In placebo-controlled studies of duloxetine in patients with major depressive disorder, non-depressed diabetic peripheral neuropathic pain, and fibromyalgia syndrome, duloxetine has a statistically significantly greater effect on pain than placebo. Path analysis suggests that in these patient populations, approximately 50, 90, and 80%, respectively, of the observed effect on pain is a direct analgesic effect rather than an indirect antidepressant effect. In fibromyalgia syndrome studies, duloxetine had similar and substantial effects on pain regardless of whether patients had comorbid major depressive disorder. Pain is a complex experience, involving both the physiological responses of the nociceptive system and the processing of that information in brain regions associated with emotion. While some effects of duloxetine on painful symptoms can be accounted for by its antidepressant action, the data strongly suggest that duloxetine also exerts a substantial direct analgesic effect over and above its antidepressant effects, in patients with major depressive disorder, diabetic peripheral neuropathic pain, and fibromyalgia syndrome. [Return to top] ------------------------------ Date: Thu, 5 Oct 2006 13:15:12 -0400 From: "Bernice A. Melsky" <bernicemelsky@xxxxx.xxx> Subject: RES: Psychological approaches in pain management: what works? Psychological approaches in pain management: what works? Curr Opin Anaesthesiol. 1998 Oct;11(5):547-52. Turk DC, Okifuji A. Department of Anesthesiology, University of Washington, Seattle, Washington, USA. PMID: 17013272 Outcome studies evaluating psychological treatments for pain vary in nature and intensity. Overall, however, treatment programs that include psychological interventions have been shown to be effective in treating postoperative pain, noncardiac chest pain, fibromyalgia syndrome, and chronic back pain. Cost analyses of the treatments indicate not only the clinical efficacy but the cost-effectiveness of psychological interventions. Issues related to subject attrition, noncompliance, and individual differences in treatment response should be addressed in future studies. [Return to top] ------------------------------ Date: Thu, 5 Oct 2006 12:14:50 -0700 From: "Cort Johnson.................via Co-Cure moderator" Subject: RES, NOTICE: Reports From the CAMDA Conference The analyses of the 2003 CDC Wichita data did not stop with the publications in the Pharmacogenomics Journal. While the CDC researchers and others took a stab at the data the CDC gave another group of independent researchers their shot at it. Researchers from Finland, Canada, the U.K., Italy, Australia, Korea and the U.S. presented their findings in a series of papers presented at the CAMDA conference at Durham, North Carolina in June of 2006. The CAMDA conference takes the form of a contest in which the presenters vie to produce the best paper. An enormous amount of very creative work resulted in a presentation of 10 papers and three posters seeking to elucidate biological characteristics unique to CFS, provide a biomarker, and open new avenues CFS research and treatment. These reports are very complex. Some were successes, some were not. The top paper may have found a biomarker for CFS, other found problems in biological pathways, altered gene networks and one or two, indirectly, suggested problems in the methylation pathway. http://www.phoenix-cfs.org/CAMDA%2006.htm Cort [Return to top] ------------------------------ Date: Thu, 5 Oct 2006 12:37:19 +0200 From: "Dr. Marc-Alexander Fluks" <fluks@xxx.xx> Subject: RES,NOT: Review CFS therapies Source: Journal of the Royal Society of Medicine Vol 99, #10, pp 506-520 Date: October 2006 URL: http://www.jrsm.org/cgi/content/full/99/10/506 [Reviews] Interventions for the treatment, management and rehabilitation of patients with chronic fatigue syndrome/myalgic encephalomyelitis: an updated systematic review -------------------------------------------------------------------------- Duncan Chambers(1,*), Anne-Marie Bagnall(2), Susanne Hempel(1), Carol Forbes(1) 1 Centre for Reviews and Dissemination, University of York, York, YO10 5DD, UK 2 School of Health and Community Care, Leeds Metropolitan University, Leeds, LS1 3HE, UK * Correspondence to: Duncan Chambers E-mail: dc510@york.ac.uk SUMMARY Objectives To determine whether any particular intervention or combination of interventions is effective in the treatment, management and rehabilitation of adults and children with a diagnosis of chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME). Design Substantive update of a systematic review published in 2002. Randomized (RCTs) and non-randomized controlled trials of any intervention or combination of interventions were eligible for inclusion. Study participants could be adults or children with a diagnosis of CFS/ME based on any criteria. We searched eleven electronic databases, reference lists of articles and reviews, and textbooks on CFS/ME. Additional references were sought by contact with experts. Results Seventy studies met the inclusion criteria. Studies on behavioural, immunological, pharmacological and complementary therapies, nutritional supplements and miscellaneous other interventions were identified. Graded exercise therapy and cognitive behaviour therapy appeared to reduce symptoms and improve function based on evidence from RCTs. For most other interventions, evidence of effectiveness was inconclusive and some interventions were associated with significant adverse effects. Conclusions Over the last five years, there has been a marked increase in the size and quality of the evidence base on interventions for CFS/ME. Some behavioural interventions have shown promising results in reducing the symptoms of CFS/ME and improving physical functioning. There is a need for research to define the characteristics of patients who would benefit from specific interventions and to develop clinically relevant objective outcome measures. INTRODUCTION Chronic fatigue syndrome (CFS) is a debilitating condition characterized by fatigue on minimal exertion accompanied by a range of other symptoms such as headaches, sleep disturbance, cognitive difficulties and muscle pain.1,2 The severity of the symptoms varies widely both between patients and over time; in severe cases patients may be confined to bed or to a wheelchair. CFS affects both adults and children. The nomenclature of the condition and the overlap between CFS and myalgic encephalomyelitis (ME) has been much debated. For this review we have used the term CFS/ME and included studies of people with a diagnosis of CFS/ME by any criteria. The aetiology of CFS/ME remains uncertain and diagnosis is based on symptoms as reported by the patients. Case definitions developed for research purposes tend to be used to aid diagnosis, the most widely used being the US Centers for Disease Control and Prevention (CDC)2 and the UK (Oxford)1 criteria. Estimates of the prevalence of CFS/ME vary depending on the case definition used. In a study of 2376 primary care patients in England, 2.6% met criteria for CFS/ME but the prevalence fell to 0.5% when those with co-morbid psychological disorders were excluded.3 The UK Department of Health Working Party on CFS/ME4 estimated that a typical general practice with 10 000 patients is likely to have 30-40 patients with CFS/ME and that about half of these would require specialist services. A variety of interventions have been used for the treatment and management of patients with CFS/ME and a number of groups have performed systematic reviews to assess the effectiveness of these interventions. Price and Couper5 assessed the effectiveness of cognitive behaviour therapy (CBT) in adults and concluded that CBT appears to be an effective and acceptable treatment, although only three relevant randomized controlled trials (RCTs) were found. Edmonds and colleagues reviewed RCTs of exercise therapy.6 Based on five RCTs they concluded that exercise therapy is a promising intervention, although they recommended more rigorous studies involving different patient groups and settings and a wider range of outcomes. A systematic review by Ross and colleagues examined how best to measure, monitor and treat disability in patients with CFS/ME.7 Disability was considered primarily in terms of ability to work. Although the authors found some small studies of interventions (including rehabilitation, CBT and graded exercise therapy [GET]) that reported improved employment outcomes, they concluded that no intervention has been proved to be effective in restoring the ability to work More broadly, Mulrow and colleagues examined the definition and management of CFS/ME,8 while a review of all available interventions for the treatment and management of CFS/ME in both adults and children was carried out at the NHS Centre for Reviews and Dissemination (CRD).9 These two reviews only covered the period up to 2001, and many studies of CFS/ME have been published since then. We recently carried out a number of systematic and scoping reviews on CFS/ME to inform the process of guideline development by the UK National Institute for Health and Clinical Excellence (NICE). In this paper we present an updated systematic review of the literature on interventions for the treatment and management of CFS/ME in adults and children. METHODS Literature search The following databases were searched: MEDLINE (1966 to May 2005), EMBASE (1980 to May 2005), PsycINFO (1872 to April 2005), CENTRAL (May 2005), Social Science Citation Index (1945 to 2005), Science Citation Index (1945 to 2005), Index to Scientific and Technical Proceedings (1982 to 2005), PASCAL (May 2005), Inside Conferences (May 2005), AMED (1985 to January 2005), and HEED (June 2005). Individual search strategies were developed for each electronic database and details of these can be obtained from the authors. The search was broad, with the objective of identifying all studies of CFS/ME and related synonyms and covering several research questions. No language restrictions were applied. Additional references were sought by screening reference lists of retrieved articles, textbooks on CFS/ME, and stakeholder submissions from the NICE Guideline Development Group on diagnosis and management of CFS/ME. Inclusion criteria and study selection Two reviewers independently assessed all titles and abstracts identified from the searches for potential relevance to the review questions, and potentially relevant papers were retrieved in full. Two reviewers independently assessed these studies for possible inclusion, using the specified inclusion criteria. A third reviewer resolved differences. The inclusion and exclusion criteria were: Intervention - any intervention or combination of interventions used in the treatment, management or rehabilitation of people with CFS/ME. Population - adults and/or children aged five years or more with a diagnosis of CFS/ME based on any criteria. Outcomes - all outcomes reported in included studies were considered. Study design - only randomized or controlled clinical trials were eligible for inclusion. Data extraction Data were extracted from study reports by one reviewer and the results were checked by a second reviewer. Any discrepancies were resolved by reference to the original study, with a third reviewer being consulted if necessary. Only between-group comparisons were considered. Validity assessment The criteria for validity assessment described by Bagnall et al.9 and based on the CRD recommendations10 were used to allocate a validity score, ranging from 0 to 20, to each study. Assessment of validity was based on method of randomization and allocation concealment (randomized studies only); baseline comparability of groups; adjustment for confounding factors and appropriateness of the control group (controlled studies only); blinding; completeness of follow-up; handling of drop-outs and missing data; objectivity of outcome assessment; appropriateness of statistical analysis; whether the groups were treated identically apart from the named intervention; and sample size/statistical power. Validity was assessed by one reviewer and checked by another. Disagreements were resolved by discussion and reference to a third reviewer if necessary. Data synthesis Data were grouped by intervention into pre-specified broad categories and synthesized qualitatively. In evaluating the effects of interventions, a study was classified as showing some effect (positive or negative) of treatment if any of the outcomes measured showed a significant (P<50.05) difference between the treatment and control groups. Studies were classified as showing an overall effect of treatment if there was a significant difference between the treatment and control groups for more than one clinical outcome. Studies of pre-specified subgroups of patients (children and those with severe CFS/ME) were considered separately. RESULTS The overall literature search identified 10,768 items, of which 70 met the inclusion criteria for the review (Figure 1). Two studies included in the review by Bagnall et al. were excluded from the updated review, one because it included patients with chronic mononucleosis11 and one because a full report was subsequently published.12 Fifteen papers that were ordered as potentially meeting inclusion criteria had not arrived at the time of writing.13-27 One paper in the Russian language was identified as potentially meeting inclusion criteria but has not been translated.28 The paper is about a yeast extract supplement but it is unclear whether patients all had CFS. Of the studies included in the review, 59 were RCTs and the remainder non-randomized controlled trials (Table 1). Of the newly included studies (Table 2), 15 showed some beneficial effect of the intervention and eight showed an overall beneficial effect. Validity scores ranged from 2 to 19 for the included RCTs and from 0 to 14 for the controlled trials. Controlled trials generally scored less well than RCTs on all validity criteria. A high degree of heterogeneity in interventions and outcomes was evident. The evidence supporting the effectiveness of CBT has been strengthened by one recent good quality RCT in children and adolescents29 which found an overall positive effect of the intervention. CBT was associated with a significant positive effect on fatigue, symptoms, physical functioning and school attendance. Most other new studies of CBT and modified CBT have also favoured the treatment for one or more outcomes but these were either lower quality RCTs or non-randomized studies. GET has recently been studied in two moderate quality RCTs.30,31 These studies have broadened the evidence base for GET because, unlike earlier studies, they involved non-UK settings and patients who met the 1994 CDC case definition criteria for CFS/ME. As with CBT, the overall results of studies to date suggest that this intervention may have positive effects on the symptoms of CFS/ME. Improvements in measures of physical function were also found in all five RCTs of GET published to date.30-34 No severely affected patients were included in the studies of GET. Two new studies of immunological therapies (a controlled trial of inosine pranobex35 and a relatively low quality RCT of staphylococcus toxoid36) were added to the updated review. Both of these treatments showed benefits for some outcomes but were also associated with relatively high levels of adverse events. Overall there is still insufficient evidence about the effectiveness of therapies of this type. Treatment of CFS/ME with pharmacological therapies has given disappointing results in most cases. A recent large RCT of the acetylcholinesterase inhibitor galantamine hydrobromide37 found no significant differences between groups and 120 of 434 patients (27.6%) withdrew from the trial. An RCT of hydrocortisone published in 200238 found a significant difference between groups for fatigue, but this study scored poorly for validity. Two other recent studies of steroid treatment39,40 found no significant effect, in line with the mixed results reported in 2002. The only new study of complementary/alternative therapies was an RCT of homeopathic treatment41 that showed significant differences favouring the treatment group for one of five measures of fatigue and one of five measures of functional limitations. This trial used rigorous methodology but there is also a published study showing no effect of homeopathic treatment42 and further studies are clearly required. A supplement of acetyl-L-carnitine and propionyl-L-carnitine showed an overall positive effect in one moderate quality RCT published in 2004.43 Other supplements (essential fatty acids44 and magnesium45) have also given promising results in single studies, although a later study of essential fatty acids failed to replicate the results of the first study.46 The trial of magnesium supplementation has apparently not been replicated. The evidence base for supplements and miscellaneous interventions for CFS/ME remains very limited. There is limited evidence about adverse effects associated with behavioural interventions. Withdrawals from treatment in RCTs suggest that there may be an issue but the evidence is often difficult to interpret because of poor reporting. In one RCT of CBT,47 two patients attributed a deterioration in their symptoms to the effects of the treatment. Another RCT of CBT reported high withdrawal rates in all three intervention groups, but the reasons for withdrawal were not reported.48 In the study of GET by Fulcher and White,32 one patient in each group withdrew because of worsening symptoms. In the RCT of patient education to encourage GET,33 21 of 148 patients (14.1%) entering the trial withdrew; 19 of these were in the groups randomized to GET, but the reasons for withdrawal were not reported clearly enough to be sure how many were attributable to adverse events. Eleven patients withdrew because of adverse events in a RCT of GET with or without fluoxetine,34 but it is not clear which intervention group they were in. New studies of behavioural interventions included in the update (Table 2) did not report any withdrawals caused by adverse events, although again the reasons for withdrawal were often not reported. Several studies of immunological/antiviral, pharmacological and nutritional interventions have reported withdrawals because of adverse effects, including recent studies of Staphylococcus toxoid,36 galanthamine hydrobromide37 and hydrocortisone/fludrocortisone.39 Recent studies of CBT29 and modified CBT49 in children and young people both reported that school attendance was significantly better in the treatment group compared with controls. One study supported the effectiveness of immunoglobulin treatment in children50 but this intervention may also have harmful effects. DISCUSSION Statement of principal findings A number of RCTs suggest that behavioural interventions, including elements of CBT, GET and rehabilitation, may reduce symptoms and improve physical functioning of people with CFS/ME. Immunological and anti-viral treatments may have beneficial effects but are also associated with harmful side-effects. Most pharmacological treatments have not shown beneficial effects. Strengths and weaknesses of the study Review methodology Our review was supported by a search of the literature that was designed to be as comprehensive as possible, with the objective of identifying all published studies of interventions for CFS/ME and related conditions that met pre-specified inclusion criteria. We searched for conference abstracts and dissertations as well as standard journal articles, and we attempted to locate unpublished reports and ongoing clinical trials. Publication bias needs to be considered in any systematic review; studies with statistically significant or unexpected results are more likely to be published than those showing non-significant results. Various statistical tests to assess publication bias are available, notably funnel plots, but the reliability of these is questionable and they are no longer recommended by the Cochrane Collaboration. We decided not to assess publication bias statistically for this reason and because of the wide range of interventions and outcomes included in the review. However, the fact that only one included study51 reported a negative effect of the intervention suggests that a degree of publication bias may be present in the CFS/ME literature. A fundamental problem in evaluating interventions for CFS/ME is that the wide variety of outcome measures used in the included studies makes it difficult to compare the effects of interventions across studies. Even when studies evaluated the same outcome, they used a variety of scales and measures to do so. This heterogeneity made it impossible to combine studies by meta-analysis. Standardized measures of treatment effect (effect sizes) can be calculated when studies measure the same outcome in different ways but the data required for this (sample size, mean treatment effect and standard deviation in each group) were not reported in many included studies. We have summarized our results (Table 1) in a way designed to convey as much information as possible in a relatively small space, but this presentation has limitations. Achievement of statistically significant differences between groups may be influenced by sample size in the study and results may be statistically but not clinically significant. Our measure of ‘overall effect’ represents an attempt to deal with this issue by showing which studies reported a statistically significant treatment effect on two or more clinical outcomes. A summary of the results of all included studies showing the magnitude of treatment effects is available from the authors and will be included in an updated version of the report by Bagnall and colleagues9 that will be available from the Centre for Reviews and Dissemination (http://www.york.ac.uk/inst/crd/index.htm). Included studies As noted above, development of standardized and objective outcome measures and agreement on their use in studies remain largely unmet goals. There is also a lack of longterm follow-up data for most interventions, although a five-year follow-up of the RCT of CBT by Deale and colleagues showed maintained benefit of the intervention for several outcomes52 and a two-year follow-up of one RCT of GET was published in 2004.53 The studies included in our review also show a lack of uniformity in terms of case definitions for CFS/ME, study inclusion and exclusion criteria and the basic information provided about the participants. For example, baseline functional status and duration of illness are not always reported. It is therefore difficult to assess the generalizability of the findings of many of these studies. Although we have discussed all the studies evaluating a particular intervention together, the treatment offered to patients receiving a particular type of therapy in practice may vary considerably, particularly for behavioural interventions. For example, in the CBT study by Stulemeijer et al.,29 participants in the intervention group received ten individual therapy sessions over five months in a hospital child psychology department, whereas in the study by Whitehead et al.54 the intervention was a form of 'brief CBT' delivered by general practitioners. Further standardization of methods for delivering behavioural interventions in research and practice would be desirable. Strengths and weaknesses in relation to other studies This updated systematic review confirms and extends the conclusions of previous reviews in this area.5,6,8,9 Evidence reviews also informed guidelines for the treatment or management of CFS/ME published in Australia55 and the Royal College of Paediatrics and Child Health (RCPCH) guidelines covering children and young people.56 The Australian guidelines concluded that CBT and GET 'may be effective for some people with CFS' (based on level 1 and 2 evidence, respectively). This is similar to the conclusions of our review. The recommendations for children and young people were largely developed by consensus because of a lack of specific evidence for this age group. GET and CBT were recommended for consideration based on extrapolation from studies in adults. The effectiveness of CBT for adolescents is supported by a recent high-quality RCT,29 although this had only 69 participants. Meaning of the study and implications for clinicians/policy makers Our results demonstrate that there are a considerable number of studies evaluating interventions for the treatment and management of CFS/ME and that many of them have used robust research methods; the majority of the included studies were RCTs and many of these were of high methodological quality (Table 1). However, RCTs generally scored poorly for concealment of treatment allocation and many failed to use an intention-to-treat analysis. These issues should be addressed in designing future clinical trials of interventions for CFS/ME. In view of the chronic nature of CFS/ME, future trials should be designed, as far as practicable, to collect long-term data on effectiveness and adverse events. A number of issues may limit the uptake and availability of effective interventions for CFS/ME. Behavioural interventions require the participation of trained therapists and this may raise issues both of cost and the availability of personnel. This is particularly true for CBT, which is regarded as a valid therapy option for a range of conditions. Improving the organization and delivery of psychological therapies has been identified as a priority for the UK National Health Service.57 Unanswered questions/further research Homeopathy and supplements (essential fatty acids and magnesium) have shown beneficial effects but only in one or two trials and further rigorous trials of these interventions would be helpful. Similarly, very few studies have assessed the effectiveness of interventions for children and young people and for severely affected patients. No rigorous evaluations of pacing were identified. A large trial known as PACE (Pacing, Activity and Cognitive behaviour therapy: a randomized Evaluation), involving patients attending specialist CFS/ME clinics across the UK, is underway and is due for completion in 2009. This trial is designed to compare specialist medical care against specialist medical care with the addition of adaptive pacing therapy, CBT or GET. Patient perceptions and preferences regarding interventions have been investigated but are not generally reported in studies of effectiveness. Some studies of behavioural interventions have reported significant rates of withdrawal from treatment or loss to follow-up, as high as 20-40% in some studies.48,54 Withdrawals not related to adverse events may reflect patient dissatisfaction with treatment. Our review did not find any new evidence of adverse effects (sufficient to cause withdrawal from treatment) associated with GET or CBT. However, reasons for withdrawals were often poorly reported and should be investigated in more detail in future studies. The protocols for many clinical studies require patients to attend a clinic for treatment and/or assessment. These conditions may exclude people severely affected with CFS/ME from taking part and hence bias the sample towards those with less severe symptoms. Surveys by patient organizations highlight the fact that those with the worst symptoms often receive the least support from health and social services.58 The balance between effectiveness and adverse effects of interventions may be different in more severely affected compared with less severely affected patients and methods of delivery/doses may need to be different. Research to evaluate the effectiveness of interventions for severely affected patients should be considered a priority. The FINE (Fatigue Intervention by Nurses Evaluation) trial is designed to evaluate a pragmatic rehabilitation therapy delivered by nurses in patients' homes, and hence accessible to severely affected patients.59 This trial is expected to end in 2008. Footnotes Acknowledgments We thank Vickie Orton for carrying out the literature searches and Paul Wilson for helpful comments. Authors' contributions Carol Forbes prepared the project proposal and managed the project. All authors participated in designing the study, selection of studies for the review, data extraction, data analysis and interpretation, and writing the paper, and approved the final manuscript. Guarantor Duncan Chambers is guarantor for this paper. Ethical approval Was not required. Funding/Support This project was funded by the National Institute for Health and Clinical Excellence who commissioned the National Collaborating Centre for Primary Care (part of the Royal College of General Practitioners) to produce guidelines for ‘The Diagnosis and Management of Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (or Encephalopathy) in Adults and Children’. The work forms part of the independent synthesis of research evidence to support the development of these guidelines. The views expressed in this publication are those of the authors and not necessarily those of the NCC-PC, RCGP or the Institute. The funding source had no influence on study design; in the collection, analysis, and interpretation of the data; in the writing of the report; and the decision to submit the paper for publication. Competing interests None declared. FIGURE CAPTIONS Figure 1 (A) QUORUM statement checklist of the systematic review. Figure 1 (B) QUORUM statement flow diagram of the systematic review. RCT, randomized controlled trial; CCT, controlled clinical trial TABLES Table 1 Summary of results of studies included in the review. Controlled studies are shaded in the table, all other studies are RCTs ------------------------------------------------------------------------------------- Treatment Number of Outcomes Any Overall Validity score patients investigated effect effect (Maximum 20) ------------------------------------------------------------------------------------- Behavioural CBT60 60 PH; PS; QOL + + 18 CBT48 270 PH; PS; QOL + + 16 CBT47 60 PH; PS; QOL + + 15 CBT29 69 PH; QOL + + 16 CBT + DLE61 90 PH; PS; LAB; QOL + = 13 Rehab62 47 PH; QOL + + 9 Rehab63 130 PH; PS; QOL + + 8 Rehab64 97 PH; PS; QOL + = 7 CBT54 65 PH; PS; QOL = = 3 CBT/rehab49 56 PH; QOL + = 2 CBT65 44 PH; PS; QOL = = 1 GET & Fluoxetine34 136 PH; PS; QOL + = 17 GET32 66 PH; PS; LAB; QOL + + 17 GET33,53 148 PH; PS; QOL + + 17 GET31 61 PS; PH; LAB + + 9 GET30 49 PH + + 9 Immunological Immunoglobulin50 71 PH + + 16 Immunoglobulin66 30 PH; LAB; QOL = = 15 Immunoglobulin67 49 PS; QOL + = 13 Immunoglobulin68 99 PH; PS; LAB; QOL = = 13 Staphylococcus 98 PH + + 14 toxoid36 Staphylococcus 28 PS; QOL + = 9 toxoid69 Alpha interferon70 30 LAB; QOL + = 11 Interferon71 20 PH = = 6 Acyclovir51 27 PH; PS; LAB; QOL - = 15 Ampligen72 92 RU; PH; PS + + 12 Terfenadine73 30 PH; QOL = = 12 Gancyclovir74 11 PH = = 4 Inosine pranobex35 16 PH; LAB; QOL + = 6 Pharmacological Hydrocortisone75 32 PH; QOL + = 18 Hydrocortisone76 70 PH; PS; QOL = = 14 Hydrocortisone38 120 PH; LAB + = 2 Hydrocortisone and 80 PH; PS; LAB; QOL = = 14 fludrocortisone39 Fludrocortisone77 100 PH; PS; LAB; QOL = = 18 Fludrocortisone78 25 PH; PS; QOL = = 16 Topical nasal 28 PH = = 3 corticosteroids40 Moclobemide79 90 PH; PS; LAB; QOL = = 19 Fluoxetine80 107 PH; PS; QOL = = 12 Selegiline81 25 PH; PS; QOL + = 11 Galantamine 434 PH; PS = = 15 hydrobromide37 Galanthamine 49 PH; PS; QOL = = 9 hydrobromide82 Oral NADH83 26 QOL + + 12 Pharmacological Oral NADH84 20 PH = = 3 Clonidine85 10 PS = = 12 Phenelzine86 24 PH; PS; QOL = = 10 Sulbutiamine87 326 PH; QOL = = 10 Dexamphetamine88 20 PH; QOL + = 8 Growth hormone89 20 PH = = 5 Melatonin90 30 PH; PS + + 5 Complementary/Alternative Homeopathy41 103 PH + = 17 Any homeopathic 64 QOL = = 6 remedy42 Massage therapy91 20 PH; PS; LAB + + 9 Osteopathy92 58 PH; PS; QOL = = 0 Supplements General supplements93 53 PH = = 10 General supplements94 42 PH; QOL = = 10 General supplements95 12 PH = = 6 Essential fatty 63 LAB; QOL + + 17 acids*^44 Essential fatty 50 PS; QOL = = 16 acids*46 Magnesium45 34 PH; PS; LAB; QOL + + 15 Liver extract96 15 PH; PS; QOL = = 10 Acetyl-L-carnitine and 90 PH; PS + + 10 propionyl-L-carnitine43 Pollen extract97 22 PH; PS; QOL; LAB = = 9 Acclydine and amino 90 PH; LAB + = 3 acids98 Medicinal mushrooms99 70 PH = = 3 Other interventions Combination100 72 PH + + 19 Combination101 71 QOL = = 3 Combination102 52 PS; QOL + = 2 Low sugar, low yeast 57 PH; PS = = 11 diet (Hobday et al., unpublished data) Buddy/mentor103 12 PH; PS; QOL + = 4 Group therapy104 14 PH; QOL = = 1 ------------------------------------------------------------------------------------- +, positive effect of treatment; -, negative effect of treatment; =, no effect of treatment; rehab, rehabilitation; DLE, dialyzable leukocyte extract Outcome codes: PH, physical; PS, psychological; LAB, laboratory and physiological; QOL, quality of life and general health; RU, resource use. Outcomes which showed a significant difference between intervention and control groups are highlighted in bold * Essential fatty acids (both studies) were 36mg gamma-linoleic acid (GLA), 17mg eicosapentanoic acid (EPA), 11mg docosahexanoic acid (DHA), 255mg linoleic acid (LA), plus 10 IU vitamin E Table 2 Results of new studies included in the updated review ------------------------------------------------------------------------------------------------------------------------------ Intervention Author (Year), Results number of ----------------------------------------------------------------------------------------------- participants Physical Psychological Physiological Quality of life Drop-outs/ Validity and general Adverse effect score ------------------------------------------------------------------------------------------------------------------------------ Behavioural CBT Whitehead (2002) Fatigue: no Anxiety and Disability: no At 6 months, 8 3 ^54 n=65 significant Depression: no significant in treatment difference significant difference group and 11 between difference between groups in control group groups between groups were lost to follow-up Rehabilitation Cox (2002) Physical Emotional Maintaining 6 months after 7 (NB ^64 n=97 functioning distress: no activity and discharge, 14 controlled and fatigue: significant accommodating treatment group trial) no significant differences to illness: and 16 in control differences between groups significant group did not between groups difference in return favour of questionnaires treatment group (P<0.03) Rehabilitation Cox (1999)63 Physical/ Perceived ability, Illness 5 withdrew from 8 (NB n=130 functional anxiety, depression, management: experimental controlled status, fatigue, emotional distress: significant group, 18 from trial) pain, symptoms: significant difference in control group significant difference between favour of difference groups for treatment between groups emotional group (P<0.03) for fatigue distress (P<0.03) symptoms (P<0.02) and pain (P<0.05) Rehabilitation Taylor (2004) Symptoms: Quality of life: No withdrawals 9 ^62 n=47 significant significant interaction interaction (P<0.05) (P<0.05) CBT Stulemeijer Physical School 6 patients 16 (2005)29 n=69 functioning, attendance: dropped out fatigue, significant during treatment. symptoms: difference in 7 were missing significant favour of from CBT group difference in treatment and 2 from control favour of CBT group (P=0.04) group at final group (P<0.003) assessment Modified CBT Viner (2004) CFS severity: Global wellness, No withdrawals 2 (NB ^49 n=56 better result in school controlled intervention attendance: trial) group, significance significantly not reported better in treatment group (P<0.05) GET Moss-Morris CGI, fatigue: 3/25 dropped out 9 (2005)30 n=49 significant of treatment and difference in 3/24 did not return favour of questionnaires at treatment group 12 weeks (P<0.03) GET Wallman (2004) Fatigue: Depression, Resting and One excluded 9 ^31 n=61 significantly anxiety: target heart after randomization better in significantly rate and blood because BMI too treatment group better in pressure, high to participate (P=0.027) treatment group exercise test in exercise test. (P=0.027) values: None reported comparisons during the study not made between groups Immunological Inosine Diaz-Mitoma Symptoms, Cognitive Immune function: Global 1 withdrawal in 6 pranobex (2003)35 n=16 fibromyalgia function: no significant severity, each group. tender points: significant improvements activities of Transient no significant differences in treatment daily living, elevation of difference between groups group (P<0.03) Karnofsky serum uric acid between groups Performance (presumably in differences treatment between groups group) Staphylococcus Global impression, 10 dropouts 14 toxoid Zachrisson symptoms, pain: during study. (2002)36 n=98 statistically 13 patients significant in the treatment difference in group and 7 in favour of treatment the placebo group group for CGI experienced side (P<0.001) and effects. 'feeling good' item on fibromyalgia impact questionnaire Pharmacological Galantamine Blacker (2004) Global Cognitive 130 patients 15 hydrobromide ^37 n=434 impression, function: no withdrew. 389 fatigue, significant patients reported symptoms: no difference adverse events, of significant between groups which 88 withdrew differences between groups Hydrocortisone Cleare (2002) Fatigue: Hormone levels: 2 ^38 n=120 'significantly' greater increase in greater cortisol response improvement in to HCRH in treatment group treatment group (P not reported) (significance not reported) Hydrocortisone Blockmans Fatigue: no Anxiety and Blood pressure: SF-36, 9 in treatment 14 and (2003)39 n=80 significant depression: no no significant wellbeing: no group and 11 in fludrocortisone differences significant differences significant placebo group between groups differences between groups differences dropped out. Only between groups between groups one dropped out due to adverse events Topical Kakumanu (2001 Fatigue, Daily activity: 3 nasal ^40 n=28 daytime no significant corticosteroids sleepiness, improvement with muscle pain: treatment no significant improvement Oral NADH Santaella Symptoms: no 11 dropped out 3 (2004)84 n=20 significant of 31 initially difference randomized. No between groups adverse events were reported in treatment group Dexamphetamine Olson (2003) Fatigue, sleep: SF36 scores: Reduced food 8 ^88 n=20 significant no significant consumption difference in difference reported by 5 favour of between groups patients in treatment group treatment group, for fatigue one in placebo (P<0.02) group Clonidine Morriss (2002) Cognitive One patient 12 ^85 n=10 function: no withdrew after significant GP prescribed effects fluoxetine Melatonin vs Williams Symptoms, Anxiety, 12 of initial 5 phototherapy (2002)90 n=30 fatigue: depression: 42 patients improved sleep significant withdrew, 10 (P=0.03), effects of due to time and vitality treatment social demands (P=0.016) and of the study mental health (P=0.046) with melatonin, worsening of bodily pain (P=0.044) Complementary/Alternative Fatigue, 11 withdrew from 17 Homeopathy Weatherley- functional treatment arm Jones (2004) limitations: (5 did not ^41 n=103 significant complete differences in treatment) and 8 favour of placebo arm (6 treatment group did not complete for fatigue treatment) (P=0.04) and some physical dimensions of the Functional Limitations Profile (P value not reported) Supplements Vermeulen Global 8 patients 10 Acetyl-L- (2004)43 n=90 improvement, Attention, withdrew to carnitine and fatigue, concentration: side effects propionyl-L- pain: 'significant' and 8 withdrew carnitine significant improvements due to lack of improvement in all groups efficacy. in general fatigue in PLC (P=0.004) and combined group (P<0.001); significant improvement in mental fatigue in ALC group (P=0.015) Acclydine De Becker Global IGF-1 levels: 3 (NB and amino (2001)98 n=90 improvement, significantly controlled acids symptoms: more trial) improvements improvement in seen in intervention intervention than placebo group above group control group (P<0.0002) but groups were not compared statistically Pollen Ockerman Fatigue, Depression: Erythrocyte 1 withdrawal 9 extract (2000)97 n=22 sleep, comparisons fragility: due to moving symptoms: were not made comparisons away. 'Slight comparisons between groups were not made intestinal were not between groups inconvenience' made between was the only groups side effect for a few days in 1 or 2 patients RM-10: Rothschild Symptoms: 2 dropped out 3 medicinal (2002)99 n=70 improved of treatment mushrooms more in the group, not treatment reported for group placebo group. (measure of significance not presented) General Brouwers Fatigue, 3 dropped out 10 supplements (2002)93 n=53 symptoms, from the improvement, supplement functional group due to impairment, nausea, and activity: no one in each significant group for differences other reasons between groups Other interventions Group Soderberg Fatigue: Quality of One withdrawal 1 therapy (2001)104 n=14 results not life: in control group reported comparisons were not made between groups Low sugar (2005, Fatigue: no Anxiety, General health: 8 in the LSLY arm 11 low yeast unpublished) significant depression: no no significant and 9 in the diet Hobday n=57 differences significant differences control arm were between differences between groups lost to follow-up groups between groups ------------------------------------------------------------------------------------------------------------------------------ REFERENCES 1. Sharpe MC, Archard LC, Banatvala JE, et al. 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A feasibility study comparing two treatment approaches for chronic fatigue syndrome in adolescents. Arch Dis Child2005; 90:369-72 28. Dotsenko VA, Mosiichuk LV, Paramonov AE. [Biologically active food additives for correction of the chronic fatigue syndrome]. Vopr Pitan 2004;73:17-21 29. Stulemeijer M, de Jong LW, Fiselier TJ, Hoogveld SW, Bleijenberg G. Cognitive behaviour therapy for adolescents with chronic fatigue syndrome: randomised controlled trial. BMJ2005; 330:14 30. Moss-Morris R, Sharon C, Tobin R, Baldi JC. A randomized controlled graded exercise trial for chronic fatigue syndrome: outcomes and mechanisms of change. J Health Psychol2005; 10:245-59 31. Wallman KE, Morton AR, Goodman C, Grove R, Guilfoyle AM. Randomised controlled trial of graded exercise in chronic fatigue syndrome. Med J Aust2004; 180:444-8 32. Fulcher KY, White PD. Randomised controlled trial of graded exercise in patients with the chronic fatigue syndrome. BMJ1997; 314:1647-52 33. Powell P, Bentall RP, Nye FJ, Edwards RH. Randomised controlled trial of patient education to encourage graded exercise in chronic fatigue syndrome. BMJ2001; 322:387-90 34. Wearden AJ, Morriss RK, Mullis R, et al. Randomised, double-blind, placebo-controlled treatment trial of fluoxetine and graded exercise for chronic fatigue syndrome. Br J Psychiatry1998; 172:485-90 35. Diaz-Mitoma F, Turgonyi E, Kumar A, Lim W, Larocque L, Hyde BM. Clinical improvement in chronic fatigue syndrome is associated with enhanced natural killer cell-mediated cytotoxicity: the results of a pilot study with Isoprinosine. J Chronic Fatigue Syndr2003; 11:71-93 36. Zachrisson O, Regland B, Jahreskog M, Jonsson M, Kron M, Gottfries CG. Treatment with staphylococcus toxoid in fibromyalgia/chronic fatigue syndrome-a randomised controlled trial. European Journal of Pain: EJP 2002;6:455-66 37. Blacker CVR, Greenwood DT, Wesnes KA, et al. Effect of galantamine hydrobromide in chronic fatigue syndrome: A randomized controlled trial. JAMA2004; 292:1195 38. Cleare A. Hydrocortisone treatment in CFS. Int J Neuropsychopharmacol 2002; 5(Suppl 1):S35 39. Blockmans D, Persoons P, Van Houdenhove B, Lejeune M, Bobbaers H. Combination therapy with hydrocortisone and fludrocortisone does not improve symptoms in chronic fatigue syndrome: a randomized, placebo-controlled, double-blind, crossover study. Am J Med2003; 114:736-41 40. Kakumanu S, Mende C, Lehman E, Yeageer M, Craig T. The effect of topical nasal corticosteroids in patients with chronic fatigue syndrome and rhinitis. J Allergy Clin Immunol2001; 107:S153 41. Weatherley-Jones E, Nicholl JP, Thomas KJ, et al. A randomised, controlled, triple-blind trial of the efficacy of homeopathic treatment for chronic fatigue syndrome. J Psychosom Res 2004;56:189-97 42. Awdry R. Homeopathy may help ME. Int J Alternat Complement Med1996; 14:12-6 43. Vermeulen RC, Scholte HR. Exploratory open label, randomized study of acetyl- and propionylcarnitine in chronic fatigue syndrome. Psychosom Med2004; 66:276-82 44. Behan PO, Behan WM, Horrobin D. Effect of high doses of essential fatty acids on the postviral fatigue syndrome. Acta Neurol Scand 1990;82:209-16 45. Cox IM, Campbell MJ, Dowson D, Davies S, Walden RJ. Magnesium and chronic fatigue syndrome. Lancet1991; 337:1295 46. Warren G, McKendrick M, Peet M. The role of essential fatty acids in chronic fatigue syndrome. A case-controlled study of red-cell membrane essential fatty acids (EFA) and a placebo-controlled treatment study with high dose of EFA. Acta Neurol Scand1999; 99:112-6 47. Sharpe M, Hawton K, Simkin S, et al. Cognitive behaviour therapy for the chronic fatigue syndrome: a randomized controlled trial. BMJ1996; 312:22-6 48. Prins JB, Bleijenberg G, Bazelmans E, et al. Cognitive behaviour therapy for chronic fatigue syndrome: a multicentre randomised controlled trial. Lancet2001; 357:841-7 49. Viner R, Gregorowski A, Wine C, et al. Outpatient rehabilitative treatment of chronic fatigue syndrome (CFS/ME). Arch Dis Child 2004;89:615-9 50. Rowe KS. Double-blind randomized controlled trial to assess the efficacy of intravenous gammaglobulin for the management of chronic fatigue syndrome in adolescents. J Psychiatr Res1997; 31:133-47 51. Straus SE, Dale JK, Tobi M, et al. Acyclovir treatment of the chronic fatigue syndrome. Lack of efficacy in a placebo-controlled trial. N Engl J Med1988; 319:1692-8 52. Deale A, Husain K, Chalder T, Wessely S. Long-term outcome of cognitive behavior therapy versus relaxation therapy for chronic fatigue syndrome: a 5-year follow-up study. Am J Psychiatry2001; 158:2038-42 53. Powell P, Bentall RP, Nye FJ, Edwards RH. Patient education to encourage graded exercise in chronic fatigue syndrome. 2-year followup of randomised controlled trial. Br J Psychiatry2004; 184:142-6 54. Whitehead L, Campion P. Can general practitioners manage Chronic Fatigue Syndrome? A controlled trial. J Chronic Fatigue Syndr 2002;10:55-64 55. Royal Australasian College of Physicians. Chronic fatigue syndrome. Clinical practice guidelines-2002. Med J Aust2002; 176:S19-55 56. Royal College of Paediatrics and Child Health. Evidence Based Guideline for the Management of CFS/ME (Chronic Fatigue Syndrome/Myalgic Encephalopathy) in Children and Young People. London: Royal College of Paediatrics and Child Health; 2004 57. Department of Health. Organising and Delivering Psychological Therapies. London: Department of Health;2004 58. Action for M.E. Severely Neglected: M.E. in the UK-Membership Survey London: Action for M.E.;2001 59. Wearden AJ, Riste L, Dowrick C, et al. Fatigue Intervention by Nurses Evaluation- the FINE trial. A randomised controlled trial of nurse led self-help treatment for patients in primary care with chronic fatigue syndrome: study protocol. BMC Medicine2006; 4:9 60. Deale A, Chalder T, Marks I, Wessely S. Cognitive behavior therapy for chronic fatigue syndrome: a randomized controlled trial. Am J Psychiatry 1997;154:408-14 61. Lloyd AR, Hickie I, Brockman A, et al. Immunologic and psychologic therapy for patients with chronic fatigue syndrome: a double-blind, placebo-controlled trial. Am J Med1993; 94:197-203 62. Taylor RR, Braveman B, Hammel J. Developing and evaluating community-based services through participatory action research: two case examples. Am J Occup Ther2004; 58:73-82 63. Cox DL. An Evaluation of an Occupational Therapy Inpatient Intervention for Chronic Fatigue Syndrome [Ph.D]. London: King's College London, 1999 64. Cox DL. Chronic fatigue syndrome: An evaluation of an occupational therapy inpatient intervention. Br J Occup Ther2002; 65:461-68 65. Friedberg F, Krupp LB. A comparison of cognitive behavioral treatment for chronic fatigue syndrome and primary depression. Clin Infect Dis1994; 18 (Suppl 1):S105-10 66. Peterson PK, Shepard J, Macres M, et al. A controlled trial of intravenous immunoglobulin G in chronic fatigue syndrome. Am J Med1990; 89:554-60 67. Lloyd A, Hickie I, Wakefield D, Boughton C, Dwyer J. A double-blind, placebo-controlled trial of intravenous immunoglobulin therapy in patients with chronic fatigue syndrome. Am J Med1990; 89:561-8 68. Vollmer-Conna U, Hickie I, Hadzi-Pavlovic D, et al. Intravenous immunoglobulin is ineffective in the treatment of patients with chronic fatigue syndrome. Am J Med1997; 103:38-43 69. Andersson M, Bagby JR, Dyrehag LE, Gottfries CG. Effects of staphylococcus toxoid vaccine on pain and fatigue in patients with fibromyalgia/chronic fatigue syndrome. European Journal of Pain: EJP 1998;2:133-42 70. See DM, Tilles JG. a-Interferon treatment of patients with chronic fatigue syndrome. Immunol Invest1996; 25:153-64 71. Brook MG, Bannister BA, Weir WR. Interferon-alpha therapy for patients with chronic fatigue syndrome. J Infect Dis1993; 168:791-2 72. Strayer DR, Carter WA, Brodsky I, et al. A controlled clinical trial with a specifically configured RNA drug, poly(I).poly(C12U), in chronic fatigue syndrome. Clin Infect Dis1994; 18(Suppl 1):S88-95 73. Steinberg P, McNutt BE, Marshall P, et al. Double-blind placebo- controlled study of the efficacy of oral terfenadine in the treatment of chronic fatigue syndrome. J Allergy Clin Immunol1996; 97:119-26 74. Lerner AM, Zervos M, Chang CH, et al. A small, randomized, placebo-controlled trial of the use of antiviral therapy for patients with chronic fatigue syndrome [comment]. Clin Infect Dis2001; 32:1657-8 75. Cleare AJ, Heap E, Malhi GS, Wessely S, O'Keane V, Miell J. Lowdose hydrocortisone in chronic fatigue syndrome: a randomised crossover trial. Lancet1999; 353:455-8 76. McKenzie R, O'Fallon A, Dale J, et al. Low-dose hydrocortisone for treatment of chronic fatigue syndrome: A randomized controlled trial. JAMA1998; 280:1061-66 77. Rowe PC, Calkins H, DeBusk K, et al. Fludrocortisone acetate to treat neurally mediated hypotension in chronic fatigue syndrome: a randomized controlled trial. JAMA2001; 285:52-9 78. Peterson PK, Pheley A, Schroeppel J, et al. A preliminary placebo- controlled crossover trial of fludrocortisone for chronic fatigue syndrome. Arch Intern Med1998; 158:908-14 79. Hickie IB, Wilson AJ, Wright J, Bennett BK, Wakefield D, Lloyd AR. A randomized, double-blind, placebo-controlled trial of moclobemide in patients with chronic fatigue syndrome. J Clin Psychiatry 2000;61:643-48 80. Vercoulen J, Swanink CMA, Zitman FG, et al. Randomised, double-blind, placebo-controlled study of fluoxetine in chronic fatigue syndrome. Lancet1996; 347:858-61 81. Natelson BH, Cheu J, Hill N, et al. Single-blind, placebo phase-in trial of two escalating doses of selegiline in the chronic fatigue syndrome. Neuropsychobiology1998; 37:150-4 82. Snorrason E, Geirsson A, Stefansson K. Trial of a selective acetylcholinesterase inhibitor, galanthamine hydrobromide, in the treatment of chronic fatigue syndrome. J Chronic Fatigue Syndr1996; 2:35-54 83. Forsyth LM, Preuss HG, MacDowell AL, Chiazze L Jr, Birkmayer GD, Bellanti JA. Therapeutic effects of oral NADH on the symptoms of patients with chronic fatigue syndrome. Ann Allergy Asthma Immunol1999; 82:185-91 84. Santaella ML, Font I, Disdier OM. Comparison of oral nicotinamide adenine dinucleotide (NADH) versus conventional therapy for chronic fatigue syndrome. P R Health Sci J.2004; 23:89-93 85. Morriss RK, Robson MJ, Deakin J. Neuropsychological performance and noradrenaline function in chronic fatigue syndrome under conditions of high arousal. Psychopharmacology (Berl)2002; 163:166-73 86. Natelson BH, Cheu J, Pareja J, Ellis P, Policastro T, Findley TW. Randomized, double-blind, controlled placebo phase in trial of low dose phenelzine in the chronic fatigue syndrome. Psychopharmacology (Berl) 1996;124:226-30 87. Tiev KP, Cabane J, Imbert JC. Treatment of chronic postinfectious fatigue: randomized double-blind study of two doses of sulbutiamine (400-600 mg/day) versus placebo. Rev Med Interne1999; 20:912-8 88. Olson LG, Ambrogetti A, Sutherland DC. A pilot randomized controlled trial of dexamphetamine in patients with chronic fatigue syndrome. Psychosomatics2003; 44:38-43 89. Moorkens G, Wynants H, Abs R. Effect of growth hormone treatment in patients with chronic fatigue syndrome: A preliminary study. Growth Horm IGF Res 1998;8:131-33 90. Williams G, Waterhouse J, Mugarza J, Minors D, Hayden K. Therapy of circadian rhythm disorders in chronic fatigue syndrome: no symptomatic improvement with melatonin or phototherapy. Eur J Clin Invest 2002;32:831-7 91. Field TM, Sunshine W, Hernandez-Reif M, et al. Massage therapy effects on depression and somatic symptoms in chronic fatigue syndrome. J Chronic Fatigue Syndr1997; 3:43-51 92. Perrin RN, Edwards J, Hartley P. An evaluation of the effectiveness of osteopathic treatment on symptoms associated with Myalgic Encephalomyelitis. A preliminary report. J Med Eng Technol 1998;22:1-13 93. Brouwers FM, Van Der Werf S, Bleijenberg G, Van Der Zee L, Van Der Meer JW. The effect of a polynutrient supplement on fatigue and physical activity of patients with chronic fatigue syndrome: a double-blind randomized controlled trial. QJM2002; 95:677-83 94. Martin RWY, Ogston SA, Evans JR. Effects of vitamin and mineral supplementation on symptoms associated with chronic fatigue syndrome with Coxsackie B antibodies. J Nutr Med1994; 4:11-23 95. Stewart W, Rowse C. Supplements help ME says Kiwi study. J Altern Complement Med1987; 5:19-20 96. Kaslow JE, Rucker L, Onishi R. Liver extract-folic acid-cyanocobalamin vs placebo for chronic fatigue syndrome. Arch Intern Med 1989;149:2501-3 97. Ockerman PA. Antioxidant treatment of chronic fatigue syndrome. Clinical Practice of Alternative Medicine2000; 1:88-91 98. De Becker P, Nijs J, Van HE, McGregor N, De MK. A double-blind, placebo-controlled study of acclydine in combination with amino acids in patients with chronic fatigue syndrome. AHMF Proceedings, "Myalgic Encephalopathy/Chronic Fatigue Syndrome The Medical Practitioners' Challenge in 2001".2001 99. Rothschild PR, Huertas JG. Ambulatory naturopathic treatment of chronic fatigue immune deficiency syndrome (CFIDS) with RM-10 caplets. Progress in Nutrition2002; 4:77-96 100. Teitelbaum JE, Bird B, Greenfield RM, Weiss A, Muenz L, Gould L. Effective treatment of chronic fatigue syndrome and fibromyalgia- A randomized, double-blind, placebo-controlled, intent-to-treat study. J Chronic Fatigue Syndr2001; 8:3-28 101. Marlin RG, Anchel H, Gibson JC, Goldberg WM, Swinton M. An evaluation of multidisciplinary intervention for chronic fatigue syndrome with long-term follow-up, and a comparison with untreated controls. Am J Med 1998;105:110S-14S 102. Goudsmit E. Learning to Cope with Post-Infectious Fatigue Syndrome, a Follow-up Study. Brunel,1996 103. Schlaes J, Jason L. A buddy/mentor program for PWCs. CFIDS Chronicle 1996:21-5 104. Soderberg S, EvengÃ¥rd B. Short-term group therapy for patients with chronic fatigue syndrome. Psychother Psychosom 2001;70:108-11 -------- (c) 2006 The Royal Society of Medicine [Return to top] ------------------------------ Date: Thu, 5 Oct 2006 13:42:35 -0700 From: Co-Cure moderators <cocuremoderator@xxxxx.xxx> Subject: MED: Lyme Disease: Let's Dispel the Myths >From ME Essential, Issue 100. October 2006 pages 20 and 21. Lyme Disease - let's dispel the myths LD specialist Dr. Darrel Ho-Yen urges caution over the bug that can be confused with ME The Internet has fuelled hysteria about Lyme disease. Lyme disease (LD) was discovered in 1975, with the first human case due to Borrelia burgdorferi being identified in 1983. Whereas many may know that I wrote the first book on ME, Better Recovery from Viral Illnesses, in 1985, and that this book is now in its fourth edition, many may not know that my first scientific publication on Lyme disease was in 1989, and that our laboratory in Inverness provides a Lyme testing service for Scotland. More importantly, I receive many emails, letters and telephone calls on LD from all over the world. Such communications have one thing in common: patients are worried about LD. Such anxieties and concerns are based on what they have heard or read and what they are being told by friends and relatives. These myths are many and varied: The Internet has the best information on Lyme disease This seems a very reasonable statement as the Internet has access to the most experts worldwide. The difficulty is separating the right information from the wrong. There needs to be judgement on what is being said. Unfortunately, looking for the right information can be like looking for a needle in a haystack. It may be difficult to find. In many cases, information on LD and ME is wrong. Doctors are ignorant of LD This appears to be an outrageous statement but has elements of truth in it. LD is a recently identified illness and is described as "an emerging infection." This means that many doctors have not studied this infection at medical school and that more information is emerging on this disease. This is not uncommon in medicine and indeed is to be expected. It also has to be balanced by the fact that not all areas of Britain have equal prevalence of LD. There are many urban areas where LD is very uncommon whereas in rural areas there is greater awareness and knowledge. Again, this is not a judgement on the medical profession but simply a reflection of reality. Those doctors in rural areas have to diagnose and manage LD. Most ME is Lyme Disease LD is characterised by early and late disease. The clinical syndromes of early disease are well recognised, such as the characteristic rash (erythema migrans); whereas late disease has characteristic clinical syndromes (for example, dermatological, cardiac, rheumatoid), but also includes a fatigue state. Therefore, it is only the late disease fatigue state that has common features with ME. Overall, this may represent only 10% of all LD infections. It is certainly not the majority of LD infections and most ME sufferers do not have LD. In the Highlands of Scotland, we have the greatest tick populations and it has been my routine in the investigation of ME patients to have them tested for LD. In this large series of patients who have had very significant exposure to ticks, the number of ME patients who have LD as the cause of their illness is around 5%. Antibiotics can cure LD This is a very attractive proposition. The truth of the matter is that in LD, early disease is amenable to antibiotic treatment and is curative. Unfortunately, late disease does not have the same response to antibiotics. In other countries, this has meant that prolonged treatment with antibiotics (often a year or longer) has been recommended. The very need for such prolonged treatment with antibiotics suggests that the success rate is not good. Indeed, it is difficult to separate the natural improvement that occurs with chronic disease from the effects of antibiotic treatment. Antibiotic treatment has limited success in late LD patients with symptoms comparable to that of ME. Instead, such patients should be managed, as is explained in my book, Better Recovery from Viral Illnesses, fourth edition, www.dodonabooks.co.uk All laboratories produce dependable results All NHS laboratories in Britain have to be accredited by Clinical Pathology Accreditation (UK) Ltd. If there is a diagnosis of LD without such accreditation, the diagnosis is suspect. Many patients are also seeking diagnosis by European or American Laboratories, and many such laboratories do not have appropriate accreditation. It is important to recognise that accreditation allows the user to have confidence in the report. Unaccredited laboratories can produce suspect results and may be influenced by the patient paying for the test. Within the accredited laboratory, all of its procedures have to be reproducible and subject to internal and external quality assurance. This guarantees that quality of the product to the user. Anyone receiving a diagnosis of LD should ensure that this is from an accredited laboratory. Misleading expert comment Experts have said that LD is ten times more common than is reported. This is absolutely true. Unfortunately, this statement is usually applied to all LD infections: from asymptomatic, flu-like illness to the well-defined clinical presentations. The number of patients that fall into the group of late LD with a comparable illness such as ME is small. LD accounts for 5% of ME patients in an area where there is great tick exposure. In future, if there is better diagnosis of LD, the amount of patients could double. However, the important consideration is how these patients should be managed. Summary LD is a new, emerging infection. Much is being written and discovered about this infection, and most of it is exciting and very helpful. Unfortunately, the Internet and certain groups have emphasised 10% of the information on LD rather than the 90%. It is important that all ME patients have a balanced approach to information on LD, especially as the management of late LD patients is similar to that of ME patients in which there are no obvious infectious disease causes. The answer is in making a balanced judgement, taking responsibility for your illness and sticking to guidelines. To blame others for not getting a diagnosis or appropriate management may not be helpful. In the end, it is a matter of what makes you better. *Dr. Darrel Ho-Yen is head of microbiology at the Raigmore Hospital, Inverness. (Further facts) (Picture of an engorged tick "The culprit" a tick) Fears over Lyme Disease as ticks flourish From the Daily Mail, September 1st. Rising temperatures have sparked a boom in the number of ticks carrying a dangerous blood-borne disease, experts have warned. The increase in levels of the insect has put people in danger of contracting Lyme Disease, which if left undiagnosed can trigger serious heart and joint problems. The rise was noticed after scientists were instructed by the Government to investigate why increasing numbers of farm animals were developing a virus transmitted by the parasites. They found there had been an apparent rise in ticks in recent months in Britain and warned this also had alarming implications for humans. Last year there were 600 laboratory confirmed cases of Lyme Disease in England and Wales, however some believe as many as 2,000 people may now be catching it every year. People are particularly at risk when in forests or in long grass where they are more likely to be bitten by the insects. The Department for Environment, Food and Rural Affairs (Defra) commissioned Professor Sarah Randolph from the Zoology Department at Oxford University to investigate what was triggering the rise. Although her work will not be completed for another year, she already has results back from 136 locations across the country. Based on the findings so far, she concluded: "Evidence does seem to indicate an increase in tick numbers. Everyone does seem to be concerned with an increase in incidence of certain diseases. Then there is also the very important issue of ticks' hosts which are mostly deer in the UK and also sheep and cattle." The disease is caused by a bacteria which ticks carry and is transmitted into the person when it begins to draw blood. Lyme Disease was discovered following a cluster of cases in the 1970s among young people living in Old Lyme in Connecticut, USA. However it is thought to have been around in Europe since the 1880s. It often begins with flu-like symptoms and then several days or weeks later 60 per cent of people notice an expanding rash. At this stage it can be treated with antibiotics, but if it is allowed to progress it can become very difficult to beat. It can then lead to long-term fatigue, plus create problems in the heart, joints and nervous system. ME Essential October 2006. [Return to top] ------------------------------ Date: Thu, 5 Oct 2006 20:47:16 -0400 From: "Marly Silverman <beatcfsfms@xxxxx.xxx> via Co-Cure Moderator" Subject: NOT,MED: IACFS 8th Annual Conference on Chronic Fatigue Syndrome, Fibromyalgia, Gulf War Syndrome, and other related illnesses [Note: For those who may wish to print this notice, a properly type-set version exists in PDF format at http://www.co-cure.org/conf8.pdf ] P.A.N.D.O.R.A. Hope. The only antidote! © PATIENT ALLIANCE FOR NEUROENDOCRINEIMMUNE DISORDERS ORGANIZATION FOR RESEARCH AND ADVOCACY - 501 c 3 - ID # 550795076 C/O VINA + COMPANY, 255 Alhambra Circle, Suite 715, Coral Gables, Florida 33134 Phone: 305-441-1591 Volunteer Help line: 954-783-6771 - www.pandoranet.info October 5, 2006 AN OPEN INVITATION TO OUR COMMUNITY Dear Friends, From January 10-14, 2007, we are co-hosting, with the International Association of Chronic Fatigue Syndrome (IACFS), their 8th Annual Conference on Chronic Fatigue Syndrome, Fibromyalgia, Gulf War Syndrome, and other related illnesses -www.iacfs.net to be held at the ocean-front Bahia Mar Resort in Fort Lauderdale. Some highlights of the 2007 international patient and professional conference are: * Presentation of the 2007 Advocates Extraordinaire/Sand Castles Scholarship Awards" a special leadership and advocacy agenda. Goals of this program are to: * Refresh skills of strong active advocates and encourage new ones to join our ranks. * Enable patients, family members, and/or caregivers become successful advocates on behalf of our community as well as an opportunity for sharing, supporting an embracing each other as a big family. * Presentations by special advocates, encouraging them to share their success stories (and hurdles) with others in our community: * Provision of a unique time to network within our international community * Allow members of the many nonprofit organizations and well organized groups, who have similar goals, the opportunity to get acquainted in a more intimate environment; share resources; and foster lifelong friendships, respect, and encouragement. * Exchange and debate ideas to strengthen cause and overall mission. * Support of the International Association for Chronic Fatigue Syndrome (IACFS) which is among the few professional medical associations that share a most important component of our entire community's mission - that research for chronic fatigue syndrome and fibromyalgia be placed in the forefront. * Establishment of a strong scientific research environment to foster greater opportunities and find cures for the illnesses for which we are advocating: * Meet the many researchers; physicians; and federal, state, and local health agencies, including the Centers of Disease Control and Prevention and the National Institute of Health, the Office of Research on Women's Health and many more. * Enhancing and creating "unity in action" by displaying a strong community front to strengthen our overall community advocacy and educational efforts. Save the dates January 10-14, 2007. Share P.A.N.D.O.R.A.'s flyer with friends, family, medical and allied health care professionals, and potential exhibitors and sponsors. A visit to South Florida in January, when most of the country is shivering from the cold, will be a wonderful winter respite. The weather will be fabulous, and Florida's sandy beaches will be extremely inviting during the days of the conference. I look forward to Well-Coming© you in Florida at the IACFS 2007 conference! In Good Health and In Beauty, Marly C. Silverman Founder P.A.N.D.O.R.A., Inc. Co-Chair - IACFS Patient Conference Planning Committee Built on Hope - Strong on Advocacy - Finding a Cure through Research [Return to top] ------------------------------ Date: Thu, 5 Oct 2006 21:45:50 -0400 From: Rika Kageyama via Co-Cure Moderator <ray@xxxxx.xxx> Subject: MED: CFS, possibly the immune dysfunction Dear all on the Co-Cure, This is Rika Kageyama from Tokyo, Japan. I was diagnosis with the CFS in 1989 (onset 1979), developed the RP (relpasing polychondritis) in 1995, the Lymph-TB in 2002 and currently the Colon-TB. Quite a department store of immune related disease. I will share my recent episode here. Currently I have been taking the prednisolne for 17.5mg/day (started from a mild dosage, 20mg/day, but I flared the RP symptoms when reduced the dosage. So, we have been stay on the dosage, 17.5mg/day). I am taking the prednisolone for long term. As long as I also cope with my TB (extra-plumonary, currently "colon TB"), I don't know what will happen in my future. My trachea symptoms have been progressed very gradually (dropping the oxygen saturation level very-very gradually. Luckily, I still have around 95). No obvious narrowing or abnormal for the visible tests though. The problem is that (some might remember but) I can not cure my TB due to the chemical allergy against the anti- TB agents. (I can not use four of four anti TB agents to cure as the CDC has recommended). Obviously, my TB is recurring. I have to use the prednisolone to control my RP symptoms. I believe my symptoms are not severe as I have to take the immuno supressants, such as immuran and azatioprin, or methotrexate. So, for the moment, I don't worry about the worst scenario. But, I do know it is the problem of "time". I have been under the very odd (troublesome) situation. Still need more investigation about the relationship between "my" CFS (chronic fatigue syndrome - real disease) and "my" RP. (Possibly, about "my" TB, also). I was told by my rheumatologist at the university hospital that I have to be hospitalized again for the investigation as soon as my colon TB will be subsided (Probably, in the spring in next year). Regarding the RP (relapsing polychondritis), my hospital is the university hospital at the University of Tokyo. My physician (Rheumatologist) is Prof. Kazuhiko Yamamoto. I will let you know when I learn something from the further investigation at the university. (I don't know if they will let me know some important thing though! Well, at least they will publish something for public or in journals). I believe the university and its hospital has broad minded for all of the patients and researchers in the world. My situation is much serious than I expected and their situation is more troublesome than they thought. I share this because, to me, all I have experienced have been the immune related diseases (CFS, RP, TB). My sed-rate, CRP have been normal as usual. Hugs to all, Rika Kageyama From Tokyo, Japan *CFS 1979 *RP 1995 *TB (extra-pulmonary) 2002- [Return to top] ------------------------------ Date: Thu, 5 Oct 2006 23:05:23 -0700 From: "Mary Schweitzer..........via Co-Cure moderators" Subject: RES,ACT: Royal Colleges Review of CFS therapies I want to thank Dr. Fluks for the copy of the Royal Colleges review of ME/CFS therapies by Duncan Chambers, Anne-Marie Bagnall, Susanne Hempel, and Carol Forbes. I found it strange that the authors wrote so positively of cognitive behavior therapy (CBT) and graded exercise therapy (GET): "As with CBT, the overall results of studies to date suggest that [GET] may have positive effects on the syptoms of CFS/ME" when in the same paragraph they admit that "Most ... studies of CBT and modified CBT have also favoured the treatment for one or more outcomes but these were either lower quality [random control trials] RCTs or non-randomized studies ... No severely affected patients were included in the studies of GET." They mentioned only two studies of immune therapies, both "associated with relatively high levels of adverse events." And then, "Treatment of CFS/ME with pharmacological therapies has given disappointing results in most cases.' Finally, their "statement of principal findings": "A number of [random control trials] RCTs suggest that behavioural interventions, including elements of CBT, GET and rehabilitation, may reduce symptoms and improve physical functioning of people with CFS/ME. Immnological and anti-viral treatments may have beneficial efects but are also associated with harmful side-effects. Most pharmacological treatments have not shown beneficial efects." That was not how I read their own measurement of success or failure (a ranking where 0 is a total failure and 20 is total success) in the table included with the study. There were eight studies using cognitive behavior therapy (CBT). The quality scores ranged from 1 to 18, with an average of 10.5 and a median of 9. The three "rehab" studies showed an average and median score of 8. Graded exercise therapy (GET) was successful when used in conjunction with fluoxetine (florinef), a treatment for NMH/POTS (overall score of 17). Four other studies did show positive results, with an average score of 13. The method of scoring apparently did not take into account the problem of the number of patients withdrawing from the studies, and it is also well to remember the controversy swirling around GET with regard to studies that "cherry-pick" their patients (i.e., choose only those patients well enough to be able to exercise in the first place). To repeat, as the authors themselves stated, "No severely affected patients were included in the studies of GET." Of four studies using immunoglobin, one had positive impacts and rated a score of 16. The others did not have statistically significant effects, yet somehow rated scores of 15, 13, and 13 respectively. Ampligen had positive scores for "any" and "overall" effect - the best their analysis coud do - and ranked 11, better than most of the CBT studies. Other pharmaceuticals that ranked as high as CBT using their system, but did not have a positive "overall effect" score, included Alpha interferon (11), Acyclovir (15), and terfenadine (12). Clonidine, Phenelzine, and Sulbutiamine had neither positive nor negative impacts, but ranked as high as CBT - 12, 10, and 10. In terms of supplements, two "essential fatty acids" studies had positive results and very high rankings - 16 and 17 respectively. Carnitine, liver extract, and magnesium also scored as high as CBT in terms of therapies (10, 10, and 15). Ampligen returns in disguise as a "combination intervention" that had not only positive results but scored 19 - the best score of any treatment at all, including CBT and GET. Finally, a low-sugar, low-yeast diet had equivocal results yet a score of 11. I remain perplexed at the conclusions that they drew. Either there was something wrong with their methodology (their scoring system) - or the conclusions they drew had nothing to do with the study they conducted. Mary M. Schweitzer, Ph.D. [Return to top] ------------------------------ Date: Fri, 6 Oct 2006 12:42:58 -0400 From: "Bernice A. Melsky" <bernicemelsky@xxxxx.xxx> Subject: RES: Quality of life and associated clinical distress in fibromyalgia [Quality of life and associated clinical distress in fibromyalgia] [Article in Italian] Reumatismo. 2006 Jul-Sep;58(3):226-9. Cacace E, Ruggiero V, Anedda C, Denotti A, Minerba L, Perpignano G. Policlinico Universitario, Reumatologia I, Monserrato, Cagliari, Italia. cacace@pacs.unica.it PMID: 17013440 OBJECTIVES: Fibromyalgia (FM) is a syndrome characterized by chronic, diffuse musculoskeletal pain and by a low pain threshold at specific anatomical points (tender points). Numerous other conditions (Irritable bowel syndrome, tension-type headache, migraine headaches, etc.) may overlap with FM. Aim of this study was to evaluate the quality of life and associated clinical distress in patients with FM. METHODS: 53 females affected by primary fibromyalgia and 40 healthy females were examined were examined by an experienced rheumatologist and interviewed using the Fibromyalgia Impact Questionnaire (FIQ). Clinical monitoring included Visual Analogue Scale for pain and pain pressure threshold measurements. RESULTS: Mean FIQ scores were 66.39+/-14.94 in FM patients and 13.15+/-5.37 in control subjects and the difference was statistically significant. Among associated clinical distress higher frequencies have been found for paraesthesia (87%), sleep disturbance (72%), tension type headache (70%), oto-vestibule syndrome (72%) and irritable colon (60%). An R.O.C. bend was developed in the presence of paraesthesias and oto-vestibule syndromes at the same time. This allowed us to identify a FIQ cut off value of 66.85 so FM patients were divided into 2 groups according to their FIQ scores: severe degree and mild or slight degree. CONCLUSIONS: Based on our data, it would appear possible to use a FIQ value equal to or higher than 66.85 for the clinical picture of FM to be classified as severe. [Return to top] ------------------------------ Date: Fri, 6 Oct 2006 12:47:50 -0400 From: "Bernice A. Melsky" <bernicemelsk@xxxxx.xxx> Subject: RES: Lessons Learned Combining N-of-1 Trials to Assess Fibromyalgia Therapies Lessons Learned Combining N-of-1 Trials to Assess Fibromyalgia Therapies. J Rheumatol. 2006 Oct;33(10):2069-77. Zucker DR, Ruthazer R, Schmid CH, Feuer JM, Fischer PA, Kieval RI, Mogavero N, Rapoport RJ, Selker HP, Stotsky SA, Winston E, Goldenberg DL. PMID: 17014022 OBJECTIVE: Applying population research to individual treatment requires understanding the connections between patient-specific characteristics, population-based studies, and treatment responses. Conducting practice-based research using individual-focused (N-of-1) trials may aid this process. We combined N-of-1 trials to compare fibromyalgia therapies and to assess the feasibility and outcomes of this approach for practice-based effectiveness research. METHODS: Community- and center-based rheumatologists enrolled patients with fibromyalgia syndrome in randomized, double-blind, multi-crossover, N-of-1 trials comparing amitriptyline and the combination amitriptyline and fluoxetine. Fibromyalgia Impact Questionnaire outcomes were used for the individuals' treatment and combined across patients for sample-based analyses. Outcomes were compared with results from more standard trial designs. RESULTS: Eight rheumatologists enrolled 58 patients in N-of-1 trials. Most physicians and patients had not previously participated in clinical trials. Using several analytic methods, the pooled results showed a better outcome score (mean difference: -6.1 ± 2.0 to -8.0 ± 3.7 points) in patients taking combination therapy. These population results are similar to published outcomes from a more traditional crossover trial. Neither practice type nor patient characteristics were significantly associated with the observed treatment-effect variation. Most participants, irrespective of selected treatment, felt their individual N-of-1 trials were helpful. CONCLUSION: Implementation of the combined N-of-1 methodology is feasible in rheumatology practices and results confirm greater fibromyalgia improvement with combination therapy. This research approach broadens participation, although our trials' specifics likely influenced enrollment eligibility. In addition to individual benefits, combining N-of-1 trial data provides population research benefits. This patient-focused approach should be further explored to bridge research and practice. [Return to top] ------------------------------ Date: Fri, 6 Oct 2006 12:51:12 -0400 From: "Bernice A. Melsky" <bernicemelsky@xxxxx.xxx> Subject: RES: New treatment options using 5-HT3 receptor antagonists in rheumatic diseases New treatment options using 5-HT3 receptor antagonists in rheumatic diseases. Curr Top Med Chem. 2006;6(18):2035-42. Muller W, Fiebich BL, Stratz T. Hochrhein-Institut fur Rehabilitationsforschung, Bergseestrasse 61, D-79713 Bad Sackingen, Germany. mehrer@hri.de PMID: 17017973 In vitro studies have shown that a blockade of 5-HT3 receptors brings about a reduction of tumor necrosis factor, IL-1 beta, IL-2, IL-6 as well as a decrease in prostaglandins. Clinical trials have provided evidence of pain reduction in a subgroup of fibromyalgia syndrome and, moreover, have demonstrated that tropisetron injected locally for insertion tendinoses and myofascial syndromes with associated trigger points leads to an alleviation of pain that is comparable to injections with the combination of corticosteroids and local anesthetics. The effects achieved by intra-articular injections in cases of osteoarthritis and rheumatoid arthritis paralleled those exerted by intraarticular injection of corticosteroids. In addition, the positive effects produced by systemically administered tropisetron on scleroderma need to be considered since they suggest that this therapeutic principle can also be applied systemically in immunologic processes. [Return to top] ------------------------------ Date: Sat, 7 Oct 2006 12:16:00 -0400 From: "Bernice A. Melsky" <bernicemelsky@xxxxx.xxx> Subject: RES: Fibromyalgia: diagnosis, pathogenesis, and treatment Fibromyalgia: diagnosis, pathogenesis, and treatment. Curr Opin Anaesthesiol. 2001 Oct;14(5):533-9. Geenen R, Jacobs JW. Department of Health Psychology, Utrecht University, Utrecht, the Netherlands; and bDepartment of Rheumatology and Clinical Immunology, University Medical Center, Utrecht, the Netherlands. PMID: 17019142 Fibromyalgia is characterized by chronic widespread pain and the presence of tender points, often accompanied by several non-specific symptoms, such as fatigue, depressive mood, and sleep disturbances. The apparent overlap between fibromyalgia and other syndromes, such as chronic fatigue and irritable bowel, is not sufficient cause to consider all these syndromes as manifestations of a single syndrome. Fibromyalgia is a multifaceted problem. Central afferent pain amplification and perhaps also impaired descending pain inhibition are supposed to underlie widespread pain. Neuroendocrine perturbations, sleep disturbances, health beliefs, mood disorder, and physical deconditioning play a role in the modulation and perseverance of pain and other symptoms. It is extremely difficult to mitigate chronic generalized pain and to deal with other symptoms in fibromyalgia. A uniform intervention strategy is missing. Essential in the tailored management of fibromyalgia are an enhancement of functional capacities and quality of life, and the symptomatic treatment of individual symptoms such as pain, distress, and sleep disturbances. Rather than analysing monotherapy per se, the objective in future evaluations should be to try to find the combined pharmacological or non-pharmacological treatment of choice for specific subgroups of patients. [Return to top] ------------------------------ Date: Sat, 7 Oct 2006 12:20:28 -0400 From: "Bernice A. Melsky" <bernicemelsky@xxxxx.xxx> Subject: RES: Central pain Central pain. Curr Opin Anaesthesiol. 2002 Oct;15(5):575-81. Cohen S, Abdi S. [a] Pain Management Center, Department of Anesthesia, Walter Reed Army Medical Center, Washington, District of Columbia, USA; and [b] MGH Pain Center, Department of Anesthesia and Critical Care, Massachusetts General Hospital, Boston, Massachusetts, USA. PMID: 17019257 PURPOSE OF REVIEW: As a result of its accompanying co-morbidity, our lack of understanding regarding its mechanisms, and its resistance to conventional treatment, central pain is one of the most formidable challenges pain physicians are faced with. The objective of this review is to summarize recent advances in our understanding of the etiology, clinical presentation, and treatment of central pain, with special emphasis being placed on studies published within the past year. RECENT FINDINGS: Recent evidence suggests that not only injuries commonly associated with central pain, such as strokes and spinal cord lesions, but also disorders such as fibromyalgia, phantom limb pain and tension-type headaches may involve central phenomena. Perhaps because of the lack of clinical trials, treatment is still largely based on traditional prescribing methods and anecdotal evidence. Recent studies have indicated possible roles for tricyclic antidepressants, anti-seizure medications, and motor cortex stimulation in the treatment of central pain. SUMMARY: Injury to the spinothalamocortical pathways is a necessary, but not sufficient factor in the pathogenesis of central pain. Perhaps because of the similarities in mechanisms, there is considerable overlap between effective treatments for central pain and those for peripheral neuropathic pain. Our poor understanding of the etiology of central pain and the relative lack of effective treatments emphasize the need for further research into this elusive disorder. [Return to top] ------------------------------ Date: Sat, 7 Oct 2006 12:24:09 -0400 From: "Bernice A. Melsky" <bernicemelsky@xxxxxx.xxx> Subject: RES: Reduced Presynaptic Dopamine Activity in Fibromyalgia Syndrome Demonstrated With Positron Emission Tomography: A Pilot Study Reduced Presynaptic Dopamine Activity in Fibromyalgia Syndrome Demonstrated With Positron Emission Tomography: A Pilot Study. J Pain. 2006 Oct 3; [Epub ahead of print] Wood PB, Patterson Ii JC, Sunderland JJ, Tainter KH, Glabus MF, Lilien DL. Departments of Family Medicine and Anesthesiology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, Louisiana; Department of Psychiatry, Louisiana State University Health Sciences Center-Shreveport, Shreveport, Louisiana. PMID: 17023218 Although the pathophysiology underlying the pain of fibromyalgia syndrome (FMS) remains unknown, a variety of clinical and investigational findings suggests a dysregulation of dopaminergic neurotransmission. We therefore investigated presynaptic dopaminergic function in 6 female FMS patients in comparison to 8 age- and gender-matched controls as assessed by positron emission tomography with 6-[(18)F]fluoro-L-DOPA as a tracer. Semiquantitative analysis revealed reductions in 6-[(18)F]fluoro-L-DOPA uptake in several brain regions, indicating a disruption of presynaptic dopamine activity wherein dopamine plays a putative role in natural analgesia. Although the small sample size makes these findings preliminary, it appears that FMS might be characterized by a disruption of dopaminergic neurotransmission. PERSPECTIVE: An association between FMS and reduced dopamine metabolism within the pain neuromatrix provides important insights into the pathophysiology of this mysterious disorder. [Return to top] ------------------------------ Date: Mon, 9 Oct 2006 01:33:13 +0200 From: Jan van Roijen <j.van.roijen@xxxxx.xx> Subject: act,res: is hysteria real?-brain images say yes ~~~~~~~~~~~~~~~~~~~~~~~~~~~~ Send an Email for free membership ~:~:~:~:~:~:~:~:~:~:~:~:~:~:~:~:~:~:~:~ >>>> Help ME Circle <<<< >>>> 3 October 2006 <<<< Editorship : j.van.roijen@chello.nl Outgoing mail scanned by Norton AV ~:~:~:~:~:~:~:~:~:~:~:~:~:~:~:~:~:~:~:~ From: Jill McLaughlin <jillmclaughlin@comcast.net> This story ran in the New York Times a few weeks ago. It looks like another ploy in the on-going battle by psychosomatic practitioners to legitimize their hypothesis that hysteria (neurasthenia) can be proven. It should be noted that Peter Halligan is one of the less visible movers and shakers in the Wessely school cadre that works closely with UnumProvident in providing "evidence" that they can use in denying disability claims or re-categorizing them as mental illness so that instead of a life-time of benefits they only have to pay for two years. His track record speaks for itself. Notice also the reference to the mind-body paradigm which includes behavioral and psychosomatic medicine in addition to social medicine and close ties to this new public health paradigm which is in perpetual conflict with clinical medicine and hard scientific evidence. The article also gets into differences between eastern and western medicine also part of the rhetoric of this paradigm. The article also notes that "patients with medically unexplained symptoms account for up to 40 percent of all primary care consultations." Most of those studies are poorly constructed with few controls on key variables such as intensity or actual tests done to exclude an organic cause. Jill McLaughlin `````````````````````````` http://query.nytimes.com/search/query?ppds=bylL&v1=ERIKA%20KINETZ&fdq=19960101&amp;td=sysdate&amp;sort=newest&amp;ac=ERIKA%20KINETZ&amp;inline=nyt-per Is Hysteria Real? Brain Images Say Yes ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ By ERIKA KINETZ Published: September 26, 2006 Hysteria is a 4,000-year-old diagnosis that has been applied to no mean parade of witches, saints and, of course, Anna O. But over the last 50 years, the word has been spoken less and less. The disappearance of hysteria has been heralded at least since the 1960's. What had been a Victorian catch-all splintered into many different diagnoses. Hysteria seemed to be a vanished 19th-century extravagance useful for literary analysis but surely out of place in the serious reaches of contemporary science. The word itself seems murky, more than a little misogynistic and all too indebted to the theorizing of the now-unfashionable Freud. More than one doctor has called it "the diagnosis that dare not speak its name.' Nor has brain science paid the diagnosis much attention. For much of the 20th century, the search for a neurological basis for hysteria was ignored. The growth of the ability to capture images of the brain in action has begun to change that situation. Functional neuroimaging technologies like single photon emission computerized tomography, or SPECT, and positron emission tomography, or PET, now enable scientists to monitor changes in brain activity. And although the brain mechanisms behind hysterical illness are still not fully understood, new studies have started to bring the mind back into the body, by identifying the physical evidence of one of the most elusive, controversial and enduring illnesses. Despite its period of invisibility, hysteria never vanished - or at least that is what many doctors say. People who say it is vanished need to come and work in some tertiary hospitals where they will see plenty of patients, Kasia Kozlowska, a psychiatrist at the Children's Hospital at Westmead in Sydney, Australia, and the author of a 2005 review of the subject in The Harvard http://topics.nytimes.com/top/reference/timestopics/organizations/h/harvard_university/index.html?inline=nyt-org Review of Psychiatry, wrote in an e-mail message. But it did change its name. In 1980, with the publication of the third edition of its Diagnostic and Statistical Manual of Mental Disorders, the American Psychiatric Association http://topics.nytimes.com/top/reference/timestopics/organizations/a/american_psychiatric_assn/index.html?inline=nyt-org officially changed the diagnosis of "hysterical neurosis, conversion type" to conversion disorder. "Hysteria, to me, has always been a pejorative term, because of its association with women, said Dr. William E. Narrow, the associate director of the research division of the American Psychiatric Association. "I think the fact we got rid of that word is a good thing." Unofficially, a host of inoffensive synonyms for hysterica have appeared: functional, nonorganic, psychogenic, medically unexplained. Medically unexplained and functiona encompass a broader swath of distress than just conversion disorder by some accounts, patients with medically unexplained symptoms account for up to 40 percent of all primary care consultations. But clinicians seeking to avoid the wrath of patients who do not appreciate being told that their debilitating seizures are hysterical in origin also use these blander terms. Throughout that cloud of shifting nomenclature, people have kept getting sick. "The symptoms themselves have never changed," said Patrik Vuilleumier, a neurologist at the University of Geneva. "They are still common in practice." Common, perhaps. Well studied, no. There is still no consensus on how conversion disorder should be classified, and not all physicians agree on diagnostic criteria. The epidemiology is hazy; one commonly cited statistic is that conversion disorder accounts for 1 percent to 4 percent of all diagnoses in Western hospitals. In addition, patients have heterogeneous symptoms that affect any number of voluntary sensory or motor functions, like blindness, paralysis or seizures. The two things all patients have in common are, first, that they are not faking the illness and, second, that despite extensive testing, doctors can find nothing medically wrong with them. The scientific studies that have been conducted on conversion disorder generally have small sample sizes and methodological differences, complicating the comparison of results from different scientific teams and making general conclusions difficult. "It's one of those woolly areas, and it has this pejorative association," said Peter W. Halligan, a professor of neuropsychology at Cardiff University in Wales and the director of Cardiff's new brain imaging center. Some people say, "That's a Freudian throwback, let's go into real science." Hysteria actually predates Freud. The word itself derives from "hystera," Greek for uterus, and ancient doctors attributed a number of female maladies to a starved or misplaced womb. Hippocrates built on the uterine theory; marriage was among his recommended treatments. Then came the saints, the shamans and the demon-possessed. In the 17th century, hysteria was said to be the second most common disease, after fever. In the 19th century, the French neurologists Jean-Martin Charcot and Pierre Janet laid the groundwork for contemporary approaches to the disease. Then Charcot's student, a young neurologist named Sigmund Freud http://topics.nytimes.com/top/reference/timestopics/people/f/sigmund_freud/index.html?inline=nyt-per , radically changed the landscape and, some argue, popularized hysteria. Freud's innovation was to explain why hysterics swooned and seized. He coined the term "conversion" to describe the mechanism by which unresolved, unconscious conflict might be transformed into symbolic physical symptoms. His fundamental insight that the body might be playing out the dramas of the mind has yet to be supplanted. Scores of European doctors for generations had thought hysteria was something wrong with the physical body: an unhappy uterus, nerves that were too thin, black bile from the liver, said Mark S. Micale, an associate professor at the University of Illinois at Urbana-Champaign and the author of Approaching Hysteria (Princeton University Press, 1994). Something somatic rooted in the body is giving rise to fits, spells of crying, strange aches and pains. Freud reverses that direction of causality. He says what the cases on his couch in Vienna are about is something in the psyche or the mind being expressed physically in the body. For neuroscientists now, there is no such division between the physical brain and the mind. The techniques allow scientists to see disruptions in brain function, which lets them sketch a physical map of what might be going on in the minds of modern-day hysterics. Many questions remain unanswered, but the results have begun to suggest ways in which emotional structures in the brain might modulate the function of normal sensory and motor neural circuits. In the last decade, a number of brain imaging studies have been done on patients suffering from hysterical paralysis. Patients with hysterical paralysis have healthy nerves and muscles. Their problem is not structural but functional: something has apparently gone wrong in the higher reaches of the human mind that govern the conception of movement and the will to move. The dumb actors in this dance are fine; it's the brilliant but complex director that has a problem. Movement is the product of a multistage process. There is initiation (I want to move my arm); then planning, in which the muscles prepare for coordinated action; and finally execution, in which you actually move your arm. In theory, paralysis could result from a malfunction at any stage of this process. (Charcot had a similar idea back in the 1890's.) In a 1997 paper published in the journal Cognition, Dr. Halligan, of Cardiff, and John C. Marshall and their colleagues analyzed the brain function of a woman who was paralyzed on the left side of her body. First they spent large amounts of money on tests to ensure that she had no identifiable organic lesion. When the woman tried to move her paralyzed leg, her primary motor cortex was not activated as it should have been; instead her right orbitofrontal and right anterior cingulate cortex, parts of the brain that have been associated with action and emotion, were activated. They reasoned that these emotional areas of the brain were responsible for suppressing movement in her paralyzed leg. "The patient willed her leg to move," Dr. Halligan said. "But that act of willing triggered this primitive orbitofrontal area and activated the anterior cingulate to countermand the instruction to move the leg. She was willing it, but the leg would not move." Subsequent studies have bolstered the notion that parts of the brain involved in emotion may be activated inappropriately in patients with conversion disorder and may inhibit the normal functioning of brain circuitry responsible for movement, sensation and sight. Such imaging studies may one day be useful as diagnostic tools. Conversion disorder has long been a troubling diagnosis because it hinges on negative proof: if nothing else is wrong with you, maybe you've got it. This has led to some obvious problems. For one thing, it means hysteria has been a dumping ground for the unexplained. A number of diseases, including epilepsy http://topics.nytimes.com/top/news/health/diseasesconditionsandhealthtopics/epilepsy/index.html?inline=nyt-classifier and syphilis http://topics.nytimes.com/top/news/health/diseasesconditionsandhealthtopics/syphilis/index.html?inline=nyt-classifier , once classified as hysterical, have with time and advancing technology acquired biomedical explanations. Such specious history makes patients skeptical of the diagnosis, even though the rates of misdiagnosis have gone down. (One widely cited 1965 study reported that over half of the patients who received a diagnosis of conversion disorder would later be found to have a neurological disease; more recent studies put the rate of misdiagnosis between 4 percent and 10 percent.) 'It helps to have some information from functional imaging to support the diagnosis, Dr. Vuilleumier said. That helps make the treatment and the diagnosis in the same language. The patient is coming to you with bodily language. The patient is not saying, I'm afraid. It's I'm paralyzed. If you can go to the patient with bodily language, it helps. Such physical evidence might help hack away at prejudice among medical practitioners too. "Hysterical patients take a bad rap in the medical profession," said Deborah N. Black, an assistant professor of neurology at the University of Vermont http://topics.nytimes.com/top/reference/timestopics/organizations/u/university_of_vermont/index.html?inline=nyt-org . "We don't like them, " Dr. Black said. "Somewhere deep down inside, we really think they're faking it. When we see a patient with improbable neurological signs, the impulse is to say: Come on, get off it. Sure you can move that leg. The other reason we don't like them is they don't get better, and when we can't do well by them we don't like them." The embodiment of distress is common across cultures, and the suffering tend to find acceptable manifestations for their pain. The "jinn" (evil spirits) in Oman are thought to cause convulsions. In Nigeria and India, common somatic symptoms include hot, peppery sensations in the head, hands or feet. Among Caribbean women, ataque de nervios, headache, trembling, palpitations, upset stomach is a common complaint. One study of British veterans found that over the course of the 20th century, post-traumatic disorders did not disappear, but rather changed form: the gut replaced the heart as the most common locus of weakness. Both its persistence and its pervasiveness suggest that hysteria may be derived from an instinctual response to threat. Total shutdown, in the form of paralysis, for example, is not an entirely untoward or unheard of response to an untenable situation. (Think of deer in the headlights.) But the broadest consensus within the scientific community does not pertain to what is known about hysteria, but instead to how much remains unknown. "We're only at the beginning" Dr. Halligan said. Correction: Sept. 30, 2006 A picture in Science Times on Tuesday with an article about new research into hysteria was published in error, based on information from the photo agency. It showed an ancient bas-relief depicting Asclepius, the god of healing and medicine. It was not of Hippocrates, who suggested marriage as a treatment for hysteria. [Return to top] ------------------------------ Date: Mon, 9 Oct 2006 16:01:17 +0200 From: Jan van Roijen <j.van.roijen@xxxxx.xx> Subject: act,med: Latest APPG Developments (UK) ~~~~~~~~~~~~~~~~~~~~~~~~~~~~ Send an Email for free membership ~:~:~:~:~:~:~:~:~:~:~:~:~:~:~:~:~:~:~:~ >>>> Help ME Circle <<<< >>>> 9 October 2006 <<<< Editorship : j.van.roijen@chello.nl Outgoing mail scanned by Norton AV ~:~:~:~:~:~:~:~:~:~:~:~:~:~:~:~:~:~:~:~ PERMISSION TO REPOST Campaigning for Research into Myalgic Encephalomyelitis ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ RiME Hi, Another meeting has taken place outside Westminster involving the APPG Chair and 'outside parties'. See the below letter for details. RiME has written to the Parliamentary Commissioner Sir Philip Mawer (House of Commons SW1A OAA) with its concerns. If you share our concerns, please do likewise. And please send us a copy. It is important that collections of letters are banked on these matters. If someone in authority were to say, 'there were few, if any complaints... ' one can then say otherwise. The letter below was drafted by two of RiME's supporters. They say, 'feel free to use it as a guide'. Good wishes, Paul `````````````````````` All Party Parliamentary Group on ME (APPG) Dear Sir Philip, Concerns were raised at the end of last year about a meeting re. the APPG on ME. The Chair of the APPG Des Turner MP, Action for ME, the ME Association, and the Sussex/Kent ME Group met outside the Palace of Westminster to discuss a business plan for the APPG involving issues such as supporting the development of the NHS services. You stated 30/1/2006: ... I have now heard Dr Turner's account of the meeting he attended in Sussex about which you expressed concern... Dr Turner has explained that the meeting was a completely informal one with the local Sussex ME Group... Representatives of AfME and MEA were present and, since they currently provide the secretariat for the APPG, it seemed sensible to take the opportunity to have an informal discussion to set up a program for the Group's first two meetings. Dr Turner has confirmed his wish that... the APPG should operate in a fair and open manner. I'm sorry, but I fail to see how a meeting which involves outside interested parties and 'sets up a program for the Group's first two meetings' can be informal. It just doesn't add up. Moreover, this meeting was not a 'one-off'. There has been a further meeting... Posted by: "Colin Barton" colin.sussexme@xxxxx.xxx Fri Sept. 1, 2006 12:44 pm (PST) There was a meeting today in Brighton between the APPG chairman Des Turner MP and officers from the main national charities Action for ME and The ME Association. The meeting was to discuss the way forward for the parliamentary group and how best they can work in the interests of those with ME/CFS. It is plain wrong and undemocratic that an APPG should conduct its business this way. All meetings should be held at the Palace of Westminster and be advertised and conducted in the usual way. Please note each of the private parties who attended the Sept. 1 meeting toe the Govt line and, in turn, support psychiatric/ psychological models of treatment. Those who subscribe to a different view (the majority with ME, in my opinion) were excluded. The Maidstone Group, for example, within Sussex/Kent, has condemned the new NHS Centres in Kent, and is boycotting them. Please note, also, that correspondence sent to the APPG expressing opposition to the 'CFS/ME' Clinics is not being answered eg The Chair of RiME presented the APPG Chair at the July 20 APPG meeting with a dossier; it contained 34 letters from people around the UK condemning the Clinics, and a covering letter. There has been no reply. APPG meetings at Westminster are now open to the public. But one questions the value of the latter's attendance if (1) agendas are prescribed (2) the business is tightly led and dominated by those who were at the recent Brighton meeting. 'Open and fair'? I don't think so. You said it is up to a Group's officers to see fair play prevails. This is all very well, but if they don't attend meetings or show little, if any, interest, abuses will go unquestioned. Re. the July 20 meeting - the AGM - none of the other four officers attended. The Sept. 1 posting refers to Dr Turner as Chair of the APPG on ME, but on whose authority? The AGM was not quorate (only two MPs turned up) and he was not re-elected. Would you please look into this? I feel it is up to you Sir Philip to see these abuses are stopped. If necessary, by a tightening of APPG Rules. Could one suggest two new clauses: (1) That all APPG meetings must be held inside the Palace of Westminster (2) That APPG Chairs cannot meet outside the Palace of Westminster with private interest Groups to set business agendas for their particular Group. This could be the thin end of the wedge. What if, next, the Chair of APPGs to do with medical matters accept invitations from pharmaceutical companies to discuss business agendas. Would this be appropriate and in the spirit of democracy? RiME 10 Carters Hill Close Mottingham SE9 4RS rimexx@tiscali.co.uk www.erythos.com.RiME [Return to top] ------------------------------ Date: Mon, 9 Oct 2006 19:19:53 +0200 From: Jan van Roijen <j.van.roijen@xxxxx.xx> Subject: med: Lyme Disease & ME -Followup ~~~~~~~~~~~~~~~~~~~~~~~~~~~~ Send an Email for free membership ~:~:~:~:~:~:~:~:~:~:~:~:~:~:~:~:~:~:~:~ >>>> Help ME Circle <<<< >>>> 9 October 2006 <<<< Editorship : j.van.roijen@chello.nl Outgoing mail scanned by Norton AV ~:~:~:~:~:~:~:~:~:~:~:~:~:~:~:~:~:~:~:~ Reference: *Lyme Disease & ME -Dr. Darrel Ho-Yen*; Help ME Circle, 6 October 2006, which can be found at Co-Cure: http://listserv.nodak.edu/cgi-bin/wa.exe?A2=ind0610a&L=co-cure&T=0&P=4190 ```````````````` From: DEnlander@aol.com Followup on the excellent overview by Dr Ho-Yen of Inverness ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ The diagnosis of Lymes Disease in not obvious to a large number of physicians. The classic " bulls-eye " rash is only present in 30-40% of patients. This rash surrounds the site of the tick bite. The classic tick that transmits the bacteria, the borellia spirochete, is a minutely small deer tick. Most times this tick bites the patient, fills itself with the patients blood and falls off. So, frequently, the presence of the tick is not obvioius especially if there is no rash. The patient may develop symptoms that overlap M.E., massive fatigue, "brain fog" pains in muscle and joints etc. In our practice a lymes screen is performed on all M.E./ CFS patients to rule out this condition. Unfortunately the Lymes test is frequently inaccurate. A specialty lab in Palo Alto, California, Igenix Lab, has developed a series of tests that are accepted as reliable. Treatment of Lymes disease is by daily oral antibiotic for 6 weeks, if that is unsuccessful then the physician must resort to daily intravenous infusion of Rocephin, a stronger antibiotic also for 6 weeks. Like its counter part M.E., Lymes Disease can be a devastating condition. Derek Enlander M.D. New York [Return to top] ------------------------------ Date: Mon, 9 Oct 2006 20:21:40 +0200 From: "Dr. Marc-Alexander Fluks" <fluks@xxx.xxx> Subject: RES,NOT: Fitness and Exercise in CFS and FM Source: Arthritis & Rheumatism Vol. 54, No. 10, pp 3351-3362 Date: October 2006 URL: http://www3.interscience.wiley.com/cgi-bin/abstract/113384607/ABSTRACT The Influence of Aerobic Fitness and Fibromyalgia on Cardiorespiratory and Perceptual Responses to Exercise in Patients With Chronic Fatigue Syndrome -------------------------------------------------------------------------- Dane B. Cook(1,*), Paul R. Nagelkirk(2), Ashok Poluri(3), John Mores(3) and Benjamin H. Natelson(3) 1 Dane B. Cook, PhD: University of Wisconsin, Madison; 2 Paul R. Nagelkirk, PhD: University of Medicine and Dentistry of New Jersey-New Jersey Medical School, Newark; 3 Ashok Poluri, MD, John Mores, MA, Benjamin H. Natelson, MD: Ball State University, Muncie, Indiana. * Address correspondence and reprint requests to Dane B. Cook, PhD, University of Wisconsin, Madison, Department of Kinesiology, Room 2033-Unit II Gym, 2000 Observatory Drive, Madison, WI 53706. E-mail: dcook@education.wisc.edu. Submitted for publication January 23, 2006; accepted in revised form June 26, 2006. Supported by NIH grant AI-32247. Objective. To investigate cardiorespiratory and perceptual responses to exercise in patients with chronic fatigue syndrome (CFS), accounting for comorbid fibromyalgia (FM) and controlling for aerobic fitness. Methods. Twenty-nine patients with CFS only, 23 patients with CFS plus FM, and 32 controls completed an incremental bicycle test to exhaustion. Cardiorespiratory and perceptual responses were measured. Results were determined for the entire sample and for 18 subjects from each group matched for peak oxygen consumption. Results. In the overall sample, there were no significant differences in cardiorespiratory parameters between the CFS only group and the controls. However, the CFS plus FM group exhibited lower ventilation, lower end-tidal CO_2, and higher ventilatory equivalent of carbon dioxide compared with controls, and slower increases in heart rate compared with both patients with CFS only and controls. Peak oxygen consumption, ventilation, and workload were lower in the CFS plus FM group. Subjects in both the CFS only group and the CFS plus FM group rated exercise as more effortful than did controls. Patients with CFS plus FM rated exercise as significantly more painful than did patients with CFS only or controls. In the subgroups matched for aerobic fitness, there were no significant differences among the groups for any measured cardiorespiratory response, but perceptual differences in the CFS plus FM group remained. Conclusion. With matching for aerobic fitness, cardiorespiratory responses to exercise in patients with CFS only and CFS plus FM are not different from those in sedentary healthy subjects. While CFS patients with comorbid FM perceive exercise as more effortful and painful than do controls, those with CFS alone do not. These results suggest that aerobic fitness and a concurrent diagnosis of FM are likely explanations for currently conflicting data and challenge ideas implicating metabolic disease in the pathogenesis of CFS. Chronic fatigue syndrome (CFS) is a medically unexplained illness characterized by persistent or relapsing fatigue lasting at least 6 consecutive months that substantially reduces physical activity and is accompanied by 4 or more of the following symptoms: impaired memory or concentration, sore throat, tender lymph nodes, muscle and/or multiple-joint pain, headaches, unrefreshing sleep, and postexertional malaise (1). Proposed etiologies of this illness include cardiovascular, respiratory, and metabolic abnormalities, as well as altered effort sense (2,3). Dysfunction of these systems could result in the premature development of fatigue and may help to explain the postexertional malaise and exacerbation of symptoms commonly reported by CFS patients. Exercise has been used as a stressor to determine whether stimulation of the cardiorespiratory system could provide insight into the mechanisms that underlie symptoms of fatigue in CFS. Results of studies to determine the metabolic, cardiorespiratory, and perceptual responses to exercise in CFS have been equivocal (4-15). Explanations for the discordant results include nonstandard testing procedures including different exercise protocols for CFS patients and controls, problematic exercise testing criteria for peak effort, use of physically active controls, and nonstandardized assessment of perceived exertion. Aside from methodologic issues, major limitations have included failure to control for aerobic fitness or to account for common comorbid illnesses, particularly fibromyalgia (FM). A critical issue for research in CFS and FM is whether "abnormal" exercise responses observed in previous studies are truly a phenomenon of the illness or are an epiphenomenon of extreme sedentary behaviors. Controlling for aerobic fitness would allow for a clear test of this issue and determine whether "chronic fatigue syndrome" or physical deconditioning is the likely explanation for previous findings. Moreover, accounting for comorbid illnesses such as FM may help to determine whether illness heterogeneity is an impor- tant contributing factor in physiologic and perceptual responses to exercise. FM is a chronic disorder characterized by diffuse musculoskeletal pain, sleep disturbance, fatigue, stiffness, and presence of multiple tender points. Importantly, FM is the most common comorbid condition in CFS patients, with 43­70% fulfilling the American College of Rheumatology (ACR) diagnostic criteria for FM (16­19). Previous exercise studies have not routinely assessed whether subjects with CFS had comorbid FM and have not evaluated its effects. This is important because patients diagnosed as having both CFS and FM report higher levels of physical disability and pain com- pared with patients with CFS only (17). It is plausible that the pain associated with FM involves different pathophysiologic mechanisms than the fatigue associ- ated with CFS. Alternatively, painful muscle symptoms could affect a patient's willingness to exert peak effort during exercise. Therefore, the presence of comorbid FM could have specific, albeit presently unknown, effects on both physiologic and perceptual responses to exercise. The present study was undertaken to compare cardiorespiratory and perceptual responses during a maximal exercise test in patients with CFS alone (CFS only), CFS patients with coexisting FM, and sedentary healthy controls. Based on previous observations that CFS patients did not differ in either peak oxygen consumption or perceived exertion compared with sedentary healthy controls (5) and that CFS patients with comorbid FM reported greater impairment of physical functional status and more distress than patients with CFS only (17), we hypothesized that patients with CFS only would not differ from controls in cardiorespiratory and perceptual responses to exercise when expressed relative to peak exercise capacity, but that patients with CFS plus FM would demonstrate decreased cardiorespiratory capacity and elevated perception of pain and effort compared with sedentary healthy subjects. In addition to controlling statistically for differences in aerobic fitness, we analyzed data from 18 subjects in each group matched (within 1 ml/kg/min 1) for peak oxygen consumption, thereby controlling for differences in both aerobic capacity and exercise time. PATIENTS AND METHODS Subjects. The study sample included 3 groups of subjects, ranging in age from 18 to 55 years: patients with a diagnosis of CFS alone (n=29; 68% female), patients with a diagnosis of CFS and FM (n=23; 69% female), and healthy controls (n=32; 53% female). Prior to enrollment in the study, all subjects underwent a thorough medical evaluation by a nurse practitioner trained in the diagnosis of CFS and FM. All CFS patients met the 1994 Centers for Disease Control and Prevention (CDC) case definition of CFS (1). Patients with comorbid FM were diagnosed based on the ACR 1990 criteria (19). Sedentary healthy control subjects were recruited from a control subject pool at the New Jersey CFS Cooperative Research Center (CRC). "Sedentary" was defined as working in an occupation that did not require moderate to intense physical labor and not participating in physical exercise for more than 1 session per week. In order to quantify physical activity and verify the sedentary status of the control group, participants filled out the Godin Leisure-Time Exercise Questionnaire (20). The Godin Questionnaire is a recall measure of usual physical activity level. It asks for the individual to report the average number of times that he or she participates in certain activities for more than 15 minutes over a usual 1-week period. The exercise categories include strenuous (running, jogging, soccer, etc.), moderate (fast walking, tennis, easy swimming, etc.), and mild (yoga, fishing, easy walking, etc.). Scores are obtained by multiplying the number of times reported for each activity level by an estimated metabolic equivalent level for that category (strenuous =9, moderate =5, mild =3). These products are summed for the total activity score. Exclusion criteria for CFS patients were based on the clinical criteria listed in the CDC case definition (1), including the following: 1) any active medical condition that might explain the patient's chronic fatigue, 2) any unresolved previously diagnosed medical condition that might explain the patient's chronic fatigue, 3) any current or past diagnosis of major depression with psychotic or melancholic features, 4) alcohol or other substance abuse currently or within 2 years prior to the onset of the chronic fatigue, and 5) a body mass index of >= 45 kg/m2. Sedentary healthy controls were excluded if they had a history of cardiovascular, respiratory, neurologic, or major psychiatric disorders or were taking any medications other than oral contraceptives. In order to further reduce heterogeneity, we restricted our analyses to only those subjects who could complete a maximal exercise test based on standardized criteria for volitional effort. Additionally, the groups were matched on age (p/m 3 years), height (p/m 4 cm), weight (p/m 5 kg), and years of education (p/m 2 years). Recruitment. Participants were recruited from a large patient pool available through the CRC. Participants volunteered through advertisements for the CRC or were contacted by CRC personnel. All participants were given the opportunity to volunteer for a number of research protocols that were supported by the CRC. A total of 92 participants volunteered for the present study. Of the 92, 5 were excluded from participation prior to completion of the exercise test. All 5 had chronic fatigue, and the reasons for exclusion were as follows: 1) patient (male, age 27 years) did not meet case definition criteria for CFS (determined during history and physical examination); 2) patient (male, age 29 years) had not eaten that day and was feeling light-headed; 3) patient (female, age 28 years) was found to have asthma; and 4) 2 patients (both female, ages 29 years and 42 years) were not comfortable with the experimental preparation and devices. A total of 87 participants completed the exercise test, of whom 84 (96.6%) met standard criteria for peak effort. Of the 3 who did not meet criteria, 2 were female patients with CFS plus FM (ages 53 years and 44 years) and 1 was a male control subject (age 46 years). Thus, the vast majority of volunteers were capable of exerting peak effort during cycling exercise. Experimental procedures. The testing was performed under controlled environmental conditions (20-24 C and 40-60% relative humidity), between 11:00 AM and 2:00 PM. Subjects reported to the Human Performance Laboratory located at the Veterans Affairs Medical Center (VAMC) in East Orange, New Jersey, having abstained from smoking for 2 hours, from ingesting caffeine for 4 hours, and from exercising for 24 hours prior to testing. After providing informed consent (approved by human subjects committees of both the VAMC and the University of Medicine and Dentistry of New Jersey), subjects completed the Profile of Mood States (POMS) scale (21). This scale assesses feelings of fatigue and vigor for the week preceding the testing day. They also completed a Short- Form McGill Pain Questionnaire (MPQ) (22) to determine resting muscle pain prior to testing. Instrumentation. Prior to exercise testing, subjects were instrumented for monitoring of heart rate and metabolic responses to exercise. Modified lead II electrocardiography was used to monitor heart rate throughout the test. Expired air was collected breath by breath during exercise, using a 2-way non-rebreathing valve (Hans-Rudolph, Kansas City, MO), and was analyzed with the Max-1 metabolic measurement system (Physio-Dyne Instruments, Quoge, NY) for assessment of O_2 consumption (VO_2), CO_2 production (VCO_2), respiratory rate, and ventilation (VE). From the directly collected measures we derived measures of ventilatory equivalents of carbon dioxide (VE/VCO_2) and oxygen (VE/VO_2) for statistical analysis. The system was calibrated prior to each test, using standard gases with known concentrations and with a calibrated 3-liter sy- ringe. End-tidal CO_2 was measured breath by breath using an infrared expired gas analyzer (POET II; Criticare Systems, Waukesha, WI). The ventilatory threshold (VT) was deter- mined using the V-slope method as described by Sue et al (23). Maximal exercise testing. Following instrumentation, subjects were seated on an electronically braked cycle ergometer (Sensormedics, Loma Linda, CA) with the seat and handlebars adjusted for optimal performance, and allowed a few minutes to habituate to the cycle and various monitoring devices. The exercise test began with a 3-minute warm-up pedaling at 20W. Subjects were instructed to maintain a pedaling cadence of 60-70 revolutions per minute. Following the warm-up period, work intensity was increased by 5W every 20 seconds until the subject reached volitional exhaustion or a point when he or she could no longer maintain the prescribed pedaling rate. The subjects were verbally encouraged to con- tinue pedaling as long as possible. Peak effort was determined based on meeting at least 2 of the following criteria: 1) respiratory exchange ratio >= 1.1, 2) achievement of 85% of age-predicted maximum heart rate, 3) rating of perceived exertion (RPE) >=17, and 4) a change in VO_2 of <200 ml with an increase in work. Examination of individual exercise tests revealed that the majority of subjects met the first 3 of these criteria (86% of patients with CFS only, 83% of patients with CFS plus FM, 81% of controls), while the fourth criterion was rarely met. Thus, the groups were well matched for both subjective and objective indices of effort. Ratings of perceived exertion. RPEs were obtained during the last 10 seconds of every minute during the exercise test and every 30 seconds during recovery, using the Borg 6-20 category scale (24). Before exercise, subjects were given standard instructions on the proper use of the Borg 6-20 category scale. Briefly, subjects were instructed 1) that the Borg 6-20 scale would be used to determine the intensity of effort or stress felt in the legs only, during exercise and recovery, 2) that each number represents a category of sensation that is ordered according to its intensity, and 3) that the verbal anchors ("very light," "light," "somewhat hard," "hard," etc.) should be used to help determine the level of effort at that particular moment. Subjects were also provided cognitive anchors at the high and low ends of the perceptual continuum. Specifically, they were instructed that a 6 on the scale refers to the amount of effort exerted in their legs while they are sitting in a chair (i.e., no effort), while a 20 refers to the most effort imaginable (i.e., carrying a child out of a burning building or finishing a marathon). Ratings of leg muscle pain. Leg muscle pain intensity ratings were obtained during the last 10 seconds of every minute during exercise and every 30 seconds during recovery. Pain intensity was measured with the use of a validated category-ratio pain intensity scale (25) ranging from 0 (no pain at all) to 10 (extremely intense pain, almost unbearable). Subjects were instructed 1) that the 0-10 pain intensity scale would be used to determine the intensity of pain felt in the leg muscles only, during exercise and recovery, 2) that pain was defined as the intensity of hurt that was felt in the leg muscles, 3) that each number represents a category of sensation that is ordered according to its intensity, and 4) that the verbal anchors ("no pain," "weak pain," "moderate pain," "strong pain," "extremely intense pain," etc.) should be used to help determine the level of pain intensity at that particular moment. Statistical analysis. Statistical analyses were conducted using SPSS for Windows (version 12.0.1; SPSS, Chicago, IL). Subject characteristics, variables at the VT, and peak exercise variables in experimental and control groups were compared using analysis of variance (ANOVA). Tukey's post hoc analyses were used to further determine group differences. Differences in cardiorespiratory features (VO_2, VE, respiratory rate, VE/VO_2, VE/VCO_2, heart rate, end-tidal CO_2) and perception (pain and RPE) during exercise were analyzed using ANOVA with repeated measures for exercise intensity. Analyses of whole group sample (n=84). To control statistically for the effect of fitness differences on perception and cardiorespiratory responses, dependent variables were expressed and analyzed relative to each individual's peak oxygen consumption, by repeated-measures ANOVA. Complete pain and RPE data were available for workloads associated with 30­100% of peak oxygen consumption, and complete cardiorespiratory data for peak VO_2 of 400100%. Therefore, the repeated-measures analyses were conducted using these respective intensities. Tukey's post hoc analyses were used to further determine significant main effects. Greenhouse-Geisser adjustments for degrees of freedom were used when a significant difference (P<0.05) was shown with Mauchly's test of sphericity. Linear regressions of log-transformed data were used to further characterize significant interaction terms by providing curve estimates of the growth functions of the physiologic and perceptual variables. Analyses of the subgroup sample matched on fitness n=54). In order to more definitively determine the effect of aerobic fitness on cardiorespiratory and perceptual responses to exercise, we performed the same set of analyses described above on a subset of participants matched (within 1 ml/kg/min^-1) for peak oxygen consumption. Eta-square values are reported to demonstrate the magnitude of the differences between the whole group and the fitness-matched subgroup samples. RESULTS Characteristics of the study subjects. Demographic and baseline cardiorespiratory and questionnaire data on both the entire group and the subgroup matched for fitness are presented in Table 1. As intended, there were no significant differences among the groups for age, height, weight, years of education, or baseline heart rate. Physical activity. Whole group. Although our control subjects would be considered sedentary by normal physical activity standards (26), there was a significant group main effect of total physical activity (P=0.001). Tukey's post hoc analyses indicated that the control group was significantly more active than both the CFS only group (P=0.001) and the CFS plus FM group (P=0.04), while the CFS only and CFS plus FM groups were not significantly different from one another. The range of scores for self-reported physical activity was large (CFS only group 0-64, CFS plus FM group 0-92, control group 9-84). Examination of the subscales of the Godin questionnaire revealed that controls engaged in strenuous and moderate activities significantly more than either the CFS only or the CFS plus FM patients (for strenuous activity, P=0.02 and P=0.03, respectively; for moderate activity, P=0.01 and P=0.03, respectively) and in minimal effort activities significantly more than the CFS only group (P=0.006). Fitness-matched subgroup. Group differences in total physical activity were reduced but not eliminated when the data were examined in the groups matched for fitness (P=0.03), with controls engaging in moderate activities significantly more frequently than the CFS only group (P=0.03) or the CFS plus FM group (P=0.007). Baseline questionnaire data. Whole group. MPQ data on the entire sample indicated a significant main effect for group (P=0.001), with both the CFS only group (P=0.05) and the CFS plus FM group (P=0.001) reporting significantly more resting pain than controls and the CFS plus FM group reporting more pain than the CFS only group (P=0.001). POMS data indicated significant main effects for fatigue (P=0.001), vigor (P=0.001), depression (P=0.007), tension/anxiety (P=0.003), and confusion (P=0.001), but not for anger/hostility. Healthy control subjects reported different levels of each measured symptom than the CFS only group, and their responses for each variable, with the exception of self-reported depression and anger/hostility, were significantly different from those of the CFS plus FM group. There were no significant differences between the CFS only and CFS plus FM groups. Fitness-matched subgroup. In the matched sample, only the CFS plus FM group reported greater resting muscle pain than controls (P=0.01). The results on the POMS followed the same pattern as described for the whole group analyses. Cardiorespiratory responses to maximal exercise. Heart rate. Whole group. Heart rate responses during exercise are depicted in Figure 1. Repeated- measures ANOVA indicated a significant main effect for exercise intensity (P<0.001) and a significant group-by-exercise intensity interaction (P=0.03, eta2=0.08), but no group main effect. Linear regression of the log-transformed heart rate and relative oxygen consumption data revealed a lower slope for the CFS plus FM group (0.46) compared with the CFS only group (0.54) and the control group (0.54), indicating a slower increase in heart rate in the CFS plus FM group compared with the other groups. Fitness-matched subgroup. Group differences in heart rate were eliminated (P=0.16, eta2=0.05) when the data were examined in the subgroups matched for aerobic fitness. Ventilation. Whole group. Ventilation responses during exercise are shown in Figure 1. There were significant main effects for exercise intensity (P<0.001) and group (P=0.02, eta2=0.14), as well as a significant group-by-exercise intensity interaction (P=0.02, eta2=0.12). Post hoc analyses indicated that the CFS plus FM group had significantly lower VE throughout exercise compared with the control group (P=0.02), but not with the CFS only group. There were no significant differences between the CFS only and control groups. Linear regression of the log-transformed ventilation and relative oxygen consumption data revealed no differ- ences in the slopes among the groups (CFS plus FM 1.20, CFS 1.25, control 1.28). Fitness-matched subgroup. Differences in VE were eliminated (group P=0.46, eta2=0.03; interaction P=0.4, eta2=0.04) when the data were examined in the subgroups matched for aerobic fitness. Ventilatory equivalents of oxygen and carbon dioxide. Whole group. VE/VO_2 and VE/VCO_2 during exercise are depicted in Figure 2. For VE/VO_2, there was a significant main effect for exercise intensity (P<0.001), but no significant main effect for group or for the interaction. For VE/VCO_2, there were significant main effects for exercise intensity (P<0.001) and group (P=0.04, eta2=0.08), but no group-by-exercise intensity interaction. There were no significant group differences in the pairwise comparisons. Fitness-matched subgroup. There were no significant differences among the groups for either VE/VO2 (P=0.7, eta2=0.01) or VE/VCO_2 (P=0.5, eta2=0.03) when the data were analyzed in the subgroups matched for aerobic fitness. End-tidal carbon dioxide. Whole group. For end-tidal CO_2, significant main effects for exercise intensity (P<0.001) and group (P=0.017, eta2=0.11), but not for the interaction, were observed (Figure 2). Post hoc analyses indicated that end-tidal CO_2 throughout exercise was significantly reduced in the CFS plus FM group compared with the control group (P=0.016), but not the CFS only group. There were no significant differences between the CFS only group and the control group. Fitness-matched subgroup. Differences in endtidal CO_2 were eliminated (P=0.08, eta2=0.10) when the data were analyzed in the fitness-matched subgroups. Perceptual responses to maximal exercise. Leg muscle pain. Whole group. Pain intensity ratings during exercise are shown in Figure 3. There were significant main effects for exercise intensity (P<0.001) and group (P=0.005, eta2=0.12), but no interaction. Post hoc analyses indicated that the CFS plus FM group rated exercise as significantly more painful than either the CFS only group (P=0.02) or the control group (P=0.007). There were no significant differences between the CFS only and control groups. Fitness-matched subgroup. The pattern of results was unchanged (P=0.03, eta2=0.13) when differences in fitness and exercise time were accounted for in the matched subgroup analysis, except that findings in the CFS plus FM group were no longer significantly different from those in the CFS only group. Perceived exertion. Whole group. Figure 3 shows the RPE data in each group. There were significant main effects for exercise intensity (P<0.001) and group (P<0.001, eta2=0.21), as well as a significant group-by-exercise intensity interaction (P=0.04, eta2=0.05). Post hoc analyses indicated that both the CFS plus FM group (P<0.001) and the CFS only group (P=0.01) rated exercise as significantly more effortful than did controls. However, there were no significant differences between the CFS plus FM and CFS only groups. Linear regression of the log-transformed data on perceived exertion revealed similar slopes among the groups (CFS plus FM 0.56, CFS only 0.57, control 0.62). Fitness-matched subgroup. When differences in fitness were accounted for, there was a significant main effect for group (P=0.001, eta2=0.25). Post hoc analyses indicated that the RPEs of the CFS only group were not significantly different from those of the controls, while the CFS plus FM group continued to rate exercise as more effortful than the control group (P<0.001), but with no significant difference from the CFS only group (P=0.06). Responses at the ventilatory threshold. Whole group. Exercise responses at the VT are shown in Table 2. Each group reached the VT at a similar relative intensity, as demonstrated by the percentage of peak VO_2. There were no differences among groups for respiratory rate, respiratory exchange ratio, or heart rate. Significant group main effects occurred for VO2 (P=0.001), VCO_2 (P=0.001), VE (P=0.02), VE/VO_2 (P=0.02), VE/VCO_2 (P=0.009), watts (workload) (P=0.001), pain (P=0.03), and perceived exertion (P=0.02). Compared with controls, both the CFS only and the CFS plus FM groups had significantly lower VO2 (CFS P=0.009, CFS plus FM P=0.001), VCO_2 (CFS P=0.008, CFS plus FM P=0.003), and watts (CFS P=0.03, CFS plus FM P=0.002). In addition, the CFS plus FM group exhibited significantly lower VE (P=0.04) as well as higher VE/VO_2 (P=0.02), VE/VCO2 (P=0.009), and RPE (P=0.02) compared with controls and significantly higher pain levels compared with the CFS only group (P=0.03) and the control group (P=0.001). Fitness-matched subgroup. In analyses of the subgroups matched for fitness, all differences observed at the VT were eliminated with the exception of pain and RPE; the CFS plus FM group rated exercise as significantly more painful (P=0.03) and more effortful (P=0.001) than did the controls. Peak responses. Whole group. Table 3 shows peak responses to exercise in the various study groups. There were no significant differences in peak exercise responses for pain, RPE, heart rate, respiratory exchange ratio, or breathing frequency. Significant group main effects were found for peak VO_2 (P=0.002), watts (P=0.001), total exercise time (P=0.001), and VE (P 0.01). Post hoc analyses showed a significant difference between the CFS plus FM group and controls for each of these parameters. The range of aerobic fitness values in the groups was large (CFS only 17-40 ml/kg/min^-1, CFS plus FM 14-33 ml/kg/min^-1, controls 18-49 ml/kg/min^-1). However, there were no significant differences between the CFS only and the CFS plus FM groups. Fitness-matched subgroup. All differences in peak exercise responses, including peak oxygen consumption and peak exercise time, were eliminated when the data were analyzed in the fitness-matched subgroups. DISCUSSION In the present study, we sought to extend and improve on previous investigations of high-intensity exercise among patients with CFS. Earlier studies have yielded equivocal results for various reasons, including use of poorly matched control groups and questionable exercise testing procedures. Some investigations have utilized tests lasting twice as long as standard protocols designed to identify a metabolic maximum, others have used different exercise protocols for CFS patients and control participants, and others have failed to adhere to accepted criteria for maximal effort. However, even carefully controlled studies with appropriate exercise tests and objective indicators of maximal effort have not produced consistent results. We believe the results of the present investigation provide 2 primary explanations for inconsistencies in findings with regard to exercise responses among CFS patients: 1) many of the patients included in previous investigations also had FM, and 2) previous studies did not account adequately for differences in aerobic fitness. The present investigation is the first study of short-term exercise in CFS patients in which a concomitant diagnosis of FM was controlled for and data were examined in groups closely matched for aerobic fitness and exercise performance. Several of our findings would not have been revealed had we failed to account for the presence of comorbid FM. Indeed, for virtually all of the primary dependent variables, the CFS only group did not differ from a group of sedentary healthy controls. Further, the results of the study would have been misleading had differences in aerobic fitness not been accounted for. After fitness was controlled for, we found that CFS patients with comorbid FM perceived exercise as more painful and effortful, but did not differ in their cardio-respiratory responses. Thus, concurrent diagnoses and differing levels of disease burden combined with the use of control subjects who had greater aerobic capacity may have confounded the results of many earlier investigations. Several studies have depicted the exercise capacities of CFS patients as being reduced compared with healthy controls (7,8,10,15), whereas others have shown "low normal" VO_2max values (4,5,11,13). Severe deconditioning may result in abnormal exercise responses and may partly explain why some patients report postexercise exacerbation of symptoms. However, this hypothesis has not been systematically tested. Further, investigators in those studies have concluded that cardiovascular, ventilatory, or metabolic abnormalities revealed through exercise testing may explain the CFS patients' exercise intolerance and provide insight into pathophysiologic mechanisms of the disease. Specifically, depressed maximal and submaximal heart rates, lower respiration during exercise, slower oxygen saturation recovery in muscle following exercise, and general autonomic differences in CFS patients compared with healthy controls have been reported (10,27-30). Inbar et al (10) reported that patients with CFS exhibited significantly lower heart rates at equal relative exercise intensities compared with sedentary healthy controls and concluded that the observed pattern of slow cardiac acceleration was not characteristic of a deconditioned response, but instead suggested that insufficient cardiac pacing or abnormally low sympathetic drive might explain the low heart rate response and thus the patients' exercise intolerance. Similarly, Montague et al (30) reported normal resting cardiac function in CFS patients, but a slow acceleration of heart rate during exercise, leading to limitations in capacity. Inbar and colleagues (10) also noted that CFS patients had lower VE and end-tidal CO_2 at relative and peak exercise intensities, but concluded that these were probably the result, not the cause, of low exercise tolerance. DeBecker et al (7), studying a large cohort of CFS patients (n=427) and controls (n=204), reported significantly reduced exercise capacity in the CFS group and speculated that the marked exercise impairment in that group was due to an inability to achieve target heart rates and thus was reflective of impaired cardiac function. However, the use of questionable criteria for maximal exercise and different exercise protocols for patients and controls could have contributed to these observations. Importantly, in none of these studies were differences in aerobic capacity controlled for or the occurrence of comorbid FM determined in the CFS participants. In the present study, similar conclusions to those discussed above would have been drawn had all subjects who met standard criteria for peak volitional effort been included. Statistically controlling for differences in peak exercise capacity by expressing the data relative to each subject's peak oxygen consumption value allowed for the inclusion of subjects who had low aerobic fitness, but who could complete the maximal exercise protocol based on a priori­set standards. Thus, when the entire sample was considered, patients with CFS only did not differ from healthy controls with respect to virtually any cardiorespiratory variable including maximal or sub-maximal heart rates, total minute ventilation, or end-tidal CO_2 level. However, patients with both CFS and FM exhibited slower accelerating heart rates during exercise compared with healthy controls, indicated by lower heart rates at each percentage of their peak exercise capacity and a lower slope throughout exercise. They also demonstrated lower VE and end-tidal CO_2 and higher VE/VCO_2 levels at given relative workloads compared with healthy controls. These results occurred throughout the maximal exercise test as well as when the data were examined at the VT, indicating that the differences occurred when the groups were exerting similar metabolic efforts. One potential explanation for these results is simply that patients with CFS and FM exerted inadequate effort during the exercise test, failing to attain a true "peak." This explanation is unlikely, however, since all of the subjects met objective criteria for maximal effort. Another potential explanation could relate to the fact that the CFS plus FM group exhibited lower end-tidal CO_2 levels during exercise than controls. Thus, chemoreceptor stimulation by partial pressure of CO2 may have been diminished in the CFS plus FM group, leading to lower VE during exercise. However, when we compared the groups after matching for peak oxygen consumption, and thus exercise time, every observed cardiorespiratory difference was eliminated. This finding strongly suggests that results obtained in the entire sample were the result of comparing groups at equivalent relative intensities but different total exercise times. To illustrate the above point, we compare 2 subjects, 1 from the CFS plus FM group and 1 from the control group. The CFS plus FM participant (female; peak VO_2 25 ml/kg/min^-1) exercised for a total of 7 minutes and reached 55% of peak oxygen consumption after only 2 minutes of exercise. The control participant (female; peak VO_2 39 ml/kg/min^-1) exercised for a total of 13 minutes and reached 55% of peak oxygen con- sumption after 6 minutes of exercise. Corresponding heart rates were 111 beats per minute and 136 beats per minute, respectively. Thus, statistically controlling for differences in aerobic fitness by expressing the data as a function of relative intensity (i.e., 55%) may diminish differences at the group level, but cannot fully account for meaningful differences in total exercise time between less fit and more fit subjects. The present findings also indicate that, in general, the aerobic capacities of CFS patients do not differ significantly from those of sedentary control subjects, unless there is a comorbid diagnosis of FM. Even then, it was possible to match the majority of the CFS plus FM patients (18 of 23) to both CFS only patients and sedentary controls. Thus, group differences in the entire sample were due to the inclusion of controls who were fit although sedentary (mean p/m SD peak VO_2 36.6 p/m 5 ml/kg/min^-1) and patients with CFS only or CFS plus FM who had relatively lower levels of fitness (peak VO2 28.7 p/m 8 ml/kg and VO_2 20 p/m 4 ml/kg/min^-1, respectively). The above results contrast with those obtained for physical activity. Despite our attempts to enroll healthy controls who were matched with the CFS subjects in terms of levels of physical activity, the 2 CFS groups engaged in significantly less self-reported physical activity than the control subjects. However, this difference did not translate into widespread differences in aerobic capacity among the groups. This may indicate a floor effect for the relationship between physical activity and aerobic fitness, since the mean aerobic capacities in the entire sample were at or below the 20th percentile for population averages. In fact, total physical activity was weakly (r=0.13) correlated with peak oxygen consumption (aerobic fitness) in the total sample. This finding highlights the importance of obtaining an objective measure of aerobic capacity (i.e., peak oxygen consumption) to determine fitness, but does not dismiss the utility of self-reported physical activity to screen for physical activity behaviors. Several reports have described elevated ratings of effort in CFS, and the authors have speculated that central dysregulation of effort sense may be a contributing factor to both the increased perception of fatigue and the decreased exercise tolerance in these subjects (8,9,12,14,31,32). In a recent study, Wallman et al (32) used a submaximal exercise protocol to determine physiologic and perceptual responses in CFS patients and controls matched for physical activity history and found that physiologic responses to the test were similar, but that RPEs were elevated in the CFS patients. They concluded that reduced exercise capacity in CFS may be due to "abnormal" perception of exertion, perhaps due to impairment of the neural mechanisms that regulate effort sense. However, they also found that peak exercise capacity was significantly lower in their CFS patients than in their controls. Therefore, comparisons made at any given absolute workload represented a greater relative workload for CFS patients. This could in part explain the elevated effort ratings. Wallman and colleagues did not determine whether their CFS patients also had comorbid FM. We previously reported that perceived exertion was elevated in women with CFS when the data were expressed as a function of absolute (exercise time) exercise intensity, but these differences did not remain when the data were expressed as relative (percent peak oxygen consumption) to peak exercise capacity (5). This finding challenged the notion that CFS was an illness of altered effort sense and highlighted the importance of appropriate reference criteria when making group comparisons. In the present study, when we analyzed the entire sample, both the CFS only and the CFS plus FM patients rated exercise as requiring more effort than did healthy controls, even after statistical controlling for differences in peak aerobic fitness. However, when we compared groups matched for aerobic fitness, only the CFS plus FM patients rated cycling exercise as requiring more effort than controls. This demonstrates that controlling for fitness and accounting for comorbid FM are important considerations when assessing exercise perceptions and tolerance in patients with CFS. Thus, with these controls in place and with the use of identical exercise testing procedures, CFS patients do not perceive a short-term session of exercise as requiring more effort than do matched sedentary controls. These results are consistent with our previous findings and extend them to a different mode of exercise (cycling). The findings suggest that reports of elevated RPEs in patients with CFS are likely an epiphenomenon of extremely low aerobic fitness and/or the inclusion of subjects with comorbid FM, and not a phenomenon of central alterations in effort sense. Another potential, yet unexplored, explanation for reports of elevated RPEs in CFS is that exercise may be more painful and that nociceptive signals from the contracting muscle contribute to an increase in effort sense. Indeed, some have speculated that reduced motivation or increased symptomatology, such as pain, may limit the CFS patient's ability to attain maximal exertion (2). To our knowledge, this is the first study to determine naturally occurring muscle pain during exercise in CFS. Our patients with CFS only did not report greater leg muscle pain during exercise than the healthy controls. This was the case for both the entire sample tested and the subgroup that was matched for aerobic fitness. This finding may appear odd, particularly since muscle and joint pain are part of the symptom list used in diagnosing CFS and are common in most CFS patients (1). However, naturally occurring muscle pain from exercise may represent a different phenomenon from chronic symptoms of muscle and joint pain that occur during rest (25). These results also suggest that CFS patients without comorbid FM have normal nociceptive processing during exercise and that muscle contractions do not result in a hyperalgesic state in these patients. In contrast to the CFS only group, the CFS plus FM patients reported greater muscle pain throughout exercise compared with the control group; muscle pain during exercise in the CFS plus FM group was also significantly higher than that reported by patients in the CFS only group. While the initial muscle pain ratings were similar among the groups, muscle pain increased at a greater rate in the CFS plus FM patients. These results suggest that normal inhibition of pain signals from the contracting muscle may be intact in patients with CFS but impaired in patients with comorbid FM, and are consistent with data suggesting abnormal central processing and regulation of pain (33) and hyperalgesia resulting from skeletal muscle contractions (34) in FM. The exacerbation of symptoms following exercise re- ported by CFS patients could be due to the presence of comorbid FM and augmented afferent nociceptive signaling from contracting skeletal muscle. The fact that patients with CFS plus FM rate exercise as more painful than patients with CFS only has important implications with regard to exercise prescription. Extra care should be taken when prescribing an exercise program for an individual with diagnoses of both CFS and FM, since painful skeletal muscle contractions could lead to peripheral and/or central hyperalgesia with a resulting increase in widespread pain. In theory, pain perception could be used to regulate the mode and intensity of exercise and to individually tailor the exercise program to account for differences in physical function and levels of disability due to pain. The primary limitation of the present study is the failure to include an FM only group. Testing patients with FM but without CFS would have allowed us to draw more definitive conclusions regarding the impact of FM alone on cardiorespiratory and perceptual responses to exercise. Future research to determine these responses during exercise, as well as in response to exercise training, in both CFS patients and FM patients would be an important next step. The results of the present investigation highlight the importance of considering aerobic fitness level and the presence of comorbid illness in studies of exercise in CFS and provide insight regarding the functional and aerobic capacity of individuals with single and dual diagnoses. Specifically, we demonstrate that a concomitant diagnosis of FM may greatly impact the psychological responses to exercise in CFS patients, but that neither the diagnosis of CFS nor the diagnosis of FM has a meaningful effect on cardiorespiratory responses to short-term cycling exercise as used in this study. Given the substantial overlap of CFS and FM, equivocal findings of previous research are likely due to a failure to effectively control for differences in aerobic capacity between patients and controls and a failure to account for comorbidity in CFS patients. These results also seriously challenge hypotheses implicating metabolic disease in the pathogenesis of medically unexplained fatigue and pain. FIGURE CAPTIONS Figure 1. Heart rate and ventilation (VE) in relation to relative exercise intensity, in patients with chronic fatigue syndrome only (CFS) (n=29), patients with CFS plus fibromyalgia (CFS+FM) (n=23), and sedentary healthy controls (Con) (n=32). Data are presented for the entire sample and for subgroups (each n=18) matched for peak aerobic capacity during cycle ergometry. Values are the mean p/m SEM. b min^-1 beats per minute 1; VO_2 = O_2 consumption. Figure 2. Ventilatory equivalent of oxygen (VE/VO_2) and ventilatory equivalent of carbon dioxide (VE/VCO_2) in relation to relative exercise intensity in patients with CFS only (n=29), patients with CFS plus FM (n=23), and sedentary healthy controls (n=32). Data are presented for the entire sample and for subgroups (each n=18) matched for peak aerobic capacity during cycle ergometry. Values are the mean p/m SEM. See Figure 1 for other definitions. Figure 3. Muscle pain intensity and perceived exertion responses to exercise in relation to relative exercise intensity in patients with CFS only (n=29), patients with CFS plus FM (n=23), and sedentary healthy controls (n=32). Data are presented for the entire sample and for subgroups (each n=18) matched for peak aerobic capacity during cycle ergometry. Values are the mean p/m SEM. RPE rating=of perceived exertion (see Figure 1 for other definitions). TABLES Table 1. Baseline characteristics of the study subjects* -------------------------------------------------------------------------------------------------------------------------------------- Overall study population Fitness-matched subgroup -------------------------------------------------- --------------------------------------------------- CFS only CFS plus FM Controls CFS only CFS plus FM Controls (n=29) (n=23) (n=32) (n=18) (n=18) (n=18) p/m p/m p/m p/m p/m p/m -------------------------------------------------------------------------------------------------------------------------------------- % female 68 69 53 72 72 77 Age, years 39.8 9 40.9 8 37.0 12 41.4 10 41.2 8 40.8 12 Height, cm 170.0 10 166.3 9 168.9 12 168.5 10 166.4 10 163.9 9 Weight, kg 71.7 13 69.4 18 74.7 19 69.8 12.5 70.8 18.5 70.9 22.6 Education, years 16.3 2.7 16.0 2.5 16.7 2.8 16.4 2.7 16.0 2.5 17.4 2.9 Heart rate, beats/minute^-1 72 10 76 13 72 10 73 10 75 12 74 9 Physical activity score** Strenuous 0.4 1.1*** 0.4 1.2 1.5 1.9 0.47 1 0.33 1 0.61 1 Moderate 1.1 1.9*** 1.2 2.1 3.1 3.3 1.2 2*** 0.8 2 3.6 4 Minimal 1.8 1.8*** 3.9 2.6 2.7 2.5 2.2 2 3.3 2*** 3.4 3 Total 14.9 18.0*** 22.3 24.8*** 37.5 22.4 16.6 21 17.7 21 33.6 21 Pain score**** 2.1 4*** 5.2 4***** 0.4 1 2.0 3.8 4.8 3.0*** 0.2 0.4 Mood****** Fatigue 16.1 7*** 19.4 4*** 2.9 3 16.4 7*** 19.6 5*** 3.4 4 Depression 11.2 12*** 6.2 6 3.2 5 12.0 13*** 7.1 7 4.0 6 Tension/anxiety 10.5 9*** 7.6 5*** 4.8 4 10.0 8*** 8.4 6*** 4.9 5 Anger/hostility 5.9 7 4.1 5 3.3 4 6.0 7 4.4 5 4.0 4 Vigor 9.2 7*** 8.3 5*** 22.8 6 9.9 8*** 8.4 5*** 22.6 6 Confusion 11.1 6*** 10.0 4*** 3.3 3 11.9 7*** 9.8 4*** 3.2 3 Total 45.7 39*** 38.0 17*** 5.1 18 46.4 40*** 39.4 18*** 3.1 21 -------------------------------------------------------------------------------------------------------------------------------------- * Except where indicated otherwise, values are the mean p/m SD. CFS=chronic fatigue syndrome; FM=fibromyalgia. ** Determined using the Godin Leisure-Time Exercise Questionnaire (20). *** P<0.05 versus controls. **** Determined using the Short-Form McGill Pain Questionnaire (22). ***** P<0.05 versus controls and versus the CFS only group. ****** Determined using the Profile of Mood States (21). Table 2. Exercise responses at the ventilatory threshold* -------------------------------------------------------------------------------------------------------------------------------------- Overall study population Fitness-matched subgroup -------------------------------------------------- --------------------------------------------------- CFS only CFS plus FM Controls CFS only CFS plus FM Controls p/m p/m p/m p/m p/m p/m -------------------------------------------------------------------------------------------------------------------------------------- % peak VO_2 58 0.08 59 0.06 57 0.06 58 0.08 59 0.05 58 0.06 VO_2, ml 1001 217** 929 196** 1257 432 914 132 968 192 962 239 VCO_2 , ml 909 234** 867 203** 1173 427 822 154 908 202 882 203 RER 0.9 0.08 0.9 0.08 0.9 0.08 0.9 0.08 0.9 0.08 0.9 0.08 VE, liters/minute^-1 29 6 28 6** 34 9 27 4 30 5 27 5 RR, breaths/minute^-1 24 5 23 5 25 4 24 6 23 4 25 4 VE/VO_2 29 4 31 3** 28 3 29 4 31 3 29 4 VE/VCO_2 32 4 33 3** 30 4 33 4 34 3 32 4 Heart rate, beats/minute-1 109 17 107 14 112 17 104 16 107 12 106 13 Watts 70 19** 62 17** 90 37 65 12 62 19 62 14 RPE, 6-20 scale 11 2 13 2** 10 2 11 2 13 2** 10 2 Pain, 0-10 scale 1.6 2 3.2 2*** 1.1 1 1.4 2 2.5 2** 0.9 1 -------------------------------------------------------------------------------------------------------------------------------------- * Values are the mean p/m SD. CFS=chronic fatigue syndrome; FM=fibromyalgia; VO_2=O_2 consumption; VCO_2 production; RER=respiratory exchange ratio; VE=ventilation; RR=respiratory rate; VE/VO_2=ventilatory equivalent of oxygen; VE/VCO_2=ventilatory equivalent of CO ; RPE=rating of perceived exertion. ** P<0.05 versus controls. *** P<0.05 versus controls and versus the CFS only group. Table 3. Peak exercise responses* -------------------------------------------------------------------------------------------------------------------------------------- Overall study population Fitness-matched subgroup -------------------------------------------------- --------------------------------------------------- CFS only CFS plus FM Controls CFS only CFS plus FM Controls p/m p/m p/m p/m p/m p/m -------------------------------------------------------------------------------------------------------------------------------------- VO_2, ml/kg/minute^-1 25.7 6 23.4 4** 29.7 8 24.0 4 24.2 4 24.3 4 Heart rate, beats/minute 169 14 163 20 173 16 169 14 169 10 166 16 RER 1.2 0.1 1.2 0.1 1.2 0.1 1.2 0.1 1.2 0.1 1.2 0.1 VE, liters/minute^-1 77 20 68 15** 88 30 72 12 72 14 68 13 RR, breaths/minute^- 1 47 10 41 8 46 10 47 11 41 8 43 9 Watts 150 39 129 26** 177 60 138 22 133 23 135 31 Exercise time, minutes 9.5 2.6 8.1 1.7** 11.2 3.9 8.7 1.4 8.4 1.5 8.4 1.9 RPE, 6­20 scale 18.1 1.3 18.5 1.4 18.0 1.5 18.0 1 18.4 1 18.0 2 Pain, 0-10 scale 4.8 2.8 6.7 3.6 5.5 3.2 4.6 3 6.4 4 4.5 3 -------------------------------------------------------------------------------------------------------------------------------------- * Values are the mean p/m SD. 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McCully KK, Smith S, Rajaei S, Leigh JS Jr, Natelson BH. Blood flow and muscle metabolism in chronic fatigue syndrome. Clin Sci (Lond) 2003;104:641-7. 30. Montague TJ, Marrie TJ, Klassen GA, Bewick DJ, Horacek BM. Cardiac function at rest and with exercise in the chronic fatigue syndrome. Chest 1989;95:779-84. 31. Edwards RH, Gibson H, Clague JE, Helliwell T. Muscle histopa- thology and physiology in chronic fatigue syndrome. Ciba Found Symp 1993;173:102-17. 32. Wallman KE, Morton AR, Goodman C, Grove R. Physiological responses during a submaximal cycle test in chronic fatigue syndrome. Med Sci Sports Exerc 2005;36:1682-8. 33. Cook DB, Lange G, Ciccone DS, Liu WC, Steffener J, Natelson BH. Functional imaging of pain in patients with primary fibromy- algia. J Rheumatol 2004;31:364-78. 34. Staud R, Robinson ME, Price DD. Isometric exercise has opposite effects on central pain mechanisms in fibromylagia patients com- pared to normal controls. Pain 2005;118:176-84. -------- (c) 2006, American College of Rheumatology [Return to top] ------------------------------ Date: Mon, 9 Oct 2006 15:53:20 -0400 From: "Bernice A. Melsky" <bernicemelsky@xxxxx.xxx> Subject: RES: Alpha2 receptors and agonists in pain management Alpha2 receptors and agonists in pain management. Curr Opin Anaesthesiol. 2001 Oct;14(5):513-518. Smith H, Elliott J. [a] Department of Anesthesia, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA; and [b] Kansas City School of Medicine, Department of Anesthesiology, St Luke's Hospital of Kansas City, MO, USA. PMID: 17019139 Alpha2 agonists have been in clinical use for decades, primarily in the treatment of hypertension. In recent years, alpha2 agonists have found wider application, particularly in the fields of anesthesia and pain management. It has been noted that these agents can enhance analgesia provided by traditional analgesics, such as opiates, and may result in opiate-sparing effects. This has important implications for the management of acute postoperative pain and chronic pain states, including disorders involving spasticity or myofascial pain, neuropathic pain, and chronic daily headaches. The clinical utility of these agents is ever expanding, as they are gaining broader use in neuraxial analgesia, and new applications are continuously under investigation. The alpha2 agonists that are currently employed in anesthesia and pain management include clonidine, tizanidine, and dexmedetomidine. Moxonidine and radolmidine, which are not currently in clinical use in humans, may offer favorable side-effect profiles when compared with traditional alpha2 agonists, and may thereby allow for more widespread pain management applications. [Return to top] ------------------------------

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