Chronic fatigue syndrome

Chronic fatigue syndrome (CFS), also referred to as myalgic encephalomyelitis (ME), is a complex, fatiguing, long-term medical condition that causes worsening symptoms after physical or mental activity, a greatly diminished capacity to accomplish tasks that had been routine prior to the illness, and unrefreshing sleep.[11][12][1][4][2]^:7 Difficulty sitting and standing upright or cognitive dysfunction are also present.[12] Other common symptoms may involve numerous body systems in those affected.[12][1]

Chronic fatigue syndrome
Other names	Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS),[1] myalgic encephalomyelitis (ME), post-viral fatigue syndrome (PVFS), chronic fatigue immune dysfunction syndrome (CFIDS), systemic exertion intolerance disease (SEID), others[2]^:20
Specialty	Primary care, neurology, rheumatology, infectious diseases, physical therapy, occupational therapy, mental health, behavioral health[2]^:223
Symptoms	Worsening of symptoms with activity, long-term fatigue, others[1]
Usual onset	40 to 60 years old[3]
Duration	Often years[4]
Causes	Unknown[1]
Risk factors	Female gender, virus and bacterial infections, genetics, major injury, bodily response to severe stress and others[5][6]^:1–2
Diagnostic method	Based on symptoms[1]
Treatment	Symptomatic[7][8]
Frequency	approximately 1% globally[9][10]

While the cause is not understood, proposed mechanisms include biological, genetic, infectious, and physical or psychological stress affecting body chemistry.[5][13] Diagnosis is based on a person's symptoms because there is no confirmed diagnostic test.[14] The fatigue in CFS is not due to strenuous ongoing exertion, is not much relieved by rest and is not due to a previous medical condition.[12] Fatigue is a common symptom in many illnesses, but the unexplained fatigue and severity of functional impairment found in CFS is comparatively rare in these other illnesses.[15]

Persons with CFS may recover or improve over time, but there are no approved therapies or medications for the illness; treatment is directed toward symptomatology.[7][16] The CDC recommends the use of pacing (personal activity management) to reduce the worsening of symptoms resulting from mental or physical activity.[7] Limited evidence suggests rintatolimod, counseling therapies, and graded exercise therapy might benefit some patients.[17]

The incidence of CFS is approximately 1 in every 100 persons seen in primary care settings, but estimates vary widely due to different criteria used in epidemiological studies.[10][18][9] Studies estimate that 836,000 to 2.5 million Americans and 250,000 people in the UK have CFS.[1][19] CFS occurs 1.5 to 2 times more often in women than in men.[10] It most commonly affects adults between ages 40 and 60 years,[3] but can occur at other ages including in children.[20] Other studies suggest that around 1 in 200 children have CFS, and is more common in adolescents than younger children.[2]^:182[20] Chronic fatigue syndrome is a major cause of school absence.[2]^:183 There is agreement that CFS has a negative effect on health, happiness and productivity, but there is also controversy over many aspects of the disorder. Physicians, researchers and patient advocates promote different names[21] and diagnostic criteria, while evidence for proposed causes and treatments is often contradictory or of low quality.[22]

Signs and symptoms

The United States Centers for Disease Control and Prevention (CDC) recommends the following criteria for diagnosis:[12]

1. Greatly lowered ability to do activities that were usual before the illness. This drop in activity level occurs along with fatigue and must last six months or longer.
2. Worsening of symptoms after physical or mental activity that would not have caused a problem before illness. This is known as post-exertional malaise (PEM).
3. Sleep problems

Additionally, one of the following symptoms must be present:[12]

• Problems with thinking and memory (cognitive dysfunction, sometimes described as "brain fog")
• While standing or sitting upright; lightheadedness, dizziness, weakness, fainting or vision changes may occur (orthostatic intolerance)

Other common symptoms

Many, but not all people with ME/CFS report:[12]

• Muscle pain, joint pain without swelling or redness, and headache
• Tender lymph nodes in the neck or armpits
• Sore throat
• Irritable bowel syndrome
• Chills and night sweats
• Allergies and sensitivities to foods, odors, chemicals, lights, or noise
• Shortness of breath
• Irregular heartbeat

The CDC proposes that persons with symptoms resembling those of CFS consult a physician to rule out several treatable illnesses: Lyme disease,[23] "sleep disorders, major depressive disorder, alcohol/substance abuse, diabetes mellitus, hypothyroidism, mononucleosis (mono), lupus, multiple sclerosis (MS), chronic hepatitis and various malignancies."[24] Medications can also cause side effects that mimic symptoms of CFS.[23] Central sensitization, or increased sensitivity to sensory stimuli such as pain have been observed in CFS. Sensitivity to pain increases post-exertionally, which is opposite to the normal pattern.[25]

Onset

Gradual or sudden onset of the illness may occur, and studies have mixed results as to which occurs more frequently.[2]^:158:181

Physical functioning

The functional capacity of individuals with CFS varies greatly.[26] Some persons with CFS lead relatively normal lives; others are totally bed-ridden and unable to care for themselves.[27] For the majority of persons with CFS, work, school, and family activities are significantly reduced for extended periods of time.[28] The severity of symptoms and disability is the same regardless of gender,[29] and many experience strongly disabling chronic pain.[30] Persons report critical reductions in levels of physical activity.[31] Also, a reduction in the complexity of activity has been observed.[32] Reported impairment is comparable to other fatiguing medical conditions[33] including late-stage AIDS,[34] lupus, rheumatoid arthritis, chronic obstructive pulmonary disease (COPD), and end-stage kidney disease.[35] CFS affects a person's functional status and well-being more than major medical conditions such as multiple sclerosis, congestive heart failure, or type II diabetes mellitus.[36][37]

Often, there are courses of remission and relapse of symptoms, which make the illness difficult to manage. Persons who feel better for a period may overextend their activities, and the result can be a worsening of their symptoms with a relapse of the illness.[35]

25% of people with CFS are house-bound or bedridden for long periods during their illness, often for decades.[2]^:32[4] An estimated 75% are unable to work because of their illness.[38] More than half were on disability benefits or temporary sick leave, and less than a fifth worked full-time.[27] Children that become ill with CFS are a major cause of school absence.[2]^:183

People with CFS have decreased scores on the SF-36 quality of life questionnaire, especially in the sub scales on vitality, physical functioning, general health, physical role and social functioning; however, the sub scales for "role emotional" and mental health in CFS patients were consistent with or not substantially lower than healthy controls.[39] Loss of economic production and costs due to CFS are estimated at between $18 and $51 billion a year in the U.S.[40] Direct healthcare costs are estimated at between $9 and $14 billion annually in the U.S. alone.[38]

Cognitive functioning

Cognitive dysfunction is one of the more disabling aspects of CFS due to its negative impact on occupational and social functioning. Cognitive symptoms are mainly due to deficits in attention, memory, and reaction time. Measured cognitive abilities are found to be below projected normal values and likely to affect day-to-day activities; for example, increases in common mistakes, forgetting scheduled tasks, or having difficulty responding when spoken to.[41]

Simple and complex information processing speed, and functions entailing working memory over long time periods are moderately to extensively impaired. These deficits are generally consistent with the patient's perceptions. Perceptual abilities, motor speed, language, reasoning, and intelligence do not appear to be significantly altered. When poorer health status was reported, a person's perception of their cognitive problems was also frequently greater. Better physical functioning in people with CFS is associated with less visuo-perceptual difficulty and fewer language processing complaints.[41]

Inconsistencies of subjective and observed values of cognitive dysfunction reported across multiple studies are likely caused by a number of factors. Differences of research participants' cognitive abilities pre and post illness onset are naturally variable, and are difficult to measure because of a lack of specialized analytical tools that can consistently quantify the specific cognitive difficulties in CFS.[41]

There is an increased frequency of neuropsychiatric and neuropsychological symptoms in persons with CFS.[42]

Cause

The cause of CFS is unknown.[43] Genetic, physiological and psychological factors are thought to work together to precipitate and perpetuate the condition.[13] A 2016 report by the Institute of Medicine states that CFS is a biologically based illness, but that the biologic abnormalities are not sensitive or specific enough to be useful as a diagnosis.[43]

Because it may begin as a flu-like illness with a sudden onset, various infectious causes have been proposed; however, there is insufficient evidence to support such causation.[44][2] Infections proposed include mononucleosis, Chlamydophila pneumoniae, human herpesvirus 6, and Lyme disease. Inflammation may be involved.[45] Often, the illness will follow a viral illness, such as mononucleosis or gastroenteritis.[46]

Risk factors

All ages, ethnic groups and income levels are susceptible to the illness. The CDC states that Caucasians may be diagnosed more frequently than other races in America,[4] but the illness is at least as prevalent among African Americans and Hispanics.[3] A 2009 meta-analysis showed that compared with Caucasians, African Americans and Native Americans have a higher risk of CFS, though it specifically excluded other more common ethnicities worldwide, and it acknowledged that studies and data were limited.[47]

More women than men get CFS.[4] A large 2020 meta-analysis estimated that between 1.5 and 2 times more cases are women. The review acknowledged that different case definitions and diagnostic methods within datasets yielded a wide range prevalence rates.[10] The CDC estimates CFS occurs up to 4 times more often in women than in men.[3] The illness can occur at any age, but most frequently in persons between the ages of 40 and 60.[3] CFS is less prevalent among children and adolescents than among adults.[20]

Blood relatives of those who have CFS appear to be more predisposed.[48]

Psychological stress, childhood trauma, perfectionist personalities, old age, lower middle education, low physical fitness, preexisting psychological illness, and allergies may be risk factors for developing chronic fatigue syndrome. This has led some to believe that stress-related visceral responses underlie CFS.[49][50] Pre-existing depressive and anxiety disorders, as well as high expectation of parents and family history were predisposing factors identified in another review.[51]

People with CFS and their relatives tend to attribute their illness to physical causes (such as a virus or pollution) rather than to psychological causes.[13][52] Such attributions are associated with increased symptoms and impairment, and worse outcomes over time.[13] However, according to the CDC, "CFS is a biological illness, not a psychologic disorder", and those affected "are neither malingering nor seeking secondary gain".[53]

Viral and other infections

The term post-viral fatigue syndrome (PVFS) is used as an alternative name for CFS which occurs after viral infection.[6] A recent review found Epstein-Barr Virus (EBV) antibody activity to be higher in patients with CFS, and that a subset of patients with CFS were likely to have increased EBV activity compared to controls.[54] Viral infection is a significant risk factor for CFS, with one study finding 22% of people with Epstein-Barr virus have chronic fatigue six months later, and 9% having strictly defined CFS.[55] A systematic review found that fatigue severity was the main predictor of prognosis in CFS, and did not identify psychological factors linked to prognosis.[56] One review found risk factors for developing CFS after mononucleosis, dengue fever or the bacterial infection Q-fever include longer bed-rest during the illness, poorer pre-illness physical fitness, attributing symptoms to physical illness, belief that a long recovery time is needed, as well as pre-infection distress and fatigue. The same review found biological factors such as CD4 and CD8 activation and liver inflammation are predictors of sub-acute fatigue, but not CFS,[57] however these findings are not generally accepted due to the use of the Oxford criteria in selecting patients. The CDC does not recognize attribution of symptoms as a risk factor.[5]

A study comparing diagnostic labels found that people labelled with ME had the worst prognosis while those with PVFS had the best. It is unclear, however, whether this is due to those with more severe symptoms being labelled with ME, or if there is an adverse effect to being labelled with ME.[58]

Pathophysiology

Difference between adolescents with chronic fatigue syndrome and healthy controls shows less salient network activity in certain regions of the brain

Neurological

A range of neurological structural and functional abnormalities are found in people with CFS including lowered metabolism at the brain stem, and reduced blood flow to areas of the brain; these differences are consistent with neurological illness but not depression or psychological illness.[6] Tentative evidence suggests a relationship between autonomic nervous system dysfunction and diseases such as CFS, fibromyalgia, irritable bowel syndrome, and interstitial cystitis. However, it is unknown if this relationship is causative.[59] Reviews of CFS literature have found autonomic abnormalities such as decreased sleep efficiency, increased sleep latency, decreased slow wave sleep, and abnormal heart rate response to tilt table tests suggesting a role of the autonomic nervous system in CFS. However, these results were limited by inconsistency.[60][61][62] Some neuroimaging studies have observed prefrontal and brainstem hypometabolism; however, studies have been limited by sample size.[63] Neuroimaging studies in persons with CFS have identified changes in brain structure and correlated them with various symptoms. Results were not consistent across the neuroimaging brain structure studies, and more research is needed to resolve the discrepancies.[64][65] The World Health Organization classes chronic fatigue syndrome as a central nervous system disease.[66]

Immunological

Immunological abnormalities are frequently observed in those with CFS. Decreased NK cell activity is found more often in people with CFS and this correlates with severity of symptoms.[5][67] People with CFS have an abnormal response to exercise, including increased production of complement products, increased oxidative stress combined with decreased antioxidant response, and increased Interleukin 10, and TLR4, some of which correlates with symptom severity.[68] Increased levels of cytokines have been proposed to account for the decreased ATP production and increased lactate during exercise;[69][70] however, the elevations of cytokine levels are inconsistent in specific cytokine, albeit frequently found.[2][71] Similarities have been drawn between cancer and CFS with regard to abnormal intracellular immunological signaling. Abnormalities observed include hyperactivity of Ribonuclease L, a protein activated by IFN, and hyperactivity of NF-κB.[72]

Endocrine

Evidence points to abnormalities in the hypothalamic-pituitary-adrenal axis (HPA axis) in some, but not all, persons with CFS, which may include slightly low cortisol levels,[73] a decrease in the variation of cortisol levels throughout the day, decreased responsiveness of the HPA axis, and a high serotonergic state, which can be considered to be a "HPA axis phenotype" that is also present in some other conditions, including posttraumatic stress disorder (PTSD) and some autoimmune conditions.[74] It is unclear whether or not decreased cortisol levels of the HPA axis plays a primary role as a cause of CFS,[75][76][77] or has a secondary role in the continuation or worsening of symptoms later in the illness.[78] In most healthy adults, the cortisol awakening response shows an increase in cortisol levels averaging 50% in the first half-hour after waking. In people with CFS, it appears this increase is significantly less, but methods of measuring cortisol levels vary, so this is not certain.[79]

Autoimmunity has been proposed to be a factor in CFS; however, the only relevant finding is a subset of patients with increased B Cell activity and autoantibodies, possibly as a result of decreased NK cell regulation or viral mimicry.[80]

Diagnosis

There are no characteristic laboratory abnormalities to diagnose CFS, while physical abnormalities can be found no single finding is considered sufficient for diagnosis.[81][6] Blood, urine and other tests are used to rule out other conditions which could be responsible for the symptoms.[14][82][2] The CDC states that a medical history should be taken and a mental and physical examination should be done to aid diagnosis.[14]

Suggested diagnostic tools

The CDC recommends considering the questionnaires and tools described in the Institute of Medicine report, which includes:

• The Chalder Fatigue Scale
• Multidimensional Fatigue Inventory
• Fisk Fatigue Impact Scale
• The Krupp Fatigue Severity Scale
• DePaul Symptom Questionnaire
• CDC Symptom Inventory for CFS
• Work and Social Adjustment Scale (WSAS)
• SF-36 / RAND-36[2]^:270

A two-day cardiopulmonary exercise test (CPET) is not necessary for diagnosis, although lower readings on the second day may be helpful in supporting a claim for social security disability. A two-day CPET cannot be used to rule out chronic fatigue syndrome.[2]^:216

Definitions

Main article: Clinical descriptions of chronic fatigue syndrome

Notable definitions include:[83]

• Centers for Disease Control and Prevention (CDC) definition (1994),[84] the most widely used clinical and research description of CFS,[13] is also called the Fukuda definition and is a revision of the Holmes or CDC 1988 scoring system.[85] The 1994 criteria require the presence of four or more symptoms beyond fatigue, while the 1988 criteria require six to eight.[86]
• The ME/CFS 2003 Canadian Clinical working definition[87] states: "A patient with ME/CFS will meet the criteria for fatigue, post-exertional malaise and/or fatigue, sleep dysfunction, and pain; have two or more neurological/cognitive manifestations and one or more symptoms from two of the categories of autonomic, neuroendocrine, and immune manifestations; and the illness persists for at least 6 months".
• The Myalgic Encephalomyelitis International Consensus Criteria (ICC) published in 2011 is based on the Canadian working definition and has an accompanying primer for clinicians[88][6] The ICC does not have a six months waiting time for diagnosis. The ICC requires post-exertional neuroimmune exhaustion (PENE) which has similarities with post-exertional malaise, plus at least three neurological symptoms, at least one immune or gastrointestinal or genitourinary symptom, and at least one energy metabolism or ion transportation symptom. Unrefreshing sleep or sleep dysfunction, headaches or other pain, and problems with thinking or memory, and sensory or movement symptoms are all required under the neurological symptoms criterion.[88] According to the ICC, patients with post-exertional neuroimmune exhaustion but only partially meet the criteria should be given the diagnosis of atypical myalgic encephalomyelitis.[6]
• The 2015 definition by the National Academy of Medicine (then referred to as the "Institute of Medicine") is not a definition of exclusion (differential diagnosis is still required).[2] "Diagnosis requires that the patient have the following three symptoms: 1) A substantial reduction or impairment in the ability to engage in pre-illness levels of occupational, educational, social, or personal activities, that persists for more than 6 months and is accompanied by fatigue, which is often profound, is of new or definite onset (not lifelong), is not the result of ongoing excessive exertion, and is not substantially alleviated by rest, and 2) post-exertional malaise* 3) Unrefreshing sleep*; At least one of the two following manifestations is also required: 1) Cognitive impairment* 2) Orthostatic intolerance" and notes that "*Frequency and severity of symptoms should be assessed. The diagnosis of ME/CFS should be questioned if patients do not have these symptoms at least half the time with moderate, substantial, or severe intensity."[2]

Clinical practice guidelines are generally based on case descriptions, with the aim of improving diagnosis, management and treatment. An example is the CFS/ME guideline for the National Health Services in England and Wales, produced in 2007,[86] (presently being updated).[89] Other guidance can be found at the New York Department of Health.[90]

Differential diagnosis

Certain medical conditions can cause chronic fatigue and must be ruled out before a diagnosis of CFS can be given. Hypothyroidism, anemia,[91] coeliac disease (that can occur without gastrointestinal symptoms),[92] diabetes and certain psychiatric disorders are a few of the diseases that must be ruled out if the patient presents with appropriate symptoms.[86][84][91] Other diseases, listed by the Centers for Disease Control and Prevention, include infectious diseases (such as Epstein–Barr virus, influenza, HIV infection, tuberculosis, Lyme disease), neuroendocrine diseases (such as thyroiditis, Addison's disease, adrenal insufficiency, Cushing's disease), hematologic diseases (such as occult malignancy, lymphoma), rheumatologic diseases (such as fibromyalgia, polymyalgia rheumatica, Sjögren's syndrome, giant-cell arteritis, polymyositis, dermatomyositis), psychiatric diseases (such as bipolar disorder, schizophrenia, delusional disorders, dementia, anorexia/bulimia nervosa), neuropsychologic diseases (such as obstructive sleep apnea, parkinsonism, multiple sclerosis), and others (such as nasal obstruction from allergies, sinusitis, anatomic obstruction, autoimmune diseases, some chronic illness, alcohol or substance abuse, pharmacologic side effects, heavy metal exposure and toxicity, marked body weight fluctuation).[91] Ehlers Danlos syndromes (EDS) may also have similar symptoms.[93]

Persons with fibromyalgia (FM, or fibromyalgia syndrome, FMS), like those with CFS, have muscle pain, severe fatigue and sleep disturbances. The presence of allodynia (abnormal pain responses to mild stimulation) and of extensive tender points in specific locations differentiates FM from CFS, although the two diseases often co-occur.[94]

Depressive symptoms, if seen in CFS, may be differentially diagnosed from primary depression by the absence of anhedonia, decreased motivation, and guilt; and the presence of somatic symptoms such as sore throat, swollen lymph nodes, and exercise intolerance with post exertional exacerbation of symptoms.[91]

Management

Main article: Chronic fatigue syndrome treatment

There is no approved pharmacological treatment, therapy or cure for CFS[7][86] although various drugs have been or are being investigated.[95] A 2014 report prepared by the Agency for Healthcare Research and Quality stated that there are wide variations in patient management, that many receive a multifaceted approach to treatment, and that no medications have been approved by the U.S. Food and Drug Administration (FDA) for the treatment of ME/CFS, although several have been used off label. The report concluded that although counseling and graded exercise therapy (GET) have shown some benefits, these interventions have not been studied fully enough to recommend them for all persons affected. The report expressed concern that GET appears to be associated with worsening symptoms in some.[96] The CDC no longer recommends these interventions, and there is some evidence of patient harm.[97][98]

The CDC guide for the management of CFS states that while there is no cure, a number of methods might improve symptoms.[7] Treatment strategies for sleep problems, pain, (depression, stress, and anxiety) dizziness and lightheadedness (orthostatic Intolerance), and memory and concentration problems are enumerated. Other useful topics mentioned that patients and doctors might discuss include carefully monitoring and managing activity to avoid worsening of symptoms, counseling to cope with the impact the illness may have on quality of life, proper nutrition and nutritional supplements that may support better health, complementary therapies that might help increase energy or decrease pain.[7]

The United Kingdom's National Institute for Health and Clinical Excellence (NICE) 2007 guideline directed toward clinicians, specifies the need for shared decision-making between the patient and healthcare professionals, and acknowledges the reality and impact of the condition and the symptoms. The NICE guideline covers illness management aspects of diet, sleep and sleep disorders, rest, relaxation, and pacing. Referral to specialist care for cognitive behavioural therapy, graded exercise therapy and activity management (pacing) programmes are recommended to be offered as a choice to patients with mild or moderate CFS.[99] In 2017 NICE announced its guidance for CFS/ME needed to be updated,[100] and publication is expected in December 2020.[101]

Comorbid conditions can occur in CFS which may interact with and exacerbate the symptoms of CFS. Appropriate medical intervention for these conditions may be beneficial. The most commonly diagnosed include: Fibromyalgia, Irritable bowel syndrome, Depression, Anxiety, as well as Allergies and chemical sensitivities.[102]

Pacing

Pacing, or activity management, is an illness management strategy based on the observation that symptoms tend to increase following mental or physical exertion,[7] and was recommended for CFS in the 1980s.[103] It is now commonly used as a management strategy in chronic illnesses and in chronic pain.[104]

There are two forms: symptom-contingent pacing, where the decision to stop (and rest or change an activity) is determined by a self awareness of an exacerbation of symptoms; and time-contingent pacing, which is determined by a set schedule of activities which a patient estimates he or she is able to complete without triggering post-exertional malaise (PEM). Thus the principle behind pacing for CFS is to avoid over-exertion and an exacerbation of symptoms. It is not aimed at treating the illness as a whole. Those whose illness appears stable may gradually increase activity and exercise levels, but, according to the principle of pacing, must rest if it becomes clear that they have exceeded their limits.[103] Use of a heart rate monitor with pacing to monitor and manage activity levels is recommended by a number of patient groups and the UK's 2007 NICE guideline.[105][100]

Energy envelope theory

Energy envelope theory is considered to be consistent with pacing, and is a management strategy suggested in the 2011 international consensus criteria for ME, which referred to using an "energy bank budget". Energy envelope theory was devised by psychologist Leonard Jason, a former sufferer of CFS.[106] Energy Envelope Theory states that patients should stay within the envelope of energy available to them, and avoid pushing through, which will reduce the post-exertional malaise "payback" caused by overexerting and may help them make "modest gains" in physical functioning.[107][108] Several studies have found energy envelope theory to be a helpful management strategy, noting that it reduces symptoms and may increase the level of functioning in CFS.[109][110][108] Energy envelope theory does not recommend unilaterally increasing or decreasing activity and is not intended as a therapy or cure for CFS.[109] It has been promoted by various patient groups.[111][112] Some patient groups recommend using a heart rate monitor to increase awareness of exertion, and allow patients to stay within their aerobic threshold envelope.[113][114] Despite a number of studies showing positive results for energy envelope theory, randomized controlled trials are lacking.

Exercise

Stretching, movement therapies and toning exercises are recommended for pain in patients with CFS, and pain medication is also suggested. In many chronic illnesses aerobic exercise is beneficial, but in chronic fatigue syndrome the CDC does not recommend it. The CDC states:[7]

"Any activity or exercise plan for people with ME/CFS needs to be carefully designed with input from each patient. While vigorous aerobic exercise can be beneficial for many chronic illnesses, patients with ME/CFS do not tolerate such exercise routines. Standard exercise recommendations for healthy people can be harmful for patients with ME/CFS. However, it is important that patients with ME/CFS undertake activities that they can tolerate..."

Counseling

The CDC states that counseling may help patients cope with pain caused by CFS, and that talking with a professional counselor or therapist may help people to more effectively manage the symptoms that affect their quality of daily life.[7]

Nutrition

A proper diet is a significant contributor to the health of any individual. Medical consultation about diet and supplements are recommended for persons with CFS.[7]

Persons with CFS, can benefit from a balanced diet and properly supervised administation of nutritional support if deficiencies are detected by medical testing. There are risks and benefits of nutritional supplements, including interactions with prescribed medications.[115][7]

Therapies

Cognitive behavioral therapy

The CDC states that speaking with a therapist may help people cope with the illness.[7] A 2015 National Institutes of Health report concluded that while counseling and behavior therapies could produce benefits for some people, they may not yield improvement in quality of life, and because of this limitation such therapies should not be considered as a primary treatment, but rather should be used only as one component of a broader approach.[116] This same report stated that although counseling approaches have shown benefit in some measures of fatigue, function and overall improvement, these approaches have been inadequately studied in subgroups of the wider CFS patient population. Further concern was expressed that reporting of negative effects experienced by patients receiving counseling and behavior therapies had been poor.[96] A report by the Institute of Medicine published in 2015 states that it is unclear whether CBT helps to improve cognitive impairments experienced by patients.[2]^:265 The rationale behind the use of CBT to change beliefs about the illness is disputed.[97]

A 2008 Cochrane Review concluded that CBT did reduce the symptom of fatigue, but noted that the benefits of CBT may diminish after the therapy is completed, and that due to study limitations "the significance of these findings should be interpreted with caution".[22] A 2014 systematic review reported that there was only limited evidence that patients increased levels of physical activity after receiving CBT. The authors concluded that, as this finding is contrary to the cognitive behavioural model of CFS, patients receiving CBT were adapting to the illness rather than recovering from it.[117]

Patient organisations have long criticised the use of CBT as a treatment for CFS, and the rationale behind the model is disputed.[98][118] In 2012 the ME Association (MEA) commenced an opinion survey of 493 patients who had received a CBT treatment in the UK. Based on the finding of this survey, in 2015 the MEA concluded that CBT in its current form should not be recommended as a primary intervention for people with CFS[119] In a letter published online in the Lancet in 2016, Dr Charles Shepherd, medical advisor to the MEA, expressed the view that the contention between patients and researchers lay in "a flawed model of causation that takes no account of the heterogeneity of both clinical presentations and disease pathways that come under the umbrella diagnosis of ME/CFS".[120] In 2019, a large UK survey of people with ME/CFS reported that CBT was ineffective for more than half of people, and Graded Exercise Therapy caused deterioration in most people.[121]

Graded exercise therapy

Previously, a 2014 National Institutes of Health report concluded that while Graded Exercise Therapy (GET) could produce benefits, it may not yield improvement in quality of life and that because of this limitation, GET should not be considered as a primary treatment, but instead be used only as one component of a broader approach. The report also noted that a focus on exercise programs had discouraged patient participation in other types of physical activity, due to concerns of precipitating increased symptoms.[116] A July 2016 addendum to this report recommended that the Oxford criteria not be used when studying ME/CFS. If studies based on the Oxford criteria were excluded, there would be insufficient evidence of the effectiveness of GET on any outcome.[98]

A 2002 Cochrane review updated in 2019 stated that exercise therapy probably has a positive effect on fatigue in adults, and slightly improves sleep, however the long term effects are unknown, and this has limited relevance to current definitions of ME/CFS.[122][8] Cochrane have announced that a new review to look at exercise therapies in chronic fatigue syndrome is to start in 2020.[8][123] As with CBT, patient organisations have long criticised the use of exercise therapy, most notably GET, as a treatment for CFS.[118] In 2012 the MEA commenced an opinion survey of patients who had received GET. Based on the findings of this survey, in 2015 the MEA concluded that GET in its current delivered form should not be recommended as a primary intervention for persons with CFS.[119]

Adaptive pacing therapy

Adaptive pacing therapy was popularised by the 'PACE trial', a study that has caused much controversy among both patients and practitioners.[17] Adaptive pacing therapy (APT), not to be confused with pacing,[124] is a therapy rather than a management strategy.[125] APT is based on the idea that CFS involves a person only having a limited amount of available energy, and using this energy wisely will mean the "limited energy will increase gradually".[125]^:5 A large clinical trial known as the PACE trial found APT was no more effective than usual care or specialized medical care.[126] Unlike pacing, ADT is based on the cognitive behavioral model (CBM) of chronic fatigue syndrome and involves increasing activity levels, which it states may temporarily increase symptoms.[127] In APT, the patient first establishes a baseline level of activity which can be carried out consistently without any post-exertional malaise ("crashes"). APT then states the patient should plan to increase their activity, as able. However, APT also requires a patient to restrict their activity level to only 70% of what they feel able to do, while also warning against too much rest.[125] This has been described as contradictory and Jason states that in comparison eh pacing, this 70% limit restricts the activities that patients are capable of resulting in a lower level of functioning.[124] Jason and Goudsmit, who first described pacing and energy envelope theory for CFS, have both criticized APT for being inconsistent with the principles of pacing and highlighted significant differences.[124] APT was promoted by Action for ME, the patient charity involved in the PACE trial, until 2019.[127]

Rintatolimod

Rintatolimod is a double-stranded RNA drug developed to modulate an anti-viral immune reaction through activation of toll-like receptor 3. In several clinical trials of CFS, the treatment has shown a reduction in symptoms, but improvements were not sustained after discontinuation.[128] Evidence supporting the use of rintatolimod is deemed low to moderate.[17] The US FDA has denied commercial approval, called a new drug application (NDA), citing several deficiencies and gaps in safety data in the trials, and concluded that the available evidence is insufficient to demonstrate its safety or efficacy in CFS.[129][130] Rintatolimod has been approved for marketing and treatment for persons with CFS in Argentina,[131] and in 2019 FDA regulatory requirements were met for exportation of rintatolimod to the country.[132]

Prognosis

A systematic review described improvement and occupational outcomes of people with CFS found that "the median full recovery rate was 5% (range 0–31%) and the median proportion of patients who improved during follow-up was 39.5% (range 8–63%). Return to work at follow-up ranged from 8 to 30% in the three studies that considered this outcome." ... "In five studies, a worsening of symptoms during the period of follow-up was reported in between 5 and 20% of patients." A good outcome was associated with not attributing illness to a physical cause, and having a sense of control over symptoms. Other factors were occasionally, but not consistently, related to outcome, including age at onset, a longer duration of follow-up, and less fatigue severity at baseline. The review concludes that "irrespective of the biology of CFS, patients’ beliefs and attributions about the illness are intricately linked with the clinical presentation, the type of help sought and prognosis"[133] Another review found that children have a better prognosis than adults, with 54–94% having recovered by follow-up compared to less than 10% of adults returning to pre-illness levels of functioning.[134]

Epidemiology

The incidence of CFS is approximately 1% globally; 17 to 24 million persons.[9][10] Estimates of CFS vary widely due to the use of different definitions of CFS, the settings of the study populations and the methodology used to exclude study participants with alternative diagnoses.[18][10] Eight hundred thirty six thousand to 2.5 million Americans have CFS, but most remain undiagnosed.[1] Approximately 250,000 people in the UK are affected with the illness.[19] Females are diagnosed about 1.5 to 2 times more often with CFS than males.[10] It is estimated that around 1 in 200 children have CFS, and more adolescents are affected with the illness than younger children.[2]^:182[20]

History

Main article: History of chronic fatigue syndrome

Myalgic encephalomyelitis

• From 1934 onwards, outbreaks of a previously unknown illness began to be recorded by doctors.[135][136] Initially considered to be occurrences of poliomyelitis, the illness was subsequently referred to as "epidemic neuromyasthenia".[136]
• In the 1950s, the term "benign myalgic encephalomyelitis" was used in relation to a comparable outbreak at the Royal Free Hospital in London.[137] The descriptions of each outbreak were varied, but included symptoms of malaise, tender lymph nodes, sore throat, pain, and signs of encephalomyelitis.[138] The cause of the condition was not identified, although it appeared to be infectious, and the term "benign myalgic encephalomyelitis" was chosen to reflect the lack of mortality, the severe muscular pains, symptoms suggesting damage to the nervous system, and to the presumed inflammatory nature of the disorder. Björn Sigurðsson disapproved of the name, stating that the illness is rarely benign, doesn't always cause muscle pain, and is possibly never encephalomyelitic.[135] The syndrome appeared in sporadic as well as epidemic cases.[139]
• In 1969, benign myalgic encephalomyelitis appeared as an entry to the International Classification of Diseases under Diseases of the nervous system.[140]
• In 1986, Ramsay published the first diagnostic criteria for ME, in which the condition was characterized by: 1) muscle fatiguability in which, even after minimal physical effort, 3 or more days elapse before full muscle power is restored; 2) extraordinary variability or fluctuation of symptoms, even in the course of one day; and 3) chronicity.[141]
• By 1988, the continued work of Ramsay had demonstrated that, although the disease rarely resulted in mortality, it was often severely disabling.[2]^:28–29 Because of this, Ramsay proposed that the prefix "benign" be dropped.[137][142][143]

Chronic fatigue syndrome

• In the mid-1980s, two large outbreaks of an illness which resembled mononucleosis drew national attention in the United States. Located in Nevada and New York, the outbreaks involved an illness characterized by "chronic or recurrent debilitating fatigue, and various combinations of other symptoms, including a sore throat, lymph node pain and tenderness, headache, myalgia, and arthralgias". An initial link to the Epstein-Barr virus saw the illness acquire the name "chronic Epstein-Barr virus syndrome".[2]^:29[85]
• In 1987, the CDC convened a working group tasked with reaching a consensus on the clinical features of the illness. The working group concluded that CFS was not new, and that the many different names given to it previously reflected widely differing concepts of the illness's cause and epidemiology.[144] The CDC working group chose "chronic fatigue syndrome" as a more neutral and inclusive name for the illness, but noted that "myalgic encephalomyelitis" was widely accepted in other parts of the world.[85]
• In 1988, the first definition of CFS was published. Although the cause of the illness remained unknown, there were several attempts to update this definition, most notably in 1994.[84]
• The most widely referenced diagnostic criteria and definition of CFS for research and clinical purposes was published in 1994 by the CDC.[58]
• In 2006, the CDC commenced a national program to educate the American public and health care professionals about CFS.[145]

Other medical terms

A range of both theorised and confirmed medical entities and naming conventions have appeared historically in the medical literature dealing with ME and CFS. These include:

• Epidemic neuromyasthenia: a term used for outbreaks with symptoms resembling poliomyelitis.[135][146]
• Iceland disease and Akureyri disease: synonymous terms used for an outbreak of fatigue symptoms in Iceland.[147]
• Low natural killer syndrome, a term, used mainly in Japan, reflecting research showing diminished in-vitro activity of natural killer cells (NKs) isolated from patients.[148][149]
• Neurasthenia has been proposed as an historical diagnosis that occupied a similar medical and cultural space to CFS.[150]
• Royal Free disease: named after the historically significant outbreak in 1955 at the Royal Free Hospital used as an informal synonym for "benign myalgic encephalomyelitis".[151]
• Tapanui Flu: a term commonly used in New Zealand, deriving from the name of a town, Tapanui, where numerous people have the syndrome.[152]

Society and culture

Naming

Many names have been proposed for the illness. Currently, the most commonly used are "chronic fatigue syndrome", "myalgic encephalomyelitis", and the umbrella term "ME/CFS". Reaching consensus on a name is challenging because the cause and pathology remain unknown.[2]^:29–30

The term "chronic fatigue syndrome" has been criticized by some patients as being both stigmatizing and trivializing, and which in turn prevents the illness from being seen as a serious health problem that deserves appropriate research.[153] While many patients prefer "myalgic encephalomyelitis", which they believe better reflects the medical nature of the illness,[141][154] there is resistance amongst some clinicians toward the use of myalgic encephalomyelitis on the grounds that the inflammation of the central nervous system (myelitis) implied by the term has not been demonstrated.[155][156]

A 2015 report from the Institute of Medicine proposes the illness be renamed "systemic exertion intolerance disease" and suggests new diagnostic criteria for it. Many patients, clinicians, and researchers believe lengthy, disproportionate symptom exacerbation after physical or mental exertion is a core symptom (also known as post-exertional malaise).[2][157][158]

Economic impact

Reynolds et al. (2004)[159] estimated that the illness caused about $20,000 per person with CFS in lost productivity which totals to $9.1 billion per year in the United States.[160] This is comparable to other chronic illnesses that extract some of the biggest medical and socioeconomic costs.[161] A 2008 study[162] calculated that the total annual cost burden of ME/CFS to society in the US was extensive, and could approach $24.0 billion.[163]

Awareness day

May 12 is designated as ME/CFS International Awareness Day.[164] The day is observed so that stakeholders have an occasion to improve the knowledge of "the public, policymakers, and healthcare professionals about the symptoms, diagnosis, and treatment of ME/CFS, as well as the need for a better understanding of this complex illness."[165] It was chosen because it is the birthday of Florence Nightingale, who had an illness appearing similar to ME/CFS or fibromyalgia.[164][166]

Doctor–patient relations

Presentation of a petition to the National Assembly for Wales relating to M.E. support in South East Wales.

Some in the medical community do not recognize CFS as a real condition, nor is there agreement on its prevalence.[167][168][169] There has been much disagreement over proposed causes, diagnosis, and treatment of the illness.[170][171][172][173][174] This uncertainty can significantly affect doctor-patient relations. A 2006 survey of GPs in southwest England found that despite more than two thirds of them accepting CFS/ME as a recognizable clinical entity, nearly half did not feel confident with making the diagnosis and/or treating the disease. Three other key factors that were significantly, positively associated with GPs' attitudes were knowing someone socially with CFS/ME, being male and seeing more patients with the condition in the last year.[175]

From the patient perspective, one 1997 study found that 77% of individuals with CFS reported negative experiences with health care providers.[36] In a more recent metaanalysis of qualitative studies, a major theme identified in patient discourses was that they felt severely ill, yet blamed and dismissed.[176] Another recent study of themes in patient newsgroup postings noted key themes relating to denial of social recognition of suffering and feelings of being accused of "simply faking it". Another theme that emerged strongly was that achieving diagnosis and acknowledgement requires tremendous amounts of "hard work" by patients.[169][177]

Blood donation

In 2010, a variety of national blood banks adopted measures to discourage or prohibit individuals diagnosed with CFS from donating blood, based on concern following the 2009 claim of a link[178] between CFS and a retrovirus which was subsequently shown to be unfounded. Organizations adopting these or similar measures included the Canadian Blood Services,[179] the New Zealand Blood Service,[180] the Australian Red Cross Blood Service[181] and the American Association of Blood Banks,[182] In November 2010, the UK National Blood Service introduced a permanent deferral of donation from ME/CFS patients based on the potential harm to those patients that may result from their giving blood.[183] Donation policy in the UK now states, "The condition is relapsing by nature and donation may make symptoms worse, or provoke a relapse in an affected individual."[184]

Controversy

Main article: Controversies related to chronic fatigue syndrome

There has been much contention over the cause, pathophysiology,[50] nomenclature,[185] and diagnostic criteria of chronic fatigue syndrome.[170][171] Historically, many professionals within the medical community were unfamiliar with CFS, or did not recognize it as a real condition; nor was there agreement on its prevalence or seriousness.[168][169][186] Some people with CFS reject any psychological component.[187]

Two British psychiatrists, in 1970, reviewed the case notes of 15 outbreaks of benign myalgic encephalomyelitis and concluded that it was caused by mass hysteria on the part of patients, or altered medical perception of the attending physicians.[188][189] Their conclusions were based on previous studies which found many normal physical test results, a lack of a discernible cause and a higher prevalence of the illness in females. Consequently, the authors recommended that the disease should be renamed "myalgia nervosa". Despite strong refutation by Dr. Melvin Ramsay and other medical professionals, the proposed psychological hypothesis created great controversy, and convinced a generation of health professionals in the UK that this could be a plausible explanation for the condition, resulting in neglect by many medical specialties. The specialty that did take a major interest in the illness was psychiatry.[189]

Because of the controversy, sociologists hypothesized that stresses of modern living might be a cause of the illness, while some in the media used the term "Yuppie flu" and called it a disease of the middle class. People with disabilities from CFS were often not believed and called malingerers.[189] The November 1990 issue of Newsweek ran a cover story on CFS which, although supportive of an organic cause of the illness, also featured the term 'yuppie flu', reflecting the stereotype that CFS mainly affected yuppies. The implication was that CFS is a form of burnout. The term 'yuppie flu' is considered offensive by both patients and clinicians.[190][191]

In 2009, the journal Science[178] published a study that identified the XMRV retrovirus in a population of people with CFS. Other studies failed to reproduce this finding,[192][193][194] and in 2011, the editor of Science formally retracted its XMRV paper[195] while the Proceedings of the National Academy of Sciences similarly retracted a 2010 paper which had appeared to support the finding of a connection between XMRV and CFS.[196]

Research funding

United Kingdom

The lack of research funding and the funding bias towards biopsychosocial studies and against biomedical studies has been highlighted a number of times by patients groups and a number of UK politicians.[197] A parliamentary inquiry by an ad hoc group of parliamentarians in the United Kingdom, set up and chaired by former MP, Dr Ian Gibson, called the Group on Scientific Research into CFS/ME,[100]^:169–186[198] was addressed by a government minister claiming that few good biomedical research proposals have been submitted to the Medical Research Council (MRC) in contrast to those for psychosocial research. They were also told by other scientists of proposals that have been rejected, with claims of bias against biomedical research. The MRC confirmed to the Group that, from April 2003 to November 2006, it has turned down 10 biomedical applications relating to CFS/ME and funded five applications relating to CFS/ME, mostly in the psychiatric/psychosocial domain.

In 2008, the MRC set up an expert group to consider how the MRC might encourage new high-quality research into CFS/ME and partnerships between researchers already working on CFS/ME and those in associated areas. It currently lists CFS/ME with a highlight notice, inviting researchers to develop high-quality research proposals for funding.[199] In February 2010, the All-Party Parliamentary Group on ME (APPG on ME) produced a legacy paper, which welcomed the recent MRC initiative, but felt that there has been far too much emphasis in the past on psychological research, with insufficient attention to biomedical research, and that it is vital that further biomedical research be undertaken to help discover a cause and more effective forms of management for this disease.[200]

There has been controversy surrounding psychologically-oriented models of the disease and behavioral treatments conducted in the UK.[201]

United States

In 1998 it became known almost 13 million dollars for CFS research had been redirected or improperly accounted for by the United States CDC, and officials at the agency mislead Congress about the irregularities. The agency stated that they needed the funds to respond to other public health emergencies. The director of a U.S. national patient advocacy group charged the CDC had a bias against studying the disease. The CDC pledged to improve their practices and to restore the 13 million dollars to CFS research over three years.[202]

On 29 October 2015 the National Institutes of Health declared its intent to increase research on ME/CFS. The NIH Clinical Center was to study individuals with ME/CFS, and the National Institute of Neurological Disorders and Stroke (NINDS) would lead the Trans-NIH ME/CFS Research Working Group as part of a multi-institute research effort.[203]

Notable cases

In 1989, The Golden Girls (1985–1992) featured chronic fatigue syndrome in a two-episode arc, "Sick and Tired: Part 1 and 2," in which protagonist Dorothy Zbornak, portrayed by Bea Arthur, after a lengthy battle with her doctors in an effort to find a diagnosis for her symptoms, is finally diagnosed with CFS.[204] American author Ann Bannon had CFS.[205] Laura Hillenbrand, author of the popular book Seabiscuit, has struggled with CFS since age 19.[206][207]

Research

The different case definitions used to research the illness influence the types of patients selected for studies,[81] and research also suggests subtypes of patients may exist within a heterogeneous population.[160][208][209][210] In one of the definitions, symptoms are accepted that may suggest a psychiatric disorder, while others specifically exclude primary psychiatric disorders.[83] The lack of a single, unifying case definition was criticized in the Institute of Medicine's 2015 report for "creating an unclear picture of the symptoms and signs of the disorder" and "complicating comparisons of the results" (study results).[2]^:72

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External links

• "CDC — Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)". Centers for Disease Control. Retrieved 2020-05-20.

Classification	D ICD-11: E849 ICD-10: G93.3 ICD-10-CM: G93.3, R53.82 ICD-9-CM: 323.9 780.71 MeSH: D015673 DiseasesDB: 1645
External resources	MedlinePlus: 001244 eMedicine: med/3392 ped/2795 Patient UK: Chronic fatigue syndrome