From The Journal of Internal Medicine, July 2011 (manuscript accepted 15 July 2011 and published online on 20 July 2011)
Myalgic Encephalomyelitis: International Consensus Criteria
Bruce M Carruthers, MD, CM, FRCP(C) (coeditor); Independent, Vancouver, B.C., Canada
Marjorie I van de Sande, BEd, GradDip Ed (coeditor); Independent, Calgary, AB, Canada
Kenny L De Meirleir, MD, PhD; Department of Physiology and Medicine, Vrije University of Brussels, Himmunitas Foundation, Brussels, Belgium.
Nancy G Klimas, MD; Department of Medicine ,University of Miami Miller School of Medicine and Miami Veterans Affairs Medical Center, Miami, FL, USA
Gordon Broderick, PhD; Department of Medicine, University of Alberta, Edmonton, AB, Canada
Terry Mitchell, MA, MD, FRCPath; Honorary Consultant for NHS at Peterborough/Cambridge, Lowestoft, Suffolk, United Kingdom.
Don Staines, MBBS, MPH, FAFPHM, FAFOEM; Gold Coast Public Health Unit, Southport, Queensland; Health Sciences and Medicine, Bond University, Robina, Queensland, Australia AC
Peter Powles, MRACP, FRACP, FRCP(C), ABSM; Faculty of Health Sciences, McMaster University and St. Joseph’s Healthcare Hamilton, Hamilton, ON, Canada.
Nigel Speight, MA, MB, BChir, FRCP, FRCPCH, DCH; Independent, Durham, United Kingdom
Rosamund Vallings, MNZM, MB, BS, MRCS, LRCP; Howick Health and Medical Centre, Howick, New Zealand.
Lucinda Bateman, MS, MD; Fatigue Consultation Clinic, Salt Lake Regional Medical Center: adjunct faculty – Internal Medicine, Family Practice, University of Utah, Salt Lake City, UT, USA.
Barbara Baumgarten-Austrheim, MD; ME/CFS Center, Oslo University Hospital HF, Norway. David S Bell, MD, FAAP; Department of Paediatrics, State University of New York, Buffalo, NY.
Nicoletta Carlo-Stella, MD, PhD; Independent, Pavia, Italy
John Chia, MD; Harbor-UCLA Medical Center, University of California, Los Angeles; EV Med Research, Lomita, CA, USA
Austin Darragh, MA, MD, FFSEM. (RCPI, RCSI), FRSHFI Biol I (Hon); University of Limerick, Limerick, Ireland
Daehyun Jo, MD, PhD; Pain Clinic, Konyang University Hospital, Daejeon, Korea
Don Lewis, MD; Donvale Specialist Medical Centre, Donvale, Victoria, Australia
Alan R Light, PhD; Depts or Anesthesiology, Neurobiology and Anatomy,University of Utah, Salt Lake City, Utah, USA.
Sonya Marshall-Gradisbik, PhD; Health Sciences and Medicine, Bond University, Robina, Queensland, Australia.
Ismael Mena, MD; Depart. Medicina Nuclear, Clinica Las Condes, Santiago, Chile
Judy A Mikovits, PhD; Whittemore Peterson Institute, University of Nevada, Reno, NV USA
Kunihisa Miwa, MD, PhD; Miwa Naika Clinic, Toyama, Japan
Modra Murovska, MD, PhD; A. Kirchenstein Institute of Microbiology and Virology, Riga Stradins University, Riga, Latvia,
Martin L Pall, PhD; Department of Biochemistry & Basic Medical Sciences, Washington State University, Portland, OR, USA
Staci Stevens, MA; Department of Sports Sciences, University of the Pacific, Stockton, CA USA.
This is an Accepted Article that has been peer-reviewed and approved for publication in the Journal of Internal Medicine, but has yet to undergo copy-editing and proof correction. Please cite this article as an “Accepted Article”; doi: 10.1111/j.1365- 2796.2011.02428.x
Running Title: ME: Intl. Consensus Criteria
The label “chronic fatigue syndrome” (CFS) has persisted for many years because of lack of knowledge of the etiological agents and of the disease process. In view of more recent research and clinical experience that strongly point to widespread inflammation and multisystemic neuropathology, it is more appropriate and correct to use the term “myalgic encephalomyelitis”(ME) because it indicates an underlying pathophysiology. It is also consistent with the neurological classification of ME in the World Health Organization’s International Classification of Diseases (ICD G93.3). Consequently, an International Consensus Panel consisting of clinicians, researchers, teaching faculty and an independent patient advocate was formed with the purpose of developing criteria based on current knowledge. Thirteen countries and a wide range of specialties were represented. Collectively, members have approximately 400 years of both clinical and teaching experience, authored hundreds of peer reviewed publications, diagnosed or treated approximately 50,000 ME patients, and several members coauthored previous criteria. The expertise and experience of the panel members as well as PubMed and other medical sources were utilized in a progression of suggestions/drafts/reviews/revisions. The authors, free of any sponsoring organization, achieved 100% consensus through a Delphi type process.
The scope of this paper is limited to criteria of ME and their application. Accordingly, the criteria reflect the complex symptomatology. Operational notes enhance clarity and specificity by providing guidance in the expression and interpretation of symptoms. Clinical and research application guidelines promote optimal recognition of ME by primary physicians and other health care providers, improve consistency of diagnoses in adult and paediatric patients internationally, and facilitate clearer identification of patients for research studies.
Myalgic encephalomyelitis (ME), also referred to in the literature as chronic fatigue syndrome (CFS), is a complex disease involving profound dysregulation of the central nervous system (CNS) [1-3] and immune system [4-8], dysfunction of cellular energy metabolism and ion transport [9-11], and cardiovascular abnormalities [12-14]. The underlying pathophysiology produces measurable abnormalities in physical and cognitive function and provides a basis for understanding the symptomology. Thus, the development of International Consensus Criteria that incorporate current knowledge should advance the understanding of ME by health practitioners, and benefit both the physician and patient in the clinical setting as well as clinical researchers.
The problem with broadly inclusive criteria [15, 16] is that they do not select homogeneous sets of patients. The Centers for Disease Control prevalence estimates increased tenfold from 0.24% using the Fukuda criteria  to 2.54% using the Reeves empirical criteria . Jason et al.  suggest there are flaws in Reeves’ methodology because it is possible to meet the empirical criteria for ME without having any physical symptoms and it does not discriminate ME/CFS patients from those with Major Depressive Disorder. Patient sets that include people who do not have the disease lead to biased research findings, inappropriate treatments, and waste scarce research funds .
Some symptoms of the Fukuda criteria overlap with depression whereas the Canadian Consensus Criteria  differentiate ME patients from those who are depressed and identify patients who are more physically debilitated and have greater physical and cognitive functional impairments .
International Consensus Criteria
The Canadian Consensus Criteria were used as a starting point, but significant changes were made. The six-month waiting period before diagnosis is no longer required. No other disease criteria require that diagnoses be withheld until after the patient has suffered with the affliction for six months. Notwithstanding periods of clinical investigation will vary and may be prolonged, diagnosis should be made when the clinician is satisfied that the patient has ME rather than having the diagnosis restricted by a specified time factor. Early diagnoses may elicit new insights into the early stages of pathogenesis; prompt treatment may lessen the severity and impact.
Using “fatigue” as a name of a disease gives it exclusive emphasis and has been the most confusing and misused criterion. No other fatiguing disease has “chronic fatigue” attached to its name – e.g. cancer/chronic fatigue, multiple sclerosis/chronic fatigue – except ME/CFS. Fatigue in other conditions is usually proportional to effort or duration with a quick recovery, and will recur to the same extent with the same effort or duration that same or next day. The pathological low threshold of fatigability of ME described in the following criteria often occurs with minimal physical or mental exertion, and with reduced ability to undertake the same activity within the same or several days.
The International Consensus Criteria (Table 1) identify the unique and distinctive characteristic patterns of symptom clusters of ME. The broad spectrum of symptoms alerts medical practitioners to areas of pathology and may identify critical symptoms more accurately [18-20]. Operational notes following each criterion provide guidance in symptom expression and contextual interpretation. This will assist the primary clinician in identifying and treating ME patients in the primary care setting.
(Please insert Table 1 here : click here )
Criteria Are Supported by Research
Criterial symptoms are supported by a study of more than 2,500 patients that determined which symptoms had the greatest efficacy to identify ME patients . Investigations of gene expression [23-27] and structure further support the criteria at a molecular level including anomalies of increased oxidative stress [4, 28], altered immune and adrenergic signalling [29, 30], and altered oestrogen receptor expression . In addition, evidence supporting a genetic predisposition to ME points to modifications in serotonin transporter genes [32, 33], the glucocorticoid receptor gene , as well as HLA class II involvement . The potential combinatorial effects of these modifications have received limited attention [36, 37]. Some early broad based studies show a lack of objective findings such as no association with HLA genotype . A study of patients from a twin registry suggested that environmental factors may outweigh any genetic predisposition in broad based patient populations .
Underlying problems of inconsistent findings in research studies have been identified [40, 41] and include a need for studies to be based on larger sample sizes with a more clearly defined phenotype; in particular one that recognizes the likely existence of significant subgroups within the patient population. In a study of the Reeves empirical criteria , Jason et al  reported that thirty-eight percent (38%) of patients diagnosed with Major Depressive Disorder were misclassified as having CFS and only ten percent (10%) of patients identified as having CFS actually had ME. Accordingly, the primary goal of this consensus report is to establish a more selective set of clinical criteria that would identify patients who have neuroimmune exhaustion with a pathological low-threshold of fatigability and symptom flare in response to exertion. This will enable like patients to be diagnosed and enrolled in research studies internationally under a case definition that is acceptable to physicians and researchers around the world.
A. Post-Exertional Neuroimmune Exhaustion (PENE pen׳-e)
“Malaise – a vague feeling of discomfort or fatigue”  is an inaccurate and inadequate word for the pathological low-threshold fatigability and post-exertional symptom flare. Pain and fatigue are crucial bioalarm signals that instruct patients to modify what they are doing in order to protect the body and prevent further damage. Post-exertional neuroimmune exhaustion is part of the body’s global protection response and is associated with dysfunction in the regulatory balance within and between the nervous, immune and endocrine systems, and cellular metabolism and ion transport [43-47]. The normal activity/rest cycle, which involves performing an activity, becoming fatigued, and taking a rest whereby energy is restored, becomes dysfunctional.
Numerous papers document abnormal biological responses to exertion, such as loss of the invigorating effects of exercise , decreased pain threshold [48-50], decreased cerebral oxygen and blood volume/flow [51-54], decreased maximum heart rate , impaired oxygen delivery to muscles , elevated levels of nitric oxide metabolites , and worsening of other symptoms . Patients reach the anaerobic threshold and maximal exercise at a much lower oxygen consumption level . Reported prolonged effects of exertion include elevated sensory signalling to the brain  that is interpreted as pain and fatigue , elevated cytokine activity , delay in symptom activation  and a recovery period of at least 48 hours . When an exercise test was given on two consecutive days, some patients experienced up to a 50% drop in their ability to produce energy on the second evaluation . Both submaximal and self-paced physiologically limited exercise resulted in post-exertional malaise .
B. Neurological Impairments
Some viruses and bacteria can infect immune and neural cells and cause chronic inflammation. Structural and functional pathological abnormalities  within the brain and spinal cord suggest dysregulation of the CNS control system and communication network , which play crucial roles in cognitive impairment and neurological symptoms . Neuroinflammation of the dorsal root ganglia, gatekeepers of peripheral sensory information traveling to the brain, has been observed in spinal autopsies. (Chaudhuri A. Royal Society of Medicine Meeting 2009) Identified cerebrospinal fluid proteomes distinguish patients from healthy controls and post-treatment Lyme disease .
Neuroimaging studies report irreversible punctuate lesions , an approximate 10% reduction in gray matter volume [67, 68], hypoperfusion [69-74] and brain stem hypometabolism . Elevated levels of lateral ventricular lactate are consistent with decreasedcorticalbloodflow,mitochondrialdysfunctionandoxidativestress. Research suggests that dysregulation of the CNS and autonomic nervous system alters processing of pain and sensory input [48, 61, 76, 77]. Patients’ perception that simple mental tasks require substantial effort is supported by brain scan studies that indicate greater source activity and more regions of the brain are utilized when processing auditory and spatial cognitive information [78-80]. Poor attentional capacity and working memory are prominent disabling symptoms [20, 78, 81].
C. Immune Impairments
Most patients have an acute infectious onset with flu-like and/or respiratory symptoms. A wide range of infectious agents have been reported in subsets of patients including Xenotropic murine leukemia virus-related virus (XMRV)  and other murine leukemia virus (MLV)-related viruses , enterovirus [84-86], Epstein Barr virus , human herpes virus 6 and 7 [88-90], Chlamydia , cytomegalovirus , parvovirus B19  and Coxiella burnetti . Chronic enterovirus infection of the stomach and altered levels of D Lactic acid producing bacteria in the gastrointestinal tract have been investigated [85, 94]. Possibly the initial infection damages part of the CNS and immune system causing profound deregulation and abnormal responses to infections . Publications describe decreased natural killer cell signalling and function, abnormal growth factor profiles, decreased neutrophil respiratory bursts and Th1, with a shift towards a Th2 profile [4-8, 95, 96]. Chronic immune activation , increases in inflammatory cytokines, pro-inflammatory alleles [4-8, 97-99], chemokines and T lymphocytes, and dysregulation of the antiviral riboneuclease L (RNase L) pathway [64, 100-103] may play a role in causing flu-like symptoms, which aberrantly flare in response to exertion [5, 95].
D. Energy Production/Transport Impairments
The consistent clinical picture of profound energy impairment suggests dysregulation of the mitochondria and cellular energy metabolism and ion transport, and channelopathy [9- 11, 103, 104]. A biochemical positive feedback cycle called the ‘NO/ONOO- cycle’ may play a role in maintaining the chronic nature of ME, the presence of oxidative stress [105-107], inflammatory cytokine elevation [97-99] and mitochondrial dysfunction [108-111], and result in reduced blood flow and vasculopathy [109, 110].
Findings of “small heart” with small left ventricular chamber and poor cardiac performance in patient subsets [112, 113] support previous reports of cardiac and left ventricular dysfunction [114-116], which predispose to orthostatic intolerance [14, 117]. Low blood pressure and exaggerated diurnal variation may be due to abnormal blood pressure regulation . Altered control and reduced cortisol production during and following exercise may be involved. Orthostatic intolerance is associated with functional impairment and symptom severity . Measurable vascular abnormalities suggest that the brain is not receiving sufficient circulating blood volume in an upright position [12, 117], which is intensified when standing in one place such as a grocery store check-out line.
Significant reduction in heart rate variability during sleep is associated with poor sleep quality and suggests a pervasive state of nocturnal sympathetic hypervigilance .
Application of Criteria
Diagnostic criteria serve two necessary but divergent functions – the first is diagnosing individuals in a clinical setting and the second is identifying patient sets for research studies.
A. Clinical Application
1. General Considerations
a. Determine whether symptom cluster patterns are congruent with those expected from dysfunction of an underlying causal system.
b. Symptoms interact dynamically within a stable cluster because they share the same deep causal roots. Patients’ contextual observations are essential in determining the expression of interaction of symptom patterns and severity of their impact.
c. Symptom severity impact must result in a 50% or greater reduction of a patient’s premorbid activity level for a diagnosis of ME. Mild: approximately 50% reduction in activity, moderate: mostly housebound, severe: mostly bedbound, and very severe: bedbound and dependent on help for physical functions.
d. Symptom severity hierarchy should be determined periodically to help orient and monitor treatment.
e. Criterial subgroups: Post-exertional neuroimmune exhaustion is the hallmark feature. It may be helpful to subgroup according to which of the other diagnostic criterial patterns best represent a patient’s cluster of most severe symptoms: neurological, immune, energy metabolism/transport, or eclectic (symptoms widely distributed among subgroups).
f. Separate primary symptoms from secondary symptoms and aggravators. Distinguish primary symptom complexes formed by a disease process from secondary effects of coping with the disease, such as anxiety about finances. Determine the effects and burden of aggravators and stress enhancers such as fast paced environments and exposure to toxins.
g. Determine total illness burden by assessing symptom severity, interaction and overall impact. Consider all aspects of the patient’s life – physical, occupational, educational, social and personal activities of daily living. Patients who prioritize their activities may be able to do one important activity by eliminating or severely reducing activities in other aspects of their life.
h. The International Symptom Scale should not be part of the initial clinical interview because it may disturb the weighting and significance of results obtained for an individual patient. When used periodically, it can help position the patient within the group, orient the treatment program and monitor its effectiveness.
2. Paediatric Considerations
a. If possible, interview a young person with both parents because each may remember different symptoms or interactive events that may help determine onset and when the illness began to interfere with daily function.
b. Children cannot be expected to judge pre-illness function with current function. Assess impact by comparing hobbies, educational, social and sport activities the child participated in before illness with present activity level.
c. Children may appear irritable when they are asked to do something when they feel exhausted. On the other hand, they are often able to accommodate fatigue by resting, which may be inappropriately interpreted as being lazy.
d. School Phobia: Young patients spend most of their out-of-school hours resting whereas children with school phobia will be socializing and participating in activities. However, it is possible that school phobia may become a secondary symptom because of bullying or academic difficulties due to having ME.
e. Natural Course: Children can be very severely afflicted but those whose symptoms are of mild to moderate severity generally are more likely to have them go into remission than adults. Prognosis cannot be predicted with certainty.
B. Research Application
A clinical diagnosis must be confirmed before a patient can provide useful general knowledge about the disease. The data obtained from patients allows controlled and meaningful observations and suggests hypotheses to be tested and confirmed or refuted.
1. General Considerations
a. Patients should meet the full criteria for epidemiological studies. If specific subgroups or atypical ME are included in a research study, that should be clearly indicated.
b. Specificity: Because critical symptoms are compulsory, it ensures proper selection of patients. Key operational guidelines enhance clarity and specificity. Ranking the hierarchy of the most troublesome symptoms may be helpful in some studies.
c. Reliability: Symptoms must not be viewed as a nominal checklist. The International Consensus Criteria focus on symptom patterns, which increase reliability. The International Symptom Scale ensures consistency in the way questions are asked and further increases reliability of data collected in different locations. Patients should complete the International Symptom Scale prior to entering a research study.
2. Optional Considerations
Classifying patients by subgroups to enable comparison of patients within the diagnosis of ME may be helpful in some studies.
a. Onset: acute infectious or gradual
b. Onset severity may be a good predictor of severity in the chronic phase.
c. Symptom severity: mild, moderate, severe, very severe d. Criterial subgroups: neurological, immune, energy metabolism/transport, or eclectic
(See clinical application for symptom severity and criterial subgroups.)
The International Consensus Criteria provide a framework for the diagnosis of ME that is consistent with the patterns of pathophysiological dysfunction emerging from published research findings and clinical experience. Symptom patterns interact dynamically because they are causally connected. This has been formally addressed by some investigators who have used well-established multivariate statistical techniques, such as common factor or principal component analyses to identify symptom constructs [121, 122]. Others have extended the use of such methods to guide the analysis of gene expression profiles  and to delineate patient sub-groups . Consistent with this approach, the panel is developing an International Consensus Symptom Scale (ICSS) that will build on these underlying interactions. However a necessary first step in establishing a quantitative score for any diagnostic instrument is the specification of measurable factors that are most relevant to the illness. Establishing such criteria was the primary objective of this work and we believe the International Consensus Criteria will help clarify the unique signature of ME.
It is important to note that the current emphasis must primarily remain a clinical assessment, with selection of research subjects coming later. For this reason the panel is developing Physicians’ Guidelines, which will include diagnostic protocol based on the International Consensus Criteria and treatment guidelines that reflect current knowledge. Individuals meeting the International Consensus Criteria have myalgic encephalomyelitis and should be removed from the Reeves empirical criteria and the National Institute for Clinical Excellence (NICE) criteria for chronic fatigue syndrome. These guidelines are designed specifically for use by the primary care physician in the hope of improving rapid diagnosis and treatment by first-line medical care providers. This may result in the development of an additional short form version that would build on the relationships linking symptoms to formulate an abbreviated screening protocol. For the first time clinical, paediatric and research applications are provided, which will advance the understanding of myalgic encephalomyelitis and enhance consistency of diagnoses internationally. The compulsory critical criteria allow comparable data to be collected in various locations and may assist in developing consistent biomarkers and further insights into the mechanism and etiology of myalgic encephalomyelitis.
KEY WORDS: myalgic encephalomyelitis, chronic fatigue syndrome, criteria, definition, diagnosis. Funding This Consensus paper is free of sponsorship. All authors contributed their time and expertise on a volunteer basis and no one received any payments or honorariums.
Conflict of Interest Statement.
All authors have disclosed potential conflicts of interest and all members declare that they have no competing interests. Acknowledgements The panel would like to gratefully acknowledge the participation and support of the patients and their families in the research described herein and upon which these guidelines are based.
Author Contributions Coeditors – conception, drafting of paper and revisions: B.M. Carruthers, M.I. van de Sande.
Initial suggestions and subsequent critical reviews: K.L. De Meirleir, N.G. Klimas, G. Broderick, T. Mitchell, D. Staines, A.C.P. Powles, N. Speight, R. Vallings, L. Bateman, B. Baumgarten- Austrheim, D.S. Bell, N. Carlo-Stella, J. Chia, A. Darragh, D. Jo, D. Lewis, A.R. Light, S. Marshall- Gradisbik, I. Mena, J.A. Mikovits, K. Miwa, M. Murovska, M.L. Pall, S. Stevens.
Final approval and consensus: There was 100% consensus by the authors on the final consensus paper. B. M. Carruthers, M. I. van de Sande, K.L. De Meirleir, N.G. Klimas, G. Broderick, T. Mitchell, D. Staines , A.C.P. Powles, N. Speight, R. Vallings, L. Bateman, B. Baumgarten-Austrheim, D.S. Bell, N. Carlo-Stella, J. Chia, A. Darragh, D. Jo, D. Lewis, A.R. Light, S. Marshall-Gradisbik, I. Mena, J.A. Mikovits, K. Miwa, M. Murovska, M.L. Pall, S. Stevens.
Consensus Coordinator: M. van de Sande
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