By K. Kimberly McCleary, President & CEO
On July 20, 2011, the Journal of Internal Medicine e-published ahead of print “Myalgic Encephalomyelitis: International Consensus Criteria.” The panel of authors, led by coeditors Bruce M. Carruthers, MD, CM, FRCP(C) and Marjorie I. van de Sande, BEd, GradDip Ed, includes 26 authors from Australia (3 authors), Belgium (1), Canada (4), Chile (1), Ireland (1), Italy (1), Japan (1), Korea (1), Latvia (1), New Zealand (1), Norway (1), the United Kingdom (2) and the United States (8). The paper specifically cites 123 publications to support its recommendations. [Update: The final version has been published in the October 2011 issue of the Journal of Internal Medicine and is available open access: http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2796.2011.02428.x/full]
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.
Past definitions for CFS and ME/CFS have been designed for either research or clinical settings, although there has been cross-over in how they were and are used. In contrast, the Journal of Internal Medicine paper states: “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.”
New Criteria Overview
ME is described as “an acquired neurological disease with complex global dysfunctions. Pathological dysregulation of the nervous, immune and endocrine systems, with impaired cellular energy metabolism and ion transport are prominent features. Although signs and symptoms are dynamically interactive and causally connected, the criteria are grouped by regions of pathophysiology to provide general focus.”
Of particular note is that other definitions have established a minimum duration of illness (either four or six months). The new ME definition removes this requirement: “…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.” One of the questions arising from the new definition is whether individuals with a more transient illness will be considered to have ME.
Diagnosis begins with assessment of post-exertional neuroimmune exhaustion (PENE), rather than fatigue. “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. The normal activity/rest cycle, which involves performing an activity, becoming fatigued, and taking a rest whereby energy is restored, becomes dysfunctional.”
In addition to the required feature of PENE, the individual must have seven other symptoms: three that demonstrate neurological impairment; three that demonstrate immune impairment; and one that demonstrates energy production/transport impairment. These are described more fully below. The term “atypical ME” is used when an individual “meets criteria for post-exertional neuroimmune exhaustion but has two or less than required of the remaining criterial symptoms. Pain or sleep disturbance may be absent in rare cases.”
The paper provides severity subgroups: “Symptom severity impact must result in a 50 percent or greater reduction of a patient’s premorbid activity level for a diagnosis of ME. Mild: approximately 50 percent reduction in activity; Moderate: mostly housebound; severe: mostly bedbound; and Very Severe: bedbound and dependent on help for physical functions.”
Special considerations are noted for making the diagnosis in the pediatric setting, including guidelines about distinguishing ME from school phobia.
The following co-occurring conditions are identified: “Fibromyalgia, myofascial pain syndrome, temporomandibular joint syndrome, irritable bowel syndrome, interstitial cystitis, Raynaud’s phenomenon, prolapsed mitral valve, migraines, allergies, multiple chemical sensitivities, Hashimoto’s thyroiditis, Sicca syndrome, reactive depression. Migraine and irritable bowel syndrome may precede ME but then become associated with it. Fibromyalgia overlaps.” From reading the text, it does not appear that this list is intended to represent the only comorbid conditions that should be considered. For instance, specific forms of orthostatic intolerance (postural orthostatic tachycardia syndrome and neurally mediated hypotension) are referenced in the description of energy production and transport impairments.
In addressing exclusionary conditions, the authors state, “…exclusion of alternate explanatory diagnoses is achieved by the patient’s history, physical examination, and laboratory/biomarker testing as indicated. It is possible to have more than one disease but it is important that each one is identified and treated. Primary psychiatric disorders, somatoform disorder and substance abuse are excluded. Paediatric: ‘primary’ school phobia.”
As stated earlier, the central feature of ME under this definition is post-exertional neuroimmune exhaustion (PENE). To meet the criteria, an individual must have PENE, described in the following manner: “This cardinal feature is a pathological inability to produce sufficient energy on demand with prominent symptoms primarily in the neuroimmune regions.
1. Marked, rapid physical and/or cognitive fatigability in response to exertion, which may be minimal such as activities of daily living or simple mental tasks, can be debilitating and cause a relapse.
2. Post-exertional symptom exacerbation: e.g. acute flu-like symptoms, pain and worsening of other symptoms.
3. Post-exertional exhaustion may occur immediately after activity or be delayed by hours or days.
4. Recovery period is prolonged, usually taking 24 hours or longer. A relapse can last days, weeks or longer.
5. Low threshold of physical and mental fatigability (lack of stamina) results in a substantial reduction in pre-illness activity level.”
The individual must demonstrate neurological impairment by meeting a total of at least three symptoms from three of these four categories:
1. Neurocognitive impairment
a. Difficulty processing information: slowed thought, impaired concentration
b. Short-term memory loss
b. Significant pain can be experienced in muscles, muscle-tendon junctions, joints, abdomen or chest. It is non-inflammatory in nature and often migrates.
3. Sleep disturbance
4. Neurosensory, perceptual and motor disurbances
a. Neurosensory and perceptual
The individual must demonstrate immunological impairment by meeting a total of at least three symptoms from three of these five categories:
1. Flu-like symptoms may be recurrent or chronic and typically activate or worsen with exertion
2. Susceptibility to viral infections with prolonged recovery periods
3. Gastointestinal tract
5. Sensitivities to food, medications, odours or chemicals
The individual must have one of the following symptoms that demonstrate energy production/transport impairment:
3. Loss of thermostatic stability
4. Intolerance of extremes of temperature
Further descriptions of each of these symptom clusters are provided in Table 1 that accompanies the text. (Table 1 has been reproduced by the CFIDS Association of America under limited license from John Wiley & Sons, Inc., publisher of the Journal of Internal Medicine. Copyright to the original material and all other rights reserved by John Wiley & Sons, Inc.)
The authors also provide additional directives for applying these symptom lists in clinical settings vs. research settings. The panel is at work on Physicians Guidelines and an International Consensus Symptom Scale. They specifically state that only subjects who fully meet ME criteria should be included in epidemiological research.
Acceptance for particular disease definitions may come by several different routes. The most common route is for an authoritative institution to lead and “sponsor” development, publication and circulation of a definition. The 1990 American College of Rheumatology criteria for fibromyalgia is one example. This ME publication was developed as an independent effort, free of sponsorship. The panel reflects diverse expertise and experience with CFS, ME/CFS and ME; however, none of the participants represent professional organizations, funding agencies or policy-making institutions like the National Institutes of Health and U.S. Centers for Disease Control & Prevention in the United States or the Medical Research Council in the United Kingdom. Such participation might have added “clout” that could influence more rapid acceptance and utilization at an institutional level, however it might have also resulted in a different product.
While it lacks the implied institutional endorsement of the 1994 criteria for CFS led by authors at the CDC, this consensus report has a major advantage over the 2003 Canadian clinical criteria for ME/CFS with its publication in a journal with wide circulation in the medical community. (The Journal of Internal Medicine has an impact factor of 5.935, compared to the now-defunct Journal of Chronic Fatigue Syndrome that was never linked to PubMed.) The version published electronically on July 20, 2011, is a provisional paper, with the final version due out in print later this year. It will be interesting to follow formal responses that may be generated through Letters to the Editor and other commentary and analyses, particularly by those who have worked on earlier case definition efforts for CFS, ME and ME/CFS (CFS/ME). The next meeting of the U.S. Department of Health and Human Services CFS Advisory Committee will be a potential venue for discussion of impacts on funding and policy (including Social Security disability), with a recommendation that the U.S. federal agencies adopt ME/CFS as a replacement for CFS still under review by the Secretary of Health and discussion of case definition a regular feature of agency reports and discussion.
It is hoped that this consensus report will be broadly viewed as a positive development in the effort to identify criteria that enhance patient care and research. The response so far reflects a mostly enthusiastic reception, although there is some disappointment about the lack of objective measures to support symptom criteria. The paper provides a theoretical construct, with no data provided to demonstrate whether application of this criteria set results in a more homogeneous patient population than other criteria. There is also some concern about the possibility that the following statement in the paper’s Conclusions might have the unintended effect of jeopardizing or impeding access to or payments from government and private insurance coverage systems that do not presently recognize ME: “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.” In the United States, most systems (including Social Security) utilize the 1994 CFS definition by Fukuda et al. rather than the 2005 empiric definition by Reeves et al., but the ambiguity about which one constitutes the present “CDC definition” gives rise to concerns about the impact of this statement when applied in the medical-legal context.
The CFIDS Association considers the ME International Consensus Criteria to be an important publication with potentially far-reaching implications for research, policy and education. We are reviewing it closely and will be seeking input from our Scientific Advisory Board (three members of which are authors on the paper) and others about how these criteria might impact comparability with existing literature, funding, health care delivery, reimbursement, disability payments/applications, general awareness and understanding and a wide range of other practical issues.
Myalgic Encephalomyelitis: International Consensus Criteria. Bruce M Carruthers, Marjorie I van de Sande, Kenny L De Meirleir, Nancy G Klimas, Gordon Broderick, Terry Mitchell, Don Staines, Peter Powles, Nigel Speight, Rosamund Vallings, Lucinda Bateman, Barbara Baumgarten-Austrheim, David S Bell, Nicoletta Carlo-Stella, John Chia, Austin Darragh, Daehyun Jo, Don Lewis, Alan R Light, Sonya Marshall-Gradisbik, Ismael Mena, Judy A Mikovits, Kunihisa Miwa, Modra Murovska, Martin L Pall, Staci Stevens. Journal of Internal Medicine. Accepted Article, July 20, 2011 doi: 10.1111/j.1365-2796.2011.02428.x (http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2796.2011.02428.x/full)
K. Kimberly McCleary has served as the Association’s chief staff executive since 1991.
Note: Post updated on July 27, 2011 to add link to Table 1 (http://www.research1st.com/wp-content/uploads/2011/07/Carruthers-JIM-Table-1.pdf) reproduced by the CFIDS Association of America under limited license from John Wiley & Sons, Inc., publisher of the Journal of Internal Medicine. Copyright to the original material and all other rights reserved by John Wiley & Sons, Inc.