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Myalgic encephalomyelitis/chronic fatigue syndrome
Specialty	Neurology, rheumatology

Chronic fatigue syndrome (CFS) is the most common name given to a poorly understood, variably debilitating disorder or disorders of uncertain causation.

Symptoms of CFS include widespread muscle & joint pain, cognitive difficulties, chronic, often severe mental and physical exhaustion and other characteristic symptoms in a previously healthy and active person. Fatigue is a common symptom in many illnesses, but CFS is a multi-systemic disease and is relatively rare by comparison. Diagnosis (other than the 1991 UK Oxford criteria) requires a number of features, the most common being severe mental and physical exhaustion which is "unrelieved by rest" (1994 Fukuda definition), and may be worsened by even trivial exertion (a mandatory diagnostic criterion according to some systems). Most diagnostic criteria require that symptoms must be present for at least six months, and all state the symptoms must not be caused by other medical conditions. CFS patients may report many symptoms which are not included in all diagnostic criteria, including muscle weakness, cognitive dysfunction, hypersensitivity, orthostatic intolerance, digestive disturbances, depression, poor immune response, and cardiac and respiratory problems. It is unclear if these symptoms represent co-morbid conditions or are produced by an underlying etiology of CFS. The condition may be managed rather than treated, with full resolution in only 5-10% of cases.

CFS is thought to have an incidence of 4 adults per 1,000 in the United States. For unknown reasons, CFS occurs more often in women than men, and in people in their 40s and 50s. The illness is estimated to be less prevalent among children and adolescents, but studies are contradictory as to the degree. Despite promising avenues of research there remains no medical test which is widely accepted to be diagnostic of CFS. It remains a diagnosis of exclusion based largely on patient history and symptomatic criteria, although a number of tests can aid diagnosis.

Whereas there is agreement on the genuine threat to health, happiness, and productivity posed by CFS, various physicians groups, researchers, and patient activists promote different nomenclature, diagnostic criteria, etiologic hypotheses, and treatments, resulting in controversy about nearly all aspects of the disorder. The name CFS itself is controversial, as advocacy groups as well as some experts feel it trivializes the illness and have supported efforts to change it. The World Health Organization's ICD uses the terms post-viral fatigue syndrome and benign myalgic encephalomyelitis. Another alternative name for CFS is chronic fatigue immune dysfunction syndrome.

Nomenclature

The nomenclature of the condition(s) has been challenging, since consensus is lacking within the clinical, research, and patient communities regarding its defining features and causes. Authorities on the illness look upon the condition as a central nervous system, metabolic, (post-)infectious, cardiovascular, immune system or psychiatric disorder, and consider the possibility that it is not a single homogenous disorder (with a range of possible clinical presentations), but a group of several distinct disorders with many clinical characteristics in common.

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 neuromyasthenia, Iceland disease, myalgic encephalomyelitis (ME, particularly in the United Kingdom, Canada, New Zealand and Australia), myalgic encephalitis, myalgic encephalopathy, post-viral fatigue syndrome, raphe nucleus encephalopathy, Royal Free disease, Tapanui flu and yuppie flu (now considered pejorative).

Signs and symptoms

Onset

The majority of CFS cases start suddenly, usually accompanied by a "flu-like illness" which is more likely to occur in winter, while a significant proportion of cases begin within several months of severe adverse stress. Because some people have a case of flu-like or other respiratory infection such as bronchitis, from which they seem never to fully recover, an Australian research group states that post-viral fatigue syndrome could be a subset of CFS. The accurate prevalence and exact roles of infection and stress in the development of CFS however are currently unknown.

Symptoms

It can be inferred from the 2003 Canadian clinical working definition of the disorder (referred to as ME/CFS) that there are 8 categories of symptoms:

• Fatigue: Unexplained, persistent, or recurrent physical and mental fatigue/exhaustion that substantially reduces activity levels and is not relieved (or not completely relieved) by rest.
• Post-exertional malaise: An inappropriate loss of physical and mental stamina, rapid muscular and cognitive fatigability, post exertional malaise and/or fatigue and/or pain and a tendency for other associated symptoms to worsen with a pathologically slow recovery period of usually 24 hours or longer. According to the authors of the Canadian clinical working definition of ME/CFS, the malaise that follows exertion is often reported to be similar to the generalized pain, discomfort and fatigue associated with the acute phase of influenza. Although common in CFS, this may not be the most severe symptom in the individual case, where other symptoms (such as headaches, dizziness, neurocognitive difficulties, pain and sleep disturbances) can dominate.
• Sleep dysfunction: "Unrefreshing" sleep/rest, poor sleep quantity, insomnia or rhythm disturbances. A study found that most CFS patients have clinically significant sleep abnormalities that are potentially treatable. Several studies suggest that while CFS patients may experience altered sleep architecture (such as reduced sleep efficiency, a reduction of deep sleep, prolonged sleep initiation, and alpha-wave intrusion during deep sleep) and mildly disordered breathing, overall sleep dysfunction does not seem to be a critical or causative factor in CFS. Sleep may present with vivid disturbing dreams, and exhaustion can worsen sleep dysfunction.

• Pain: Pain is often widespread and migratory in nature, including a significant degree of muscle pain and/or joint pain (without joint swelling or redness, and may be transitory). Other symptoms include headaches (particularly of a new type, severity, or duration), lymph node pain, sore throats, and abdominal pain (often as a symptom of irritable bowel syndrome). Patients also report bone, eye and testicular pain, nerve pain and painful skin sensitivity. Chest pain has been attributed variously to microvascular disease or cardiomyopathy by researchers, and many patients also report painful tachycardia. A systematic review assessing the studies of chronic pain in CFS found that although the exact prevalence is unknown, it is strongly disabling in patients, but unrelated to depression.

• Neurological/cognitive manifestations: Common occurrences include confusion; forgetfulness; mental fatigue/brain fog; impairment of concentration and short-term memory consolidation; disorientation; difficulty with information processing, categorizing and word retrieval; perceptual and sensory disturbances (e.g. spatial instability and disorientation and inability to focus vision); ataxia (unsteady and clumsy motion of the limbs or torso); and muscle weakness and "twitches". There may also be cognitive or sensory overload (e.g. photophobia and hypersensitivity to noise and/or emotional overload, which may lead to "crash" periods and/or anxiety). A review of research relating to the neuropsychological functioning in CFS was published in 2001 and found that slowed processing speed, impaired working memory and poor learning of information are the most prominent features of cognitive dysfunctioning in patients with CFS, which couldn't be accounted solely by the severity of the depression and anxiety.

• Autonomic manifestations: Common occurrences include orthostatic intolerance, neurally mediated hypotension (NMH), postural orthostatic tachycardia syndrome (POTS), delayed postural hypotension, lightheadedness, extreme pallor, nausea and irritable bowel syndrome, urinary frequency and bladder dysfunction, palpitations with or without cardiac arrhythmias, and exertional dyspnea (perceived difficulty breathing or pain on breathing).

• Neuroendocrine manifestations: Common occurrences include poor temperature control or loss of thermostatic stability, subnormal body temperature and marked daily fluctuation, sweating episodes, recurrent feelings of feverishness and cold extremities, intolerance of extremes of heat and cold, digestive disturbances and/or marked weight change - anorexia or abnormal appetite, loss of adaptability and worsening of symptoms with stress.

• Immune manifestations: Common occurrences include tender lymph nodes, recurrent sore throat, recurrent flu-like symptoms, general malaise, new sensitivities to food and/or medications and/or chemicals (which may complicate treatment). At least one study has confirmed that most CFS patients reduce or cease alcohol intake, mostly due to personal experience of worsening symptoms (although the cause of this is unknown and may not be strictly "immunological" as implied by the symptom list).

Activity levels

Patients report critical reductions in levels of physical activity and are as impaired as persons whose fatigue can be explained by another medical or a psychiatric condition. According to the CDC, studies show that the degree of functional impairment in some CFS patients may be comparable with other chronic medical conditions such as multiple sclerosis, lupus, rheumatoid arthritis, heart disease, end-stage renal failure and chronic obstructive pulmonary disease (COPD). The severity of symptoms and disability is the same in both genders, and chronic pain is strongly disabling in CFS patients, but despite a common diagnosis the functional capacity of CFS patients varies greatly. While some patients are able to lead a relatively normal life, others are totally bed-bound and unable to care for themselves. A systematic review found that in a synthesis of studies, 42% of patients were employed, 54% were unemployed, 64% reported CFS-related work limitations, 55% were on disability benefits or temporary sick leave, and 19% worked full-time.

Causes and pathophysiology

The mechanisms and processes (pathogenesis) of Chronic Fatigue Syndrome are unknown, but are the subjects of many research studies, including physiological and epidemiological studies. Searching for the etiology and pathological pathways of CFS is complicated since sub-groups of patients may have different causes for a convergent set of symptoms of CFS that produces a common clinical outcome. Hypotheses being researched include viral infection, hypothalamic-pituitary-adrenal axis abnormalities (though it is unclear if this is a cause, or consequence, of CFS), immune dysfunction, mental and psychosocial factors causing or contributing towards CFS. Because of social prejudices assuming that psychological disorders are not biological or "real", many patients object to the idea that the CFS is a mental disorder. Other hypotheses include oxidative stress and genetic predisposition.

Some researchers say that exposure to chemicals, infectious agents, stress, and other insults in early life may be a component of later-life CFS. Another idea is that a virus or another infectious agent might provoke an abnormal immune response in some people that does not get switched off and becomes chronic.

The central nervous system is important in CFS. Research has been reported on a "Hyperserotonergic state and hypoactivity of the hypothalamic-pituitary-adrenal axis (HPA axis)" in CFS. Genetic factors may be the basis for some of these changes. A 2008 study of gene polymorphisms indicates genetic predisposition possibly resulting in enhanced activity of serotonin. Another report says that low cortisol levels can be responsible: "hypocortisolaemia might sensitize the hypothalamic-pituitary-adrenal axis to development of persistent central fatigue after stress."

Some researchers conclude from these reports that nervous and immune system involvements are not separate. "Nervous and immune systems mutually cooperate via release of mediators of both neurological and immunological derivation. Hormone (ACTH) is a product of the HPA axis which stimulates secretion of corticosteroids from adrenals. In turn, corticosteroids modulate the immune response by virtue of their anti-inflammatory activity. On the other hand, catecholamines, products of the sympathetic nervous system (SNS), regulate immune function by acting on specific beta-adrenergic receptors. Conversely, cytokines released by certain immune cells, upon stimulation, are able to cross the blood-brain-barrier, thus modulating nervous functions (e.g., thermoregulation, sleep, and appetite). However, cytokines are locally produced in the brain, especially in the hypothalamus, thus contributing to the development of appetite, thermoregulation, sleep and behavioural effects. Besides pathogens and/or their products, the so-called stressors are able to activate both HPA axis and SNS, thus influencing immune responses."

Clinical descriptions

Among several competing clinical descriptions of CFS, some of the most notable are:

• The Ramsay definition (1986)

• The Holmes et al (1988) scoring system, sometimes called "CDC 1988"

• The Oxford criteria (1991)

• The "Fukuda" CDC definition (1994), or "CDC 1994"

• The Carruthers et al (2003) Canadian Case definition for ME/CFS

• The NICE (UK) 2007 criteria, a multidisciplinary clinical practice guideline published in 2007 by the UK's National Institute for Health and Clinical Excellence (NICE)

Case definitions in CFS have largely been established to define patients for research study purposes, and have certain limitations when used for general practitioner purposes. Several studies have found that using different case definitions ( eg broad vs conservative ) has major influence on the types of patients selected and have also supported the distinction between specific subgroups of CFS to be identified and/or for the case definition to be further clarified with emphasis on using empirical studies: An international CFS study group for the CDC found in 2003 that ambiguities in the CDC 1994 CFS research case definition contribute to inconsistent case identification.

There is no conclusive diagnostic test for CFS, and testing is generally used to rule out other potential causes for symptoms.

Clinical practice guidelines, with the aim of improving diagnosis, several countries have now produced these, which are generally based on case descriptions but these documents have the aim of guiding decisions and criteria regarding diagnosis, management, and treatment. Modern medical guidelines are based on an examination of current evidence within the paradigm of evidence-based medicine and they usually include summarized consensus statements. Guidelines are usually produced at national or international levels by medical associations or governmental bodies.

Management

Many patients do not fully recover from CFS, even with treatment. Some management strategies are suggested to reduce the consequences of having CFS. Medications, other medical treatments, and complementary and alternative medicine are considered.

Psychological therapy

Perhaps the most effective management strategy for CFS is cognitive behavioral therapy (CBT), a form of psychological therapy. A meta-analysis of 15 randomized, controlled cognitive behavioral therapy trials with 1043 participants concluded that psychological therapy had significantly better results than standard therapies of CFS. In this analysis, CBT also worked better than other types of psychological therapies. CBT has special value for treating medically unexplained symptoms (MUS) like CFS according to Deary et al. who write, "a broadly conceptualized cognitive behavioural model of MUS suggests a novel and plausible mechanism of symptom generation and has heuristic value."

Exercise therapy

Meta-analysis of multiple randomized, controlled trials of exercise therapy of patients diagnosed with CFS shows improvements in fatigue symptoms over controls. Some patient organisations dispute the results of the CBT and exercise therapies.

Other

Medications thought to have promise in alleviating stress-related disorders include antidepressant and immunomodulatory agents "such as staphypan Berna, lactic acid bacteria, kuibitang and intravenous immunoglobulin. CFS patients are less susceptible to placebo effects than predicted, and have a low placebo response compared to patients with other diseases. CFS is associated with chemical sensitivity, and some patients often respond to a fraction of a therapeutic dose that is normal for other conditions.

Additional therapies recommended by different sources include adaptive pacing, therapies based on the "envelope theory", and Yoga.

Prognosis

Recovery

A systematic review of 14 studies of the outcome of untreated 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." It is not known whether any patients truly "recover" entirely from the illness, or achieve remission from a relapsing, remitting illness. Few untreated patients report a total "cure".

Deaths

CFS is unlikely to increase the risk of an early death. A systematic review of 14 studies of the outcome of CFS reported 8 deaths, but none were considered directly attributable to CFS. To date there have been two studies directly addressing life expectancy in CFS. In a preliminary 2006 study of CFS self-help group members, it was reported that CFS patients were likely to die at a younger than average age for cancer, heart failure, and suicide. However, a much larger study of 641 CDC criteria diagnosed patients with CFS, who were followed up for a mean of 9 years, showed no excess risk of dying from any cause.

People diagnosed with CFS may die, as in the case in the UK of Sophia Mirza, where the coroner recorded a verdict of "Acute anuric renal failure due to dehydration arising as a result of CFS." According to Sophia's mother, Sophia became intolerant to water and managed only 4 fluid ounces per day. The pathologist said, "ME describes inflammation of the spinal cord and muscles. My work supports the inflammation theory...The changes of dorsal root ganglionitis seen in 75% of Sophia's spinal cord were very similar to that seen during active infection by herpes viruses." This was seen as a form of recognition by the ME community. Previous cases have listed CFS as the cause of death in the US and Australia

Epidemiology

Due to problems with the definition of CFS, estimates of its prevalence vary widely. Studies in the United States have previously found between 75 and 420 cases of CFS for every 100,000 adults. The CDC states that more than 1 million Americans have CFS and approximately 80% of the cases are undiagnosed. All ethnic and racial groups appear susceptible to the illness, and lower income groups are slightly more likely to develop CFS. 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. Blood relatives of people who have CFS appear to be more predisposed. However, CFS is not contagious. Caretakers, partners and others in close contact with persons with CFS for years do not develop CFS any more frequently (excluding blood relatives, as earlier).

Epidemiological research on children and adolescents has received minimal focus according to a 2006 research review. Among minors, prevalence appears to be lower than for adults and various studies have found a range of 50-80% of the cases occur in girls. The authors hypothesize the differences in estimates of ME/CFS among pediatric studies may result because of the lack of a reliable pediatric case definition.

Disease associations

Some diseases show a considerable overlap with CFS. According to an article in American Family Physician in 2002, Multiple Sclerosis, Thyroid disorders, anemia, and diabetes are but a few of the diseases that must be ruled out if the patient presents with appropriate symptoms.

People with fibromyalgia (FM, or Fibromyalgia Syndrome, FMS) have muscle pain and sleep disturbances. Fatigue and muscle pain occurs frequently in the initial phase of various hereditary muscle disorders and in several autoimmune, endocrine and metabolic syndromes; and are frequently labelled as CFS or fibromyalgia in the absence of obvious biochemical/metabolic abnormalities and neurological symptoms. Those with multiple chemical sensitivity (MCS) are sensitive to chemicals and have sleep disturbances. Many veterans with Gulf War syndrome (GWS) have symptoms almost identical to CFS. One study found several parallels when relating the symptoms of Post-polio syndrome with CFS, and postulates a possible common pathophysiology for the illnesses.

Although post-Lyme syndrome and CFS share many features/symptoms, a study found that patients of the former experience more cognitive impairment and the patients of the latter experience more flu-like symptoms.

One review (2006) found that there was a lack of literature to establish the discriminant validity of undifferentiated somatoform disorder from CFS. The author stated that there is a need for proponents of chronic fatigue syndrome to distinguish it from undifferentiated somatoform disorder. The author also mentioned that the experience of fatigue as exclusively physical and not mental is captured by the definition of somatoform disorder but not CFS. Hysterical diagnoses are not merely diagnoses of exclusion but require criteria to be met on the positive grounds of both primary and secondary gain. Primary Depression can be excluded in the differential diagnosis due to the absence of anhedonia and la belle indifference, the variability (lability) of mood, and the presence of sensory phenomena and somatic signs such as ataxia, myclonus and most importantly, exercise intolerance with paresis, malaise and general deterioration. Feeling depressed is also a commonplace reaction to the losses caused by chronic illness which can in some cases become a comorbid situational depression.

Co-morbidity

Many CFS patients will also have, or appear to have, other medical problems or related diagnoses. Co-morbid fibromyalgia is common, although there are differences in pain complaints. Fibromyalgia occurs in a large percentage of CFS patients between onset and the second year, and some researchers suggest fibromyalgia and CFS are related. Similarly, multiple chemical sensitivity (MCS) is reported by many CFS patients, and it is speculated that these similar conditions may be related by some underlying mechanism, such as elevated nitric oxide/peroxynitrite. As previously mentioned, many CFS sufferers also experience symptoms of irritable bowel syndrome, temporomandibular joint pain, headache including migraines, and other forms of myalgia. Clinical depression and anxiety are also commonly co-morbid. 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 with women in the general USA population.

Social issues

Many patients report that a chronic fatigue syndrome diagnosis carries a considerable stigma, and has frequently been viewed as malingering, hypochondria, phobia, "wanting attention" or "yuppie flu". As there is no objective test for the condition at this time, it has been argued that it is easy to invent or feign CFS-like symptoms for financial, social, or emotional benefits. CFS sufferers argue in turn that the perceived "benefits" are hardly as generous as some may believe, and that CFS patients would greatly prefer to be healthy and independent. A study found that CFS patients endure a heavy psychosocial burden. 2,338 respondents of a survey by a UK patient organization highlights that those with the worst symptoms often receive the least support from health and social services. A study found that CFS patients receive worse social support than disease-free cancer patients or healthy controls, which may perpetuate fatigue severity and functional impairment in CFS. A survey by the Thymes Trust found that children with CFS often state that they struggle for recognition of their needs and/or they feel bullied by medical and educational professionals. The ambiguity of the status of CFS as a medical condition may cause higher perceived stigma. A study suggests that while there are no gender differences in CFS symptoms, men and women have different perceptions of their illness and are treated differently by the medical profession. Anxiety and depression often result from the emotional, social and financial crises caused by CFS. While few studies have been made, it is believed that CFS patients are at a high risk of suicide.

History

Attempts to describe conditions similar to CFS date back to at least the 17th century.

A major outbreak of a condition similar to CFS in 1934 at the Los Angeles County Hospital infected all or most of its nurses and doctors. It was referred to as Atypical Poliomyelitis, and was generally believed to be a form of polio.

The outbreak that gave rise to the name Benign Myalgic Encephalomyelitis (see Chronic fatigue syndrome outbreaks) occurred at London's Royal Free Hospital in 1955, inflicting mostly the hospital staff, and formed the basis of descriptions by Achenson, Ramsay, and others.

(Benign) Myalgic Encephalomyelitis was first classified into the International Classification of Diseases in 1969 under Diseases of the nervous system.

The name Chronic Fatigue Syndrome has been attributed to the 1988 article, "Chronic fatigue syndrome: a working case definition", (Holmes definition). This research case definition was published after US Centers for Disease Control epidemiologists examined patients at the Lake Tahoe outbreak.

In 2006 the CDC estimated there were more than 1 million cases of CFS in the US and commenced a public awareness program.

Since inception, the condition has been steeped in controversy. Despite continuous research and many findings, indicating also likely subsets of patients, the present state of study on this condition is fragmented and contentious.

Controversy

CFS is an illness with a long history of controversies. The name "chronic fatigue syndrome" itself is not universally accepted and is believed by some patients and advocacy groups to trivialize the illness. In addition, different countries and medical systems use different names to describe the condition - myalgic encephalomyelitis was first used in 1956 and is currently used by the ICD and in the United Kingdom while in the United States, CFS is the dominantly-used term. In other parts of the world the terminology may not be fixed and could be used interchangeably. It is also uncertain and controversial whether CFS is a single condition, or several conditions that produce a similar set of symptoms due to different causes.

For years, many professionals within the medical community did not recognize CFS as a real condition, nor was there agreement on its prevalence. There has been much disagreement over proposed causes, diagnosis, and treatment of the illness. The context of contested causation may affect the lives of the individuals diagnosed with CFS, affecting the patient-doctor relationship, the doctor's confidence in their ability to diagnose and treat, ability to share issues and control in diagnosis with the patient, and raise problematic issues of reparation, compensation, and blame. The etiology is unknown and a major divide exists over whether funding for research and treatment should focus on physiological, psychological or psychosocial aspects of CFS. The division is especially great between patient groups and psychological and psychosocial treatment advocates in Great Britain. Sufferers describe the struggle for healthcare and legitimacy due to bureaucratic denial of the condition because of its lack of a known etiology. Disagreements over how the condition is dealt with by health care systems has resulted in an expensive and prolonged conflict for all involved.

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