• DOI:10.7326/M15-0338
• Corpus ID: 24156332

National Institutes of Health Pathways to Prevention Workshop: Advancing the Research on Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

@article{Green2015NationalIO,
  title={National Institutes of Health Pathways to Prevention Workshop: Advancing the Research on Myalgic Encephalomyelitis/Chronic Fatigue Syndrome},
  author={Carmen R. Green and Penney Cowan and Ronit Elk and Kathleen O’neil and Angela L. Rasmussen},
  journal={Annals of Internal Medicine},
  year={2015},
  volume={162},
  pages={860-865}
}

• C. Green, P. Cowan, +2 authors A. Rasmussen
• Published 16 June 2015
• Medicine
• Annals of Internal Medicine

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic, complex, multifaceted condition characterized by extreme fatigue and other symptoms, including pain, impaired memory, sleep disturbance, and insomnia that are not improved by rest. Persons with ME/CFS may have substantial disability, and some may even become homebound and bedbound. The cause and pathogenesis remain unknown, and there are no laboratory diagnostic tests or known cures for ME/CFS. One million persons (mostly women) are affected. Myalgic encephalomyelitis/chronic fatigue syndrome is an unmet public health issue with an estimated economic burden between $2 billion and $7 billion in the United States. It results in major disability for many persons. Limited knowledge and research funding create an additional burden for patients and health care providers. The research and health care community has frustrated its constituents by not appropriately assessing and treating the disease and by allowing patients to be stigmatized. On 9 and 10 December 2014, the National Institutes of Health (NIH) convened the Pathways to Prevention Workshop: Advancing the Research on Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Its purposes were to identify research gaps, determine methodological and scientific weaknesses, and provide future research recommendations. An independent panel considered a systematic review of the scientific evidence report done by the Pacific Northwest Evidence-based Practice Center and opinions presented by a group of experts and the ME/CFS community during the public meeting. They weighed the evidence and developed conclusions. The Appendix lists the panel members, speakers, and working group members. This article presents their findings and recommendations. The report is also available at https://prevention.nih.gov/programs-events/pathways-to-prevention/workshops/me-cfs/workshop-resources. Incidence, Prevalence, and Manifestations Myalgic encephalomyelitis/chronic fatigue syndrome clearly exists, but a universally accepted definition is absent. A workshop speaker stated that the Centers for Disease Control and Prevention estimates that 1 million adults in the United States have ME/CFS. The lack of a universally accepted case definition makes determining incidence and prevalence difficult and leads to variability in such estimates. The lack of a specific and sensitive diagnostic test and clearly defined diagnostic criteria has hampered research on pathogenesis, treatment, and conceptualization of ME/CFS as a distinct entity. The syndrome has a tremendous effect at the individual, family, and societal level. Clinicians have a poor understanding of the condition, and patients are typically underserved. Studies are fraught with methodological problems, preventing a clear understanding of who is affected. There are no agreed-on variables for defining ME/CFS and no accurate ways to identify and diagnose it; as 1 speaker pointed out, the syndrome has 163 possible combinations of symptoms. Small sample sizes; inclusion of participants with differing symptoms across studies; and the dearth of men, minorities, homebound persons, and rural residents in current studies limit their applicability. Some instruments used to evaluate ME/CFS are not validated, are inappropriate, and may be misleading. All of these issues contribute to inconclusive research results and a lack of definitive knowledge about incidence, prevalence, and potential causes and treatments. Fatigue has been the defining symptom and focus of recent research. According to a workshop speaker, patients with ME/CFS have neurocognitive dysfunction with abnormalities on functional magnetic resonance imaging and positron emission tomography. Strong evidence indicates that immunologic and inflammatory pathologic conditions, neurotransmitter signaling disruption, microbiome perturbation, and metabolic or mitochondrial abnormalities are potentially important for the definition and treatment of ME/CFS. Whether the available evidence in adults applies to children with similar symptoms remains unclear. Thus, other symptoms, primarily neurocognitive deficit ("brain fog"), postexertion malaise, and pain, must be explored across the life span. Other problems surrounding ME/CFS research include few disease-specific clinical trials; a disconnect on how patients, clinicians, and researchers define meaningful outcomes; a lack of well-controlled, multifaceted studies using large, diverse samples; and limited public and private research dollars. Both society and the medical profession have contributed to the disrespect and rejection experienced by patients with ME/CFS. They are often treated with skepticism, uncertainty, and apprehension and labeled as deconditioned or having a primary psychological disorder. Patients often make extraordinary efforts at extreme personal and physical costs to find a physician who will correctly diagnose and treat their symptoms; some are treated inappropriately, causing additional harm. Overall, the debilitating effects can cause financial instability due to the consequences of the illness (such as the loss of employment or a home). Ways to Foster Research and Enhance Development of Treatments The public, provider, and research communities are frustrated with the minimal progress to improve the state of science for ME/CFS over the past 20 years. Patients want their concerns to be heard, a meaningful recovery (not just incremental improvement), and a cure. Educational efforts are needed to assist patients and clinicians in better understanding ME/CFS. The scientific community also has a responsibility to address issues that are meaningful to patients. Limited patient and professional education has impaired progress in managing ME/CFS, and treatments remain unproven. Clinical studies have focused on predominately white, middle-aged women. Representative, ethnically diverse samples across the life span are lacking. Investigations of natural history and familial linkages may identify genetic predispositions and lead to early identification and preventive strategies. Although psychological repercussions (such as depression) may accompany ME/CFS, it is not a primary psychological disease. Several symptoms associated with ME/CFS substantially overlap with other pathologic diseases (such as fibromyalgia, major depressive disorder, and several chronic pain or inflammatory conditions). Although focusing on fatigue alone may identify many cases, it does not capture the essence of this complex condition. Previous studies may have inadequately excluded persons with these distinct diseases, leading to delayed or conflicting diagnoses, contradictory treatments, suboptimal care, and inappropriate health care use. Future studies that aim to better define cellular and molecular mechanisms for targeted treatments should distinguish among ME/CFS alone, ME/CFS with comorbid conditions, and other diseases. Carefully designed and adequately powered studies defining the spectrum of ME/CFS in urban and rural communities are lacking, and the available evidence base has limited applicability to an increasingly diverse society. It is critical that research studies include patients with limited access to clinical services (such as nonambulatory patients). Although research has shown that patients often have a consistent constellation of symptoms, including fatigue, postexertional malaise, neurocognitive deficit, and pain, a clear case definition, as well as validated diagnostic tools for it, is urgently needed. Agreeing on a definition and clarifying comorbid conditions could launch bench-to-bedside science. Patients with ME/CFS remain hopeful that research will lead to a cure. However, cross-sectional studies and small clinical trials with limited applicability have provided few insights into treatment. Adequately powered clinical trials require large investments of time and energy, and interventions tested in trials may be associated with harms, such as precipitating increased symptoms or medication toxicity. Existing treatment studies examining counseling and behavior therapies or graded exercise therapy demonstrate measureable improvements but may not yield improvements in quality of life (QoL). Therefore, these interventions are not a primary treatment strategy and should be used only as a component of multimodal therapy. Small clinical trials of ME/CFS, most with methodological limitations and all constrained by the lack of a gold standard for diagnosis, have led to confusion. Most studies have significant methodological limitations and take place primarily in specialty clinics in relatively homogeneous populations. These trials often use subjective, unclear, and poorly defined end points (which may not be meaningful to patients) and do not provide information explaining the high withdrawal rates. Therefore, variability in inclusion and exclusion criteria, such as the case definition, comorbid conditions, patient population, and disease severity, has significantly hampered progress in the clinical and research domains focused on assessing and treating ME/CFS. Little attention is given to how self-management may empower and improve health and QoL for patients with ME/CFS. Physicians are inadequately trained to instruct patients in self-management skills (such as pacing, realistic goals, physical self-awareness, basic rights, understanding emotions, exercise, and relaxation), and limited data demonstrate the efficacy of self-management on health outcomes. The focus on exercise programs has discouraged patient participation in any type of physical activity (such as mild stretching) due to concerns of precipitating increased symptoms. There is little understanding of the inciting event or the cellular and molecular mechanisms that underlie ME/CFS, preventing quantitative assessments of disease severity or prognosis. Failure to give adequate attention to the severity of the p