Chronic Fatigue Syndrome

Chronic Fatigue Syndrome (CFS) is a complex medical condition characterized by long-term fatigue and other symptoms. These symptoms are of such a degree that they limit a person’s ability to carry out ordinary daily activities. CFS may also be referred to as Systemic Exertion Intolerance Disease (SEID), myalgic encephalomyelitis (ME), Post-Viral Fatigue Syndrome (PVFS), Chronic Fatigue Immune Dysfunction Syndrome (CFIDS) or several other terms.[3] The life quality of persons with CFS can be extremely compromised.

Biological, genetic, infectious and psychological mechanisms have been proposed but the cause is not understood. The fatigue of CFS is not due to ongoing exertion, is not much relieved by rest, and is not due to any other medical condition. Diagnosis is based on a patient’s signs and symptoms.

There is wide agreement that CFS has a negative effect on health, well-being and productivity but there is also controversy over many aspects of the disorder. Physicians, researchers and patient advocates promote different names and diagnostic criteria while evidence for proposed causes and treatments is often contradictory or of low quality.

Evidence suggests that cognitive behavioral therapy and a gradual increase in activity suited to individual capacity can sometimes be beneficial. The medication Rintatolimod may be useful in some cases.

Estimates of the number of people suffering from this condition vary from 7 to 3,000 per 100,000 adults. About one million Americans and a quarter of a million people in the UK have CFS. Fatigue is a common symptom in many illnesses but the fatigue experienced by persons with CFS is comparatively rare. CFS occurs more often in women than in men and is less common among children and adolescents.

Signs and Symptoms

Symptoms of CFS include malaise after exertion; unrefreshing sleep, widespread muscle and joint pain, sore throat, headaches of a type not previously experienced, cognitive difficulties, chronic and severe mental and physical exhaustion. Additional symptoms may be reported, including muscle weakness, increased sensitivity to light, sounds and smells, problems standing upright, digestive disturbances, depression, painful and often slightly swollen lymph nodes, cardiac and respiratory problems. It is unclear if these symptoms represent other associated conditions or if they are produced by CFS itself. Symptoms vary from person to person by number, type and severity.

The majority of CFS cases start suddenly, usually accompanied by a “flu-like illness” while a significant proportion of cases begin within several months of severe adverse stress. An Australian prospective study found that after infection by viral and non-viral pathogens, a subset of individuals met the criteria for CFS, with the researchers concluding that “post-infective fatigue syndrome is a valid illness model for investigating one pathophysiological pathway to CFS”. However, accurate prevalence and exact roles of infection and stress in the development of CFS are currently unknown.

The most commonly used diagnostic criteria and definition of CFS for research and clinical purposes were published by the United States Centers for Disease Control and Prevention (CDC).

The CDC recommends that the following three criteria be fulfilled:

  1. A new onset (not lifelong) of severe fatigue for six consecutive months or greater duration which is unrelated to exertion, which is not substantially relieved by rest and is not a result of other medical conditions.
  2. The fatigue causes a significant reduction of previous activity levels.
  3. Four or more of the following symptoms that concurrently last six months or longer:
    1. impaired memory or concentration
    2. post-exertional malaise, where physical or mental exertions bring on “extreme, prolonged exhaustion and sickness”
    3. unrefreshing sleep
    4. muscle pain (myalgia)
    5. pain in multiple joints (arthralgia)
    6. headaches of a new kind or greater severity
    7. sore throat, frequent or recurring
    8. tender lymph nodes (cervical or axillary)

The CDC states other common symptoms include the following:

  • brain fog (feeling like one is in a mental fog)
  • difficulty maintaining an upright position, dizziness, balance problems or fainting
  • allergies or sensitivities to foods, odors, chemicals, medications, or noise
  • irritable bowel syndrome-like symptoms such as bloating, stomach pain, constipation, diarrhea and nausea
  • chills and night sweats
  • visual disturbances (sensitivity to light, blurring, eye pain)
  • depression or mood problems (irritability, mood swings, anxiety, panic attacks)

The CDC proposes that persons with symptoms resembling those of CFS consult a physician to rule out several treatable illnesses: Lyme disease, sleep disorders, major depressive disorder, alcohol/substance abuse, diabetes, hypothyroidism, mononucleosis (mono), lupus, multiple sclerosis (MS), chronic hepatitis and various malignancies. Medications can also cause side effects that mimic symptoms of CFS.

Unlike the CDC’s diagnostic criteria for CFS, the International Consensus Criteria for ME do not require the 6-month waiting period before diagnosis, noting that “no other disease criteria require that diagnoses be withheld until after the patient has suffered the affliction for 6 months.”

Despite a common diagnosis the functional capacity of individuals with CFS varies greatly. Some persons with CFS lead relatively normal lives; others are totally bed-ridden and unable to care for themselves. For the majority of persons with CFS, work, school, and family activities are significantly reduced for extended periods of time. The severity of symptoms and disability is the same in both genders, and many experience strongly disabling chronic pain. Persons report critical reductions in levels of physical activity. Also, a reduction in the complexity of activity has been observed. Reported impairment is comparable to other fatiguing medical conditions including late-stage AIDS, lupus, rheumatoid arthritis, chronic obstructive pulmonary disease (COPD), and end-stage renal disease. 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.

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.

Employment rates vary with over half unable to work and nearly two-thirds limited in their work because of their illness. More than half were on disability benefits or temporary sick leave, and less than a fifth worked full-time.

Cognitive Functioning
Cognitive symptoms are mainly from deficits in attention, memory and reaction time. The deficits are in the range of 0.5 to 1.0 standard deviations below expected and are likely to affect day-to-day activities. Simple and complex information processing speed and functions entailing working memory over long time periods were moderately to extensively impair. These deficits are generally consistent with those reported by patients. Perceptual abilities, motor speed, language, reasoning and intelligence did not appear to be significantly altered.

Many CFS patients will also have, or appear to have, other medical problems or related diagnoses. Fibromyalgia occurs in a large percentage of CFS patients between onset and the second year, and some researchers suggest fibromyalgia and CFS are related. As previously mentioned, many CFS sufferers also experience symptoms of irritable bowel syndrome, temporomandibular joint pain, headache including migraines, and other forms of myalgia. CFS patients have significantly higher rates of current mood disorders than the general population. Compared with the non-fatigued population, male CFS patients are more likely to experience chronic pelvic pain syndrome (CP/CPPS), and female CFS patients are also more likely to experience chronic pelvic pain. CFS is significantly more common in women with endometriosis compared to women in the general US population.

Risk Factors

All ethnic groups and income levels are susceptible to the illness. The CDC states that ME/CFS is “at least as common” in African Americans and Hispanics as Caucasians. A 2009 meta-analysis, however, showed that compared with the White American majority, African Americans and Native Americans have a higher risk of CFS, though it acknowledged that studies and data were limited. More women than men get CFS — between 60 and 85% of cases are women; however, there is some indication that the prevalence among men is underreported. The illness is reported to occur more frequently in people between the ages of 40 and 59. CFS is less prevalent among children and adolescents than adults. Blood relatives of people who have CFS appear to be more predisposed. There is no direct evidence that CFS is contagious.

A systematic review in 2008 included eleven primary studies that had assessed various demographic, medical, psychological, social and environmental factors to predict the development of CFS, and found many had reported significant associations to CFS. The reviewers concluded that the lack of generalizability and replication between studies meant that “none of the identified factors appear suitable for the timely identification of patients at risk of developing CFS/ME within clinical practice.”


The causes of chronic fatigue syndrome are currently unknown. Research studies have developed and explored etiological hypotheses regarding a variety of factors, including oxidative stress, genetic predisposition, infection by viruses and pathogenic bacteria, hypothalamic-pituitary-adrenal axis abnormalities, immune dysfunction as well as psychological and psychosocial factors. Although it is unclear whether such factors are causes or consequences of CFS (or both), various models have been proposed.

A substantial body of evidence points to the following abnormalities in the hypothalamic-pituitary-adrenal axis (HPA axis) in CFS patients: mild hypocortisolism, an attenuated diurnal variation in cortisol, enhanced cortisol negative feedback, and a blunted HPA axis responsiveness. It is unclear whether or not these disturbances play a primary role in the pathogenesis of CFS.

Persons diagnosed with the illness appear to have an abnormal immune response to exercise. Specifically, complement products are increased, larger oxidative stress is generated along with reduced anti-oxidant immune response, and larger interleukin-10 and toll-like receptor 4 gene expression are seen versus healthy controls. Many of these immune responses correlate with the symptom of post-exertional malaise.


There are no characteristic laboratory abnormalities to diagnose CFS, so testing is used to rule out other potential causes for symptoms. When symptoms are attributable to certain other conditions, the diagnosis of CFS is excluded. Important conditions and disorders to exclude are current/active major depression, schizophrenia, eating disorders such as anorexia nervosa and bulimia, bipolar disorder, alcohol abuse or other substance abuse. Current morbid obesity and active medical diseases need to be resolved and excluded before a diagnosis of chronic fatigue syndrome can be made.

Notable definitions include:

  • Centers for Disease Control and Prevention (CDC) definition (1994), the most widely used clinical and research description of CFS, is also called the Fukuda definition and is a revision of the Holmes or CDC 1988 scoring system. The 1994 criteria require the presence of four or more symptoms beyond fatigue, while the 1988 criteria require six to eight.
  • The ME/CFS 2003 Canadian Clinical working definition 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”.

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 Service in England and Wales, produced in 2007 by the National Institute for Health and Clinical Excellence (NICE).


Many people do not fully recover from CFS even with treatment. Cognitive behavioral therapy (CBT) and graded exercise therapy (GET) have shown moderate effectiveness in a number of randomized controlled trials. As many of the CBT and GET studies required visits to a clinic, those severely affected may not have been included. Two large surveys of patients indicated that pacing is a helpful intervention, or is considered useful by 82-96% of participants. A comprehensive rehabilitation program only rarely results in full recovery. Medication plays a minor role in management. No intervention has been proven effective in restoring the ability to work.


A systematic review of 14 studies that 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 less fatigue severity at baseline. Other factors were occasionally, but not consistently, related to outcome, including age at onset (5 of 16 studies), and attributing illness to a psychological cause and/or having a sense of control over symptoms (4 of 16 studies). 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.

A 2014 systematic review reported that estimates of recovery from CFS ranged between 0 to 66% in intervention studies and 2.6 to 62% in naturalistic studies. There was a lack of consensus in the literature on how recovery should be defined. “Recovery” was often based on limited assessments, less than a full restoration of health, and self-reports with a general lack of more objective measures, which when used, did not find significant changes in physical activity. The authors suggested that patients were still avoiding post-exertion symptom exacerbation, and could be clinically improving to a limited extent or adapting to ongoing illness rather than recovering. It was recommended using stricter and more comprehensive definitions of recovery which capture fatigue, function, patient perceptions and recovery time following physical and mental exertion.


A 2003 review states that studies have reported between 7 and 3,000 cases of CFS for every 100,000 adults.[5]Ranjith reviewed the epidemiological literature on CFS and suggested that the wide variance of the prevalence estimates may be due to the different definitions of CFS in use, the settings in which patients were selected, and the methodology used to exclude study participants with possible alternative diagnoses.[11] The Centers for Disease Control reports that more than 1 million Americans have CFS and approximately 80% of the cases are undiagnosed.[12] Approximately 250,000 people in the UK are affected with the illness according to the National Health Service.[13]

Society and Culture

A Depiction of CFS

Chronic fatigue syndrome is the most commonly used designation, but widespread approval of a name is lacking. Different authorities on the illness view CFS as a central nervous system, metabolic, infectious or post-infectious, cardiovascular, immune system or psychiatric disorder, and different symptom profiles may be caused by various disorders.

Over time and in different countries, many names have been associated with the condition(s). Aside from CFS, some other names used include Akureyri disease, benign myalgic encephalomyelitis, chronic fatigue immune dysfunction syndrome, chronic infectious mononucleosis, epidemic myalgic encephalomyelitis, epidemic neuro-myasthenia, Iceland disease, myalgic encephalomyelitis, myalgic encephalitis, myalgic encephalopathy, post-viral fatigue syndrome, raphe nucleus encephalopathy, Royal Free disease, Tapanui flu, and Yuppie Flu (the last considered pejorative). Many patients would prefer a different name such as “myalgic encephalomyelitis”, believing the name “chronic fatigue syndrome” trivializes the condition, prevents it from being seen as a serious health problem and discourages research.

A 2001 review referenced myalgic encephalomyelitis symptoms in a 1959 article by Acheson, stating ME could be a distinct syndrome from CFS. A 1999 review explained that the Royal Colleges of Physicians, Psychiatrists, and General Practitioners in 1996 advocated the use of chronic fatigue syndrome instead of myalgic encephalomyelitis or ME, which was in wide use in the United Kingdom, “because there is, so far, no recognized pathology in muscles and in the central nervous system as is implied by the term ME”. An editorial noted that the 1996 report received some acceptance, but also criticism from those advocating the use of different naming conventions, suggesting the report was biased, dominated by psychiatrists, and that dissenting voices were excluded. In 2002, a Lancet commentary noted the recent report by the “Working Group on CFS/ME” used the compromise name CFS/ME stating, “The fact that both names for the illness were used symbolizes respect for different viewpoints while acknowledging the continuing lack of consensus on a universally acceptable name.”

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 exhaustion after physical or mental exertion is a core symptom (also known as post-exertional malaise).

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

Social Issues
A study found that CFS patients report a heavy psychosocial burden. A survey by the Tymes Trust reported that children with CFS often state that they struggle for recognition of their needs or they feel bullied by medical and educational professionals.

Social Support
Individuals with CFS may receive a poorer quality of social support than in those with other illnesses. One study found that CFS patients reported an increased incidence of negative/unsatisfying interactions with family, friends, colleagues and doctors, when compared with healthy controls and breast cancer patients currently in remission.

Awareness Day
May 12 is designated as International Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Awareness Day (ME/CFS). The day is observed so that stakeholders have the opportunity to improve the knowledge of “the public, policymakers and healthcare professionals of the symptoms, diagnosis and treatment of ME/CFS, as well as the need for a better understanding of this complex illness.”

Doctor–Patient Relations
Some in the medical community do not recognize CFS as a real condition, nor is there agreement on its prevalence. There has been much disagreement over proposed causes, diagnosis, and treatment of the illness. This uncertainty can significantly affect doctor-patient relations. A 2006 survey of general medical practitioners in southwestern part of the UK found that despite more than two thirds 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 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.

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

From the patient’s perspective, a 1997 study found that 77% of individuals with ME/CFS reported negative experiences with health care providers. In a more recent metanalysis of qualitative studies, a major theme identified in patient discourses was that they felt severely ill, yet blamed and dismissed. 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.

Blood Donation
Based on the possible link between CFS and XMRV, in 2010 a variety of national blood banks adopted measures to discourage or prohibit individuals diagnosed with CFS from donating blood. Organizations adopting these or similar measures included the Canadian Blood Services, the New Zealand Blood Service, the Australian Red Cross Blood Service and the American Association of Blood Banks. 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. Donation policy in the UK now states, “CFS is generally diagnosed by excluding other conditions and may follow an infection that may or may not have been viral and which may be carried by the affected individual.”

There has been much contention over the etiology, pathophysiology, nomenclature, and diagnostic criteria of chronic fatigue syndrome. 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. Controversies still exist over funding for research and treatment of physiological versus psychological/psychosocial aspects of the illness.


The different case definitions used to research the illness influence the types of patients selected for studies and research also suggests subtypes of patients may exist within a heterogeneous population. In one of the definitions, symptoms are accepted that may suggest a psychiatric disorder while others specifically exclude primary psychiatric disorders. 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”.