NORD gratefully acknowledges Leonard Jason, PhD, and his DePaul research team, for assistance in the preparation of this report.
Myalgic encephalomyelitis (ME) is an acquired complex disorder characterized by a variety of symptoms and physical findings potentially affecting multiple systems of the body. Many cases are preceded by a viral infection, usually a flu-like or upper respiratory illness, although ME can also be preceded by a non-viral illness or other trauma such as chemical exposure. Onset is usually rapid (acute) but gradual onsets are also reported. Affected individuals do not recover from the infection and instead experience a wide variety of symptoms including an inability to produce sufficient energy to meet daily demands. Marked fatigue and weakness, sickness, cognitive dysfunction and symptom flare-up follows physical and cognitive exertion. Additional symptoms that may occur include headaches, pain, muscle weakness, neck pain, vision abnormalities (such as blurred vision), a sensation of tingling, burning or numbness of the extremities (paresthesia), bladder and bowel dysfunction, and sleep dysfunction. Cardiovascular abnormalities have also been reported. Myalgic encephalomyelitis is a chronic and disabling disorder. Severe cases often leave affected individuals bedridden or housebound. Myalgic encephalomyelitis may occur as an outbreak that affects a large group of people (epidemically) or may only affect an individual (non-epidemically).
IntroductionThere is significant controversy and debate in the medical literature about the relationship between myalgic encephalomyelitis and chronic fatigue syndrome (CFS). The first outbreak of myalgic encephalomyelitis was in 1934 and the term myalgic encephalomyelitis first appeared in the medical literature in 1956. Myalgic encephalomyelitis is recognized as a distinct disorder and has been classified as a specific neurological disorder by the World Health Organization (WHO) since 1969.
The term CFS was first used in the medical literature during the 1980s in the United States. The criteria focused more on fatigue than the encephalitic (inflammation of the brain) features of the disorder. This was unfortunate, since there is more than sufficient robust evidence which illustrates the underlying biological process involving the central nervous system, immune system, energy metabolism and stress system. Consequently, the emphasis on fatigue unfortunately led to defining the disorder being seen as a psychiatric illness. Because little was known about the cause or physiology of CFS, a wide range of patients were diagnosed with CFS even though they may have had a variety of conditions and experienced different symptoms. CFS eventually evolved into a larger disease designation that overlapped with myalgic encephalomyelitis. Consequently, some researchers, patients, government organizations, and other organizations began to use the terms interchangeably or with the combined acronym ME/CFS, creating a broad disease category.
Further, some researchers, physicians, and patient advocacy groups have pushed to abandon the illness label of CFS as they argue it is inaccurate and trivializes affected individuals. They want to reclassify these individuals as having myalgic encephalomyelitis. Other researchers, physicians, and many ME patient advocacy groups have argued against this change, noting that myalgic encephalomyelitis should retain a strict definition as a distinct neurological disease that includes measurable abnormal changes in the brain and central nervous system. Individuals who meet the stricter criteria would be diagnosed with myalgic encephalomyelitis. The term CFS should be reserved for individuals who fail to meet the more stringent criteria for myalgic encephalomyelitis and in whom no other underlying disorder or condition can be identified. Many patients who have been diagnosed with CFS would meet the more stringent criteria for myalgic encephalomyelitis. Individuals who fail to meet the criteria should be retested for an underlying condition as many individuals initially diagnosed with CFS are eventually diagnosed with an underlying condition such as cancer, multiple sclerosis, lupus, brucellosis, or another condition.
Three of the more common case definitions include the Fukuda et al. (1994) case criteria for CFS, the Canadian Consensus Criteria for ME/CFS (Carruthers et al., 2003) and the Myalgic Encephalomyelitis International Consensus Criteria (ME-ICC). The Fukuda case definition was adopted by the Centers for Disease Control and Prevention (CDC), and stresses fatigue as a primary symptom. It also requires the presence of at least four of eight symptoms including: memory and concentration impairment, sore throat, tender lymph nodes, muscle pain, joint pain, headaches, unrefreshing sleep, and post-exertional malaise). Research has indicated that individuals with a primary psychiatric illness (e.g. primary Major Depressive Disorder) may be misdiagnosed under the Fukuda criteria due to many overlapping symptoms including fatigue and sleep difficulties. The Canadian Consensus Criteria defines ME/CFS as an acquired, organic, pathophysiological multi-systemic illness that occurs in both sporadic and epidemic forms and requires core symptoms including post-exertional malaise (PEM) and neurocognitive dysfunction, in contrast to the polythetic approach of the Fukuda case definition. Lastly, the Myalgic Encephalomyelitis – International Consensus Criteria (ME-ICC) advocates for removing fatigue as a characteristic symptom and defines the disorder as an acquired neurological disease with complex global dysfunctions. The ME-ICC also defines specific symptom requirements: post-exertional neuroimmune exhaustion, neurological impairments, immune, gastrointestinal, and genitourinary impairments, and energy metabolism impairments. The Nightingale Research Foundation, a Canadian charity dedicated to myalgic encephalomyelitis, uses a strict definition that states myalgic encephalomyelitis is an acute onset biphasic epidemic or endemic infectious disease process, where there is always a measureable and persistent diffuse vascular injury of the central nervous system in both the acute and chronic phases. For more information on specific case definitions, see the Resources and References sections of this report.
Unfortunately there is no consensus on nomenclature or classification for these disorders, and different countries, organizations, and researchers continue to use different names to describe these conditions. Until a global consensus is reached on how to name and classify these disorders, confusion will persist.
A wide variety of symptoms can be associated with myalgic encephalomyelitis (ME). Again, because of the lack of a clear, agreed upon definition of the disorder, different medical sources list different symptoms as being associated with ME. Most sources describe ME as a distinct neurological disorder that can affect multiple systems of the body. Symptoms and their severity can fluctuate over the course of the illness, even from hour to hour.
The symptoms discussed below have been associated with different case definitions of ME. It is important to note that ME is highly variable and can affect individuals differently in regard to severity, progression, and specific symptom development. Most individuals will not have all of the symptoms discussed below.
Some cases of ME may develop in two phases (biphasic). The first phase is an acute primary infection phase. Affected individuals may have an infectious disease with an incubation period of approximately four to seven days. Other cases may follow a more gradual onset. Closely following this initial phase is a second phase known as the chronic phase. This second phase usually occurs two to seven days after the initial infection and is characterized by measurable widespread (diffuse) changes in the central nervous system, which are thought to be the result of an infection invading the nervous system (encephalitis), or the immune system attacking the brain (autoimmune encephalitis). A number of recent studies demonstrate that this process is a result of brain inflammation which damages or destroys the nerve cells and/or the support tissue in the brain. Brain inflammation is encephalitis, so ME does appear to be a form of encephalitis.
A characteristic or hallmark symptom of ME is marked fatigue, sickness, and symptom flare-up that follows physical and cognitive exertion (known as post-exertional neuroimmune exhaustion or post-exertional malaise). Normal activities of daily living can cause severe physical or cognitive fatigue which can last for days, weeks, or even months. A 24 hour delay in the onset of post-exertion is fairly common. Affected individuals develop a lack of stamina that causes a considerable reduction in activity level. Even mild exertion through normal, daily activities is typically associated with worsening of other symptoms.
It is important to not underestimate the neurocognitive problems in this disease, in both practical and emotional terms. The symptoms that persist create an overall feeling of “brain fog”. Significant changes in personality can be present, and will vary according to the underlying cause, the severity of the inflammation, and delays in treatment. Affected individuals may also have a variety of neurocognitive impairments such as difficulty processing information (e.g. poor concentration, slowed thought), difficulty with planning and making decisions, and substantial memory deficits. For many people, these deficits affect nearly all spheres of their daily activity, severely impacting overall daily functioning levels and posing a significant burden to families and caretakers. A variety of pain symptoms can be associated with ME, including chronic headaches and significant muscle pain (myalgia). Sleep disturbances including abnormal sleep patterns and “unrefreshing” sleep, where a person does not feel refreshed upon waking may also occur. Additional neurological symptoms may include an inability to focus vision, impaired depth perception, loss of proprioception, visual-spatial disorientation, sensitivity to sunlight, muscle weakness, unsteadiness, and poor coordination.
Additional symptoms that can occur in individuals with ME include abnormalities of the immune, gastrointestinal, and genitourinary systems. General, nonspecific symptoms normally associated with the flu or a similar illness may occur. Such symptoms include sore throat, inflammation of the sinuses (sinusitis), and abnormal enlargement of lymph nodes. Affected individuals may be particularly susceptible to viral infections. Gastrointestinal symptoms may include abdominal pain, bloating, nausea, and irritable bowel syndrome. Genitourinary symptoms include increased frequency or urgency to urinate and increased urination at night (nocturia).
Individuals with ME are at risk for cardiovascular symptoms. Affected individuals may experience palpitations with or without irregular heartbeats (arrhythmias), low blood pressure (neurally mediated hypotension), and postural orthostatic tachycardia syndrome (POTS). POTS is a condition characterized by an abnormal increase in the heart rate upon standing. Affected individuals may faint or become dizzy upon standing. Labored breathing, headaches, shakiness, nausea, and fatigue of chest wall muscles may also occur. Affected individuals may also experience abnormalities in the regulation of body temperature, including sweating episodes, cold extremities, and feeling feverish with or without a low grade fever. Some individuals may be intolerant of extreme temperatures.
Additional symptoms that have been reported in ME include seizures, paralysis, and abnormal sensitivity to certain foods, medications, odors, or chemicals.
Affected individuals are more likely to have other illnesses or conditions that occur along with ME (concurrent or comorbid illness). Such illnesses include fibromyalgia, (new) migraine syndrome, Raynaud’s phenomenon, temporomandibular joint syndrome, interstitial cystitis, and myofascial pain syndrome.
In children, ME may be characterized by brief episodes of excessive restlessness and movement (hyperactivity) followed by extreme weakness. Children may rest frequently, which can be misinterpreted as laziness. Mood swings and irritability are common. Children may not recognize symptoms of ME and may not complain. Additional symptoms that occur in children include pain, headaches, memory abnormalities, difficulty processing information, and a decline in school performance. The onset of ME in children is usually around age 12, but has been reported in children as young as 2 years of age. A specific pediatric case definition has been proposed by Jason and colleagues (2006).
The exact cause of myalgic encephalomyelitis (ME) is not fully understood, although there are several theories. Most investigators agree that the disorder is most likely the result of an abnormal immune system and brain function in response to an infection or virus. Although the brain and immune system are most likely impaired or abnormal (dysregulated) in this disorder, the exact underlying problems are unknown. A variety of additional factors that have been theorized as playing a role in the development of ME include genetic and environmental factors. Some studies have shown that ME occurs in greater frequency among relatives to the third degree (genetic predisposition). In contrast, some believe that environmental factors play a greater role than genetic ones. However, definitive evidence linking specific environmental factors to the development of myalgic encephalomyelitis is lacking.
Some researchers believe that an enterovirus infection could be an underlying cause of the disorder. Enteroviruses are small, contagious viruses consisting of ribonucleic acid and proteins. They are the second most common viral agents in humans, behind only rhinoviruses (the viruses that cause the common cold). Enteroviruses can affect anyone of any age. Individual susceptibility to enteroviruses varies. The reason why some individuals develop ME after infection with an enterovirus is unknown.
Other viruses that have been speculated to be associated with ME include cytomegalovirus (CMV/HHV-5), Epstein Barr virus (EBV/HH-4), parvovirus B19, herpes simplex virus (HHV-1 or HHV-2), human herpes virus (HHV 6 or 7), and certain bacterial infections. It is not known whether these viruses caused ME or whether they developed due to an impaired immune system in affected individuals. It was once thought that the ability of the blood-brain barrier — the specialized capillaries that prevent blood contaminants from entering the brain–to block viral entry into the CNS was adequate; however, more recent evidence indicates entry through other routes, such as along the auditory nerve. Additionally, no one virus has been identified that explains all cases of ME. Some studies suggest that in individuals with ME the viruses can trigger cascading events in the central nervous system through chronic activation of the immune system which, in turn, can result in widespread (diffuse) neurological dysfunction, changes at the cellular level, and nerve cell injury and death. Even when not actively replicating, an infection can lead to profound dysregulation of the immune response, causing neuroinflammation which destabilizes overall brain function, and producing symptoms with widely fluctuating severity levels Viruses also do not continually replicate, but do so at times of immune vulnerability, such as at times of physical or psychological stress. Unfortunately, viruses go latent, then they reactivate, and repeat this patterns, and once in your cells, any elevation of cortisol levels can cause the reactivation.
Because of the controversy regarding the definition and classification of myalgic encephalomyelitis (ME) and related disorders, determining their true frequency in the general population is difficult. The exact prevalence and incidence of ME is unknown, but one estimate places the prevalence at approximately 1 million affected individuals in the US general population. Approximately, three times as many women appear to be affected than men. Individuals of any race or ethnicity can be affected. Onset is most frequent between the ages of 30-50.
A diagnosis of myalgic encephalomyelitis (ME) is controversial and difficult. Because there are different case definitions for the disorder, a specific set of symptoms for diagnosing ME does not exist. There is ongoing debate within the medical community as to what are the most appropriate set of diagnostic criteria. There are also no consistent and universally accepted biomarkers for ME. Biomarkers are characteristics or substances that can be measured and evaluated in order to obtain a diagnosis or help obtain a diagnosis of a disorder. A diagnosis of ME is ultimately based upon identification of characteristic symptoms (depending on the specific case definition used), a detailed patient history, a thorough clinical evaluation, and a variety of specialized tests to exclude other possible diagnoses. Process of elimination, referred to as diagnosis by exclusion, is used by physicians whenever scientific knowledge is scarce, objective methods are absent, and attempt is made to rule out all other known conditions that could potentially explain patient symptoms.
Affected individuals may also undergo tests to identify or evaluate associated symptoms, including sleep evaluation studies and tests that evaluate cardiac, gastrointestinal, muscle, endocrine, or vascular function.
Treatment
There is no cure for ME. Treatment is aimed at relieving symptoms and preventing a worsening of symptoms. Decisions concerning the use of particular therapeutic interventions should be made by physicians and other members of the healthcare team in careful consultation with the patient and/or parents based upon the specifics of his or her case, a thorough discussion of the potential benefits and risks including possible side effects and long-term effects, patient preference, and other appropriate factors. A specific treatment plan will be highly individualized.
Avoiding overexertion is extremely important in maintaining health in affected individuals. Depending on the individual, a variety of therapeutic options exist for alleviating ME symptoms which may include making changes to one’s diet, physical therapy, adjusting the pacing of activity levels, lowering overall exertion by getting a service dog, adjusting sleep parameters (regularizing sleep habits, changing pillows/blankets/mattress, room darkening, temperature, etc.), avoidance of substances (e.g. mold, chemicals) or situations prone to worsen one’s symptoms, and adjusting one’s lifestyle in ways that minimize the impact of physiological and psychological stress in general.
Some researchers have studied a treatment approach called the energy envelope theory as a potential therapy for some individuals with ME. This treatment option does not involve medications (non-pharmacologic) and strives to help affected individuals self-monitor and self-regulate their energy expenditures. By learning to pace their activity levels, affected individuals can stay within their “energy envelope.” Affected individuals are taught to balance expended energy with available energy to reduce the frequency and severity of some symptoms. The energy envelope theory can help affected individuals manage symptoms and, in some cases, can significantly improve quality of life.
Certain medications have been used to treat individuals with ME. However, many affected individuals are highly sensitive to medication. Additionally, because the underlying nature of ME is not fully understood, any specific medications or treatments should be considered cautiously. Initially, any medications should be given at low doses. No medications for ME are universally effective.
Affected individuals should be treated for any pathogens, toxins, or heavy metals as persistent exposure can worsen symptoms. Referral to an infectious disease specialist is recommended. Any antibiotics or antiviral drugs should be used cautiously.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Toll-free: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov
For information about clinical trials sponsored by private sources, in the main, contact:
www.centerwatch.com
For more information about clinical trials conducted in Europe, contact: https://www.clinicaltrialsregister.eu/
JOURNAL ARTICLES
Zinn, M. L., Zinn, M. A., & Jason, L. A. Functional neural network connectivity in myalgic encephalomyelitis. NeuroRegulation. 2016;3(1), 28-50. doi:10.15540/nr.3.1.28
Zinn, M. L., Zinn, M. A., & Jason, L. A. Intrinsic Functional Hypoconnectivity in Core Neurocognitive Networks Suggests Central Nervous System Pathology in Patients with Myalgic Encephalomyelitis: A Pilot Study. Appl Psychophysiol Biofeedback. 2016. doi:10.1007/s10484-016-9331-3
Zinn, M. L., Zinn, M. A., & Jason, L. A. qEEG/LORETA in assessment of neurocognitive impairment in a patient with chronic fatigue syndrome: A case report. Clinical Research. 2016;2(1). doi:http://dx.doi.org/10.16966/2469-6714.110
Jason, L. A., Zinn, M. L., & Zinn, M. A. Myalgic Encephalomyelitis: Symptoms and Biomarkers. Curr Neuropharmacol.2015;13(5), 701-734. http://www.ncbi.nlm.nih.gov/pubmed/26411464
Jason LA, Brown M, Brown A, et al. Energy conservation/envelope theory interventions to help patients with myalgic encephalomyelitis/chronic fatigue syndrome. Fatigue. 2013;1:27-42.
Carruthers BM, van de Sande MI, De Meirleir KL, et al. Myalgic encephalomyelitis: International Consensus Criteria. J Intern Med. 2011;270:327-338. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3427890/
Chia J, Chia A, Voeller M, Lee T, Chang R. Acute enterovirus infection followed by myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and viral persistence. Clin Pathol. 2010;63:165-168. http://www.ncbi.nlm.nih.gov/pubmed/19828908
Jason LA, Boulton A, Porter NS, et al. Classification of myalgic encephalomyelitis/chronic fatigue syndrome by types of fatigue. Behav Med. 2010;36:24-31. http://www.ncbi.nlm.nih.gov/pubmed/20185398
Hempel S, Chambers D, Bagnall AM, Forbes C. Risk factors for chronic fatigue syndrome/myalgic encephalomyelitis: a systematic scoping review of multiple predictor studies. Psychol Med. 2008;38:915-926. http://www.ncbi.nlm.nih.gov/pubmed/17892624
Kerr JR, Petty R, Burke B, et al. Gene expression subtypes in patients with chronic fatigue syndrome/myalgic encephalomyelitis. J Infect Dis. 2008;197:1171-1184. http://www.ncbi.nlm.nih.gov/pubmed/18462164
Hooper M. Myalgic encephalomyelitis: a review with emphasis on key findings in biomedical research. J Clin Pathol. 2007;60:466-471. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1994528/
Jason LA, Jordan K, Miike T, et al. A pediatric case definition for myalgic encephalomyelitis and chronic fatigue syndrome. Journal of Chronic Fatigue Syndrome. 2006;13:1-44.
Jason LA, Richman JA, Rademaker AW, et al. A community-based study of chronic fatigue syndrome. Arch Intern Med. 1999;159:2129-2137. http://www.ncbi.nlm.nih.gov/pubmed/10527290
Fukuda K, Straus SE, Hickie I, et al. The chronic fatigue syndrome: A comprehensive approach to its definition and study. Ann Int Med. 1994;121:953-959.
INTERNET
Carruthers BM, van de Sande IM. Myalgic Encephalomyelitis – Adult & Paediatric: International Consensus Primer for Medical Practitioners. 2012: Carruthers & van de Sande. http://www.name-us.org/DefintionsPages/DefinitionsArticles/2012_ICC%20primer.pdf. Accessed on March 18, 2016.
Carruthers BM, van de Sande IM. Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: An overview of the Canadian consensus document. A clinical case definition and guidelines for medical practitioners. 2003. Available at: http://www.name-us.org/DefintionsPages/DefinitionsArticles/ConsensusDocument%20Overview.pdf . Accessed March 18, 2016.
Nightingale Research Foundation. The Nightingale Definition of Myalgic Encephalomyelitis (M.E.). January 29, 2007. Available at: http://www.nightingale.ca/documents/Nightingale_ME_Definition_en.pdf Accessed March 18, 2016.
Centers for Disease Control and Prevention. Chronic Fatigue Syndrome (CFS). Updated April 7, 2015. Available at: http://www.cdc.gov/cfs/ Accessed March 18, 2016.
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