Date sent: Tue, 4 Mar 2003 Editorial: Journal of Chronic Fatigue Syndrome, Vol. 11(1) 2003 pp. 1-6 Chronic Fatigue Syndrome Guidelines The Canadian ME/CFS guidelines in this journal are aimed at assisting healthcare professionals including medical general practitioners, specialist physicians, physiotherapists, occupational therapists, psychologists and social workers who deal with patients with abnormal fatigue states. This set of guidelines is now the third to be published, with the British (1) and Australian (2) guidelines preceding them. These clinical guidelines should not be confused with the research guidelines for ME/CFS (3-6). The method of development of the Canadian guidelines differs from both the British and Australian guidelines principally in the manner of selecting the committee that developed them and also in the level of evidence accepted as indicating whether research findings were considered relevant. The British and Australian guidelines were developed by selected committee (the Australian committee also included a consumer representative) from within the country to develop their guidelines. The Australian guidelines committee called for submissions from interested parties and received at least 82 submissions. They then published draft guidelines and called for additional comments and criticisms following which they published the final guidelines. Both the British and Australian guidelines have received considerable criticism from both within the health professions and from the public. Several alternative guidelines have been suggested in trying to address the criticisms. These criticisms in cluded claims of bias in the recommendations toward a psychiatric outcome and failure to understand the limitations of patients to perform exercise programs as well as many others. The Canadian guidelines differ in their development as they were developed by a committee following input from invited world leaders in the research and clinical management of ME/CFS patients. The Canadian guidelines also accepted a lower level of evidence for points in their discussion and recommendations. All three sets of guidelines are open to methodological and interpretation criticisms, however at the end of the day each is an attempt to provide what is a general guide to best practice. The Canadian guidelines represent evidence-based clinical practice guidelines developed from the best available research evidence provided by a panel of world experts. In using these guidelines the healthcare worker should also exercise their clinical judgment in evaluating the evidence in front of them and take account of individual patient preferences. The CFS guidelines have not addressed the issue of defining the list of conditions that may result in fatigue. Thus we have chosen to give a simple overview of conditions that may result in fatigue and require to be differentiated before the diagnosis of CFS. ABNORMAL FATIGUE (ASTHENIA) Fatigue can be defined as a pervasive sense of tiredness or lack of energy that is not related exclusively to exertion. It should be differentiated from muscle fatigue or weakness. In most cases fatigue is usually transitory, however if fatigue is prolonged or disabling then it usually indicates a significant problem may exist. It is now generally accepted that fatigue is a very common symptom in many different conditions. There appears to be several major clinical problems associated with the diagnosis of abnormal fatigue disorders: (1) the principle diagnostic problem is determining the cause of the fatigue; (2) the clinician should not be confused that fatigue (or myalgia or the other symptoms that occur in increased frequency with fatigue) is an entity in its own right but is a common symptom of underlying disease; and (3) to determine at what level the fatigue is clinically significant based upon determining its severity, nature and duration. Abnormal fatigue is a common symptom reported to the clinician with rates between 10-25% of new case presentations (7-12) and thus provides a significant diagnostic challenge faced by many general practitioners. The available data on the actual biological basis for the initiation of fatigue in its multiple forms has not been established and needs to be investigated with open minds and scientific rigor, and devoid of the restrictions of the many currently accepted paradigms. The causes may be singular or co-morbid, which increases the complexity for the clinicians. Whilst knowing the exact basis for the development of a disease or symptom is not a prerequisite to development of treatment regimens, ultimately the treatments should revolve around a very thorough knowledge of the etiopathogenesis of the disease. The different clinical groups that have investigated abnormal fatigue states have frequently made interpretations of their data based upon their restricted clinical paradigms, which are not necessarily supported if all the available scientific data had been assessed. These paradigms and biases are commonly seen in the literature for many diseases until the etiopathogenesis is established. In these days of evidence based medicine, a thorough assessment of the patient is required to avoid inappropriate diagnosis and treatment regimens. As the primary diagnostician, the GP should be aware of the range of illnesses that require to be assessed before a diagnosis can be made. Many common yet normal life behavioral problems can induce fatigue; these include excess physical or mental activity, shift work, sleep deprivation, dietary excesses and insufficiencies, obesity, as well as prescribed and recreational drug use/abuse. Whilst these are easily identified from history taking and are usually limited in duration, many of the other causes of abnormal fatigue require additional investigation. Most of these normal life associated causes of fatigue do not last for greater than 6 months. Table 1 shows a relatively comprehensive list of these types of conditions where a combination of history, clinical examination and laboratory investigation are required to achieve the diagnosis. Some of the viral, bacterial and zoonotic infections will show a geographic distribution and not be applicable to all the readers of this journa l. The clinical and diagnostic abilities of the clinician are very important in assessing these complex sets of disorders. TABLE 1. Overview of the Potential Causes of Abnormal Fatigue Acute or chronic infections: . Viral . Parasitic . Bacterial . Zoonotic Mood disorders Sleep disturbances inclusive of sleep apnoea Malignancy of any origin Cardiovascular disorders/conditions: . Agranulocytosis . Subacute bacterial endocarditis . Anaemia . Leukaemia . Cardiac failure . Mitral stenosis . Congenital heart disease . Myocarditis . Cor pulmonale . Thalassaemia major or minor . Endocarditis Metabolic disorders/conditions: . Avitaminosis . Euthyroid sick syndrome . Diabetes mellitus . Menopause . Electrolyte disturbances . Metabolic disorders . Phenylketonuria . Fanconi syndrome . Cystic fibrosis . Hyperparathyroidism . Hypothyroidism . Hyperthyroidism Endocrine disorders/conditions: . Acromegaly . Hypopituitarism . Addison's disease Connective tissue diseases: . Rheumatoid arthritis . Scleroderma . Lupus Chronic allergy reactions Heavy metal poisoning (e.g., lead, mercury, arsenic) Other: . ME/Chronic fatigue syndrome . Multiple sclerosis . Cushing syndrome . Myasthenia gravis . Myelodysplastic syndrome . Myelofibrosis . Sick building syndrome . Osteomalacia and rickets . Post-polio syndrome . Parkinson's disease . Temporal arteritis . Polycythaemia (rubra) vera . Ulcerative colitis . Polymyalgia rheumatica . Malabsorption syndromes . Polyneuritis . Hodgkin's disease . Rheumatic fever . Cerebrovascular accident . Cirrhosis/Uraemia . Head injury The guidelines in this edition specifically address chronic fatigue syndrome which has a specific set of diagnostic criteria not addressed in this paper. CHANNELOPATHY It has long been suggested that many of the symptoms seen in ME/CFS patients and similar fatigue syndromes may be associated with channelopathies. The paper by Nijs et al. assesses the association be- tween electrolytes and immune cells, RNase L-ratio, blood cell count and erythrocyte sedimentation rate in 27 MF/CFS patients and 20 age and sex matched healthy controls. Whilst no consistent changes were found across the groups, associations were found in subsets of patients with interesting associations being found between NK-cells, the RNase L-ratio and serum calcium levels. The authors suggest that a channelopathy in a subset of CFS-patients, probably induced by the deregulated 2.5A RNase L antiviral pathway, may exist. Further studies are required into these interesting findings. GULF WAR SYNDROME This edition includes a comprehensive review on Gulf War Syndrome. The authors suggest that Gulf War Illnesses may involve multiple, complex chronic signs and symptoms that have a great similarity with MF/CFS and Fibromyalgia. The paper discusses the exposures to complex chemical mixtures (organophosphate pesticides, anti-nerve agents, etc.), radiological (depleted uranium) and biological agents (both primary and secondary) as well as multiple vaccines. Kenny De Meirleir, MD, PhD Neil McGregor, MDSc, PhD Editors REFERENCES 1. Royal College of Physicians, Psychiatrists and General Practitioners. Chronic fatigue syndrome. Report of a Joint Working Group. London. 1996. 2. Loblay R, Stewart G, Bertouch J, et al. Chronic fatigue syndrome clinical practice guidelines-2002. MIA 2002; 176:S 17-S56. 3. Holmes G, Kaplan I, Gantz I, et al. O1ronic Fatigue Syndrome: a working case definition. Ann Intern Med 1988;108:387-389. 4. Lloyd AR, Hickie I, Boughton CR, Spencer 0, Wakefield D. The prevalence of Chronic Fatigue Syndrome in an Australian population. 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