今日の臨床サポート

慢性疲労症候群

著者: 德永健一郎 熊本赤十字病院 リウマチ・膠原病内科

監修: 岸本暢将 杏林大学医学部 腎臓・リウマチ膠原病内科

著者校正/監修レビュー済:2022/07/06
参考ガイドライン:
患者向け説明資料

概要・推奨   

  1. 慢性疲労症候群(CFS)は原因不明の持続・反復する強い倦怠感を呈する疾患である。
  1. 2015年米国医学研究所(IOM)基準でCFSを診断する。
  1. 発熱、関節炎、筋症や筋炎所見、有意なリンパ節腫脹などの症状は、通常はCFSではみられないため、もしもあった場合には原因を検索すべきである。
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  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となりま
薬剤監修について:
オーダー内の薬剤用量は日本医科大学付属病院 薬剤部 部長 伊勢雄也 以下、林太祐、渡邉裕次、井ノ口岳洋、梅田将光による疑義照会のプロセスを実施、疑義照会の対象については著者の方による再確認を実施しております。
※薬剤中分類、用法、同効薬、診療報酬は、エルゼビアが独自に作成した薬剤情報であり、 著者により作成された情報ではありません。
尚、用法は添付文書より、同効薬は、薬剤師監修のもとで作成しております。
※同効薬・小児・妊娠および授乳中の注意事項等は、海外の情報も掲載しており、日本の医療事情に適応しない場合があります。
※薬剤情報の(適外/適内/⽤量内/⽤量外/㊜)等の表記は、エルゼビアジャパン編集部によって記載日時にレセプトチェックソフトなどで確認し作成しております。ただし、これらの記載は、実際の保険適応の査定において保険適応及び保険適応外と判断されることを保証するものではありません。また、検査薬、輸液、血液製剤、全身麻酔薬、抗癌剤等の薬剤は保険適応の記載の一部を割愛させていただいています。
(詳細はこちらを参照)
著者のCOI(Conflicts of Interest)開示:
德永健一郎 : 特に申告事項無し[2022年]
監修:岸本暢将 : 講演料(田辺三菱製薬,アッヴィ,エーザイ,日本イーライリリー,旭化成ファーマ,ヤンセン,ノバルティス,中外製薬,UCB,アステラス製薬,アムジェン,ファイザー,BMS,あゆみ製薬,第一三共)[2022年]

改訂のポイント:
  1. 定期レビューを行い、各項目について加筆修正を行った。

病態・疫学・診察

疾患(疫学・病態)  
  1. 慢性疲労症候群(chronic fatigue syndrome、CFS)はCDC(米国疾病対策センター)により1988年に提唱され、欧米では筋痛性脳脊髄炎(Myalgic Encephalomyelitis:ME)とされており,ME/CFSと記載されることある。
  1. ほかの疾患で説明できず、持続・反復する強い倦怠感を呈する疾患である。
  1. 原因は不明である。疾患の機序で、中枢神経、自律神経、免疫やエネルギー代謝の関与が示唆されているが、病態理解や診断に寄与する明確な根拠は得られていない。
  1. EBウイルス[1]やSARS-CoV-2[2]などのウイルス感染症や、免疫の異常、代謝内分泌の異常、神経精神の要素などが原因として研究・報告されているが、証明されたものはない。ウイルス感染症が発症のきっかけだったという患者は多い。
  1. 慢性の倦怠感の訴えは日常診療においてよく遭遇する。CFSはその中のごく一部にすぎない。
  1. 疾患定義によっても有病率はまちまちであり疫学も不明である。
  1. 若年から中年成人に好発するが、小児例や高齢例もある。多くの報告において、男性に比べて女性が2倍。
  1. 疾患定義は複数あるが、2015年に米国医学研究所(the Institute of Medicine、IOM)から提唱されている。
  1. 6カ月以上の間、中等度、相当な、もしくは重度の症状が少なくとも半分の期間に持続する。倦怠感に加えて、労作後倦怠感、すっきりしない睡眠、認知機能低下、および起立調節に関連した症状が挙げられる。
  1. 米国医学研究所(IOM)による慢性疲労症候群(chronic fatigue syndrome、CFS)/全身性労作不耐性疾患の診断基準、2015年: >詳細情報 
問診・診察のポイント  
  1. 倦怠感の発症は比較的急性であり、上気道炎や伝染性単核球症が契機であることがしばしばある。徐々に数カ月かけて発症することもある。

これより先の閲覧には個人契約のトライアルまたはお申込みが必要です。

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文献 

Ian Hickie, Tracey Davenport, Denis Wakefield, Ute Vollmer-Conna, Barbara Cameron, Suzanne D Vernon, William C Reeves, Andrew Lloyd, Dubbo Infection Outcomes Study Group
Post-infective and chronic fatigue syndromes precipitated by viral and non-viral pathogens: prospective cohort study.
BMJ. 2006 Sep 16;333(7568):575. doi: 10.1136/bmj.38933.585764.AE. Epub 2006 Sep 1.
Abstract/Text OBJECTIVE: To delineate the risk factors, symptom patterns, and longitudinal course of prolonged illnesses after a variety of acute infections.
DESIGN: Prospective cohort study following patients from the time of acute infection with Epstein-Barr virus (glandular fever), Coxiella burnetii (Q fever), or Ross River virus (epidemic polyarthritis).
SETTING: The region surrounding the township of Dubbo in rural Australia, encompassing a 200 km geographical radius and 104,400 residents.
PARTICIPANTS: 253 patients enrolled and followed at regular intervals over 12 months by self report, structured interview, and clinical assessment.
OUTCOME MEASURES: Detailed medical, psychiatric, and laboratory evaluations at six months to apply diagnostic criteria for chronic fatigue syndrome. Premorbid and intercurrent illness characteristics recorded to define risk factors for chronic fatigue syndrome. Self reported illness phenotypes compared between infective groups.
RESULTS: Prolonged illness characterised by disabling fatigue, musculoskeletal pain, neurocognitive difficulties, and mood disturbance was evident in 29 (12%) of 253 participants at six months, of whom 28 (11%) met the diagnostic criteria for chronic fatigue syndrome. This post-infective fatigue syndrome phenotype was stereotyped and occurred at a similar incidence after each infection. The syndrome was predicted largely by the severity of the acute illness rather than by demographic, psychological, or microbiological factors.
CONCLUSIONS: A relatively uniform post-infective fatigue syndrome persists in a significant minority of patients for six months or more after clinical infection with several different viral and non-viral micro-organisms. Post-infective fatigue syndrome is a valid illness model for investigating one pathophysiological pathway to chronic fatigue syndrome.

PMID 16950834
Leila Simani, Mahtab Ramezani, Ilad Alavi Darazam, Mastooreh Sagharichi, Mohammad Amin Aalipour, Fatemeh Ghorbani, Hossein Pakdaman
Prevalence and correlates of chronic fatigue syndrome and post-traumatic stress disorder after the outbreak of the COVID-19.
J Neurovirol. 2021 Feb;27(1):154-159. doi: 10.1007/s13365-021-00949-1. Epub 2021 Feb 2.
Abstract/Text As the SARS-COV-2 becomes a global pandemic, many researchers have a concern about the long COVID-19 complications. Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is a persistent, debilitating, and unexplained fatigue disorder. We investigated psychological morbidities such as CFS and post-traumatic stress disorder (PTSD) among survivors of COVID-19 over 6 months. All COVID-19 survivors from the university-affiliated hospital of Tehran, Iran, were assessed 6 months after infection onset by a previously validated questionnaire based on the Fukuda guidelines for CFS/EM and DSM-5 Checklist for PTSD (The Post-traumatic Stress Disorder Checklist for DSM-5 or PCL-5) to determine the presence of stress disorder and chronic fatigue problems. A total of 120 patients were enrolled. The prevalence rate of fatigue symptoms was 17.5%. Twelve (10%) screened positive for chronic idiopathic fatigue (CIF), 6 (5%) for CFS-like with insufficient fatigue syndrome (CFSWIFS), and 3 (2.5%) for CFS. The mean total scores in PCL-5 were 9.27 ± 10.76 (range:0-44), and the prevalence rate of PTSD was 5.8%. There was no significant association after adjusting between CFS and PTSD, gender, comorbidities, and chloroquine phosphate administration. The obtained data revealed the prevalence of CFS among patients with COVID-19, which is almost similar to CFS prevalence in the general population. Moreover, PTSD in patients with COVID-19 is not associated with the increased risk of CFS. Our study suggested that medical institutions should pay attention to the psychological consequences of the COVID-19 outbreak.

PMID 33528827
D L Goldenberg, R W Simms, A Geiger, A L Komaroff
High frequency of fibromyalgia in patients with chronic fatigue seen in a primary care practice.
Arthritis Rheum. 1990 Mar;33(3):381-7. doi: 10.1002/art.1780330311.
Abstract/Text We administered a standardized history questionnaire and performed a tender point examination on 27 patients with debilitating fatigue of at least 6 months duration, seen in a primary care practice, as well as on 20 patients with fibromyalgia. Sixteen of the 27 patients with chronic fatigue met the full criteria for the working case definition of chronic fatigue syndrome (CFS). Eight patients with chronic fatigue denied having any current persistent, diffuse musculoskeletal pain, and their tender point scores were similar to those in 10 normal control subjects. In contrast, 19 patients with chronic fatigue (70%) had persistent, diffuse musculoskeletal pain. The results of their tender point examinations were similar to those of the patients with fibromyalgia. Thus, the majority of these patients with debilitating chronic fatigue, including those who met criteria for CFS, met the historical and tender point diagnostic criteria for fibromyalgia. The presence of current musculoskeletal pain will identify those CFS patients who have fibromyalgia.

PMID 2317224
L A Aaron, M M Burke, D Buchwald
Overlapping conditions among patients with chronic fatigue syndrome, fibromyalgia, and temporomandibular disorder.
Arch Intern Med. 2000 Jan 24;160(2):221-7.
Abstract/Text BACKGROUND: Patients with chronic fatigue syndrome (CFS), fibromyalgia (FM), and temporomandibular disorder (TMD) share many clinical illness features such as myalgia, fatigue, sleep disturbances, and impairment in ability to perform activities of daily living as a consequence of these symptoms. A growing literature suggests that a variety of comorbid illnesses also may commonly coexist in these patients, including irritable bowel syndrome, chronic tension-type headache, and interstitial cystitis.
OBJECTIVE: To describe the frequency of 10 clinical conditions among patients with CFS, FM, and TMD compared with healthy controls with respect to past diagnoses, degree to which they manifested symptoms for each condition as determined by expert-based criteria, and published diagnostic criteria.
METHODS: Patients diagnosed as having CFS, FM, and TMD by their physicians were recruited from hospital-based clinics. Healthy control subjects from a dermatology clinic were enrolled as a comparison group. All subjects completed a 138-item symptom checklist and underwent a brief physical examination performed by the project physicians.
RESULTS: With little exception, patients reported few past diagnoses of the 10 clinical conditions beyond their referring diagnosis of CFS, FM, or TMD. In contrast, patients were more likely than controls to meet lifetime symptom and diagnostic criteria for many of the conditions, including CFS, FM, irritable bowel syndrome, multiple chemical sensitivities, and headache. Lifetime rates of irritable bowel syndrome were particularly striking in the patient groups (CFS, 92%; FM, 77%; TMD, 64%) compared with controls (18%) (P<.001). Individual symptom analysis revealed that patients with CFS, FM, and TMD share common symptoms, including generalized pain sensitivity, sleep and concentration difficulties, bowel complaints, and headache. However, several symptoms also distinguished the patient groups.
CONCLUSIONS: This study provides preliminary evidence that patients with CFS, FM, and TMD share key symptoms. It also is apparent that other localized and systemic conditions may frequently co-occur with CFS, FM, and TMD. Future research that seeks to identify the temporal relationships and other pathophysiologic mechanism(s) linking CFS, FM, and TMD will likely advance our understanding and treatment of these chronic, recurrent conditions.

PMID 10647761
D Buchwald, D Garrity
Comparison of patients with chronic fatigue syndrome, fibromyalgia, and multiple chemical sensitivities.
Arch Intern Med. 1994 Sep 26;154(18):2049-53.
Abstract/Text BACKGROUND: Chronic fatigue syndrome (CFS), fibromyalgia (FM), and multiple chemical sensitivities (MCS) are conditions associated with fatigue and a variety of other symptoms that appear to share many clinical and demographic features. Our objectives were to describe the similarities and differences among patients with CFS, FM, and MCS. Additional objectives were to determine how frequently patients with MCS and FM met the criteria for CFS and if they differed in their health locus of control.
METHODS: Demographic, clinical, and psychosocial measures were prospectively collected in 90 patients, 30 each with CFS, FM, and MCS. Patients were recruited from a university-based referral clinic devoted to the evaluation and treatment of chronic fatigue and three private practices. Variables included demographic features, symptoms characteristic of each condition, psychological complaints, a measure of health locus of control, and information on health care use.
RESULTS: Overall, the three patient groups were remarkably similar in demographic characteristics and the presence of specific symptoms. Patients with CFS and FM frequently reported symptoms compatible with MCS. Likewise, 70% of patients with FM and 30% of those with MCS met the criteria for CFS. Health care use was substantial among patients with CFS, FM, and MCS, with an average of 22.1, 39.7, and 23.3 visits, respectively, to a medical provider during the prior year. Health locus of control did not differ among the three populations.
CONCLUSIONS: In general, demographic and clinical factors and health locus of control do not clearly distinguish patients with CFS, FM, and MCS. Symptoms typical of each disorder are prevalent in the other two conditions.

PMID 8092909
S E Straus, J K Dale, M Tobi, T Lawley, O Preble, R M Blaese, C Hallahan, W Henle
Acyclovir treatment of the chronic fatigue syndrome. Lack of efficacy in a placebo-controlled trial.
N Engl J Med. 1988 Dec 29;319(26):1692-8. doi: 10.1056/NEJM198812293192602.
Abstract/Text Twenty-seven adults with a diagnosis of the chronic fatigue syndrome were enrolled in a double-blind, placebo-controlled study of acyclovir therapy. The patients had had debilitating fatigue for an average of 6.8 years, accompanied by persisting antibodies to Epstein-Barr virus early antigens (titers greater than or equal to 1:40) or undetectable levels of antibodies to Epstein-Barr virus nuclear antigens (titers less than 1:2) or both. Each course of treatment consisted of intravenous placebo or acyclovir (500 mg per square meter of body-surface area) administered every eight hours for seven days. The same drug was then given orally for 30 days (acyclovir, 800 mg four times daily). There were six-week observation periods before, between, and after the treatments. Three patients had acyclovir-induced nephrotoxicity and were withdrawn from the study. Of the 24 patients who completed the trial, similar numbers improved with acyclovir therapy and with placebo (11 and 10, respectively). Neither acyclovir treatment nor clinical improvement correlated with alterations in laboratory findings, including titers of antibody to Epstein-Barr virus or levels of circulating immune complexes or of leukocyte 2',5'-oligoadenylate synthetase. Subjective improvement correlated with various measures of mood. We conclude that acyclovir, as used in this study, does not ameliorate the chronic fatigue syndrome. We believe that the clinical improvement observed in most patients reflected either spontaneous remission of the syndrome or a placebo effect.

PMID 2849717
C H Bombardier, D Buchwald
Outcome and prognosis of patients with chronic fatigue vs chronic fatigue syndrome.
Arch Intern Med. 1995 Oct 23;155(19):2105-10.
Abstract/Text BACKGROUND: There are few data on the natural history and prognosis of persons with chronic fatigue (CF) or CF syndrome (CFS). Therefore, we compared functional outcomes in patients with each condition and tested the validity of various prognostic indicators.
METHODS: Four hundred forty-five (89%) of 498 consecutive referral patients were surveyed an average of 1.5 years after an initial evaluation. Data from the initial evaluation were used to predict outcomes.
RESULTS: Sixty-four percent of all patients reported improvement, but only 2% reported complete resolution of symptoms. Patients initially diagnosed as having CFS reported greater symptom severity and lower level of functioning at follow-up than did patients with CF. Major depression predicted unemployment in the CF group. Older age, longer duration of illness, and a lifetime history of dysthymia predicted less improvement in the CF group. Current dysthymia predicted less improvement for the CFS group.
CONCLUSIONS: The case definition of CFS according to the Centers for Disease Control and Prevention identifies chronically fatigued patients with poorer prognosis. In a tertiary care setting, recovery from CF or CFS is rare, but improvement is common. Prognostic indicators vary for the two groups, but the coexistence of dysthymia suggests poorer outcomes generally.

PMID 7575071
Emmert Roberts, Simon Wessely, Trudie Chalder, Chin-Kuo Chang, Matthew Hotopf
Mortality of people with chronic fatigue syndrome: a retrospective cohort study in England and Wales from the South London and Maudsley NHS Foundation Trust Biomedical Research Centre (SLaM BRC) Clinical Record Interactive Search (CRIS) Register.
Lancet. 2016 Apr 16;387(10028):1638-43. doi: 10.1016/S0140-6736(15)01223-4. Epub 2016 Feb 10.
Abstract/Text BACKGROUND: Mortality associated with chronic fatigue syndrome is uncertain. We investigated mortality in individuals diagnosed with chronic fatigue syndrome in secondary and tertiary care using data from the South London and Maudsley NHS Foundation Trust Biomedical Research Centre (SLaM BRC) Clinical Record Interactive Search (CRIS) register.
METHODS: We calculated standardised mortality ratios (SMRs) for all-cause, suicide-specific, and cancer-specific mortality for a 7-year observation period using the number of deaths observed in SLaM records compared with age-specific and sex-specific mortality statistics for England and Wales. Study participants were included if they had had contact with the chronic fatigue service (referral, discharge, or case note entry) and received a diagnosis of chronic fatigue syndrome.
FINDINGS: We identified 2147 cases of chronic fatigue syndrome from CRIS and 17 deaths from Jan 1, 2007, to Dec 31, 2013. 1533 patients were women of whom 11 died, and 614 were men of whom six died. There was no significant difference in age-standardised and sex-standardised mortality ratios (SMRs) for all-cause mortality (SMR 1·14, 95% CI 0·65-1·85; p=0·67) or cancer-specific mortality (1·39, 0·60-2·73; p=0·45) in patients with chronic fatigue syndrome when compared with the general population in England and Wales. This remained the case when deaths from suicide were removed from the analysis. There was a significant increase in suicide-specific mortality (SMR 6·85, 95% CI 2·22-15·98; p=0·002).
INTERPRETATION: We did not note increased all-cause mortality in people with chronic fatigue syndrome, but our findings show a substantial increase in mortality from suicide. This highlights the need for clinicians to be aware of the increased risk of completed suicide and to assess suicidality adequately in patients with chronic fatigue syndrome.
FUNDING: National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London.

Copyright © 2016 Roberts et al. Open Access article distributed under the terms of CC BY. Published by Elsevier Ltd.. All rights reserved.
PMID 26873808
P G O'Malley, E Balden, G Tomkins, J Santoro, K Kroenke, J L Jackson
Treatment of fibromyalgia with antidepressants: a meta-analysis.
J Gen Intern Med. 2000 Sep;15(9):659-66. doi: 10.1046/j.1525-1497.2000.06279.x.
Abstract/Text BACKGROUND: Fibromyalgia is a common, poorly understood musculoskeletal pain syndrome with limited therapeutic options.
OBJECTIVE: To systematically review the efficacy of antidepressants in the treatment of fibromyalgia and examine whether this effect was independent of depression.
DESIGN: Meta-analysis of English-language, randomized, placebo-controlled trials. Studies were obtained from searching MEDLINE, EMBASE, and PSYCLIT (1966-1999), the Cochrane Library, unpublished literature, and bibliographies. We performed independent duplicate review of each study for both inclusion and data extraction.
MAIN RESULTS: Sixteen randomized, placebo-controlled trials were identified, of which 13 were appropriate for data extraction. There were 3 classes of antidepressants evaluated: tricyclics (9 trials), selective serotonin reuptake inhibitors (3 trials), and S-adenosylmethionine (2 trials). Overall, the quality of the studies was good (mean score 5.6, scale 0-8). The odds ratio for improvement with therapy was 4.2 (95% confidence interval [95% CI], 2.6 to 6.8). The pooled risk difference for these studies was 0.25 (95% CI, 0.16 to 0.34), which calculates to 4 (95% CI, 2.9 to 6.3) individuals needing treatment for 1 patient to experience symptom improvement. When the effect on individual symptoms was combined, antidepressants improved sleep, fatigue, pain, and well-being, but not trigger points. In the 5 studies where there was adequate assessment for an effect independent of depression, only 1 study found a correlation between symptom improvement and depression scores. Outcomes were not affected by class of agent or quality score using meta-regression.
CONCLUSION: Antidepressants are efficacious in treating many of the symptoms of fibromyalgia. Patients were more than 4 times as likely to report overall improvement, and reported moderate reductions in individual symptoms, particularly pain. Whether this effect is independent of depression needs further study.

PMID 11029681
J H Vercoulen, C M Swanink, F G Zitman, S G Vreden, M P Hoofs, J F Fennis, J M Galama, J W van der Meer, G Bleijenberg
Randomised, double-blind, placebo-controlled study of fluoxetine in chronic fatigue syndrome.
Lancet. 1996 Mar 30;347(9005):858-61. doi: 10.1016/s0140-6736(96)91345-8.
Abstract/Text BACKGROUND: No somatic treatment has been found to be effective for chronic fatigue syndrome (CFS). Antidepressant therapy is commonly used. Fluoxetine is recommended in preference to tricyclic agents because it has fewer sedative and autonomic nervous system effects. However, there have been no randomised, placebo-controlled, double-blind studies showing the effectiveness of antidepressant therapy in CFS. We have carried out such a study to assess the effect of fluoxetine in depressed and non-depressed CFS patients.
METHODS: In this randomised, double-blind study, we recruited 44 patients to the depressed CFS group, and 52 to the non-depressed CFS group. In each group participants were randomly assigned to receive either fluoxetine (20 mg once daily) or placebo for 8 weeks. The effect of fluoxetine was assessed by questionnaires, self-observation lists, standard neuropsychological tests, and a motion-sensing device (Actometer), which were applied on the day treatment started and on the last day.
FINDINGS: The two groups were well matched in terms of age, sex distribution, employment and marital status, and duration of CFS. There were no significant differences between the placebo and fluoxetine-treated groups in the change during the 8-week treatment period for any dimension of CFS. There was no change in subjective assessments of fatigue, severity of depression, functional impairment, sleep disturbances, neuropsychological function, cognitions, or physical activity in the depressed or the non-depressed subgroup.
INTERPRETATION: Fluoxetine in a 20 mg daily dose does not have a beneficial effect on any characteristic of CFS. The lack of effect of fluoxetine on depressive symptoms in CFS suggests that processes underlying the presentation of depressive symptoms in CFS may differ from those in patients with major depressive disorder.

PMID 8622391
B H Natelson, J Cheu, J Pareja, S P Ellis, T Policastro, T W Findley
Randomized, double blind, controlled placebo-phase in trial of low dose phenelzine in the chronic fatigue syndrome.
Psychopharmacology (Berl). 1996 Apr;124(3):226-30. doi: 10.1007/BF02246661.
Abstract/Text Because of the striking similarity of the clinical manifestations produced by use of the drug reserpine and seen in patients with the chronic fatigue syndrome (CFS), we theorized that CFS was a disorder of reduced central sympathetic drive. Because of the pharmacology of control of this central sympathetic system, we further postulated that CFS symptoms would respond quickly to low dose treatment with a monamine oxidase inhibitor. To test these hypotheses, we designed a randomized, double blind placebo controlled study using phenelzine. No patient in the trial had a diagnosis of lifetime or current psychiatric disorder and none had depressed mood in the range of clinically depressed patients on a paper and pencil test of depression. Patients in the placebo group received placebo for 6 weeks while those in the drug treatment group were treated in three 2-week segments-placebo, 15 mg phenelzine every other day, and then 15 mg daily. This treatment regimen produced a significant pattern of improvement compared to worsening in 20 self report vehicles of CFS symptoms, illness severity, mood or functional status. Thus the data support our hypothesis of reduced sympathetic drive, although an alternative hypothesis of pain alleviation is also possible. The study design also allowed us to evaluate patients for a placebo effect: no evidence for this was found, suggesting that CFS is not an illness due to patients' being overly suggestible.

PMID 8740043
S Reid, T Chalder, A Cleare, M Hotopf, S Wessely
Chronic fatigue syndrome.
BMJ. 2000 Jan 29;320(7230):292-6. doi: 10.1136/bmj.320.7230.292.
Abstract/Text
PMID 10650029
P C Rowe, H Calkins
Neurally mediated hypotension and chronic fatigue syndrome.
Am J Med. 1998 Sep 28;105(3A):15S-21S. doi: 10.1016/s0002-9343(98)00167-3.
Abstract/Text A substantial body of clinical evidence now supports an association between various forms of hypotension and both idiopathic chronic fatigue and the chronic fatigue syndrome (CFS). Patients with CFS have a high prevalence of neurally mediated hypotension, and open treatment of this autonomic dysfunction has been associated with improvements in CFS symptoms. Randomized trials are now in progress to evaluate the efficacy of treatments directed at neurally mediated hypotension in those with CFS patients, and the results of these trials should help guide more basic inquiries into the mechanisms of orthostatic intolerance in affected individuals.

PMID 9790477
P C Rowe, H Calkins, K DeBusk, R McKenzie, R Anand, G Sharma, B A Cuccherini, N Soto, P Hohman, S Snader, K E Lucas, M Wolff, S E Straus
Fludrocortisone acetate to treat neurally mediated hypotension in chronic fatigue syndrome: a randomized controlled trial.
JAMA. 2001 Jan 3;285(1):52-9. doi: 10.1001/jama.285.1.52.
Abstract/Text CONTEXT: Patients with chronic fatigue syndrome (CFS) are more likely than healthy persons to develop neurally mediated hypotension (NMH) in response to prolonged orthostatic stress.
OBJECTIVE: To examine the efficacy of fludrocortisone acetate as monotherapy for adults with both CFS and NMH.
DESIGN: Randomized, double-blind, placebo-controlled trial conducted between March 1996 and February 1999.
SETTING: Two tertiary referral centers in the United States.
PATIENTS: One hundred individuals aged 18 to 50 years who satisfied Centers for Disease Control and Prevention criteria for CFS and had NMH provoked during a 2-stage tilt-table test. Eighty-three subjects had adequate outcome data to assess efficacy.
INTERVENTION: Subjects were randomly assigned to receive fludrocortisone acetate, titrated to 0.1 mg/d (n = 50) or matching placebo (n = 50) for 9 weeks, followed by 2 weeks of observation after discontinuation of therapy.
MAIN OUTCOME MEASURE: Proportion of subjects in each group with at least a 15-point improvement on a 100-point global wellness scale.
RESULTS: Baseline demographic and illness characteristics between the groups were similar; CFS had been present for at least 3 years in 71%. Using an intention-to-treat analysis, 7 subjects (14%) treated with fludrocortisone experienced at least a 15-point improvement in their wellness scores compared with 5 (10%) among placebo recipients (P =.76). No differences were observed in several other symptom scores or in the proportion with normal follow-up tilt test results at the end of the treatment period.
CONCLUSIONS: In our study of adults with CFS, fludrocortisone as monotherapy for NMH was no more efficacious than placebo for amelioration of symptoms. Failure to identify symptomatic improvement with fludrocortisone does not disprove the hypothesis that NMH could be contributing to some of the symptoms of CFS. Further studies are needed to determine whether other medications or combination therapy are more effective in treating orthostatic intolerance in patients with CFS.

PMID 11150109
Lillebeth Larun, Kjetil G Brurberg, Jan Odgaard-Jensen, Jonathan R Price
Exercise therapy for chronic fatigue syndrome.
Cochrane Database Syst Rev. 2016 Feb 7;2:CD003200. doi: 10.1002/14651858.CD003200.pub4. Epub 2016 Feb 7.
Abstract/Text BACKGROUND: Chronic fatigue syndrome (CFS) is characterised by persistent, medically unexplained fatigue, as well as symptoms such as musculoskeletal pain, sleep disturbance, headaches and impaired concentration and short-term memory. CFS presents as a common, debilitating and serious health problem. Treatment may include physical interventions, such as exercise therapy, which was last reviewed in 2004.
OBJECTIVES: The objective of this review was to determine the effects of exercise therapy (ET) for patients with CFS as compared with any other intervention or control.• Exercise therapy versus 'passive control' (e.g. treatment as usual, waiting-list control, relaxation, flexibility).• Exercise therapy versus other active treatment (e.g. cognitive-behavioural therapy (CBT), cognitive treatment, supportive therapy, pacing, pharmacological therapy such as antidepressants).• Exercise therapy in combination with other specified treatment strategies versus other specified treatment strategies (e.g. exercise combined with pharmacological treatment vs pharmacological treatment alone).
SEARCH METHODS: We searched The Cochrane Collaboration Depression, Anxiety and Neurosis Controlled Trials Register (CCDANCTR), the Cochrane Central Register of Controlled Trials (CENTRAL) and SPORTDiscus up to May 2014 using a comprehensive list of free-text terms for CFS and exercise. We located unpublished or ongoing trials through the World Health Organization (WHO) International Clinical Trials Registry Platform (to May 2014). We screened reference lists of retrieved articles and contacted experts in the field for additional studies
SELECTION CRITERIA: Randomised controlled trials involving adults with a primary diagnosis of CFS who were able to participate in exercise therapy. Studies had to compare exercise therapy with passive control, psychological therapies, adaptive pacing therapy or pharmacological therapy.
DATA COLLECTION AND ANALYSIS: Two review authors independently performed study selection, risk of bias assessments and data extraction. We combined continuous measures of outcomes using mean differences (MDs) and standardised mean differences (SMDs). We combined serious adverse reactions and drop-outs using risk ratios (RRs). We calculated an overall effect size with 95% confidence intervals (CIs) for each outcome.
MAIN RESULTS: We have included eight randomised controlled studies and have reported data from 1518 participants in this review. Three studies diagnosed individuals with CFS using the 1994 criteria of the Centers for Disease Control and Prevention (CDC); five used the Oxford criteria. Exercise therapy lasted from 12 to 26 weeks. Seven studies used variations of aerobic exercise therapy such as walking, swimming, cycling or dancing provided at mixed levels in terms of intensity of the aerobic exercise from very low to quite rigorous, whilst one study used anaerobic exercise. Control groups consisted of passive control (eight studies; e.g. treatment as usual, relaxation, flexibility) or CBT (two studies), cognitive therapy (one study), supportive listening (one study), pacing (one study), pharmacological treatment (one study) and combination treatment (one study). Risk of bias varied across studies, but within each study, little variation was found in the risk of bias across our primary and secondary outcome measures.Investigators compared exercise therapy with 'passive' control in eight trials, which enrolled 971 participants. Seven studies consistently showed a reduction in fatigue following exercise therapy at end of treatment, even though the fatigue scales used different scoring systems: an 11-item scale with a scoring system of 0 to 11 points (MD -6.06, 95% CI -6.95 to -5.17; one study, 148 participants; low-quality evidence); the same 11-item scale with a scoring system of 0 to 33 points (MD -2.82, 95% CI -4.07 to -1.57; three studies, 540 participants; moderate-quality evidence); and a 14-item scale with a scoring system of 0 to 42 points (MD -6.80, 95% CI -10.31 to -3.28; three studies, 152 participants; moderate-quality evidence). Serious adverse reactions were rare in both groups (RR 0.99, 95% CI 0.14 to 6.97; one study, 319 participants; moderate-quality evidence), but sparse data made it impossible for review authors to draw conclusions. Study authors reported a positive effect of exercise therapy at end of treatment with respect to sleep (MD -1.49, 95% CI -2.95 to -0.02; two studies, 323 participants), physical functioning (MD 13.10, 95% CI 1.98 to 24.22; five studies, 725 participants) and self-perceived changes in overall health (RR 1.83, 95% CI 1.39 to 2.40; four studies, 489 participants). It was not possible for review authors to draw conclusions regarding the remaining outcomes.Investigators compared exercise therapy with CBT in two trials (351 participants). One trial (298 participants) reported little or no difference in fatigue at end of treatment between the two groups using an 11-item scale with a scoring system of 0 to 33 points (MD 0.20, 95% CI -1.49 to 1.89). Both studies measured differences in fatigue at follow-up, but neither found differences between the two groups using an 11-item fatigue scale with a scoring system of 0 to 33 points (MD 0.30, 95% CI -1.45 to 2.05) and a nine-item Fatigue Severity Scale with a scoring system of 1 to 7 points (MD 0.40, 95% CI -0.34 to 1.14). Serious adverse reactions were rare in both groups (RR 0.67, 95% CI 0.11 to 3.96). We observed little or no difference in physical functioning, depression, anxiety and sleep, and we were not able to draw any conclusions with regard to pain, self-perceived changes in overall health, use of health service resources and drop-out rate.With regard to other comparisons, one study (320 participants) suggested a general benefit of exercise over adaptive pacing, and another study (183 participants) a benefit of exercise over supportive listening. The available evidence was too sparse to draw conclusions about the effect of pharmaceutical interventions.
AUTHORS' CONCLUSIONS: Patients with CFS may generally benefit and feel less fatigued following exercise therapy, and no evidence suggests that exercise therapy may worsen outcomes. A positive effect with respect to sleep, physical function and self-perceived general health has been observed, but no conclusions for the outcomes of pain, quality of life, anxiety, depression, drop-out rate and health service resources were possible. The effectiveness of exercise therapy seems greater than that of pacing but similar to that of CBT. Randomised trials with low risk of bias are needed to investigate the type, duration and intensity of the most beneficial exercise intervention.

PMID 26852189
Abstract/Text Cognitive behavioural therapy and graded exercise therapy are promoted as evidence-based treatments for myalgic encephalomyelitis/chronic fatigue syndrome. This article explores patients' symptom responses following these treatments versus pacing therapy, an approach favoured by many sufferers. We analyse data from a large cross-sectional patient survey (n = 1428) and compare our findings with those from comparable patient surveys (n = 16,665), using a mix of descriptive statistics and regression analysis modelling. Findings from analysis of primary and secondary surveys suggest that cognitive behavioural therapy is of benefit to a small percentage of patients (8%-35%), graded exercise therapy brings about large negative responses in patients (54%-74%), while pacing is the most favoured treatment with the lowest negative response rate and the highest reported benefit (44%-82%).

PMID 28847166
P D White, K A Goldsmith, A L Johnson, L Potts, R Walwyn, J C DeCesare, H L Baber, M Burgess, L V Clark, D L Cox, J Bavinton, B J Angus, G Murphy, M Murphy, H O'Dowd, D Wilks, P McCrone, T Chalder, M Sharpe, PACE trial management group
Comparison of adaptive pacing therapy, cognitive behaviour therapy, graded exercise therapy, and specialist medical care for chronic fatigue syndrome (PACE): a randomised trial.
Lancet. 2011 Mar 5;377(9768):823-36. doi: 10.1016/S0140-6736(11)60096-2. Epub 2011 Feb 18.
Abstract/Text BACKGROUND: Trial findings show cognitive behaviour therapy (CBT) and graded exercise therapy (GET) can be effective treatments for chronic fatigue syndrome, but patients' organisations have reported that these treatments can be harmful and favour pacing and specialist health care. We aimed to assess effectiveness and safety of all four treatments.
METHODS: In our parallel-group randomised trial, patients meeting Oxford criteria for chronic fatigue syndrome were recruited from six secondary-care clinics in the UK and randomly allocated by computer-generated sequence to receive specialist medical care (SMC) alone or with adaptive pacing therapy (APT), CBT, or GET. Primary outcomes were fatigue (measured by Chalder fatigue questionnaire score) and physical function (measured by short form-36 subscale score) up to 52 weeks after randomisation, and safety was assessed primarily by recording all serious adverse events, including serious adverse reactions to trial treatments. Primary outcomes were rated by participants, who were necessarily unmasked to treatment assignment; the statistician was masked to treatment assignment for the analysis of primary outcomes. We used longitudinal regression models to compare SMC alone with other treatments, APT with CBT, and APT with GET. The final analysis included all participants for whom we had data for primary outcomes. This trial is registered at http://isrctn.org, number ISRCTN54285094.
FINDINGS: We recruited 641 eligible patients, of whom 160 were assigned to the APT group, 161 to the CBT group, 160 to the GET group, and 160 to the SMC-alone group. Compared with SMC alone, mean fatigue scores at 52 weeks were 3·4 (95% CI 1·8 to 5·0) points lower for CBT (p = 0·0001) and 3·2 (1·7 to 4·8) points lower for GET (p = 0·0003), but did not differ for APT (0·7 [-0·9 to 2·3] points lower; p = 0·38). Compared with SMC alone, mean physical function scores were 7·1 (2·0 to 12·1) points higher for CBT (p = 0·0068) and 9·4 (4·4 to 14·4) points higher for GET (p = 0·0005), but did not differ for APT (3·4 [-1·6 to 8·4] points lower; p=0·18). Compared with APT, CBT and GET were associated with less fatigue (CBT p = 0·0027; GET p = 0·0059) and better physical function (CBT p=0·0002; GET p<0·0001). Subgroup analysis of 427 participants meeting international criteria for chronic fatigue syndrome and 329 participants meeting London criteria for myalgic encephalomyelitis yielded equivalent results. Serious adverse reactions were recorded in two (1%) of 159 participants in the APT group, three (2%) of 161 in the CBT group, two (1%) of 160 in the GET group, and two (1%) of 160 in the SMC-alone group.
INTERPRETATION: CBT and GET can safely be added to SMC to moderately improve outcomes for chronic fatigue syndrome, but APT is not an effective addition.
FUNDING: UK Medical Research Council, Department of Health for England, Scottish Chief Scientist Office, Department for Work and Pensions.

Copyright © 2011 Elsevier Ltd. All rights reserved.
PMID 21334061

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