This ground-breaking letter was sent to members of the United States Department of Health and Human Services on May 12th by the newly formed National Advocacy Alliance for ME/CFS ( NAAME ). You can support this letter by signing NAAME's petition . Change the definition - change the name!
The full letter with Table 1 can be read at Onward Through the Fog .
Date: May 12, 2013
To: Secretary Sebelius, Dr. Howard Koh, Dr. Thomas Frieden, and Dr. Francis Collins
CC: Dr. Janet Woodcock, Dr. Beth Unger, Dr. Susan Maier, Dr. Nancy Lee, CFSAC members
Subject: Need for Focused Attention on Myalgic Encephalomyelitis (ME)
Dear Secretary Sebelius, Dr. Koh, Dr. Friedan, and Dr. Collins
We are writing to express our strong concerns with the Department of Health and Human Services (DHHS) current definition activities related to "Chronic Fatigue Syndrome” (“CFS”). We believe DHHS is moving in a direction that is unproductive and harmful to patients. This letter outlines the basis for these concerns and the steps we believe must be taken to rectify the situation.
Throughout the twentieth century, there have been occurrences of a complex, disabling disease characterized by unrefreshing sleep, flu-like symptoms, impairment of memory and other cognitive impairments, orthostatic intolerance, debilitating weakness, pain, fever and the hallmark symptom of post-exertional malaise (post-exertional neuroimmune exhaustion). i This disease has been shown to cause severe dysfunction of neurological, immune, endocrine and energy production systems ii and, since 1969, has been classified as a neurological disease called myalgic encephalomyelitis (ME) by the World Health Organization. iii The name myalgic encephalomyelitis is still used elsewhere and is used herein to refer to this disease and to clearly distinguish it from the non-specific term “CFS”.
Following the outbreak in Incline Village, the CDC named the disease chronic fatigue syndrome (CFS) instead of myalgic encephalomyelitis and developed the first of a number of fatigue-focused case definitions. Today, the term “ME” is rarely used in the U.S. and instead, ME patients are almost always given a diagnosis of CFS. iv
Unfortunately, according to the CDC website, “CFS” can be defined by at least 5 disparate CFS definitions (see Table 1). Three of these, the 2003 Canadian Consensus Criteria, the 2011 ME International Consensus Criteria, and the Pediatric definition, describe the essential and hallmark features of ME. But the two most commonly used definitions, the 1994 Fukuda and 1991 Oxford definitions, focus on fatigue, do not require core ME symptoms like post-exertional malaise, cognitive problems and unrefreshing sleep and allow the inclusion of primary psychiatric illness. In fact, Oxford does not require any symptoms except for 6 months of disabling fatigue for a patient to be given a diagnosis of CFS.
As a result, the term “CFS” has become an amorphous umbrella associated with a diverse set of unrelated conditions that include depression, deconditioning v , medically unexplained chronic fatigue, school phobia, and for some researchers and clinicians, fatigue due to “excessive rest” vi or “false illness beliefs”. vii In clinical practice, doctors give a CFS diagnosis to a heterogeneous mix of patients – those with ME, those with the varied conditions listed above, those who have been misdiagnosed or those whose doctors use CFS as a catchall diagnosis for fatigue.
ME is unquestionably a complex disease and its heterogeneity is real. But this “heterogeneity” is a manufactured artifact of the amalgamation of diverse definitions and unrelated patient populations into one clinical entity called “CFS”. Tragically for ME patients, this has obscured ME in a “web of confusion”, viii which has confounded ME research, virtually precluded drug development and resulted in widely divergent prevalence estimates. This confusion has also negatively impacted clinical care, led to inappropriate and sometimes harmful “one size fits all” clinical guidelines applied to all “CFS” patients and created a climate in which physicians routinely dismiss ME as not real or not serious.
There is an urgent need to stop perpetuating this confusion and start researching and treating the disease that these patients actually have – myalgic encephalomyelitis.
Given the current embrace of these non-specific “CFS” definitions and the failure to directly engage ME patients and ME experts in the current DHHS definition initiatives, we believe that the outcome of these DHHS initiatives will further exacerbate an already intolerable situation.
The following steps are necessary in order to move forward with improved research and treatment for patients with ME
The FDA Stakeholder Workshop has provided a unique opportunity to approach this disease in new ways, starting with the definition. It is time to adopt the Canadian Consensus Criteria as the baseline case definition for ME research and clinical care and move forward from there. Doing so will energize the wheels of research and drug development and begin to directly improve the lives of the many Americans stricken with this devastating disease.
We look forward to partnering with you to make this a reality for patients. We respectfully request a response to our concerns along with an explanation of how ME patients and ME experts will be engaged in this process by June 5, 2013. Do not hesitate to contact us if you need additional information.
Chronic Fatigue Syndrome, Fibromyalgia and Chemical Sensitivity Coalition of Chicago
The Fibromyalgia-ME/CFS Support Center, Inc .
CFS/Fibromyalgia Organization of Georgia, Inc.
Rocky Mountain CFS/ME and FM Association
MAME (Mothers Against Myalgic Encephalomyelitis)
Speak Up About ME
PANDORA (a.k.a. CFS Solutions of West Michigan )
Wisconsin ME/CFS Association, Inc.
Independent Patient Advocates
Bobbi Ausubel, Denise Lopez-Majano, Jean Harrison, Rich Carson, Mike Munoz, Meghan Shannon MS MFT,,Lori Chapo-Kroger, R.N.Matina Nicolson Eileen Holderman. Kati Debelic, R.N.,Donna Pearson, Marly Silverman, Mary Dimmock, Leela Play, Suzan Jackson, Pat Fero, MEPD, Justin Reilly, J.D,.Rivka Solomon, Joan Grobstein, M.D.Mary Schweitzer, Ph.D., Jill Justiss. Tamara Staples, Mindy Kitei, Charlotte von Salis, J.D., Michele Krisko Michael Walzer
Rationale for these recommendations
In October 2012, the CFS Advisory Committee (CFSAC) recommended that DHHS convene a workshop by December 31, 2012 or as soon as possible thereafter to “reach a consensus for a case definition useful for research, diagnosis and treatment of ME/CFS beginning with the 2003 Canadian Consensus Definition.” xi In recommending the 2003 Canadian Consensus Criteria as a starting point, it is clear that CFSAC was recognizing the disease, ME, as characterized above, and intended to advance a research and clinical definition for ME. The Canadian Consensus Criteria is already in use both clinically and in research, was developed by well known ME experts at the request of Health Canada xii , has been shown through numerous studies to better describe ME than either Fukuda or Oxford as discussed below and is well respected by both patients and clinicians. For all these reasons, it provides the best option to establish a disease appropriate baseline definition in the short term that can readily be further evolved in partnership with ME experts as additional data, knowledge and experience is gained, and as the definition is further operationalized and biomarkers are validated. xiii
Based on the available information, it is questionable whether CDC and NIH intend to develop a definition specific for ME or instead continue the focus on the more broadly defined CFS umbrella. Further, the NIH and CDC initiatives are both longer-term initiatives that do not address the significant issues that patients – and research - face today and every day as a result of the definitional problems – issues that could be addressed by adopting the Canadian Consensus Criteria now as discussed by CFSAC at the October, 2012 meeting.
The NIH has stated that they intend to establish a research case definition by performing an evidence-based review of the literature. But we do not know whether NIH intends to include all definitions and criteria encompassed by the “CFS” label or whether they will tease apart the different conditions currently lumped together in order to understand the nature of the separate diseases and conditions therein. Other CFS evidence based reviews, including the 2001 Mulrow review from AHRQ, xiv the review included in the 2007 NICE Guidelines xv and the 2008 Cochrane review xvi of CBT have analyzed diverse “CFS” definitions together as one patient group from which conclusions applicable to all could be drawn. However, as discussed below, these definitions and criteria do not represent the same patient population. It is essential that these diverse “CFS” definitions and criteria be separated out. Doing this will require the involvement of ME experts and patients from the beginning. To date, we do not know of any ME clinical and research experts or patients being engaged in the planning of this effort.
The CDC has stated it intends to use the outcome of the multi-site study to address the clinical case definition. The CDC website states that the multi-site study includes CFS, post-infective fatigue and ME patients and “aims to improve how we measure illness domains of CFS” xvii which the CDC says may allow patients to be sub-grouped. There are two primary concerns with this study. First, the first phase of the multi-site study does not include the measures and instruments, like the two-day cardiopulmonary exercise test, immune markers or a valid psychiatric screen, that are needed to demonstrate the hallmark symptom of PEM, to demonstrate known biological markers or to exclude psychiatric disorders. While the second phase of the study will include an exercise test, it is not clear that CDC will follow Snell’s recommendation to use an 2-day exercise test with gas exchange xviii or how the phase 1 participants will then be assessed. Secondly and more deeply concerning, is that the language on the CDC website suggests that CDC may be intending to develop a definition for the broader “CFS” and consider everything else, including ME, a subtype of CFS.
Three other CDC-related issues reinforce the concerns with the multi-site study. First is the CDC’s continued promotion, in the 2013 Medscape “A Case-Based Approach to Chronic Fatigue Syndrome” CME, of the “one size fits all” CDC CFS Toolkit in spite of CFSAC and patient recommendations xix to remove it. Second is CDC’s placement of CFS in the U.S. ICD-10-CM in the “Symptoms and Signs” chapter as a subcategory of chronic fatigue rather than in the Neurological chapter as designated in ICD-10 by the World Health Organization (WHO) and as recommended numerous times by the CFSAC since 2005. xx
But of greatest concern is the third issue - the statements on the CDC website (as in the CDC CME “Diagnosis and Management of CFS”) xxi that list five different definitions for CFS (Table 1) and state that all five definitions describe similar sets of patients for which a single set of diagnostic and treatment guidelines is appropriate. xxii Three of these definitions describe the essential and hallmark symptoms and dysfunction of ME: the 2003 Canadian Consensus Criteria, the 2011 ME International Consensus Criteria and the 2006 IACFS/ME Pediatric Case Definition. But the two most commonly used definitions — Fukuda developed by CDC and Oxford developed in the UK — do not require the core symptoms of ME and allow the inclusion of primary psychiatric illness except for schizophrenia and a few other definition-specific psychiatric disorders. For its part, Oxford doesn’t require any symptom at all except for six months of disabling fatigue.
As a result, CFS — the diagnosis that ME patients in the United States are given today xxiii — has come to be associated with deconditioning, xxiv depression or other psychiatric illness, xxv a variety of “medically unexplained” fatiguing conditions, a history of childhood abuse xxvi , “excessive rest” xxvii , maladaptive coping styles xxviii , a DSM 5 categorized mental illness called somatic symptom disorder xxix and, for some clinicians and researchers, “fear of movement” xxx or “false illness beliefs” that should be treated with cognitive behavioral therapy (CBT) as asserted in the PACE trial, an Oxford definition study. xxxi Any of these diverse patients may be given a diagnosis of CFS.
While not listed as one of the five definitions in the CDC “Diagnosis and Management of CFS” CME, there is also a sixth definition, the 2005 Reeves Empirical definition xxxii that is the basis of the upper prevalence estimate of 4 million Americans used by the CDC. xxxiii Dr. Leonard Jason of DePaul University showed that the Empirical definition resulted in a tenfold increase over earlier prevalence estimates xxxiv and led to 38% of major depressive disorder patients being misclassified as CFS. xxxv When asked by Dr. Jason about the continued publication of Empirical studies at the November 2011 CFSAC meeting, CDC’s Dr. Beth Unger said that CDC had done a study comparing approaches and found that “the patient populations are quite comparable.” xxxvi
As patients, we disagree with the assertion that these “CFS” definitions represent the same patients and that these patient populations are comparable. ME experts concur. In a study involving 143,000 patients in the UK, Dr. Luis Nacul xxxvii of the London School of Hygiene and Tropical Medicine found a prevalence of 0.19% for patients meeting Fukuda criteria but only a prevalence of 0.11% for those meeting the Canadian Consensus Criteria – almost one half of that of Fukuda. He further stated that symptoms related to issues like neurocognitive and immunological dysfunction were significantly greater in those meeting the Canadian Consensus Criteria. Dr. Bruce Carruthers, an ME expert, has reported “Some symptoms of the Fukuda criteria overlap with depression, whereas the Canadian Consensus Criteria differentiate patients with ME from those who are depressed and identify patients who are more physically debilitated and have greater physical and cognitive functional impairments.” xxxviii
Jason concurs that Fukuda symptoms - chronic fatigue plus unrefreshing sleep, joint pain, muscle pain and impairment in concentration – overlap with depression xxxix He also agrees that the Canadian Consensus Criteria select “a group of patients that have more severe functional impairments, and physical and cognitive symptoms” than Fukuda. xl xli Dr. Michael Maes of Maes Clinics in Thailand has used data mining to demonstrate that Fukuda has two qualitatively different types of patients within it – those with PEM and those without – and showed that the roughly 50% of Fukuda CFS patients with the hallmark PEM also had more severe illness, more severe feelings of infection, greater neurocognitive impairment, and significantly higher levels of immune-inflammatory variables. xlii He concluded that Fukuda CFS patients with PEM and Fukuda CFS patients without PEM “should be considered different case definitions.” xliii In a 2012 review of the definitional criteria for CFS, Yvonne Christley maintained “The differing approaches to the identification and definition of CFS are potentially compounding and strengthening associations between CFS and psychiatric disorders by taking too broad an approach to case identification.” xliv
This takes us to the heart of the problem: ME criteria mixed in with overly broad, non-specific definitions that allow primary psychiatric illness; heterogeneous patient populations identified and studied as one condition called CFS; and sloppy, inappropriate naming that interchangeably uses the terms “CFS”, “CFS/ME”, “ME/CFS”, “ME” and even just “chronic fatigue”. The resultant confusion has severely impacted ME research, drug development and clinical care and misled the medical community on the very nature of ME. Carruthers stated it simply “Patient sets that include people who do not have the disease [ME] lead to biased research findings, inappropriate treatments and waste scarce research funds.“ xlv
Dr. Jason agrees. “Such blurring of diagnostic categories will make it even more difficult to identify biological markers for this illness, and if they are not identified, many scientists will be persuaded that this illness is psychogenic.” xlvi FDA’s Dr. Sandra Kweder, in a teleconference with ME patients, acknowledged that the failure to “define the condition well” discourages drug development investment by pharmaceutical companies. xlvii
Beyond the impact on research and drug development is the impact on clinical guidance. Clinical guidance, including that from CDC, uses findings from studies based on any of these definitions and applies them indiscriminately to all patients labeled “CFS”. The prevalence estimates and findings of maladaptive coping skills, mentioned above, are two examples. Other examples include the CDC recommendations for cognitive behavioral therapy (CBT) and graded exercise therapy (GET), provided in spite of patient reports of harm from these therapies xlviii and even though the supporting studies, like PACE, used Oxford definition. PACE, whose claim of recovery is contested because of how it was measured, xlix did claim that CBT and GET were equally effective in patients that met other criteria for CFS and ME l . However, the CFS definition referenced was the Reeves definition for CFS, diluted to only require the presence of any four symptoms for only one week instead of six months. The criteria for ME patients was a modified version of the infrequently used London criteria, instead of the more commonly accepted Canadian Consensus Criteria. Such loose application of the definitional criteria in a study as widely publicized as PACE only helps to magnify the confusion on the nature of ME and its appropriate treatment.
Most tragically for ME patients, their doctors too often do not understand their disease or do not even believe that it is real. li Putting a sharp point on the depth of misunderstanding, Dr. Klimas stated "I've had patients who met post-traumatic stress disorder criteria... where their trauma was their interaction with their physician around this illness. They came to a doctor with Chronic Fatigue Syndrome; they left the doctor with PTSD." lii This misunderstanding has been fueled by conflicting study findings resulting from the disparate definitions and by the broad-based publicity covering trials like PACE. A third significant contributor is the educational outreach of CDC and Health Resources and Services Administration (HRSA) using clinical guidance materials like the CDC CFS Toolkit, which even promotes the use of the same guidance for “CFS-like” illness, defined as 6 months of fatigue but without all four symptoms required by Fukuda. liii Given these factors, it is not surprisingly that a CDC study of CFS knowledge among health care providers found that 85% of healthcare providers felt that CFS was either partly or completely a psychiatric illness. liv
Such grave misperceptions are seen widely in the medical literature. lv In the 2012 American Family Physician article, Dr. Joseph Yancey listed Oxford and Fukuda as the appropriate definitions and stated “patients with poor social adjustment, a strong belief in an organic cause for fatigue, or some sort of sickness benefit (i.e., financial incentive) tend to have worse responses to [cognitive behavioral] therapy.” lvi Further, a 2013 IOM report on Gulf War Illness lvii stated that CFS is also called myalgic encephalomyelitis and listed Fukuda and the NICE criteria lviii from Britain as the appropriate definitions. Like Fukuda, NICE does not require the core symptoms of ME. Finally, the same misperception on the nature of ME was evident at the Ampligen FDA Advisory Committee when committee member Dr. Sean Hennessey asked how the efficacy of Ampligen compares to the efficacy of cognitive behavioral therapy. lix Would the same question have been asked of a drug for multiple sclerosis or cancer?
We acknowledge that multiple research and clinical case definitions can exist for a given disease and can evolve over time as they have in other diseases. But this is very different. Here, the disease known as ME has virtually disappeared and in its place, CFS has been established as the clinical entity; an entity that is in reality a heterogeneous collection of medically unexplained and often unrelated fatiguing conditions. ME should never have been merged into this group to begin with and should certainly not be considered a subtype of this group.
There is undoubtedly value in having a framework for studying fatigue across diseases. Unfortunately, because Fukuda established a framework that first eliminated fatigue due to known causes like cancer, the opportunity to gain the types of insights seen in a recent study comparing markers in cancer with those in chronic fatigue syndrome lx is minimized. But even with the best framework, study of a common symptom like fatigue or pain across diseases can never substitute for the study of the disease itself, using a disease appropriate definition. As Carruthers stated in the ME International Consensus Criteria, “Research on other fatiguing illnesses, such as cancer and multiple sclerosis, is done on patients who have those diseases. There is a current, urgent need for ME research using patients who actually have ME.” lxi Similarly, there is a current, urgent need for treatments and clinical care guidelines appropriate for this disease and a critical need for patients to have access to doctors who believe that they are really sick.
That leaves the question of what to do about the clinical entity called “CFS” once ME patients are pulled out. This complicated issue needs to be carefully managed. First, it is likely that some of these “CFS” patients have been misdiagnosed. They need to receive an appropriate diagnosis. Second, if Maes is correct in saying that it is possible to use inflammatory markers to distinguish between chronic fatigue patients (essentially Oxford) on the one hand and ‘no-PEM’ Fukuda CFS patients on the other, then it is mandatory that these “no-PEM” Fukuda CFS patients also be pulled out, leaving only the symptom of chronic fatigue (equivalent to Oxford CFS), a symptom that can be seen in many illnesses. lxii This further calls into question the validity and utility of the “CFS” construct as a framework for studying medically unexplained fatiguing illnesses. Finally, the literature base associated with all these definitions has become hopelessly intertwined through the use of the same labels across these diverse definitions. Continuing to use the term “CFS” for all or a portion of these conditions will only confound forward progress for all. For these reasons, the entity “CFS” should be dismantled as part of the plan to resolve the definitional problems and develop more appropriate and precise definitions and names for the conditions currently all named “CFS."
i The Canadian Consensus Criteria (CCC) uses the term post-exertional malaise (PEM) and the ME International Consensus Criteria (ME-ICC) uses the term post-exertional neuroimmune exhaustion to refer to post-exertional fatigability.
ii There are numerous peer-reviewed articles that characterize this disease and the associated dysfunctions. Selected examples of these references include the following
iv ICD-9-CM Coordination and Maintenance Committee Meeting Summary of Volumes 1 and 2, Diagnosis Presentations September 14, 2011. Page 2. http://www.cdc.gov/nchs/data/icd9/2011SeptemberSummary.pdf . The moderator polled the audience and there was general agreement, by those in the audience, that the term “myalgic encephalomyelitis” is not seen in medical records.
v Joyner, M. Standing up for exercise: should deconditioning be medicalized? August 1, 2012 The Journal of Physiology, 590, 3413-3414. http://jp.physoc.org/content/590/15/3413.full
vi Pariante, C. In his December 2012 pre-publication review of “A narrative review on the similarities and dissimilarities between myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and sickness behavior” by Morris, G., Anderson, G., Galecki, P., Berk, M. and Maes, M. published in BMC Medicine 2013, 11:64. Pariante states “For many, including this reviewer, CFS/ME is predominantly a condition triggered by excessive rest in predisposed individuals following acute triggers, and its interpretation requite a psychosocial and psychiatric framework.”
vii White, P., et al, Comparison of adaptive pacing therapy, cognitive behaviour therapy, graded exercise therapy, and specialist medical care for chronic fatigue syndrome (PACE): a randomised trial. The Lancet - 5 March 2011 ( Vol. 377, Issue 9768, Pages 823-836 ) http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(11)60096-2/fulltext . The PACE trial, done in patients that met the Oxford definition, tested cognitive behavioral therapy (CBT) and graded exercise therapy (GET) which were used “on the basis of the fear avoidance theory of chronic fatigue syndrome” that “assume that the syndrome is perpetuated by reversible physiological changes of deconditioning and avoidance of activity.” The theory underlying CBT is often described as “false illness beliefs”. The CDC references this trial among others to support CBT as a treatment recommendation for CFS patients.
viii Carruthers BM, van de Sande MI, De Meirleir KL, Klimas NG, Broderick G, Mitchell T, Staines D, Powles ACP, Speight N, Vallings R, Bateman L, Bell DS, Carlo-Stella N, Chia J, Darragh A, Gerken A, Jo D, Lewis D, Light AR, Light K, Marshall- Gradisnik S, McLaren-Howard J, Mena I, Miwa K, Murovska M, Steven S. Myalgic Encephalomyelitis International Consensus Primer for Medical Practitioners. 2012. http://www.hetalternatief.org/ICC primer 2012.pdf “There is a poignant need to untangle the web of confusion caused by mixing diverse and often overly inclusive patient populations in one heterogeneous, multi-rubric pot called ‘chronic fatigue syndrome’. We believe this is the foremost cause of diluted and inconsistent research findings, which hinders progress, fosters skepticism, and wastes limited research monies”
ix The CDC CFS Toolkit http://www.cdc.gov/cfs/toolkit/index.html
x “ME/CFS: A Primer for Clinical Practitioners”. IACFS/ME. 2012. http://www.iacfsme.org/Portals/0/PDF/PrimerFinal3.pdf
The IACFS/ME is an international organization of clinicians and researchers involved in the study of ME/CFS and the clinical care of patients with ME/CFS. The primer was developed by them and published it in 2012. They are currently working on an updated version of the Primer.
xi October 2012 CFSAC recommendation on the case definition http://www.hhs.gov/advcomcfs/recommendations/10032012.html
xii Carruthers, B., et al Jain, A., De Meirleir, K., Peterson, D., Klimas, N., Lerner, M., Bested, A., Flor-Henry, P., Joshi, P., Powles, A. , Sherkey, J., van de Sande, M. Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome: Clinical Working Case Definition, Diagnostic and Treatment Protocols. Journal of Chronic Fatigue Syndrome, Vol. 11(1) 2003. http://mefmaction.com/images/stories/Medical/ME-CFS-Consensus-Document.pd f
xiii As reported by panelists at the recent FDA meeting, there are a number of known markers in use today like VO2Max and natural killer cell function that could be readily validated. Regarding patient reported symptoms, Jason has published extensively on the need to have instruments that are validated for the specific definition and that assess not just symptom presence but also symptom severity and frequency.
xiv “Defining and Managing Chronic Fatigue Syndrome. Evidence Reports/Technology Assessments”, No. 42. Mulrow CD, Ramirez G, Cornell JE, et al. Rockville (MD): Agency for Healthcare Research and Quality (US) ; 2001 Oct. . http://www.ncbi.nlm.nih.gov/books/NBK33797/
xv Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (or Encephalopathy). Diagnosis and Management of Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (or Encephalopathy) in Adults and Children. NICE Clinical Guidelines, No. 53. National Collaborating Centre for Primary Care (UK). London: Royal College of General Practitioners (UK) ; August 2007. http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0009708/ (Question 1) and http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0009708/table/appendixes.app1.tu2/
xvi Price JR, Mitchell E, Tidy E, Hunot V. Cognitive behaviour therapy for chronic fatigue syndrome in adults (Review). Cochrane Database Syst Rev. 2008 Jul 16, http://www.ncbi.nlm.nih.gov/pubmed/18646067 , http://www.cfids-cab.org/rc/Price.pdf . The review states that all participants had fatigue as their main or major complaint for at least 3,6 or 12 months. Beyond fatigue, inclusion criteria were heterogeneous. Some studies used Fukuda, some used Oxford, some used the Australian criteria and one study that used Fukuda dropped Fukuda’s requirement for four symptoms.
xvii CDC Multi-site Clinical Assessment of CFS http://www.cdc.gov/cfs/programs/clinical-assessment/index.html
xviii At the FDA ME and CFS stakeholder meeting, Dr. Chris Snell compared the various exercise tests and stated the problems with indirect measures and the importance of using a test that measures gas exchange. He also showed that single exercise tests could not distinguish between deconditioning and ME. http://www.tvworldwide.com/events/fda/130425/ - Panel 3 about minute 75 - 84
xix On June 14, 2012, the CFSAC recommended that “the Secretary asks the CDC to take the Toolkit down off the website.” On Sept 10, 2012, the patient community submitted a position paper supporting the CFSAC recommendation and outlining the issues with the Toolkit and the negative impact the Toolkit has had on patients. At the October 2012 CFSAC meeting, in response to Mr. Krafchick’s question on whether the Toolkit would be removed, Dr. Unger replied that it would not be removed. On April 19, 2013, Medscape released the “A Case-Based Approach to Chronic Fatigue Syndrome” CME which recommended the CDC CFS Toolkit as a useful resource. It is not. The Toolkit is a “one size fits all” clinical guideline, that also claims to be suitable for patients with “CFS-like’ illness, defined as fatigued for 6 months without the other symptoms of Fukuda. The information in the Toolkit is not useful and is potentially harmful for patients with ME. See these references for further information
Sept 2012 - http://www.cdc.gov/nchs/data/icd9/Topic_packet_for_September_19_2012.pdf
xxi CDC CME “Diagnosis and Management of Chronic Fatigue Syndrome” http://www.cdc.gov/cfs/education/diagnosis/index.html page 3-9.
xxii The CDC CFS Toolkit states that one set of clinical guidelines is suitable for CFS patients and CFS-like illness (6 months of fatigue but does not meet the rest of the symptom requirements for CFS). Other documents, like the 2012 CDC “Diagnosis and Management CFS” CME referenced above also give a single set of guidelines for all 5 definitions. http://www.cdc.gov/cfs/toolkit/index.html
xxiii ICD-9-CM Coordination and Maintenance Committee Meeting Summary of Volumes 1 and 2, Diagnosis Presentations September 14, 2011. Page 2. http://www.cdc.gov/nchs/data/icd9/2011SeptemberSummary.pdf
xxiv Joyner, M. Standing up for exercise: should deconditioning be medicalized? August 1, 2012 The Journal of Physiology, 590, 3413-3414. http://jp.physoc.org/content/590/15/3413.full
xxv Every ME patient tells of doctors who have insisted they are depressed, not physically sick - even today in 2013. A number of references in this paper speak to this issue, which is also highlighted in the following extract from Griffith, J., Zarrouf, F. A Systematic Review of Chronic Fatigue Syndrome: Don't Assume It's Depression. Prim Care Companion J Clin Psychiatry. 2008; 10(2): 120–128)
xxvii Pariante, C. In his December 2012 pre-publication review of “A narrative review on the similarities and dissimilarities between myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and sickness behavior” by Morris, G., Anderson, G., Galecki, P., Berk, M. and Maes, M. published in BMC Medicine 2013, 11:64. Pariante states “For many, including this reviewer, CFS/ME is predominantly a condition triggered by excessive rest in predisposed individuals following acute triggers, and its interpretation requite a psychosocial and psychiatric framework.”
xxviii Natera, U., Maloneya, E., Linb, J., Heimc, C., Reeves, W. “Coping Styles in Chronic Fatigue Syndrome: Findings from a Population-Based Study”. Psychother Psychosom 2012;81:127–129. http://www.alphagalileo.org/ViewItem.aspx?ItemId=121978&CultureCode=en
xxix Somatic Symptom Disorder (SSD) in the DSM-5, due to be released in May, 2013, can be diagnosed for any patient that meets the following criteria as determined by the health care provider
a) somatic symptoms that are distressing or significantly disrupt life
b) an excessive concern with the medical seriousness of his or her symptoms
c) experienced persistent symptoms, typically for at least 6 months
The inclusion of SSD in the DSM-5 has created significant concern for patients with ME because of this association of CFS with somatic disorder. Dr. Allen Frances has discussed this issue and the impact on patients whose diseases have been labeled as a somatic disorder. http://www.psychologytoday.com/blog/dsm5-in-distress/201212/mislabeling-medical-illness-mental-disorder Over the years, a number of authors have characterized chronic fatigue syndrome as a classic example of a somatic disorder. One example is the following 2013 presentation given by Dr. Charlotte Feinmann at the Royal College of Psychiatrists Second Public Health Seminar and which prefers the term Bodily Distress Disorder over Somatic Symptom Disorder. Slides - http://www.rcpsych.ac.uk/pdf/C Feinmann Slides.pdf Seminar http://publicmentalhealthbybhui.wordpress.com/2013/02/11/the-royal-college-of-psychiatrists-2nd-public-mental-health-seminar/
xxx Nijs J, Roussel N, Van Oosterwijck J, De Kooning M, Ickmans K, Struyf F, Meeus M, Lundberg M.
Fear of movement and avoidance behaviour toward physical activity in chronic-fatigue syndrome and fibromyalgia: state of the art and implications for clinical practice. Clin Rheumatol. 2013 May 3.
xxxi White, P., et al, Comparison of adaptive pacing therapy, cognitive behaviour therapy, graded exercise therapy, and specialist medical care for chronic fatigue syndrome (PACE): a randomised trial. The Lancet - 5 March 2011 ( Vol. 377, Issue 9768, Pages 823-836 ) http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(11)60096-2/fulltext . The PACE trial was done in patients that met the Oxford definition. PACE tested cognitive behavioral therapy (CBT) and graded exercise therapy (GET), which were, used “on the basis of the fear avoidance theory of chronic fatigue syndrome” that “assume that the syndrome is perpetuated by reversible physiological changes of deconditioning and avoidance of activity.” The theory underlying CBT is often described as “false illness beliefs”.
xxxii Reeves, W., Wagner, D., Nisenbaum, R., Jones, J., Gurbaxani, B., Solomon, L., Papanicolaou, D., Unger, E., Vernon, S., Heim, C. Chronic Fatigue Syndrome – A clinically empirical approach to its definition and study. BMC Medicine 2005, 3:19 http://www.biomedcentral.com/1741-7015/3/19
xxxiii CDC CME “Diagnosis and Management of Chronic Fatigue Syndrome” http://www.cdc.gov/cfs/education/diagnosis/index.html page 2.
xxxiv Carruthers, B., van de Sande, M., De Meirleir, K., Klimas, K., Broderick, G., Mitchell, T., Staines, D., Powles, A., Speight, N., Vallings, R., Bateman, L., Baumgarten-Austrheim, B., Bell, D., Carlo-Stella, N., Chia, J., Darragh, A., Jo, D., Lewis, D., Light. A., Marshall-Gradisbik, S., Mena, I., Mikovits, J., Miwa, K., Murovska, M., Pall, M., Stevens, S. Myalgic encephalomyelitis: International Consensus Criteria. Journal of Internal Medicine. Volume 270, Issue 4, pages 327–338, October 2011. http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2796.2011.02428.x/full
Carruthers states “The Centers for Disease Control prevalence estimates increased tenfold from 0.24% using the Fukuda criteria  to 2.54% using the Reeves empirical criteria”
xxxv Jason, L., Najar, N., Porter, N., Reh, C. Evaluating the Centers for Disease Control’s Empirical Chronic Fatigue Syndrome Case Definition. Journal of Disability Policy Studies Oct 2008, http://www.co-cure.org/Jason-7.pdf
xxxvi November 9, 2011 CFSAC meeting minutes exchange between Dr. Jason and Dr. Unger. Dr. Jason asked about the continued publication of Empirical study results (the 2005 Empirical definition has been discredited) and how the CDC intended to evolve the criteria? Dr. Unger’s response that they had done a study comparing “the standardized approach to applying the Fukuda definition [1994 definition] and the approach that we had used in the past in the Wichita studies. Everyone will find it very reassuring that the patient populations are quite comparable.” A study was to have been published in early 2012 but so far that study does not appear to be available. http://www.hhs.gov/advcomcfs/meetings/minutes/cfsac_min-11092011.pdf - page 24
xxxvii Nacul, L., Lacerda, E., Pheby, D., Campion, P., Molokhia, M., Fayyaz, S., Leite, J., Poland, F., Howe, A., Drachler, M. Prevalence of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) in three regions of England: a repeated cross-sectional study in primary care. BMC Medicine 2011, 9:91 doi:10.1186/1741-7015-9-91. http://www.biomedcentral.com/1741-7015/9/91
xxxviii Carruthers, B., van de Sande, M., De Meirleir, K., Klimas, K., Broderick, G., Mitchell, T., Staines, D., Powles, A., Speight, N., Vallings, R., Bateman, L., Baumgarten-Austrheim, B., Bell, D., Carlo-Stella, N., Chia, J., Darragh, A., Jo, D., Lewis, D., Light. A., Marshall-Gradisbik, S., Mena, I., Mikovits, J., Miwa, K., Murovska, M., Pall, M., Stevens, S. Myalgic encephalomyelitis: International Consensus Criteria. Journal of Internal Medicine. Volume 270, Issue 4, pages 327–338, October 2011. http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2796.2011.02428.x/full
xxxix Jason, L. “Defining CFS: Diagnostic Criteria and Case Definition”. CFIDS association webinar, April 2010. www. cfids.org/webinar/jason-slides041410.pdf slide 12
xl Contrasting Case Definitions for Chronic Fatigue Syndrome, Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Myalgic Encephalomyelitis Jason, L., Brown, A. Clyne, E. Bartgis, L, Evans, M., Brown, M. Eval Health Prof published online 7 December 2011http://ehp.sagepub.com/content/early/2011/10/18/0163278711424281
xli Brown, A.; Jason, L.; Evans, M.; Flores, S. Contrasting Case Definitions: The ME International Consensus Criteria vs. the Fukuda et Al. CFS Criteria. North American Journal of Psychology, Vol. 15, No. 1, March 2013. http://www.questia.com/library/1G1-322563471/contrasting-case-definitions-the-me-international .
xliii Maes, M. Anderson, G., Morris, G. Berk, M. Editorial: Diagnosis of Myalgic Encephalomyelitis: where are we now? informahealthcare.com by 126.96.36.199http://informahealthcare.com/doi/abs/10.1517/17530059.2013.776039
xliv Christley Y, Duffy T, Martin CR. A review of the definitional criteria for chronic fatigue syndrome. J Eval Clin Pract 2012 Feb;18(1):25e31. http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2753.2010.01512.x/full
xlv Carruthers, B., van de Sande, M., De Meirleir, K., Klimas, K., Broderick, G., Mitchell, T., Staines, D., Powles, A., Speight, N., Vallings, R., Bateman, L., Baumgarten-Austrheim, B., Bell, D., Carlo-Stella, N., Chia, J., Darragh, A., Jo, D., Lewis, D., Light. A., Marshall-Gradisbik, S., Mena, I., Mikovits, J., Miwa, K., Murovska, M., Pall, M., Stevens, S. Myalgic encephalomyelitis: International Consensus Criteria. Journal of Internal Medicine. Volume 270, Issue 4, pages 327–338, October 2011. http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2796.2011.02428.x/full
xlvi Jason, L., Najar, N., Porter, N., Reh, C. Evaluating the Centers for Disease Control’s Empirical Chronic Fatigue Syndrome Case Definition. Journal of Disability Policy Studies Oct 2008, http://www.co-cure.org/Jason-7.pdf
xlvii FDA teleconference with ME patients http://www.fda.gov/downloads/Drugs/NewsEvents/UCM320310.pdf . Page 16
xlviii Kindlon, T. Reporting of Harms Associated with Graded Exercise Therapy and Cognitive Behavioural Therapy in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome, Bulletin of the IACFS/ME, Fall 2011 http://www.iacfsme.org/BULLETINFALL2011/Fall2011KindlonHarmsPaperABSTRACT/tabid/501/Default.aspx
xlix A number of patients and researchers have contested the PACE claims of recovery. Further, at the FDA ME and CFS stakeholder meeting, Dr. Chris Snell discussed the use of the exercise tests in the PACE trial. http://www.tvworldwide.com/events/fda/130425/ - Panel 3 about minute 70-75
l White PD , Goldsmith K , Johnson AL , Chalder T , Sharpe M ; PACE Trial Management Group . Recovery from chronic fatigue syndrome after treatments given in the PACE trial. Psychol Med. 2013 Jan 31:1-9. [Epub ahead of print]
The recent publication from PACE states that they analyzed the data using ME criteria and the International (CDC) criteria. The International criteria was referenced as the Reeves 2003 publication “Identification of ambiguities in the 1994 chronic fatigue syndrome research case definition and recommendations for resolution” This is one of the publications that led to the Empirical definition. Further, they only required that patients had the symptoms for 1 week prior to assessment, not 6 months, to qualify for a diagnosis of CFS. Regarding the ME criteria, they used a 1994 report from Westcare for the ME diagnosis. It is not clear why they did not use Fukuda, why they only required 1 week and why they did not use the much more widely accepted Canadian Consensus Criteria or the newer ME International Consensus Criteria.
In addition to using modified versions of criteria that were either largely abandoned or seldom used to begin with, the PACE trial also used measures of recovery that are broadly disputed by the patient community. It remains to be seen how the research community will respond to the latest PACE paper but it is important to note that PACE style CBT and GET have been rejected by a number of researchers and clinicians as well as by the IACFS/ME Primer ( http://www.iacfsme.org/Portals/0/PDF/PrimerFinal3.pdf - p23 for CBT comments.)
li Every patient tells stories of doctors who told them they were depressed, dismissed their illness as made up, refused to treat them or recommended treatments that were inappropriate or harmful for ME/CFS patients. The sheer prevalence of these stories is evidence enough that there is a serious issue. The following references highlight these issues: Bernhard, T. The Stigma of Chronic Fatigue Syndrome. April 10, 2011 http://www.psychologytoday.com/blog/turning-straw-gold/201104/the-stigma-chronic-fatigue- syndromeBernhard, T. The Stigma of Chronic Fatigue Syndrome II: Readers Respond. May 6, 2011http://www.psychologytoday.com/blog/turning-straw-gold/201105/the-stigma-chronic-fatigue- syndrome-ii-readers-respond
Montoya, J. Stanford University talk on Chronic Fatigue Syndrome, March 11, 2011 - http://www.youtube.com/watch?v=Riybtt6SChU Minute 6.50 – 7:30 Dr. Montoya said “it is my dream that our medical community will produce a formal apology to patients for not having believed them all these years that they were facing a real illness.”
lii Nancy Klimas, M.D., Miami Herald, March 24, 2009. Reported onhttp://chronicfatigue.about.com/b/2009/10/15/doctor-caused-ptsd-in-fibromyalgia-chronic- fatigue-syndrome.htm
liii The CDC CFS Toolkit uses Fukuda as the basis of disease description and diagnosis and as stated above, also states that one set of clinical guidelines are suitable for CFS patients and CFS-like illness (6 months of fatigue but does not meet the rest of the symptom requirements for CFS.) http://www.cdc.gov/cfs/toolkit/index.html
liv Unger, E., Brimmer, D. Boneva, R. Jones, J. CFS Knowledge And Illness Management Behavior Among U.S. Healthcare Providers and the Public.. IACFS/ME Conference abstracts http://www.iacfsme.org/LinkClick.aspx?fileticket=%2bG6GTkbP33I%3d&tabid=499 [p. 130-131
lv There are many examples of this misperception in the literature over the years. Some of these are current publications such as the referenced publication by Yancey. Others are older as is this example from Nisenbaum. Unfortunately, it is impossible to tell whether the authors of these older studies still support these statements or not.
lvii Gulf War and Health. Volume 9: Treatment for Chronic Multisymptom Illness. Institute of Medicine. 2013 report. http://www.nap.edu/catalog.php?record_id=13539
lviii Chronic fatigue syndrome / Myalgic encephalomyelitis (or encephalopathy); diagnosis and management . National Institute for Health and Clinical Excellence. 2007. http://www.nice.org.uk/CG53
lix FDA Arthritis Advisory Committee Hearing on Ampligen. Dec 20, 2012 at 2 hours 19 minutes. http://www.fdatracker.com/2012/12/20/20121220-fda-arthritis-advisory-committee-meeting-webcast-audio-recording-heb-ampligen/ . Dr. Hennessey asked Hemispherix “to summarize the data on cognitive behavioral therapy which I understand to be effective against chronic fatigue.” CBT has been studied most extensively in studies that use the Oxford definition. One of these studies is the highly publicized PACE trial referenced above, which states “CBT was done on the basis of the fear avoidance theory of chronic fatigue syndrome. This theory regards chronic fatigue syndrome as being reversible and that cognitive responses (fear of engaging in activity) and behavioural responses (avoidance of activity) are linked and interact with physiological processes to perpetuate fatigue.” The PACE trial report states that the aim of CBT is “to change behavioural and cognitive factors assumed to be responsible for perpetuating symptoms and disability” and claims that CBT as a therapy leads to recovery. Yancey’s statement that patients that believe they have an organic illness have the poorer response to therapy was referring to CBT as the therapy.
lx Rovigatti, U. Chronic Fatigue Syndrome (CFS) and Cancer Related Fatigue (CRF): two “fatigue” syndromes with overlapping symptoms and possibly related aetiologies. Neuromuscular Disorders. Volume 22, Supplement 3 , Pages S235-S241, 1 December 2012. http://www.nmd-journal.com/article/S0960-8966(12)00627-X/abstract
lxi Carruthers, B., van de Sande, M., De Meirleir, K., Klimas, K., Broderick, G., Mitchell, T., Staines, D., Powles, A., Speight, N., Vallings, R., Bateman, L., Baumgarten-Austrheim, B., Bell, D., Carlo-Stella, N., Chia, J., Darragh, A., Jo, D., Lewis, D., Light. A., Marshall-Gradisbik, S., Mena, I., Mikovits, J., Miwa, K., Murovska, M., Pall, M., Stevens, S. Myalgic encephalomyelitis: International Consensus Criteria. Journal of Internal Medicine. Volume 270, Issue 4, pages 327–338, October 2011. http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2796.2011.02428.x/ful l
lxii Maes, M., et al., Myalgic Encephalomyelitis (ME), Chronic Fatigue Syndrome (CFS), and Chronic Fatigue (CF) are distinguished accurately: Results of supervised.... Psychiatry Research (2012), http://dx.doi.org/10.1016/j.psychres.2012.03.031 http://www.ncbi.nlm.nih.gov/pubmed/22521895
lxiii Similar tables have been published in the following sources and were used to validate the information in this table
lxiv Holmes, G., Kaplan, J., Gantz, N., Komaroff, A., Schonberger, L., Straus, S. Jones, J., Dubois, R. Cunningham-Rundles, C., Pahwa, S. Tosato, G., Zegans, L., Purtilo, D., Brown, N., Schooley, R. Brus, I.Chronic Fatigue Syndrome: A Working Case Definition. Holmes GP et.al. Annals of Internal Medicine. http://annals.org/article.aspx?articleid=701163 , http://www.ncf-net.org/patents/pdf/Holmes_Definition.pdf
lxv Sharpe M, Archard L, Banatvala J., Borysiewicz, L., Clare, A., David, A., Edwards, R., Hawton, K., Lambert, H., Lane, R., McDonald, E., Mowbray, J., Pearson, D., Peto, T., Preedy, V., Smith, A., Smith, D., Taylor, D., Tyrrell, A., Wessely, S., White, P. A report—chronic fatigue syndrome. J Roy Soc Med 1991; 84: 118-121. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1293107/ . The criteria for the Oxford CFS are
lxvi Fukuda K, et al Straus SE, Hickie I, Sharpe MC, Dobbins JG, Komaroff A. The chronic fatigue syndrome: a comprehensive approach to its definition and study. International Chronic Fatigue Syndrome Study Group. Ann Intern Med 1994;121:953-9. http://www.ncf-net.org/patents/pdf/Fukuda_Definition.pdf
lxvii Jason, L, Torres-Harding, S, Jurgens, A, Helgerson, J. Comparing the Fukuda et al. Criteria and the Canadian Case Definition for Chronic Fatigue Syndrome, Journal of Chronic Fatigue Syndrome, Vol 12, 2004 http://www.cfids-cab.org/cfs-inform/CFS.case.def/jason.etal04.pdf
lxviii Carruthers, B., et al Jain, A., De Meirleir, K., Peterson, D., Klimas, N., Lerner, M., Bested, A., Flor-Henry, P., Joshi, P., Powles, A. , Sherkey, J., van de Sande, M. Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome: Clinical Working Case Definition, Diagnostic and Treatment Protocols. Journal of Chronic Fatigue Syndrome, Vol. 11(1) 2003. http://mefmaction.com/images/stories/Medical/ME-CFS-Consensus-Document.pdf
lxix Reeves, W., Wagner, D., Nisenbaum, R., Jones, J., Gurbaxani, B., Solomon, L., Papanicolaou, D., Unger, E., Vernon, S., Heim, C. Chronic Fatigue Syndrome – A clinically empirical approach to its definition and study. BMC Medicine 2005, 3:19 http://www.biomedcentral.com/1741-7015/3
lxx Jason, L., Najar, N., Porter, N., Reh, C. Evaluating the Centers for Disease Control’s Empirical Chronic Fatigue Syndrome Case Definition. Journal of Disability Policy Studies Oct 2008 http://www.co-cure.org/Jason-7.pdf
lxxi Jason L, Jordan K, Miike T, Bell DS, Lapp C, Torres-Harding S., Rowe, K., Gurwitt, A., DeMeirleir, K., Van Hoof, E. A Pediatric Case Definition for Myalgic Encephalomyelitis and Chronic Fatigue Syndrome. J Chronic Fatigue Syndr. 2006 13: 1-44 http://www.cfids-cab.org/MESA/Jason-1a.pdf
lxxii Chronic fatigue syndrome / Myalgic encephalomyelitis (or encephalopathy); diagnosis and management . National Institute for Health and Clinical Excellence. 2007. http://www.nice.org.uk/CG53
lxxiii Carruthers, B., van de Sande, M., De Meirleir, K., Klimas, N., Broderick, G. Mitchell, T., Staines, D., Powles, P., Speight, N., Vallings, R., Bateman, L., Baumgarten-Austrheim, B., Bell, D., Carlo-Stella, N., Chia, J., Darragh, A., Jo, D., Lewis, D., Light, A., Marshall-Gradisbik, S., Mena, I., Mikovits, J., Miwa, K., Murovska, M., Pall, M., Stevens, S. Myalgic encephalomyelitis: International Consensus Criteria. Journal of Internal Medicine. Volume 270, Issue 4, pages 327–338, October 2011. http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2796.2011.02428.x/full