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Myalgic encephalomyelitis/chronic fatigue syndrome: a clinical case definition and guidelines for medical practitioners

The Canadian Consensus Document on ME/CFS
Our comparison study examined differences between patients meeting the Canadian clinicaland the Fukuda et al. criteria for ME/CFS, with people who had chronically fatiguing illnessexplained by a psychiatric condition. The Canadian Clinical Criteria selected patients with morephysical functional impairment, more fatigue/weakness, neurocognitive and neurologicalsymptoms and had more variables that significantly differentiated them from the psychiatriccomparison group than did the Fukuda et al. criteria. The findings do suggest that the Canadiancriteria point to the potential utility in designating post-exertional malaise and fatigue, sleepdysfunction, pain, clinical neurocognitive, and clinical autonomic/neuroimmunoendocrinesymptoms as major criteria.
The selection of diagnostic signs and symptoms has major implications for which individualsare diagnosed with ME/CFS and how seriously the illness is viewed by health care providers,disability insurers, rehabilitation planners, and patients and their families and friends. I hopethe results of this comparison study will encourage more physicians to USE THE CANADIANCLINICAL CRITERIA.
Leonard A. Jason, Ph D
Director: Center for Community Research, DePaul University, Chicago IL
Board of Directors: American Association for Chronic Fatigue Syndrome
The Canadian Clinical Case Definition has brilliantly rewritten the guidelines to capture, atlast, what ME/CFS is really all about. It is not that patients are fatigued. Healthy people getfatigued. Rather the definition specifically selects patients who worsen with exercise. Thistakes the emphasis away from the subjective sensation of "fatigue" and forces one to clearlydescribe the connection between fatigue and activity. This also embraces mental fatigue (lossof cognitive function and alertness) as well as physical fatigue (lack of energy and strength,often felt in the muscles). The patient must become symptomatically ill after exercise andmust also have evidence of neurocognitive, neuroendocrine, dysautonomic (e.g. orthostaticintolerance), and immune malfunction.
The Adelaide Forum agreed to UNANIMOUSLY EMBRACE THE CANADIAN CASE DEFINITIONwith a strong recommendation that it also be taken up by ME/CFS societies.
(Excerpt from the review of the Adelaide Forum, Australia, 2005) Michael Barratt, MBBS, FRCPA
In my opinion, and in the opinions of the other doctors at the Environmental Health Clinic,the ME/CFS Consensus Document is EXTREMELY PRACTICAL AND USEFUL. We have used itrepeatedly in helping to develop comprehensive individual treatment plans in collaborationwith patients. At the behest of the Ontario College of Family Physicians' (OCFP) EnvironmentalHealth Committee, and with approval of the publisher, the consensus diagnostic checklistswere posted on the OCFP website. We also use the diagnostic criteria, checklists, and treatmentsuggestions as teaching tools in the OCFP's Environmental Health Day at their Annual ScientificAssembly.
Lynn Marshall, MD, FAAEM, FRSM
Medical Director: Environmental Health Clinic,
Sunnybrook & Women's College Health Sciences Centre
Member: Environmental Health Committee, Ontario College of Family Physicians
Lecturer: University of Toronto Department of Family and Community Medicine
Assistant Professor of Family Medicine: Northern Ontario School of Medicine
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome:
A Clinical Case Definition and Guidelines for Medical Practitioners
An Overview of the Canadian Consensus Document
Bruce M. Carruthers, M.D., C.M., FRCP(C)
Marjorie I. van de Sande, B. Ed., Grad. Dip. Ed.
Copyright 2005 by Carruthers B.M. and van de Sande M.I.
All rights reserved. No part of this work may be reproduced, utilized, or transmitted in any form, electronic or
mechanical, including photocopying, microfilming, and recording, or by any information storage and retrieval system,
or by any means whatsoever without prior written permission from the authors. In our efforts to make physicians
aware of the Consensus Document and ensure that patients receive an accurate diagnosis and appropriate treatment
in a timely fashion, the authors may consider requests to reproduce this booklet providing ALL of the following
conditions are met
. This booklet must be reproduced in its entirety, with no additions, deletions, or
changes to this booklet and its contents in any manner whatsoever; no profit is made by any individual,
organization, company, university, or otherwise; and the authors are credited as the source.
In your
written request to reprint this booklet please state that you agree to all of the above conditions and indicate how you
intend to use the booklet.
The preparation of this work has been undertaken with great care to publish reliable data and information. However,
the authors are not responsible for any errors contained herein or for consequences that may ensue from use of
materials or information contained in this work. This work does not endorse any commercial product.
The National Library of Canada Cataloguing-in-Publication Data:
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Clinical Case Definition and Guidelines for Medical
Practitioners. An Overview of the Canadian Consensus Document. Carruthers, Bruce M., van de Sande,
Marjorie I.
ISBN: 0-9739335-0-X
Soft cover, alkaline paper. Includes authors' affiliations, table of contents, 1. Myalgic Encephalomyelitis/Chronic
Fatigue Syndrome (ME/CFS) – Clinical Definition/Diagnostic Criteria, 2. Diagnosis, Differential, 3. Clinical
Diagnostic Guidelines, 4. Treatment Guidelines. Copyright 2005 by B. M. Carruthers and M. I. van de Sande.
Published by: Carruthers & van de Sande
Correspondence to: Dr. Bruce M. Carruthers, email:
#2, 3657 West 16 Ave, Vancouver, B.C. V6R 3C3, Canada Reprint permission requests to: Marjorie van de Sande, email:
151 Arbour Ridge Circle N.W., Calgary, Alberta T3G 3V9, Canada
Cover Design by Robert J. van de Sande, B. Sc, E.E.
Cover Pictures (top to bottom): Xenon SPECT scan reveals pronounced worsening of
hypoperfusion following exercise; PET scan reveals decreased glucose utilization; sMRI voxel-based
morphometry technique indicates the volume of gray matter of the brain is significantly reduced and there
is an average of 8% reduction of brain tissue, although not discernable by the naked eye; and the bottom
two pictures using qEEG topography indicate the electrical sources in the gray matter (cortex). ME/CFS
patients have increased sources (indicated in red) in the left hemisphere whereas the controls have
increased sources (indicated in green) in the right hemisphere in the frontal and superior temporal cerebral
regions in beta frequencies. Patients' reduced sources in the right hemisphere may be due to interference
with the left brain inhibitory regulation of the right hemisphere during cognitive processing.
This booklet is an Overview of
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome:
Clinical Working Case Definition, Diagnostic and Treatment Guidelines
A Consensus Document
Bruce M Carruthers, Anil Kumar Jain, Kenny L De Meirleir, Daniel L Peterson, Nancy G Klimas, A
Martin Lerner,
Alison C Bested, Pierre Flor-Henry, Pradip Joshi, AC Peter Powles, Jeffrey A
Sherkey, Marjorie I van de Sande.

Journal of Chronic Fatigue Syndrome 11(1):7-115, 2003. ISBN: 0-7890-227-9 Haworth Medical Press Inc. This journal is available from The Haworth Document Delivery Service: Phone (Canada & USA) 800-722-5857. E-mail address: Authors and Affiliations: ME/CFS Consensus Document
Bruce M. Carruthers, MD, CM, FRCP(C): Specialist in Internal Medicine, Vancouver, B.C., Canada
Anil Kumar Jain, B Sc, MD: Ottawa Hospital, Ottawa, ON, Canada
Kenny L. De Meirleir, MD, Ph D: Professor of Physiology and Medicine (KDM, IC, PDB); Director of the
Human Performance Laboratory and member of the Vakgroep Internal Medicine; Vrije Universiteit Brussel, Brussels, Belgium Daniel L. Peterson, MD: Specialist in Internal Medicine, Affiliate of the Sierra Internal Medicine
Associates, Incline Village, NV, USA; ME/CFS researcher and clinician; a board member of the American Association of Chronic Fatigue Syndrome; and member of the International Chronic Fatigue Syndrome Study Group Nancy G. Klimas, MD: Clinical Professor of Medicine in Microbiology/Immunology/Allergy and Psychology,
University of Miami School of Medicine; Co-Director, E.M. Papper Laboratory of Clinical Immunology, University Miami School of Medicine; Director of AIDS Research and Co-Director of AIDS Clinical Research Unit, Miami VA Medical Center, Miami, FL, USA A. Martin Lerner, MD, PC, MACP: Clinical Professor of Internal Medicine, Wayne State University School
of Medicine; William Beaumont Hospital, Royal Oak, MI, USA Alison C. Bested, MD, FRCP(C): Haematological Pathologist; Environmental Health Clinic; Sunnybrook &
Women's College Health Sciences Centre, Toronto, ON, Canada. Pierre Flor-Henry, MB, Ch B, MD, Acad DPM, FRC, CSPQ: Clinical Director, General Psychiatry;
Director, Clinical Diagnostics and Research Centre; Clinical Professor of Psychiatry, University of Alberta, Edmonton, AB, Canada Pradip Joshi, BM, MD, FRCP(C): Clinical Associate Professor, Memorial University of Newfoundland, St.
John's, NF, Canada A. C. Peter Powles, MRACP, FRACP, FRCP(C), ABSM: Professor Emeritus, Faculty of Health Sciences,
McMasters University, Hamilton, ON; Professor, Faculty of Medicine, University of Toronto; Chief of Medicine and Sleep Disorder Consultant, St Joseph's Health Centre, Toronto; Sleep Disorder Consultant at the Sleep Disorder Clinic at St. Joseph's Healthcare, Hamilton, and Central West Sleep Affiliation, Paris, ON, Canada Jeffrey A. Sherkey, MD, CCFP(C): Formerly in Family Medicine, University Health Network, Toronto, ON,
Canada. We sincerely regret that Dr. Sherkey has since passed away. Marjorie I. van de Sande, B Ed, Grad Dip Ed: Consensus Coordinator; Advisor to the National ME/FM
Action Network, Canada
Acknowledgements for the Canadian Consensus Document

Lydia Neilson, MSM, President, and the National ME/FM Action Network for spearheading the drive for
the development of a clinical case definition, and diagnostic and treatment protocols for ME/CFS. National ME/FM Action Network, CanadaHealth Canada for establishing the "Terms of Reference" and selecting the Expert Consensus Panel
Crystaal, for sponsoring the Expert Consensus Panel Workshop without any direct involvement
James McSherry, MB, ChB, CCFP, FCFP, FABMP, FAAFP, who was a member of the Expert Consensus
Panel and contributed in the review process but was unable to attend the consensus meeting. We sincerely regret that Dr. Mc Sherry has since passed away. Kim D. Jones, RNC, Ph D, FNP, exercise physiologist, for her contribution to the exercise section.
Kerry Ellison, OT (non-practicing), for her contribution to the patient management/treatment, and
assessing disability sections Hugh Scher, LLP, for his contribution to the assessing disability section
Additional Acknowledgements for this Overview
Expert Consensus Panel for ME/CFS, for reviewing the overview
Robert J. van de Sande, B. Sc. E.E., for the cover design and formatting of the booklet
Pictures on Cover
(Reprinted with permission): Dr. Floris de Lange - sMRI voxel-based morphometry scan; Dr.
Pierre Flor-Henry – qEEG topography; PET & Xenon SPECT scans: Goldstein JA. "Chronic Fatigue
Syndromes: The Limbic Hypothesis". pp. vi, ix 1993 Haworth Medical Press. Available from document delivery
service: 1-800-HAWORTH
Jeff Brown, MSc, MBCS, CITP, CSci, for re-formatting the A4 paper layout edition and for proof reading.
Judith A. Brock, MA, for proof-reading
A Clinical Case Definition and Guidelines for Medical Practitioners

Natural Course


Co-morbid Entities
Application Notes
1. Fatigue
2. Post-Exertional Malaise and/or Fatigue
3. Sleep Dysfunction
5. Neurological/Cognitive Manifestations
6. Autonomic Manifestations
7. Neuroendocrine Manifestations
8. Immune Manifestations
Features of ME/CFS in Young People
Differences Between ME/CFS and FMS
Differences Among ME/CFS and Psychiatric Disorders


1. Sleep Disturbance
3. Fatigue
4. Cognitive Manifestations
5. Autonomic Manifestations
6. Neuroendocrine Manifestations
7. Immune Manifestations
Blood Donations


Symptom Severity and Severity Hierarch Profile
Sleep and Pain Profile
Assessing Occupational Disability


An Overview of the Canadian Consensus Document
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
DEVELOPMENT OF THE CANADIAN CONSENSUS DOCUMENT The National ME/FM Action Network of Canada definition that addressed a broader spectrum of spearheaded the drive for the development of an the pathogenesis of the illness, as well as to expert consensus document for Myalgic provide diagnostic and treatment protocols for Encephalomyelitis / Chronic Fatigue Syndrome medical practitioners. The members of the panel (ME/CFS). In response to increasing numbers of would have autonomy over their consensus patients inquiring about doctors knowledgeable about ME/CFS, the Network sent a questionnaire to doctors across Canada asking what items would Health Canada selected an Expert Consensus Panel be most helpful in assisting them with their for ME/CFS. The eleven-member Expert Consensus ME/CFS patients. The physicians concurred that a Panel received more than forty nominations clinical definition, as well as diagnostic and including numerous nominations from each treatment protocols were of prime importance. stakeholder group. The members of the Consensus Panel represented clinicians, university medical The National ME/FM Action Network then faculty, and researchers in the area of ME/CFS. approached two clinicians knowledgeable about Collectively, the members of the panel had ME/CFS and experienced in its diagnosis and diagnosed and/or treated more than twenty treatment. Dr. Bruce Carruthers of British thousand ME/CFS patients. Columbia and Dr. Anil Jain of Ontario kindly agreed to co-author a draft document. Lydia Neilson, Health Canada planned for a Consensus Workshop President of the National ME/FM Action Network, to be held on March 30 to April 1, 2001. Crystaal met with the Honourable Alan Rock, then Minister (Biovail Pharmaceuticals) funded the workshop of Health, to discuss the results of the doctors' without having any involvement with or influence survey and the draft document. The Honourable over the Consensus Document. They hired Alan Rock responded by stating the draft clinical Science and Medicine Canada to organize and definition was "a milestone in the fight against this facilitate the workshop. complex and tragic condition". The draft document went through three rounds of Health Canada established the "Terms of revisions prior to the Consensus Workshop where Reference". One stipulation was that at least one the document received consensus, in principle, member of the panel must be nominated by each with directives for various members to revise some of the five stakeholder groups of government, sections. The document was compiled by Marjorie universities, clinicians, industry, and advocacy. van de Sande and the revised document was sent There had to be at least ten members on the to the panel. There was 100% consensus by the panel, four of whom could come from outside of panel members on the final Consensus Canada. Panel members had to be practicing MDs Document. The Consensus Document has actively treating and/or diagnosing ME/CFS, or become known as the "Canadian Consensus MDs or Ph Ds involved in clinical research of the Document for ME/CFS". illness. Their mandate was to develop a clinical Importance of a Clinical Definition
The Greek origin of syndrome is syn– together, and -drome - a track for running. One must determine the
tracks of travel and observe the travel of a patient's syndrome components. Because research definitions
define a static collection of symptom entities, they have ignored or downplayed the critical dynamic
features of this syndrome, as lived by patients. The normal fatigue/pain pattern directly related to felt
causal action and adjusted by activity/rest rhythms is broken in ME/CFS. As a result there are cumulative
physical and cognitive fatigue/pain and "crashing" patterns, which are criterial in this Clinical Definition.
The objective postural cardiac output abnormalities correlate with the degree of reactive fatigue and overall
severity of ME/CFS. These findings could supply an objective marker for fatigue severity and duration, and
help explain why ME/CFS can be so disabling. It is important for the clinician to observe the dynamics of
the whole cluster of symptoms in their interaction, additive effects, and the disruption to patients' lives
over longer periods of time.
Carruthers, van de Sande
A Clinical Case Definition and Guidelines for Medical Practitioners
"Myalgic Encephalomyelitis" and "Chronic Fatigue Etiology
Syndrome" are used interchangeably and this Most patients enjoyed a healthy, active lifestyle illness is referred to as "ME/CFS". The Expert prior to the onset of ME/CFS. The importance of Consensus Panel, selected by Health Canada, viral involvement is supported by frequent infective established clinical criteria, and developed an triggers. Elevated levels of a wide variety of integrative diagnostic and treatment approach to intracellular pathogens suggest that a dysfunction in the body's response to infection plays a significant role. The presence of activated immune complexes is supported by activation of elevated ME/CFS is an acquired organic, pathophysiological, levels of T lymphocytes; poor cellular function is multi-systemic illness that occurs in both sporadic suggested by low natural killer cell cytotoxicity. and epidemic forms. Myalgic Encephalomyelitis There are confirmed findings of biochemical (ICD 10 G93.3), which includes CFS, is classified as dysregulation of the 2-5A synthetase/ribonuclease a neurological disease in the World Health
L (RNase L) antiviral defense pathway in Organization's International Classification of monocytes in many cases. Other prodomal Diseases (ICD). Chronic fatigue must not be events include immunization, anesthetics, physical confused with ME/CFS because the "fatigue" of trauma, exposure to environmental pollutants, ME/CFS represents pathophysiological exhaustion chemicals and heavy metals, and rarely blood and is only one of many symptoms. Compelling transfusions. A rapid and dramatic deterioration of research evidence of physiological and biochemical health in acute onset cases often occurs while abnormalities identifies ME/CFS as a distinct, others have a gradual onset with no obvious biological, clinical disorder. cause. In addition to infectious causes, a genetic predisposition may be considered when more than one separated family member is afflicted.
Natural Course
Epidemiological studies indicate a wide range of ME/CFS can be debilitating. In a review study of prevalence. However, in a large American sample prognosisof 6 studies indicated that 0% to 6% of more than 28,000 adults, 422 per 100,000 had (the sixth study indicated 12%) of adults return to ME/CFS, suggesting that between 125,000 and their pre-illness level of functioning. Relapses can 150,000 adult Canadians suffer from ME/CFS. It occur several years after remission. Progressive is more prevalent than lung cancer and AIDS6. degeneration of end organs, particularly cardiac or This illness affects all age groups, including pancreatic failure, may result in death, and suicide children, all racial/ethnic groups, and all is a risk. The prognosis for children and youth is socioeconomic strata. There is a higher much better. Symptom severity is the best indicator prevalence in females. Lower blood volume and of outcome, but accurate prognosis for an individual lower blood cell mass may be contributing factors cannot be predicted with certainty. Objective in their difficulty in coping with the genesis of postural cardiac output abnormalities correlate with symptom severity and reactive exhaustion. DIAGNOSTIC GUIDELINES The Clinical Definition encompasses the broad characteristic symptom patterns, which reflect cluster of symptoms and signs that give ME/CFS its specific areas of pathogenesis. distinctive character. Diagnosis is based on these An Overview of the Canadian Consensus Document
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
CLINICAL WORKING CASE DEFINITION OF ME/CFS A patient with ME/CFS will meet the criteria for fatigue, post-exertional malaise and/or
fatigue, sleep dysfunction, and pain; have two or more neurological/cognitive manifestations
and one or more symptoms from two of the categories of autonomic, neuroendocrine, and
immune manifestations; and adhere to item 7.
1. Fatigue:
The patient must have a significant degree of new onset, unexplained, persistent, or
recurrent physical and mental fatigue that substantially reduces activity level. 2. Post-Exertional Malaise and/or Fatigue: There is an inappropriate loss of physical and
mental stamina, rapid muscular and cognitive fatigability, post exertional malaise and/or fatigue and/or pain and a tendency for other associated symptoms within the patient's cluster of symptoms to worsen. There is a pathologically slow recovery period - usually 24 hours or longer. 3. Sleep Dysfunction:* There is unrefreshed sleep or sleep quantity or rhythm disturbances such
as reversed or chaotic diurnal sleep rhythms. 4. Pain:* There is a significant degree of myalgia. Pain can be experienced in the muscles, and/or
joints, and is often widespread and migratory in nature. Often there are significant headaches of
new type, pattern or severity.
5. Neurological/Cognitive Manifestations: Two or more of the following difficulties
should be present: confusion, impairment of concentration and short-term memory consolidation, disorientation, difficulty with information processing, categorizing and word retrieval, and perceptual and sensory disturbances – e.g. spatial instability and disorientation and inability to focus vision. Ataxia, muscle weakness and fasciculations are common. There may be overload phenomena: cognitive, sensory – e.g. photophobia and hypersensitivity to noise - and/or emotional overload, which may lead to "crash" periods and/or anxiety. 6. At Least One Symptom from Two of the Following Categories:
a. Autonomic Manifestations: orthostatic intolerance - neurally mediated hypotension
(NMH), postural orthostatic tachycardia syndrome (POTS), delayed postural hypotension; light-headedness; extreme pallor; nausea and irritable bowel syndrome; urinary frequency and bladder dysfunction; palpitations with or without cardiac arrhythmias; exertional dyspnea. b. Neuroendocrine Manifestations: loss of thermostatic stability – subnormal body
temperature and marked diurnal fluctuation, sweating episodes, recurrent feelings of feverishness and cold extremities; intolerance of extremes of heat and cold; marked weight change - anorexia or abnormal appetite; loss of adaptability and worsening of symptoms with stress. c. Immune Manifestations: tender lymph nodes, recurrent sore throat, recurrent flu-
like symptoms, general malaise, new sensitivities to food, medications and/or chemicals. 7. The illness persists for at least six months: It usually has a distinct onset, **although it
may be gradual. Preliminary diagnosis may be possible earlier. Three months is appropriate for children. To be included, the symptoms must have begun or have been significantly altered after the onset of this illness. It is
unlikely that a patient will suffer from all symptoms in criteria 5 & 6. The disturbances tend to form symptom clusters
that may fluctuate and change over time. Children often have numerous prominent symptoms but their order of
severity tends to vary from day to day. *There is a small number of patients who have no pain or sleep dysfunction,
but no other diagnosis fits except ME/CFS. A diagnosis of ME/CFS can be entertained when this group has an
infectious illness type onset. **Some patients have been unhealthy for other reasons prior to the onset of ME/ CFS
and lack detectable triggers at onset or have more gradual or insidious onset.
Exclusions: Exclude active disease processes that explain most of the major symptoms of fatigue,
sleep disturbance, pain, and cognitive dysfunction. It is essential to exclude certain diseases, which would
be tragic to miss: Addison's disease, Cushing's Syndrome, hypothyroidism, hyperthyroidism, iron
deficiency, other treatable forms of anemia, iron overload syndrome, diabetes mellitus, and cancer. It is
also essential to exclude treatable sleep disorders such as upper airway resistance syndrome and
obstructive or central sleep apnea; rheumatological disorders such as rheumatoid arthritis, lupus,
polymyositis and polymyalgia rheumatica; immune disorders such as AIDS; neurological disorders such as
multiple sclerosis (MS), Parkinsonism, myasthenia gravis and B12 deficiency; infectious diseases such as
1 "Overload" refers to hypersensitivities to stimuli that have changed from pre-illness status. 2 "Crash" refers to a temporary period of immobilizing physical and /or cognitive fatigue. Carruthers, van de Sande
A Clinical Case Definition and Guidelines for Medical Practitioners
tuberculosis, chronic hepatitis, Lyme disease, etc.; primary psychiatric disorders and substance abuse.
Exclusion of other diagnoses, which cannot be reasonably excluded by the patient's history and physical
examination, is achieved by laboratory testing and imaging. If a potentially confounding medical condition
is under control, then the diagnosis of ME/CFS can be entertained if patients meet the criteria otherwise.
Co-morbid Entities: Fibromyalgia Syndrome (FMS), Myofascial Pain Syndrome (MPS),
Temporomandibular Joint Syndrome (TMJ), Irritable Bowel Syndrome (IBS), Interstitial Cystitis, Irritable
Bladder Syndrome, Raynaud's Phenomenon, Prolapsed Mitral Valve, Depression, Migraine, Allergies,
Multiple Chemical Sensitivities (MCS), Hashimoto's thyroiditis, Sicca Syndrome, etc. Such co-morbid entities
may occur in the setting of ME/CFS. Others such as IBS may precede the development of ME/CFS by many
years, but then become associated with it. The same holds true for migraines and depression. Their
association is thus looser than between the symptoms within the syndrome. ME/CFS and FMS often
closely connect and should be considered to be "overlap syndromes".
Idiopathic Chronic Fatigue: If the patient has unexplained prolonged fatigue (6 months or more) but
has insufficient symptoms to meet the criteria for ME/CFS, classify it as idiopathic chronic fatigue.
Carruthers BM, Jain AK, De Meirleir KL, Peterson DL, Klimas NG, Lerner AM, Bested AC, Flor-Henry P, Joshi P, Powles ACP, Sherkey JA,
Diagnostic and Treatment Protocols.
Journal of Chronic Fatigue Syndrome 11(1):7-116, 2003. Copyright 2003, Haworth Press
Inc., Article available from The Haworth Document Delivery Service: 1-800-722-5857,,
Reprinted with permission.
Application Notes
Total illness burden is determined by
symptom severity and impact by dialogue with observing and obtaining a complete description the patient over time. of the patient's symptoms, their interactions, • The hierarchy of symptom severity will
and functional impact. vary over time and among patients. Periodic • Variability and coherence of symptoms:
ranking of the severity and hierarchy of The cluster of symptoms exhibited will vary; symptom severity helps orient the treatment however they are connected by their temporal, program and monitor its effectiveness. coherent, and causal relationships. • Separate primary symptoms from
Symptom severity and impact: Symptom
secondary symptoms and aggravators.
severity is significant if it substantially impacts Symptom dynamics and interactions, and the the patient's premorbid activity level (by an
effects of aggravators should be noted. approximate 50% reduction). Confirm
Dr. Leonard Jason's studyia and
Fukuda criteria for ME/CFS and control patients with chronic fatigue due to depression.
Patients meeting the Canadian criteria were more physically ill, had greater physical
functional impairment, greater fatigue/weakness, and more neurocognitive, neurological and
cardiopulmonary abnormalities and had more impairments that significantly differentiated
them from the psychiatric comparison group than did patients meeting the Fukuda criteria

1. Fatigue
"Fatigue" is an inappropriate label because Some patients are housebound or bedridden the fatigue experienced in ME/CFS is not and dependent on others for their daily care. normal fatigue whereby energy is promptly ME/CFS "is actually more debilitating than restored with rest. The pathological "fatigue" most other medical problems in the world" experienced in ME/CFS may combine including patients undergoing chemotherapy exhaustion, weakness, heaviness, general and HIV patients (until about two weeks malaise, lightheadedness, and sleepiness that before death). Cognitive fatiguing may be can be overwhelmingly debilitating. By evident when the patient's responses become definition, the patient's activity level is reduced slower, less coherent, and s/he experiences by approximately 50% or more. more difficulty in word and information An Overview of the Canadian Consensus Document
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
retrieval. The pathological components of 2. Post-Exertional Malaise and/or
fatigue should be identified in order to provide appropriate treatment. Orthostatic intolerance, Physical or mental exertion often causes the inability to tolerate sustained upright debilitating malaise and/or fatigue, generalized activity, may be associated with the pain, deterioration of cognitive functions, and overwhelming exhaustion, weakness, and worsening of other symptoms that may occur urgency to lie down experienced in ME/CFS. immediately after activity or be delayed. Often there is arousal fatigue due to poor Patients experience rapid muscle fatigue and sleep quality and sometimes quantity. lack endurance. These symptoms are Oxygenation fatigue is caused by insufficient suggestive of a pathophysiology which involves oxygen being delivered to the brain and immune system activation, channelopathy with tissues. In metabolic fatigue, the cells are oxidative stress and nitric oxide related unable to transform substrates of energy into toxicity, and/or orthostatic intolerance. useful functions. Muscle fatigue is common. Recovery time is inordinately long, usually a Patients who also meet the criteria of FMS day or longer, and exercise may trigger a usually experience structural fatigue. relapse. The following chart indicates some of the documented dysfunctional reactions to exercise that patients may exhibit: Response to Exercise Sense of well-being
Invigorating, anti- Feel malaise, fatigue and depressant effect worsening of symptoms1, Resting heart rate
Heart rate at maximum workload
Reduced heart rate13,14 Maximum oxygen uptake
Approximately ½ of sedentary controls13 Age-predicted target heart rate
Often cannot achieve it and should not be forced13,14 Cardiac output
Increased Sub-optimal Cerebral blood flow
Increased Decreased Cerebral oxygen
Increased Decreased15 Body temperature
Increased Decreased Respiration
Increased Breathing irregularities: shortness of breath17, shallow breathing Cognitive processing
Normal, more alert Recovery period
Often 24 hours but can last days or weeks1,12, Oxygen delivery to the muscles
Increased Impaired13 Gait kinematics

3. Sleep Dysfunction

rather than intermittent. Insomnia often Research suggests that ME/CFS patients increases when the patient is overly have disrupted circadian rhythm, sleep onset exhausted. Restless leg syndrome and difficulties, sleep maintenance disturbances periodic limb movement disorder may occur. and do not get into/or spend enough time in A subset of patients may have upper airway the deeper phases of sleep. The EEG indicates resistance syndrome, sleep apnea or other alpha waves intrude into delta waves within treatable sleep disorders. Hypersomnia is common, particularly in the The chronic pain is thought to be due to a acute stage. Sleep onset difficulties, dysfunction of the pain processing areas of the fragmented sleep, non-restorative sleep, central nervous system. Inappropriate pain morning exhaustion, and abnormal diurnal signals are sent to and from the brain and variation of sleep rhythms and energy levels body. Dysregulation of sodium channels and are common. Vivid, disturbing dreams may cellular ion transport may be involved in pain occur. Sleep problems are usually chronic Carruthers, van de Sande
A Clinical Case Definition and Guidelines for Medical Practitioners
Generalized myalgia or nonanatomical pain matter loss in the frontal and parietal lobes. may occur randomly and is often migratory. Some degree of encephalomyelitis may occur The pain may be described as sharp, shooting, in the upper spinal motor and sensory nerve deep aching, burning, throbbing, tingling, etc. roots and nerve networks transversing the Muscle spasms, and new onset headaches, brain stem. Abnormal function of ATP including tension headaches and migraines, binding cassette (ABC) transporters may are common. A subset of ME/CFS patients contribute to significant neurological also meets the criteria of fibromyalgia syndrome and/or myofascial pain syndrome. Cognitive manifestations vary and become
5. Neurological/Cognitive
more pronounced with fatigue. "Cognitive fog" or confusion, slowed processing of information Structural and functional neuroimaging and reaction time, difficulty in word retrieval or suggest that neuropathic involvement plays a speaking, concentration, attention, short-term primary role in causing a disruption of the memory consolidation, and forgetfulness are normal coordination between the brain and common. Susceptibility to interference and the body. In patients with ME/CFS, PET scans difficulty in processing complex information indicate decreased glucose metabolism in the are prominent. Selective memory processing right mediofrontal cortex, and significant deficits, such as experiencing more difficulty in hypoperfusion and hypometabolism in the recalling information when it is presented with brain stem. SPECT brain scan analysis greater semantic structure and contextual reveals significantly lower cortical/cerebellar clues, may occur against a relatively normal regional cerebral blood flow (rCBF) of the cognitive background. Patients may become frontal, parietal, temporal, occipital, and brain dyslexic when overly fatigued. Neurocognitive stem and may play a role in cognitive impairments involving concentration and impairment and activity limitations. MRI memory are cited as some of the most studies reveal elevated numbers of irreversible disruptive and functionally disabling symptoms punctuate lesions consistent with demyelination or edema, predominantly in the
Overload Phenomena: Patients are often
frontal lobes and subcortical areas. A controlled study using structural MRI voxel- hypersensitive to sensory stimulation including based morphometry technique for measuring noise, bright lights, temperature extremes, brain volume and tissue concentration showed and odours. They have difficulty focusing their that the volume of gray matter of the brain attention when there is more than one source was significantly reduced and there was an of input, such as concomitant auditory and average of 8% reduction of brain tissue, which visual input, cognitive and physical activity, was a global problem in patients. A previous and in fast-paced or confusing environments. MRI voxel-based morphometry study Emotional overload may be unduly stressful. indicated an average reduction of 11.8% in Overload phenomena may trigger a "crash" gray-matter volume in the bilateral prefrontal where the patient becomes temporarily areas of patients compared to controls. fMRI immobilized by physical and/or mental fatigue studies demonstrate that patients use and recovery is slow. more areas of the brain when involved in Motor and Perceptual Disturbances:
auditory cognitive activities, thus greater effort Muscle weakness and fasciculations are is required to do cognitive activities and may common. The patient may appear clumsy due contribute to cognitive fatigue. qEEG to loss of cognitive map, inaccurate body topography indicates elevated activity of boundaries, poor muscle coordination, and/or intracerebral electrical sources in theta and loss of balance. Difficulty with depth beta frequencies. Delta and beta perception and focusing vision may result in an frequencies were particularly elevated in the inability to accommodate walking on uneven left frontal region in eyes closed condition. surfaces, as well as spatial instability and qEEG suggests reduced sources in the right hemisphere (beta) due to interference with the left brain inhibitory regulation of the right Other symptoms: Visual accommodation and
hemisphere during verbal cognitive focusing difficulties, blurred or double vision processing33. Quantitative assessment shows and dry eyes are common. Tinnitus may enlargement of the lateral cerebral ventricular volumes that may be associated with white An Overview of the Canadian Consensus Document
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
6. Autonomic Manifestations
headaches, visual changes, sweating, and Chronic Orthostatic Intolerance
(COI), the inability to sustain upright
Delayed postural hypotension occurs
activity (standing, sitting or walking), is when there is a drop in blood pressure ten very common and may be an important minutes or more after the patient stands. component in ME/CFS. Upon limited standing, • Palpitations with or without cardiac
the patient experiences overwhelming arrhythmias
exhaustion, an urgency to lie down, confusion, • Chest pain resembling angina and/or
malaise, and worsening of other symptoms. thrombosis
Sitting and light walking are tolerated better than standing still, but no upright activity is Other common ANS symptoms
tolerated well. Lying down helps alleviate • Breathing dysregulations include
symptoms. Tilt-table testing may be helpful in breathing irregularities, sudden attacks of diagnosis but some patients may have a breathlessness, exertional dyspnea, and normal tilt-table test and still have severe COI. holding the breath inappropriately. Quiet standing in the office allows for • Intestinal irregularities: Constipation,
observation and monitoring the blood pressure diarrhea, alternating diarrhea/constipation, and pulse. Note: This must only be done with
irritable bowel syndrome (IBS), abdominal extreme CAUTION with someone standing pain, cramps, and nausea are common. beside the patient at all times in order to • Bladder dysfunction may include
support him/her if s/he begins to feel weak! bladder pain, urinary frequency, dysuria, Research suggests a low circulating • Alternating sweating and shivering
erythrocyte volume (approximately 70% of episodes
normal on average), but not plasma volume in • Painful vascular spasm in extremities
ME/CFS patients. Blood may pool in the legs, with cold or hot feelings
abdomen, and sometimes hands. This may decrease effective blood volume and 7. Neuroendocrine Manifestations
contribute to COI. Lower stroke volume and
Centrally mediated dysfunction (impaired cardiac output, and reduced circulation activation) of the hypothalamic-pituitary- correlate with symptom severity. Treadmill adrenocortical axis may be associated with walking suggests significantly reduced vagal dysfunction of the autonomic and immune power. Autonomic dysfunction underlies COI system. Significantly reduced pancreatic and its subtypes of neurally mediated exocrine function may lead to malabsorption. hypotension, postural COI, orthostatic Loss of thermostatic stability: Altered
hypotension, and orthostatic narrowing of body temperature (often subnormal but occasionally febrile), marked diurnal • Neurally mediated hypotension
fluctuation, alternating feelings of hot or (NMH) involves a precipitous drop of
cold (sometimes with unusual more than 20-25 mm of mercury of distribution), recurrent feelings of systolic blood pressure upon standing, or feverishness, and sweating episodes may standing still. Symptoms may include lightheadedness, dizziness, pressure-like • Heat/cold intolerance is common and
chest pain over the left chest, visual may be accompanied by worsening of changes, weakness, slowed verbal response, pallor, an urgency to lie down, • Marked weight change
and sometimes syncope. • Hypoglycemia
Postural orthostatic tachycardia
Hypothalamic/pituitary/adrenal axis
syndrome (POTS): Upon standing there
and ANS dysregulation may lessen is rapid action of the heart, either an patients' adaptability to stressful and increase of over 30 beats per minute or a overload situations. Stress may cause rate greater than 120 beats per minute disorientation, anxiety, worsening of other during 10 minutes of standing, plus or symptoms, and trigger a "crash". minus a drop in blood pressure. Recovery is slow. Tachycardia is more common than low blood pressure. Symptoms may include lightheadedness, dizziness, nausea, fatigue, tremor, irregular breathing, Carruthers, van de Sande
A Clinical Case Definition and Guidelines for Medical Practitioners
8. Immune Manifestations
hypothyroidism while the thyroid hormone Many infectious agents may trigger ME/CFS. A levels in the blood are normal. subset of patients appears to have human cytomegalovirus or Epstein-Barr herpes virus Acute onset patients usually exhibit more infection of the heart, and viral infections of immune dysfunction. Immune activation the brain have been discovered in autopsies. symptoms, particularly in the acute onset As human herpesvirus-6 (HHV-6) is regarded stage, may sometimes occur in the absence of as an important pathogen, those patients known viral exposure. Physical exercise and testing positive should be referred to an overload situations may trigger or exacerbate infectious disease specialist. Hypercoagulation immune symptoms. may be triggered by dysfunction of the • General malaise
endothelial cells in patients with active HHV6. • Tender lymphadenopathy, particularly
The elevated levels of many intracellular in the cervical, and axillary inguinal pathogens suggest that immune dysfunction plays a primary role. The upregulation of the • Recurrent sore throat
2-5A synthetase/RNase L pathway in ME/CFS • Faucial injection and crimson
patients indicates an activated immune state. crescents may be seen in the tonsil
This state has been linked to a perturbed apoptotic (cellular suicide) process resulting in • New sensitivities to food, medication
an accumulation of RNase L fragments and/or chemicals because the nuclei cannot ingest all the resulting fragments and cannot reutilize them. Features in Young People
The cell death and scattering of RNA debris Children may be diagnosed when suggestive may alter immunological functions and lower symptoms last more than 3 months. Numerous ATP reserves, magnesium and particularly cell symptoms may have similar severity but the potassium levels. Although testing for hierarchy of severity differs more dramatically from cleavage of the native 80 kDa RNase-L day to day than in adults. Severe exhaustion, molecule using patients meeting the Clinical weakness, pain, and mood changes make life very Definition is yet to be done, we postulate that challenging. Cognitive abilities deteriorate the results would be similar to the 80% of particularly in topics requiring analysis, multi-task patients testing positive using the 1988 activities, fast-paced or confusing environments, Holmes definition. The ratio of abnormal low and with physical and mental fatigue. Severely 37 kDa RNase-L to normal 80 kDa RNase-L3 is affected young people may be bed-ridden. associated with low oxygen consumption of Because activity level is reduced by about 50% or patients and corresponds to clinical status. PKR more, young people have difficulty or are unable is simultaneously upregulated. Perforin, a cell to maintain a full school program. Unlike school lytic protein that correlates with the cell's phobia, these young people spend most of their cytolytic potential, is reduced in Natural Killer out-of-school time resting. 51% of British students (NK) cells suggesting a molecular basis for NK with long-term school absenteeism suffered from cytotoxicity. Cytokine profiles suggest a shift ME/CFS. A supportive letter from the treating of Th1, which controls intracellular infection, to physician outlining the patient's medical condition Th22. Activated lymphocytes and elevated and limitations, and open communication between immunoglobulins, particularly IgG, have been physician and school is helpful. TEACH-ME: A found. Immune tests indicating low NK cell Sourcebook for Teachers of Young People with levels and function per cell, measurements of Myalgic Encephalomyelitis / Chronic Fatigue protein kinase 1, and activated immune Syndrome and Fibromyalgia Syndrome,44 will assist complex may be helpful2. Interferon induced teachers and parents in understanding symptoms production of 2-50 AS enzymes may lead to in young people and provide strategies for educational planning and accommodations. CLINICAL EVALUATION OF ME/CFS It is important to recognize the characteristic features of ME/CFS, as well as to exclude alternate
explanations for a patient's symptoms.
A. PATIENT HISTORY: A thorough history, including a complete description of patient's symptoms as
well as their severity and functional impact must be taken before attempting to classify them. 1. FOCUS ON THE PRINCIPAL SYMPTOMS OF ME/CFS: including post-exertional malaise, fatigue,
sleep dysfunction, pain and symptoms from neurological/cognitive, autonomic, endocrine and An Overview of the Canadian Consensus Document
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
immune dysfunctions. Examine the course of the symptoms, with special attention to the worsening of symptoms after exertion, prolonged recovery and fluctuating course. 2. PRESENTING COMPLAINT AND AGGRAVATING/AMELIORATING EVENTS
Date of onset
Trigger or prodromal event
Symptoms at onset
Progression of symptoms
Duration of symptoms
Hierarchy of quality and severity of current symptoms
Worsening of symptoms with exertion: symptoms which require prolonged recovery
Secondary symptoms & aggravators
Energy/Fatigue (great 100%): good day _%, bad day %.
Sleep Quality: good , moderate _, poor _
Pain Severity: absent _, mild _, moderate _, severe
Total burden of symptom severity & current level of physical function
3. MEDICATION HISTORY: current, past, prescribed & other therapies, & sensitivities
4. SENSITIVITIES AND ALLERGY HISTORY: including new sensitivities and allergies and change in
status of pre-existing ones 5. PAST HISTORY: earlier illnesses, exposure to environmental, work, and other toxins
Many symptoms involve more than one system. Attention paid to:
Musculoskeletal: myalgia, muscle weakness, or arthralgia
CNS: fatigue with post-exertional exacerbation, neurocognitive complaints, headaches, sleep
ANS & Cardiorespiratory: palpitations, exertional dyspnea, symptoms suggestive of neurally
mediated hypotension (NMH), postural orthostatic tachycardia syndrome (POTS), delayed postural orthostatic intolerance, vertigo, light-headedness, respiratory disturbances, extreme pallor • ANS & GI & GU: intestinal or bladder disturbances with or without IBS
Neuroendocrine: loss of thermostatic stability, heat/cold intolerance, marked weight change,
loss of adaptability and tolerance for stress and slow recovery, emotional lability • Immune: general malaise, ‘flu-like' feeling, recurrent sore throat, hypersensitivity to foods,
medications or chemicals B. PHYSICAL EXAMINATION: Standard physical exam, with attention paid to:
Musculoskeletal System: including FMS tender point exam (appendix 6). Check joints for
inflammation, hypermobility, & restricted movement. Muscle strength: _ Positive tender points /18. Meets criteria for FMS _, MPS _
CNS: including reflex examination (Reflex examination during neck flexion and extension may
accentuate abnormalities arising from cervical myelopathic changes). _ Tandem walk: forwards backwards Romberg test
Cognitive: ability to remember questions, cognitive fatiguing (e.g. serial 7 subtraction) &
cognitive interference (e.g. serial 7 subtraction & tandems done simultaneously) • Cardiorespiratory System: Arrhythmias, BP (first lying down), BP (immediately after standing).
GI System: increased bowel sounds, abdominal bloating and/or tenderness
Endocrine System: thyroid, adrenal and pituitary dysfunction
Immune System: tender lymphadenopathy in the cervical, axillary, & inguinal regions (especially
in acute stage) Crimson crescents in the tonsillar fossae C. LABORATORY AND INVESTIGATIVE PROTOCOL: A thorough work up must be done.
Routine Laboratory Tests: CBC, ESR, Ca, P, Mg, blood glucose, serum electrolytes, TSH,
protein electrophoresis screen, CRP, ferritin, creatinine, rheumatoid factor, antinuclear antibody, CPK and liver function, as well as routine urinalysis. ADDITIONAL TESTING: In addition to the routine laboratory tests, additional tests should be
chosen on an individual basis depending on the patient's case history, clinical evaluation,
laboratory findings, risk factors & co-morbid conditions.

Further Laboratory Tests: diurnal cortisol levels, 24 hour urine free cortisol; hormones including
free testosterone, B12 and folate levels, DHEA sulphate, 5-HIAA screen, abdominal ultra sound, stool for ova and parasites, NK cell activity, flow cytometry for lymphocyte activity, Western blot test for Lyme disease, chest x-ray, TB skin test, and HIV. Do testing for 37-kDa 2-5A RNase L immunoassay. Carruthers, van de Sande
A Clinical Case Definition and Guidelines for Medical Practitioners
Differential Brain Function & Static Testing: for those with positive neurological findings
X-RAY &/or MRI of Brain and Spinal Cord: to rule out multiple sclerosis (MS) and other
primary neurological disorders. MRI interpretation: it is important to look for changes
that are easily overlooked such as dynamic disc bulges/herniation or minor stenosis,
which can be important in the pathogenesis.

Tilt Table Test: (If indicated, test prior to giving medication for orthostatic intolerance.)
Sleep Study: to show decrease in time spent in stage 4 sleep or rule out treatable sleep
qEEG, SPECT and PET Scans and Spectrography: if indicated
24-HOUR HOLTER MONITORING: repetitively oscillating T-wave inversions and/or T-wave flats
during 24-hour monitoring. Note: this pattern may not be reported or subsumed under non-specific T-wave changes. _ME/CFS: If the patient's presentation meets the criteria for ME/CFS, classify the diagnosis as
ME/CFS, except when the specified exclusions are present. _Idiopathic chronic fatigue: chronic fatigue but does not meet the criteria for ME/CFS or have
alternative explanation NEW SYMPTOMS: People with ME/CFS can develop other medical problems. New symptoms
need to be appropriately investigated.

Carruthers BM, Jain AK, De Meirleir KL, Peterson DL, Klimas NG, Lerner AM, Bested AC, Flor-Henry P, Joshi P, Powles ACP, Sherkey JA,
Diagnostic and Treatment Protocols.
Journal of Chronic Fatigue Syndrome 11(1):7-116, 2003, pp.105-6. Copyright 2003,
Haworth Press Inc., Journal of Chronic Fatigue Syndrome. Available from Haworth Document Delivery Service: 1-800-722-5857,
tient Evaluation Worksheet reprinted slightly condensed, with permission.
A clear diagnosis often has a considerable therapeutic benefit as it reduces uncertainty and
orients therapy. Early diagnosis may assist in lessening the impact of ME/CFS.

Differences Between ME/CFS and
quality of life, but many objective indices can Fibromyalgia Syndrome (FMS)
differentiate ME/CFS from primary depression. ME/CFS is commonly triggered by a viral infection. • Somatoform Disorder: There is some
There is usually greater fatigue, post-exertional symptom overlap between somatoform malaise and fatigue, and cognitive, cardiac and disorders and ME/CFS. However, somatoform immune dysfunction than in FMS. Pain is the most disorder patients often have a long history of prominent feature in FMS, which is often triggered complaints starting before thirty years of age. by physical trauma. Many ME/CFS patients also In order to diagnose any type of somatoform meet the criteria for FMS. The research test3 for disorder, the symptoms cannot be "fully deregulation of an antiviral defense pathway can explained by any demonstrable general distinguish ME/CFS from FMS. Patients meeting medical condition, by the direct effects of a both criteria test the same as ME/CFS patients. substance, or by another mental disorder". Many objective biophysiological findings have Differences Between ME/CFS and
been demonstrated to underlie the symptoms Psychiatric Disorders
of ME/CFS. Patients meeting the criteria of ME/CFS is not synonymous with psychiatric ME/CFS must be excluded from the diagnosis disorder. Pay careful attention to the of Somatoform Disorder. Member countries of characteristics, dynamics of progression, and the World Health Organization (WHO) are correlation of symptoms. obliged to adhere to the regulations of the • Depression: Reactions to exercise (see chart
WHO's International Classification of Diseases on page 4) are helpful in distinguishing (ICD) and use their ICD classification. In a ME/CFS from depression. ME/CFS patients letter dated January 23, 2004, Andre l'Hours of have symptoms such as joint and muscle pain, WHO headquarters clarified that "it is not severe headaches, recurrent sore throats and permitted for the same condition to be upper respiratory infections, tender lymph classified to more than one rubic as this would nodes, cardiopulmonary symptoms, COI, mean that the individual categories and tachycardia, and a cluster of cognitive subcategories were no longer mutually impairments, which are not commonly seen in exclusive". Thus, ME (and CFS), classified
depression. Some ME/CFS patients may suffer as a neurological disease in the WHO
from reactive depression due to their ICD, cannot also be classified as
pathophysiological impairments and reduced somatoform disorder, which is classified
as a mental or behaviour disorder.

An Overview of the Canadian Consensus Document
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
TREATMENT GUIDELINES 2. All rehabilitative personnel must be
Early intervention can minimize the effects of knowledgeable about ME/CFS.
ME/CFS in some patients. The biological pathophysiology of
1. Top priorities are patient support and
ME/CFS is a reality that must be
well-being: Reduce the patient's confusion
respected and reflected in all treatment
with a positive diagnosis, reassure continuing and rehabilitative programs. Total illness
care, and give realistic hope. A climate of burden, impairments, low endurance, overload illness disbelief may lead to risk of suicide. It phenomena, and fluctuation of symptom is essential for the patient's physiological and severity and activity boundaries must be psychological well-being that s/he is able to respected. Focus on reducing symptomatology maintain autonomy concerning the pacing and and maintaining function. It is essential that complexity of activities and programs. the patient does not exceed his/her endurance limitations or activity boundaries too often or 2. Patient empowerment: Respect the
too deeply because this can cause a severe, patient's knowledge of his/her body and long-term relapse. 4. Involve the patient in setting realistic
3. Optimizing functional ability: Assist the
goals and developing an individualized,
patient in setting personal, emotional, and flexible program conducive to healing.
activity boundaries in which s/he can be as The patient must have autonomy concerning active as possible without aggravating the complexity and pacing of activities, and symptoms, and then encourage him/her to incorporate rest periods as needed. Begin the gradually extend boundaries at his/her own
program at a level that will ensure success, pace, and as able.
assist the patient in recognizing early warning signs, and plan alternate strategies for low- Guidelines
energy days. The goal is for the patient to be 1. The treating physician knows the patient
as active as possible without exacerbating best and should direct and coordinate
symptoms. Patients can explore ways to treatment and rehabilitative efforts. increase activity boundaries if and when able. SELF-HELP STRATEGIES (SHS)
A hypothesis underlying the use of Cognitive Behaviour Therapy (CBT) for ME/CFS is based
on the premise that the patient's impairments are learned due to wrong thinking and
"considers the pathophysiology of CFS to be entirely reversible and perpetuated only by the
interaction of cognition, behaviour, and emotional processes. The patient merely has to
change their thinking and their symptoms will be gone. According to this model, CBT should
not only improve the quality of the patient's life, but could be potentially curative"
Supporters suggest that "ideally general practitioners should diagnose CFS and refer patients
to psychotherapists for CBT without detours to medical specialists as in other functional
somatic syndromes"
. Proponents ignore the documented pathophysiology of ME/CFS,
disregard the reality of the patients' symptoms, blame them for their illness, and withhold
medical treatment. Their studies have often included patients who have chronic fatigue but
excluded more severe cases as well as those who have other symptoms that are part of the
clinical criteria of ME/CFS. Further, their studies fail to cure or improve physiological
impairments such as OI, sore throat, IBS, etc. Dr. A. Komaroff
, a Harvard based world
authority, stated that the evidence of biological process "is inconsistent with the hypothesis
that (the syndrome) involves symptoms that are only imagined or amplified because of
underlying psychiatric distress. It is time to put that hypothesis to rest". Some physicians,
who are cognizant of the biological pathophysiology of ME/CFS, teach patients coping skills
but call them "CBT". We urge such doctors to use the term "Self-Help Strategies" and avoid
using the terms "Cognitive Behaviour Therapy" and "Cognitive Retraining Therapy".

Carruthers, van de Sande
A Clinical Case Definition and Guidelines for Medical Practitioners
Self-help Strategies (SHS) assist patients in
reserves are prime concerns. Over- coping with their chronic illness by conserving exhaustion may increase insomnia.) energy, minimizing symptom flare-ups, and • establish a regular bedtime and do quiet maximizing coping skills and functionality. activities, or use relaxation tapes before 1. Patient Education:
• have a warm bath before bed to relax their • Meet with the patient and her/his body and keep their body warm at night meaningful others as soon as possible • reserve bed for sleep and sex after diagnosis to discuss the illness, what • give their body proper postural support to expect, develop SHS, and provide e.g. use a contoured pillow educational information. • keep the bedroom as a "worry-free • Assist patients in recognizing aggravators and early warning signs so they can stop • do calming and slowing meditations if before exceeding their activity boundaries sleep is impossible and prevent crashes. Encourage patients to take their temperature before and after 4. Balanced Diet and Nutritional
an activity. If their temperature drops Considerations: Encourage patients to
after an activity, they may have done too • eat a balanced, nutritious diet and eat meals at regular times • Provide information on relaxation and • keep well hydrated stress reduction techniques. • take a multi-enzyme tablet with meals if • Provide information regarding energy indicated or if they have IBS conservation techniques and • take nutritional supplements as needed. environmental modifications. (The biochemistry and needs of each • Encourage avoidance of known patient is unique. Chronically ill patients aggravators as much as possible in order require nutritional support for healing. If to prevent flare-ups. practical, a vitamin and mineral profile can assist in assuring that the patient is 2. Self-Development: Encourage patients to
receiving adequate nutrients and indicate • trust their feelings and experiences specific deficiencies. Start with a one-a- • set aside a time to rest and do something day vitamin/mineral supplement, replenish electrolytes, and add supplements as • set personal and activity boundaries and find their optimal activity rhythms • gradually extend boundaries, if and when 5. Body Movement and Fitness: Encourage
able, but do not exceed activity • use good body mechanics and use techniques and practices, such as yoga, to 3. Maximizing Sleep: Patients should be
• stay active within their limitations; avoid • conserve energy by pacing daytime activities and work which takes them beyond their capacity • listen to their body signals and incorporate rest periods into their day as needed. (Sleep dysfunction and low energy An Overview of the Canadian Consensus Document
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
Even though post-exertional malaise/fatigue is a
Minimize relapses: Exercise should be
hallmark feature and a criterion of ME/CFS, individualized, based on the patient's patients are often prescribed exercise unwisely. abilities/limitation, accommodate energy Research studies confirm that ME/CFS patients fluctuations, and focus on improving function. have different physiological responses to exercise Exercises must be very gentle and carefully than those who are healthy or depressed, as paced. Incorporate frequent rest breaks to indicated in the chart on page 4. While not all ensure complete recovery. Often it may be patients exhibit all of these abnormal reactions, appropriate to begin with two minute exercise most exhibit some of them. Traditional exercise periods three times weekly. The patient should programs can provoke relapses. be well hydrated before exercising. • Accommodate circulatory and cardiac
As much care must be taken in prescribing impairments: Many patients have reduced
exercise as prescribing medication to ME/CFS maximum heart rates and must not be pushed patients. Exercise must be individualized, towards standardized age-predicted target entered into cautiously, and monitored diligently. heart rates. Significantly impaired oxygen Exercise programs should adhere to the previously consumption levels suggest there may be an stated goals and guidelines and the following abnormal reliance on anaerobic energy pathways during exercise in patients with ME/CFS, thus exercises that would be aerobic 1. Initial Patient Evaluation: A thorough
for healthy individuals may be anaerobic for history and examination, with particular
patients. Any graded exercise expansion may attention to cardiac vascular responses
be inappropriate for some. to activity, must be completed before
Maximize self-efficacy: Involve patients in
considering any exercise program. The reality planning. It is imperative for them to maintain of the unique medical issues, biological autonomy over the intensity and pacing of dysfunctions and limitations, risk factors, and exercise and activities. pain generators must be identified and Cautions: There are potential dangers if ME/CFS
patients are pushed to increase their heart rate to 2. Medical Management must be optimized
age-predicted target heart rates. As indicated in before introducing exercise. Patients with less the chart on page 4, research studies suggest that severe symptoms that are under control may their hearts may be functioning at a suboptimal benefit from very gentle exercise to maintain level and many have autonomic disturbances; thus functionality. Some patients may only be able they may not be able to accommodate the normal to exercise in bed, but exercise is not
target heart rate. Externally paced "Graded recommended for all patients. Exercise Programs" or programs based on the premise that patients are misperceiving their Principles of Treatment: Exercise should be
done under the guidance of a well qualified activity limits or illness must be avoided.
exercise physiologist or physical therapist, who is knowledgeable about ME/CFS. SYMPTOM MANAGEMENT & TREATMENT The Consensus Document (pages 49-67) provides 1. Sleep Disturbance: Sleep quality and
guidelines, dosage, effects and level of evidence quantity must be taken into consideration. for commonly used pharmaceuticals, and are a. Physical remedies: See "Maximizing
ranked in order of the preference of the members Sleep" in the previous section on Self-Help of the Consensus Panel. Many patients are Strategies. Patients need to incorporate hypersensitive to medication so begin dosage at a rest periods into their day as required. lower level than recommended. Start low, go Associated sleep dysfunctions should be slow. Warn patients about possible side effects. treated, such as upper airway resistance No pharmaceutical is universally effective. Keep syndrome, and a positive pressure mask regime as simple, safe, effective, and inexpensive can be prescribed for sleep apnea. Carruthers, van de Sande
A Clinical Case Definition and Guidelines for Medical Practitioners
b. Other remedies: melatonin, valerian,
c. B12/Cyanocobalamin: Anecdotal reports
calcium and magnesium salts, aroma and studies suggest some ME/CFS patients with normal blood counts improve in c. Pharmaceuticals: Low dose tricyclic
energy level, cognitive ability, weakness, antidepressants (short-term at low dose and mood with mega dose B12 injections, but side effects can be severe, and possibly due to a reduced ability in patients must be warned about possible transporting B12 into the cells or low CNS weight gain), zopiclone, clonazepam, and L-tryptophan may be helpful. SSRIs, such as Prozac, may worsen sleep 4. Cognitive
a. Physical remedies: Some patients are
able to think better in a semi-reclined position or lying down. Speech therapy a. Physical remedies: Avoid known pain
may be helpful in treating problems with exacerbators such as prolonged sitting, word-finding, information processing and standing, writing, computer work, and any memory. Mindful meditation, mental bend over work posture; and heavy lifting, exercises, reading within one's ability and housework, and gardening. Relaxation then learning new information or skills, as techniques, local heat, a warm bath and one is able, may be of assistance. gentle stretching of muscles, mobilization b. Pharmaceuticals: Try methylphenidate,
of joints, magnetic pulsers, and Bio- modafinil, nimodipine, dextroamphetamine, Resonance therapy may assist in cyanocobalamin - see (3c) and cautions alleviating pain. Gentle massage therapy, physiotherapy, chiropractic treatments, acupuncture, EMG biofeedback, spray and 5. Autonomic Manifestations
stretch if tolerated, myofascial release Orthostatic Intolerance and Dizziness
techniques including needling to release a. Physical remedies: If dizziness is caused
taut muscles, ultrasound and electronic by proprioceptive disturbances in the neck, muscle and nerve stimulation may be instruct the patient to avoid extension or helpful in some cases. Synaptic Electronic quick rotation of the neck. If caused by Activation Technology (SEA Tech®) has orthostatic intolerance, patients should get shown promising longer term pain relief. up slowly while holding on to something SEA Tech® is contraindicated in pregnancy and avoid standing for extended periods of and if pacemakers are present. time. Use of support stockings, avoiding b. Pharmaceuticals: Use acetaminophen as
large meals and dehydration, and pumping a baseline analgesic. Short-term use of low legs intermittently when sitting may be dose tricyclic antidepressants, NSAID helpful. Immediately lying down at the first analgesics, gabapentin, and baclofen may signs of dizziness usually relieves the symptoms caused by neurally mediated hypotension (NMH) and postural 3. Fatigue: Treat sleep disturbance before
orthostatic tachycardia syndrome (POTS). attempting to treat fatigue. b. Pharmaceuticals: Before starting any
a. Physical remedies: Self-Help Strategies
pharmaceutical treatment for NMH or including setting priorities and boundaries, POTS, these conditions should be balancing activities with rest periods, confirmed by a tilt-table test. A simplifying tasks and using adaptive combination of therapies usually has the devices are important. Breathing exercises, best result. Begin by increasing salt intake restorative resting postures, massage if the patient is not hypertensive; then therapy, craniosacral therapy, and either add a beta blocker (e.g. atenolol), or aromatherapy for those without chemical an alpha 1 agonist (e.g. midodrine). sensitivities may be helpful. Midodrine is usually more effective than b. Pharmaceuticals: methylphenidate, oral
florinef for chronic orthostatic tachycardia. cyanocobalamin, modafinil, amantadine, If increased salt intake helps initially but dextroamphetamine. Most fatigue killers loses its effect, consider fludrocortisone. If have short term effects and may not help these therapies are not effective, consider overall endurance and work capacity; they paroxetine. Vertigo requires an anti- may not extend crash points. nauseant such as meclozine, but no An Overview of the Canadian Consensus Document
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
treatment is particularly effective. Hypoglycemia: food low on the glycemic
Meditative techniques may help mild cases. index may be beneficial Irritable Bowel Syndrome (IBS): Adjust
7. Immune Manifestations
diet and conduct food elimination trials to a. Immune stimulator and viral
determine food intolerance. Use modulator: ampligen. Essential fatty
antispasmodics and anti-diarrheal agents acids (EFA) have been used for their antiviral effect. b. Antiviral therapies: Valacyclovir may be
6. Neuroendocrine Manifestations
helpful for confirmed herpes infection. Herbal remedies such as wild oregano and a. Physical remedies: Self-help strategies
olive leaf extract may have antiviral (SHS) assist in developing coping skills. Relaxation techniques such as slow deep c. Antibiotic treatment for mycoplasma
breathing, listening to soothing music, a and chlamydia: Suggested antibiotic
warm relaxing bath, massage therapy, and treatments for confirmed mycoplasma or if the patient is able, gentle aquacise, chlamydia infections include doxycycline, swimming or walking can reduce tension. clarithromycin, ciprofloxacin, azithromycin Herbs such as lavender and thyme may be and bioxin. Use with caution and helpful in some cases. Some patients may accompany treatment with probiotics and benefit from supportive counseling. immune boosters. b. Pharmaceuticals: Benzodiazepines and
buspirone are commonly used. Blood Donations: Donating blood is not
recommended because it may exacerbate Depression
symptoms due to low circulating blood volume. It a. Physical remedies: Reactive depression
is possible that some patients carry infectious may result from living with a poorly agents in their blood. understood chronic illness which has the complex symptom set of ME/CFS and the Immunization: Live vaccine immunization is
greatly reduced functionality associated generally not recommended because of the risk of with it. SHS, massage, and bright light worsening symptoms and triggering relapses. therapy may be helpful. Patients who are Research has confirmed a frequent dysfunction of severely depressed should be referred for the 2-5A synthetase/ribonuclease L antiviral supportive counseling. defense pathway in many patients3. Because of b. Pharmaceuticals: SSRIs are the first
these risks, decisions regarding vaccinations must line choice but usually are ineffective in remain with the treating physician and the patient. treating fatigue and may interfere with If immunization is done, it is generally sleep. Newer antidepressants such as recommended that injections be administered by venlafaxine, nefazodone or buproprion the treating physician and the dose be divided into may be of assistance. Most ME/CFS three or four mini doses, each given a full month patients cannot tolerate a high enough apart to ensure there are no delayed reactions. dosage of tricyclic antidepressants to be effective in depression, but low doses may be effective for pain and sleep, if Great strides have been made in the knowledge about ME/CFS in the last decade. Now it is time for Herbal and mineral remedies: Patients
an intensive research program in order to bring a with low red blood cell magnesium have greater understanding and successful treatment of improved with intramuscular magnesium patients. It would be helpful to establish patient sulphate in some cases. St. John's Wort subgroups, such as those who are in the acute or may be effective in mild depression but chronic stage, mild or severe cases, and viral or should not be used for marked depression other onset. The establishment of a Centre of or taken with other antidepressants. Excellence where the same patients are used in numerous studies and the research findings shared Hypothalamic-Pituitary-Adrenal (HPA)
amongst researchers may clarify information and Axis Abnormalities
assist in the efficient use of treatment for the Pharmaceuticals: fludrocortisone, (DHEA)
different subsets of patients. dehdyroepinandrosterone Carruthers, van de Sande
A Clinical Case Definition and Guidelines for Medical Practitioners

1. Rank your symptoms in order of severity (1 being your most severe symptom) in the left column.
2. Rate severity of symptoms by putting a check mark in appropriate column to the right of symptoms.
Symptom Severity and Severity Hierarchy Profile Post-exertional fatigue: loss of physical and mental
stamina, fatigue made worse by physical exertion Long recovery period from exertion: takes more than 24
hours to recover to pre-exertion activity level Fatigue: persistent, marked fatigue that substantially reduces
Sleep Disturbance: non-restorative sleep, insomnia,
Pain: in muscles, joints, headaches
Memory disturbance: poor short term memory
Confusion and difficulty concentrating
Difficulty retrieving words or saying the wrong word
Gastrointestinal disturbance: diarrhea, IBS
Recurrent sore throat
Recurrent flu-like symptoms
Dizziness or weakness upon standing
Change in body temperature, erratic body temperature,
cold hand and feet
Heat / cold intolerance
Hot flushes, sweating episodes
Marked weight change
Breathless with exertion
Tender lymph nodes: especially at sides of neck and under
Sensitive to light, noise, or odours
Muscle weakness
New sensitivities to food / medications /chemicals
Total Check Marks in Column
Column Total

Total Score: Overall symptom severity: mild, _ moderate, _
(Mild –
occurring at rest, moderate – symptoms that occur at rest become severe with effort, unable to work,
and severe – often housebound or bed-bound.)
Other symptoms
Change in symptoms
How good is your sleep on a scale of 1-5? (5 – good restorative sleep, 1 – no sleep)
How do you feel today on a scale of 1 – 10? (10 – terrific, 1 – totally bedridden) _
Carruthers BM, Jain AK, De Meirleir K, et al. Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Clinical Working Case Definition,
Diagnostic and Treatment Protocols – A Consensus Document. Journal of Chronic Fatigue Syndrome 11(1):7-116, 2003. Copyright
2003 Haworth Press. Document available at 1-800-HAWORTH,, Reprinted
slightly modified and condensed with permission.
An Overview of the Canadian Consensus Document

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
Name Date _ to _
Please complete chart for the week before your next appointment.
Day Awakening Temp.
Temp a.m.: Take your temperature as soon as you awaken, while you are still lying down. Also indicate
if you feel cold (C), had cold feet (CF), or cold hands (CH), and if you were stiff (S). Time Slept: Indicate approximate number of hours and minutes you slept.
Sleep Quality: Good, fair, or poor. Also indicate the number of times you woke during the night
including waking up much too early, e.g. if you woke up twice (W2). Indicate if you know why you woke up – e.g. to urinate, muscle cramps, nasal congestion, etc. Pain: 0 to 10. 0 being no pain, 10 being the worst pain you have experienced.
Energy Level: Indicate your average energy level for the day - 0 being bedridden, 10 full of energy.
Temp p.m.: Take your temperature before going to bed. Indicate if you feel cold.
Min. to Fall Asleep: Indicate as best you can how many minutes it took you to fall asleep.
Was anything in particular bothering you this week, e.g. family crisis?
Pain Visual Analog Scale (Pain VAS), Body Pain Diagram Please indicate the amount of pain you have had in the last 48 hours by marking a "/" through the line. 0 1 2 3 4 5 6 7 8 9 10
Excruciating Pain
On the following diagrams, please indicate your areas of: Aching: ===== Burning Pain: xxxxx Stabbing Pain: ////// Pins & Needles: ooooo Other Pain: ppppp Describe: Pain on Day 1 Pain on Day 7 Jain AK, Carruthers BM, van de Sande MI, et al. Fibromyalgia Syndrome: Canadian Clinical Working Case Definition, Diagnostic and Treatment Protocols – A Consensus Document. Journal of Musculoskeletal Pain 11(4):3-107, 2003. Co-published simultaneously as "The Fibromyalgia Syndrome: A Clinical Case Definition for Practitioners. Russell IJ - Editor. Copyright 2004 Haworth Press Inc. Copies available from Document Delivery Service: 1-800-HAWORTH, , Reprinted slightly condensed and modified with permission from Haworth Press. Carruthers, van de Sande
A Clinical Case Definition and Guidelines for Medical Practitioners
Appendix 3: ASSESSING OCCUPATIONAL DISABILITY A. Requirements of the Occupational Disability Assessment
1. Assess symptoms of a patient's disability: Check the wording for entitlement of the specific
disability carrier. Give comprehensive explanations about how the patient's symptoms/condition impose(s) particular functional limitation on the person's ability to engage in the duties of his/her specific job, or any job for which the patient is reasonably qualified by way of education, training and experience, and which would enable the person to earn an income commensurate with that of their present job. Clinical notes should contain such assessments on a regular basis. 2. Assess prognosis: Care must be taken not to set definite deadlines in anticipating recovery and future
employability, because inability to meet these deadlines may be interpreted as malingering. 3. Assess rehabilitative potential: The treating physician is responsible for the patient's care and is in
the best position to assess the patient's condition, treatment and recovery potential. The treating physician should direct all rehabilitative efforts and his/her opinion and advice should never be supplanted by the opinions and proposals of other rehabilitative personnel. 4. Provide medical opinion: Give a comprehensive opinion, substantiated by detailed subjective/
objective evidence, regarding the impact of the patient's functional limitations, the impact of disability, and whether or not the patient's condition necessitates him/her to remain off work to prevent further deterioration. B. Medical Documentation
It is essential that documentation of severity of symptoms and disability is done on an ongoing basis.
1. Medical history: Document total illness burden, not just primary diagnosis. History should include
assessment by a family physician or specialist conversant with ME/CFS, diagnosis, abnormal laboratory findings, objective physiological findings such as OI, severity of symptoms and impact on the patient's functional abilities, duration of illness, and response to treatments. 2. Questionnaires, patient diaries, scales, etc: Have the patient complete scales on initial visit and
then every six months or so. These scales help monitor the patient's status, and assess effectiveness of treatment, general function and activities of daily living, and prognosis. Periodic, structured interviews are useful in assessing symptom severity, interaction, impact and cumulative effects. Discussion of patient's diary, questionnaires, Dr. David Bell's CFS Disability Scale, the American Medical Association's criteria for permanent impairment using peak oxygen consumption levels, heart rate and blood pressure responses during exercise tests, and the Medical Outcomes Study Short-Form Profile (SF-36) may be helpful. 3. Further Documentation: Documentation of any objective findings should be included.
4. Functional Limitations: Indicate how functional limitations affect ability to do ADL, IADL,
rehabilitative programs, and work activities. Consider physical, cognitive, and emotional functional limitations, effects of chronic symptoms, lack of endurance, impaired neurocognitive functions, unpredictability and fluctuation of symptom dynamics (even from hour to hour), and cumulative fatigue effects. 5. Assessment by vocational providers: Certified occupational therapists knowledgeable about ME/CFS,
can provide information regarding the patient's level of function in the home with consideration to a 24- hour work day. Workplace assessments should be conducted on the job site when possible with attention to physical mental, emotional, social and environmental demands and workplace aggravators. 6. Assess Prognosis: In a review of prognostic studies7, a 9-year study reported 12% and the other 5
studies indicated between 0% and 6% of patients return to their premorbid state of functioning. Generally, patients with severe acute onset symptoms and those with comorbid fibromyalgia have greater symptom severity. The more stringent the criteria are, the poorer is the prognosis. Since it is not possible to determine the prognosis of an individual case with certainty, prognosis remains a clinical estimate. 7. Provide medical opinion as to whether the patient is ready to return to work or is disabled.
Workplace Aggravators: (Adapted from) The following may cause pain, and physical and cognitive fatigue:
• prolonged sitting, writing, deskwork, handwork, telephone use, bending over workspace, standing, stairs,
driving, and walking more than a tolerated distance • unsupported extension of arms and reaching overhead; heavy lifting, carrying, housecleaning, gardening, An Overview of the Canadian Consensus Document
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
• computer work, numerical calculations, multi-tasking, tasks requiring remembering or recent events-time sequences; fast-paced and complex work surroundings, tight deadlines, sensory overload • change in or long work hours, shift work; environmental factors: cold, heat, air pollutants, chemicals; stress Tests for Abnormalities in ME/CFS es of some specialized tests)
While there is not one definite test for ME/CFS, many tests may indicate abnormalities. The standard battery of
tests may be inadequate to reveal abnormalities in ME/CFS patients. Many of the following tests are not
available in general medical laboratories but may be available in research facilities or more generally available in
the future:
Virology, etc: viral antibodies, including Coxsackie B; bacteria, including HHV6; mycoplasma, etc.
37-kDa 2-5A RNase L immunoassay: protein, activity, PKR cleavage, & elastase activity assays
Other immunological markers: NK cell levels and function per cell for low NK cell cytotoxicity; CD4-CD8
ratio; ANA; activated immune complexes – IgG sub-fractions including IgG1 and IgG3, circulating immune complexes IL2 & IL4; Th1 –Th2 response to mitogen stimulation (high levels of Th2 indicate autoimmunity), flow cytometry for activated/elevated lymphocytes; antilamin antibodies may indicate autoimmunity and brain cell damage (lamin B antibodies are evidence of autoimmunity); humoral autoimmunity for polypeptides of the nuclear envelope (NE); antibodies in neuronal cells MAP2 (kinase regulators) • Urinary markers: 24-hour urine free cortisol; elevated amino-hydroxy-N-methyl-pyrrolidine correlate with
quantity of symptoms; IAG – tryptophan metabolite, is usually positive and indicates a leaky gut, which in turn is indicative of a leaky blood brain barrier; urinary creatine & other muscle metabolites • Endocrine testing: CT scans may show reduced adrenal gland size; thyroid hormone levels with attention
to bioavailability of T3 & those with reduced level should be checked for selenium as it regulates conversion of T4 to T3; reduced HPA function • Increased 5HT neurotransmission • Chronic orthostatic intolerance: Use tilt-table test or monitor the pulse and blood pressure while
standing. Note: This monitoring must be done with caution and someone standing beside the patient. • Cardiac Dysfunction: 24-hour Holter monitoring - Specifically ask to either view the results yourself or to
report repetitive oscillating T-wave inversion and T-wave flats. This pattern is typical of many ME/CFS patients but may not be reported. • Cardiopulmonary Exercise Testing: AMA Guide for Evaluation of Permanent Impairment. Lower
cardiovascular and ventilatory values at peak exercise help determine functional capacity, and peak oxygen consumption levels determine disability categories. • Computer Science and Application (CSA™) Actigraph is a small device that measures frequency and
intensity of activity in one minute intervals for up to 22 days. Typically, less intense and shorter activity peaks followed by longer rest periods are identified. It is helpful to have the patient keep a daily diary of activities during this period and/or wear a speedometer. • CNS, ANS: Romberg test; nystagmus test (may fluctuate from positive & negative throughout the day);
altered sympathetic modulations; subnormal and/or fluctuating diurnal body temperature • Cognitive performance: decreased processing speed, working memory, information learning, etc.
SPECT scans may reveal significantly lower cortical/cerebellar regional cerebral blood flow frequently in the
frontal, parietal, temporal, occipital, brain stem and throughout the cerebral cortex. • PET scans may reveal decreased glucose metabolism in the right mediofrontal cortex, and significant
hypoperfusion and hypometabolism in the brain stem. • MRI brain scans: Elevated numbers of punctuate lesions, particularly in the frontal lobes and subcortical
areas, suggest demyelination or edema. Do spinal MRI for disc herniation and minor stenosis. • qEEG brain topography: Elevated EEG activity in theta and beta frequencies and increased intracerebral
electrical sources in left frontal region delta and beta frequencies in eyes closed condition may be identified. Reduced sources in right hemisphere (beta) may be noted during verbal cognitive processing. • Hypercoagulability: flow cytrometry - fibrinogen, thrombin/anti-thrombin complexes, etc.
Positive tests for fibromyalgia syndrome and myofascial pain syndrome should be noted.
Skin conductivity and skin temperature: The combination of a lower ability of the skin to conduct
electrical current in response to visual and auditory stimuli, and a higher skin temperature of fingers indicate a down-regulation of autonomic sympathetic tone. • Sleep studies may indicate that there is insufficient time spent in the deeper stages of sleep, and alpha
wave intrusion into delta waves within non-REM sleep. • Ocular test: slowed and marked jerkiness of saccades; difficulty with and slowed changing of visual
fixation, constricted peripheral fields; low and/or incomplete blinking; small pupils; light hypersensitivity, tear film abnormalities such as low tear break-up time, inadequate production of the oil or mucus layer in tears, rose Bengal corneal staining; visual midline shift • Allergies or sensitivities; Lung function testing; Liver function: CPK and liver function
Carruthers, van de Sande
A Clinical Case Definition and Guidelines for Medical Practitioners

1 Carruthers BM, Jain AK, De Meirleir KL, Peterson DL, Klimas NG, Lerner AM, Bested AC, Flor-Henry P, Joshi P, Powles
ACP, Sherkey JA, van de Sande MI. Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Clinical Working Case Definition, Diagnostic and Treatment Protocols. J CFS 11(1):7-115, 2003. 2 Patarca-Montero R, Mark T, Fletcher M, Klimas NG. The immunology of chronic fatigue syndrome. J CFS 6(3/4):59-
3 De Meirleir K, Bisbal C, Campine I, et al. A 36 kDa 2-5A binding protein as a potential biochemical marker for chronic
fatigue syndrome. Am J Med 108(2):99-105, 2000. 4 Vojdani A, Choppa PC, Lapp CS. Downregulation of RNase L inhibitor correlates with upregulation of interferon-
induced proteins (2-5A synthetase and RNase L) in patients with chronic fatigue immune dysfunction syndrome. J Clin Lab Immunol 50(1):1-16, 1998. 5 Kaushik N, Fear D, Richards SCM, et al. Gene expression in peripheral blood mononuclear cells from patients with
chronic fatigue syndrome. J Clin Pathol 58:826-832, 2005. 6 Jason LA, Richman JA, Rademaker AW, et al. A community-based study of Chronic Fatigue Syndrome. Arch Intern
Med 159:2129-2137, Oct. 1999. 7 Joyce J, Hotopf M, Wessely S. The prognosis of chronic fatigue and chronic fatigue syndromes: a systematic review.
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chronic fatigue syndrome (CFS). In Vivo 19(2):387-90, Mar-Apr. 2005. 11 van de Sande MI. ME/CFS and post-exertional malaise and exercise. Quest #60, National ME/FM Action Network,
12 Fukuda K, Straus SE, Hickie I, et al. Chronic Fatigue Syndrome: a comprehensive approach to its definition and study.
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16 Streeten DH. Role of impaired lower-limb venous innervation in the pathogenesis of the chronic fatigue syndrome.
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28 Buchwald D, Cheney PR, Peterson DL, et al. A chronic illness characterized by fatigue, neurologic and immunologic
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32 Lange G, Stefferner J, Cook DB, et al. Objective evidence of cognitive complaints in Chronic Fatigue Syndrome: A
BOLD fMRI study of verbal working memory. Neuroimage 26(2):513-24, Jun 1, 2005. An Overview of the Canadian Consensus Document
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

33 Flor-Henry P, Lind J, Morrison J, et al. Psychophysiological and EEG findings in chronic fatigue syndrome. [Abstract]
Presented at IPEG International Pharmaco-EEG Society-11th Biennial Congress on Pharmaco-EEG, Vienna, Austria 2000 Sept 1-3. Published in Klinische Neurophyiologie 32(1):46-65, 2001. 34 Lange G, Holodny AI, Lee HJ, et al. Quantitative assessment of cerebral ventricular volumes in chronic fatigue
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36 Streeten DH, Tomas D, Bell DS. The Roles of orthostatic hypotension, orthostatic tachycardia and subnormal
erythrocyte volume in the pathogenesis of the chronic fatigue syndrome. Am J Med 320(1):1-8, Jul 2000. 37 Peckerman A, LaManca JJ. Dahl KA, et al. Abnormal impedance cardiography predicts symptom severity in Chronic
Fatigue Syndrome. Amer J Med Science 326(2):55-60, Aug 2003. 38 Codero DL, Sisto SA, Tapp WN, et al. Decreased vagal power during treadmill walking in patients with chronic fatigue
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dysregulation in fibromyalgia and chronic fatigue syndrome. Ann N Y Acad Sci 840:684-697, May 1, 1998. 40 Lerner AM, Zervos M, Dworkin HJ, et al. New cardiomyopathy: pilot study of intravenous Ganciclovir in a subset of the
chronic fatigue syndrome. Infec Dis in Clin Pract 6:110-117, 1997. 41 Ablashi DV, Eastman HB, Owen CB, et al. Frequent HHB-6 antibody and HHV-6 reactivation in multiple sclerosis MS)
and Chronic fatigue syndrome (CFS) patients. C Clin Virol 16(3):179-191, May 1 2000. 42 Roelens S, Herst CV, D'Haese A, et al. G-actin cleavage parallels 2-5A-Dependent RNase L cleavage in peripheral blood
mononuclear cells-relevance to a possible serum-based screening test. J CFS 8(3/4):63-82, 2001. 43 Maher K, Klimas N, Fletcher MA. Flow cytometric measurement of perforin and natural killer cell activity. AACFS Fifth
International Research & Clinical Conference, Seattle, Jan. 2001, #47 44 TEACH-ME Task Force. TEACH-ME: A Sourcebook for Teachers of Young People with Myalgic Encephalomyelitis/
Chronic Fatigue Syndrome and Fibromyalgia Syndrome. Second Edition. National ME/FM Action Network, 2005. 45 Dowsett EG, Colby J. Long-term sickness absence due to ME/CFS in UK schools: an epidemiological study with medical
and educational implications. J CFS 3(2):29-42, 1997. 46 Sharpe MC, in Demitrak MA, Abbey SE (editors). Chronic Fatigue Syndrome. Guilford Press, NY 1996, pp. 248.
47 Wessley S, Nimnuan C, Sharp M. Functional somatic syndromes: one or many? Lancet 354(9182):936-939, Sept 11,
48 Komaroff AL. The biology of the Chronic Fatigue Syndrome. Amer J Med 108:99-105, Feb 2000.
49 Sheperd C. Pacing and exercise in chronic fatigue syndrome. Physiother 87(8):395-396, Aug. 2001.
50 De Meirleir K, De Becker P, Campine I. Blood transfusion and chronic fatigue syndrome. (Abstract)
Presented at the CFS Conference, Sydney, Australia,1999. 51 Waylonis GW, Ronan PG, Gordon C. A profile of fibromyalgia in occupation environments. Am J Phys Med Rehabil
73:112- 115, 1994. This short Overview only provides highlights from:
Carruthers BM, Jain AK, De Meirleir KL, Peterson DL, Klimas NG, Lerner AM,
Bested AC, Flor-Henry P, Pradip Joshi, Powles ACP, Sherkey JA, van de Sande MI.
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Clinical Working Case
Definition, Diagnostic and Treatment Protocols. A Consensus Document.
Journal of Chronic Fatigue Syndrome 11(1):7-115, 2003.
The full Consensus Document is highly recommended as an informative
resource book for medical practitioners.

Carruthers, van de Sande
The Canadian Consensus Document on
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
Fatigue Syndrome is a commonillness. Its impact on many suffererscan be profound with intrusive fatigue This is a VITAL DOCUMENT that gives a new focus and new direction to all involved
with ME/CFS. It makes available the clinical experience and understanding of physicians
and multiple symptoms. e-eminent in the field and encapsulates thousands of hours of clinical investigations that are important to sufferers from ME-CFS and all who are concernedf secondary burden of the condition is or their care, support, and the understanding of this multi-faceted organic illness.
common to all chronic illnesses and includes impoverishment and a HOPE - for patients whose multiple symptoms have so often been dismissed as psychiatric
or of biopsychosocial origin wi act on personal and th consequent loss of benefits and support when they are most needed.
CLARITY - for physicians by providing an abundance of clinical procedures and protocols
that provide objective evidence of organic multi-system and multi-organ disorders
associated with the neuroendocrine and immune systems. It is in agreement with the
long established international classification of ME-CFS as a neurological disorder, ICD-
10 G.93.3.
DIRECTION - for clinical treatments and research programmes; especially the most
recent ones concerning the need for sub-types in addressing ME/CFS and the deeper
understanding of changes in gene expression, mitochondrial dysfunction, and of
pathological changes in the endothelium with concomitant vascular damage. Mitochondrial
dysfunction offers an explanation of the debilitating fatigue that is one of the defining
features of ME-CFS and is consistent with chronic heart failure recently described in a
cohort of ME-CFS patients.
UNDERSTANDING - of the complexity and perplexity of ME-CFS as a multi-symptom,
multi-organ and multi-system illness that is increasingly recognised as an archetype of
other related illnesses such as Gulf War Syndrome, multiple chemical sensitivity (MCS),
and fibromyalgia syndrome (FMS).
Dr. Malcolm Hooper
Emeritus Professor of Medicinal Chemistry
Department of Life Sciences
University of Sunderland
Reviews and Commentaries of Encephalomyelitis/Chronic Fatigue Syndrome: Working Case Definition, Diagnostic and Treatment Protocols A Consensus Document Myalgic Encephalomyelitis/Chronic Fatigue Syndrome is a common illness. Its impact on many sufferers can be profound with intrusive fatigue and multiple symptoms. The secondary burden of the condition is common to all chronic illnesses and includes impoverishment and a significant impact on personal and family life. We recommend and endorse the Canadian Consensus Document. We regard it as an extremely important contribution to understanding the physical basis of the condition. Future research should be directed to further defining the pathophysiology of the condition together with identifying the sub groups, which undoubtedly exist, within the illness complex currently termed ME/CFS. Dr Terry Mitchell MA MD FRCPath. Consultant Haematologist. Head of Norfolk and Suffolk ME/CFS Service NHS Clinical Champion for ME/CFS in Norfolk, Suffolk and Cambridgeshire Honorary Consultant, The National ME Centre Professor L J Findley TD KLJ MD FRCP FACP Consultant Neurologist. Clinical Director, The National ME Centre Clinical Director, Fatigue Service, Barking, Havering & Redbridge NHS Trust Myalgic Encephalomyelitis/Chronic Fatigue Syndrome is a complex illness that can cause life-long disability, yet has languished for years without clear recognition by the medical community. The paradox of the illness is that it can cause severe discomfort and markedly limit daily activity, yet persons with the illness may look, to the casual observer, relatively well. Because of this paradox, many in the medical profession have ignored the seriousness In the past few years, science has made extraordinary strides in understanding the basic mechanisms of ME/CFS. Yet, because of its complexity, little of this science has reached medical practitioners to be used in relieving the suffering of patients affected with the illness. It is now possible to define abnormalities in the neurological, immune, autonomic, and neuroendocrine systems in a concise way that can paint a portrait of this disabling illness. The Canadian consensus definition of ME/CFS is a concise summary of these advances and permits a clear diagnosis for patients. The Canadian Consensus Document should be read and studied by every medical provider. David S. Bell, MD, FAAP Past Chairman: Chronic Fatigue Syndrome Advisory Committee, US Department of Health and Human Services While the primary goal was to establish a clinical case definition for ME/CFS, the ME/CFS Consensus Document is a comprehensive overview of ME/CFS, including pathophysiology, symptoms, physical findings, and treatments. This Consensus Document is clearly the most comprehensive review of ME/CFS to date. It records the experience of many long time practitioners, which provides an insight into signs and symptoms that has never been recorded elsewhere. Never before has there been a consensus on treatment. This paper considers not only pharmacotherapy, but also makes recommendations for patient education, energy conservation, pacing, stress reduction techniques, diet, and exercise. One of the most important aspects of the ME/CFS Consensus Document is that it indicates the level of proof for various recommendations. This is THE MANUAL for diagnosing and treating ME/CFS. Perhaps every office that treats patients with ME/CFS should be using this document as the diagnosis and treatment blueprint. Charles W. Lapp, MD Director: HUNTER-HOPKINS CENTER, Charlotte, North Carolina Advisory Committee for CFS: US Department of Health & Human Services Board of Directors: American Association for Chronic Fatigue Syndrome


38-42. saroj kumar

Vol. 6, No. 2, 2015 ISSN 2233-4203/ e-ISSN 2093-8950 Mass Spectrometry Letters Identification of Degradation Products in the Phosphodiesterase (PDE-4)Inhibitor Roflumilast Using High Resolution Mass Spectrometry and DensityFunctional Theory Calculations Saroj Kumar Paul* and Upendra N. Dash Department of Chemistry, Institute of Technical Education and Research (ITER), Siksha ‘O' Anusandhan University, Bhubaneswar,Odisha, India


Bundesamt für Strahlenschutz Postfach 10 01 49 braunschweig-druck GmbH, Braunschweig 2. überarbeitete Aufl age 2007 2. SOLARIEN – GERÄTETECHNIK, BETRIEB UND WARTUNG, QUALITÄTSNACHWEIS . . . . . . 2.2.2 Alterung und Nutzlebensdauer optisch wirksamer Bauteile . . . . . . . . . . . . . . 11 2.3.1 Elektrische Betriebsbedingungen und Betriebstemperatur . . . . . . . . . . . . . . 12