Chronic Fatigue

Chronic fatigue syndrome (CFS), also known as myalgic encephalomyelitis (ME), post-viral fatigue syndrome (PVFS) and various other names, is a syndrome of unknown and possibly multiple etiology, affecting the central nervous system (CNS), immune, and many other systems and organs. Most definitions other than the 1991 UK "Oxford", require a number of features, the most common being severe mental and physical depletion, which according to the 1994 Fukuda definition is "unrelieved by rest", and is usually made worse by even trivial exertion (controversially the Oxford and Fukuda require this to be optional only). However, patients usually contend that they have many, often severe symptoms which are far more onerous than the research diagnostic criteria, such as pain, muscle weakness, loss of brain function, hypersensitivity, orthostatic intolerance, digestive disturbances, depression, immune and in some cases life-threatening cardiac and respiratory problems, and it is these symptoms exacerbated by extremely low stamina that cause greatest suffering, not "fatigue", which more properly describes a normal state of recovery unrelated to pathology. Some cases resolve or improve over time, and where available, treatments bring a degree of improvement to many others.

Contents
1 History
2 Nomenclature
3 Symptoms
4 Course
4.1 Onset
4.1.1 Sudden onset cases
4.1.2 Gradual onset
4.2 Activity levels
4.3 Post-exertion symptom exacerbation
4.4 Duration
5 Diagnosis
5.1 CDC 1994 criteria (aka "Fukuda")
5.1.1 Primary symptom: incapacitating fatigue
5.1.2 Additional symptoms
5.2 Other systems
5.3 Controversies
6 Epidemiology
7 Disease associations
8 Co-morbidity
9 Proposed etiologies and corresponding treatments 
 
History
Originally studied since the late 1930s as an immunological neurological disorder under the medical term "myalgic encephalomyelitis" (ME), CFS has been classified by the World Health Organization (WHO) as a disease of the central nervous system since 1969. In 1992 and early 1993 the terms "post-viral fatigue syndrome" (PVFS) and "chronic fatigue syndrome" (CFS) were added to ME under the exclusive ICD-10 designation of G93.3.

Nomenclature
There are a number of different terms which have been at various times identified with this organic neuroimmune disorder.

Myalgic encephalomyelitis (ME, "inflammation of the brain and spinal cord with muscle pain") as a disease entity has been recognized and described in the medical literature since 1938, with the seminal paper being that by Wallis in 1957; Sir Donald Acheson's (a former Chief Medical Officer) major review of ME was published in 1959; in 1962 the distinguished neurologist Lord Brain included ME in his textbook of neurology, and in 1978 the Royal Society of Medicine accepted ME as a distinct clinical entity. In 1988 both the UK Department of Health and Social Services and the British Medical Association officially recognized it as a legitimate and potentially distressing disorder. Opponents to the term ME maintain there is no inflammation and that not all patients report muscle pain. United Kingdom and Canadian researchers and patients generally use this term in preference to CFS.
Chronic fatigue syndrome (CFS); this name was introduced in 1988 by a group of United States researchers based at the Centers for Disease Control and Prevention, and is used increasingly over other designations, particularly in the United States.
Chronic fatigue immune dysfunction syndrome (CFIDS); many people, especially patients in the United States, use the term CFIDS (pronounced [See-Fids]), which was originally an acronym for the above or "Chronic Fatigue & Immune Dysregulation Syndrome". This term was introduced by patients current with the biomedical research in an attempt to reduce the psychiatric stigma attached to "chronic fatigue", as well as the public perception of CFS as a psychiatric syndrome.
Post-viral [fatigue] syndrome (PVS or PVFS); this is a related disorder. According to original ME researcher Dr. Melvin Ramsay, "The crucial differentiation between ME and other forms of post-viral fatigue syndrome lies in the striking variability of the symptoms not only in the course of a day but often within the hour. This variability of the intensity of the symptoms is not found in post-viral fatigue states" (Ramsay 1989).
Chronic Epstein-Barr virus (CEBV) or Chronic Mononucleosis; the term CEBV was introduced by virologists Dr. Stephen Straus and Dr. Jim Jones in the United States. The Epstein-Barr virus, a neurotropic virus that more commonly causes infectious mononucleosis, was thought by Straus and Jones to be the cause of CFS. Subsequent discovery of the closely related human herpesvirus 6 shifted the direction of biomedical studies, although a vastly expanded and substantial body of published research continues to show active viral infection or reinfection of ME/CFS patients by these two viruses. As these viruses are also found in healthy controls, however, it is uncertain what role they play in CFS.
Low Natural Killer cell disease; this name is used widely in Japan. It reflects research showing a reduction in the number of natural killer cells in many CFS patients.
Yuppie Flu; this was a factually inaccurate nickname for CFS, first published in a November 1990 Newsweek article. It reflects the belief that CFS mainly affects the affluent ("yuppies"), and implies that it is a form of malingering or burnout. CFS, however, affects people of all races, genders, and social standings, and this nickname is inaccurate and considered offensive by patients. It is likely that this article contributed to the damaging public (and even medical) perception of CFS as a psychiatric or even psychosomatic condition.
Uncommonly used terms include Akureyri Disease, Iceland disease (in Iceland), Royal Free disease (after the location of an outbreak), raphe nucleus encephalopathy, and Tapanui flu (after the New Zealand town Tapanui where a doctor who investigated the disease lived).

Symptoms
According to the 1994 Fukuda definition there are eight main categories of symptoms in CFS:

Fatigue: People with CFS experience profound, overwhelming exhaustion, both mental and physical, which is worsened by exertion, and is not relieved (or not completely relieved) by rest. To receive a diagnosis of CFS, this fatigue state must last for six months.
Pain: Pain in CFS may include muscle pain, joint pain (without joint swelling or redness, and may be transitory), headaches (particularly of a new type, severity, or duration), lymph node pain, sore throats, and abdominal pain (as a symptom of irritable bowel syndrome). Patients also report; bone, eye and testicular pain, neuralgia and painful skin sensitivity. Chest pain has been attributed variously to microvascular disease or cardiomyopathy by researchers.
Cognitive problems: people with CFS may experience forgetfulness, confusion, difficulty thinking, concentration difficulties, and "mental fatigue" or "brain fog". Additional signs may be experienced; in the 2003 Canadian Definition these include aphasia, agnosia, loss of cognitive body map.
Hypersensitivity: people with CFS are often sensitive to light, sound, and some chemicals and foods. Many CFS patients report an increase in allergic-type sensitivity to foods, scents, and products, and many also report a sensitivity to medications, which can complicate treatment. Patients with pre-existing allergies, asthma, and similar conditions often report a worsening of symptoms. A remarkable feature of "classically defined" ME are "sensory storms", typified by sudden catastrophic incapacitation to noise, light, smell, which feels overwhelming; more pronounced as discrete earlier on in the illness.
Poor temperature control: people with CFS often report either running too hot or too cold, possibly due to involvement of the hypothalamus, which regulates body temperature. Many CFS patients frequently run a low fever, or report fever-like symptoms (sweating, feeling too hot or cold, etc.) without measurable fever temperature.
Sleep problems: "Unrefreshing sleep" and rest is a hallmark of CFS, and in one of the syndrome's greatest ironies, insomnia is also common, especially in the chronic phase. Maintaining a sleep schedule is extremely difficult for many patients. Vivid, "feverish" dreams are a symptom in many people with CFS, exacerbating disturbed sleep patterns. A hallmark sign of neurological disease is that exercise worsens the insomnia, i.e. the opposite to that found in well people.
Psychological/Psychiatric symptoms: emotional lability, anxiety, depression, irritability, sometimes a curious emotional "flattening", may manifest in CFS patients. It is undetermined whether any of these are directly caused by the CFS mechanism, or may be secondary symptoms created by the syndrome, as many chronic pain or illness patients also show similar psychiatric issues. However the exaggerated and sometimes random nature of emotional expression is consistent with some brain disease.
Disturbances in the autonomic nervous system and hormones:
People with CFS often have abnormalities in the autonomic nervous system such as low blood volume, orthostatic intolerance, dizziness and light-headedness, especially when standing up quickly.
Hormonal abnormalities may include abnormal vasopressin metabolism and a blunted ACTH response leading to hypothyroidism and/or low cortisol and reduced ability to respond to physiological and emotional stress. Patients sometimes show abnormally low levels of testosterone, growth hormone and other important hormones.
It should be noted that lists of diagnostic criteria (such as the Oxford and Fukuda lists) were designed for selection and exclusion of participants for research studies and, as such, are quite narrow in scope. Some patients have CFS despite the fact that their symptoms do not match the strict research diagnostic criteria.

Course

Onset
Some cases of CFS start gradually, but the majority start suddenly, often triggered by a 'flu-like viral or similar illness. People with CFS may improve or recover completely after a few or many years, or not at all. It is not known whether any CFS sufferer has truly recovered to pre-illness levels, or whether their symptoms have merely subsided enough for them to live a more normal life. Some sufferers have a remission for months or years only to later relapse, often more severely.

Sudden onset cases
Many people with CFS report a sudden, drastic start to their illness. Some people can remember a specific day or even hour when they first became ill.

Often CFS starts with, or is triggered by, another illness. Many people report getting a case of the 'flu', exposure to an allergen (a cough or sniffle caused by paint, a new pet, or construction dust), or a severe infection such as bronchitis, from which they seem never to fully recover and which slowly evolves into CFS. Other patients begin with Lyme disease, which despite adequate Lyme treatment, may 'evolve' from the clinical symptoms and definition of Lyme to those of CFS (this is permitted by the Fukuda definition). Other triggers can include car accidents, moving house, and stressful life situations. Some patients say they felt unusual or uneasy for a short period (days or weeks) before the onset.

Gradual onset
Other cases have a very slow, gradual onset, sometimes spread over years. People with gradual onsets may not realize there is anything wrong for quite some time. Patients may believe they have a minor illness, or ascribe their weakened condition to stress, and assume they will improve with time. It is only when the patient realized that their condition is truly debilitating, or the stress is removed and the symptoms remain, that the patient will begin to seek treatment.

There is no standard course for CFS. For a patient to be officially diagnosed with chronic fatigue syndrome, the symptoms must have persisted for at least six months. It is possible that not all cases of CFS are chronic: some people may have CFS for four months, recover, and never get diagnosed, some claim. However, the Fukuda paper also contains a definition of "chronic fatigue" which is reserved for those who do not meet the full criteria for CFS. Since the 50% rule of Holmes et al was dropped, it is possible that there are people with CFS whose level of disability is so low that they never seek treatment, or receive an accurate diagnosis, though this is not permitted by the Canadian definition.

Activity levels
Activity levels vary widely among CFS patients. While some are able to lead a relatively normal and active life, others are totally bed-bound and unable to care for themselves. Almost all patients find they must drastically reduce their activity from pre-illness levels, regardless of their previous level of athleticism, and must severely modify or give up physical hobbies and exercise. Many patients find themselves unable to work full-time, or at all. A considerable number of CFS cases in many countries are on disability benefits or private insurance, or have made claims and been denied.

One notable CFS sufferer is soccer legend Michelle Akers, who reported struggling with the illness for many of the later years of her career. However, more severe sufferers felt that an active professional athlete "poster child" like Akers helped to trivialize the syndrome in the eyes of the public, and made it much more difficult for highly incapacitated patients to be taken seriously. It is worth noting that the condition can strike persons of all activity levels, however.

Post-exertion symptom exacerbation
One of the most common and recognizable aspects of CFS is what is called "post-exertional malaise". When people with CFS exert themselves beyond their limits (and their limits may change daily), their symptoms worsen. The harder the exertion and the longer it lasts, the worse the symptoms will be afterward with greater recovery time. Some contend from this that prognoses such as deterioration or relapse-remission must be due to sufferers' activity patterns, however this is far from proven, since in many sufferers at least, fluctuations are not solely related to exertion but can include responses to infection, changes in temperature (e.g. hot or cold weather), physical or emotional stressors, and unknown disease process, but they maintain:

The cyclical pattern occurs when patients work harder because they "feel better" or are having a "good day", leading them to think they can exert themselves more than usual. However, the excess exertion leads to worse symptoms on the following day. Thus it is difficult for patients to maintain an even level of activity, or to tell if they are improving.

In sufferers without a diagnosis of CFS, or a proper understanding of how CFS affects exertion, this can lead to a "downward spiral", where a sufferer will try to work harder to make up for the previous day's lack instead of resting. This exhausts them further, and often can trigger a relapse or worsening of their condition.

However, many sufferers who are severely affected particularly find this "behaviourist" hypothesis simplistic and offensive as it leads to the blaming of patients and denial of social support and medical care since the condition can be seen as supposedly self-controllable and self-limiting and already scarce services may be withdrawn if the sufferer is unfortunate enough to deteriorate.

Duration
People with CFS may improve after a few months, or after many years, or never at all. They may reach a plateau at some constant level of health, or may progressively decline, although CFS does not appear to be directly fatal or damagingly progressive. Often, the symptoms change over time, or cycle through time. Relapses are common, especially after stressful life events or additional illness. Exertion can cause not merely a relapse, but a worsening of overall health. Un-diagnosed cases of CFS often worsen as the sufferer attempts to return to a 'normal' level of activity, only to make their condition worse through exertion.

Diagnosis
At this time, there is no accepted conclusive test or series of tests of chronic fatigue syndrome. CFS is therefore largely an exclusionary diagnosis. If a doctor suspects a patient may have CFS they should begin the diagnostic process by eliminating other potential causes of the patient's symptoms. "Chronic fatigue" and similar symptoms can be caused by a wide variety of conditions which should be investigated, although treatment of the patient's symptoms can begin before a complete diagnosis is made. In a patient displaying CFS symptoms, fatigue and new migraines, for example, it is safe and reasonable to treat the migraines while attempting to rule out other possible causes of the patient's fatigue.

CDC 1994 criteria (aka "Fukuda")
According to the 1994 CDC case definition, a diagnosis of CFS requires that the following conditions be met (otherwise, the diagnosis is idiopathic chronic fatigue).

Primary symptom: incapacitating fatigue
Incapacitating fatigue that is:

unexplained by medical cause,
lasts for at least 6 months,
and is not improved by rest.

Additional symptoms
The fatigue must be accompanied by a minimum of 4 of the following eight symptoms:

1) Impairment of short-term memory and concentration
2) Sore throat
3) Tender lymph nodes
4) Muscle pain
5) Multi-joint pain
6) Headaches of a new type, pattern, or severity
7) Unrefreshing sleep
8) Post-exertional malaise (fatigue lasting more than 24 hours after exertion)

Other systems
Some scoring systems, while being considered imperfect, have been proposed to quantify CFS symptoms for research purposes. These include:

Holmes et al (1988) scoring system. Also sometimes called "CDC 1988", to distinguish from the newer CDC system.
Oxford criteria (1991) (also see here and here)
Carruthers et al (2003) Canadian Case definition for ME/CFS
Other ability/disability scales designed for similar symptoms to those of CFS have also been used.

Controversies
Historically, many doctors have been unfamiliar with CFS, and some have refused to diagnose it. This situation is rapidly changing, with more doctors willing to diagnose it and more diagnoses occurring each year. In the UK, the Chief Medical Officer's report stated that all doctors should consider CFS as a serious chronic illness -- though it is not stated whether this is a serious physical illness -- and treat patients accordingly. Similar progress has been made in the United States.

There remains considerable skepticism amongst some medical professionals about the existence of CFS as a 'real' -- i.e. medical as opposed to behavioural -- condition, possibly due to the extreme uncertainty of its etiology, and the lack of accepted biomedical signs. As is common historically with new or unexplained conditions, many people are inclined to believe that a condition with few to no biomedical markers may be, or even must be, psychological in origin. This has led to frustration in many patients, who feel strongly that their disability is not psychological, but biological, in cause and effect. Some more vocal patients' groups maintain that research into CFS (ME) in the UK has been mostly hijacked by the psychologists/psychiatric lobby, who they claim hold significant power within the medical fraternity, with a resultant "abuse of patients' rights". The UK and the Netherlands have particularly seen disagreements between biomedical researchers and their adherents, and psychiatrists (particularly proponents of cognitive behavioral therapy, or CBT) and supporters of the theory that CFS is psychological in origin, and can be "cured" entirely by therapy and exercise.

Patients whose illnesses are consistent with the older and Canadian definitions tend most to resent the elevation of what they see as a trivialising, nonspecific sensation of "fatigue" to a principle descriptor. It is thus often important to be able to differentiate between the illness experience of needful patients and an epistemic construct that may or may not select the same target, until a better definition and diagnostic testing is widely accepted.

Epidemiology
Due to problems with the definition of CFS, estimates of its prevalence vary widely. Studies in the United States have found between 75 and 420 cases of CFS for every 100,000 adults.

Far more women than men get CFS — between 60 and 85% of cases are women. Members of ethnic minorities and low income classes are slightly more likely to develop CFS. Though people of all ages can get CFS, and precise statistics are not available, the prevalence among children and adolescents appears to be lower than for adults. Among minors with CFS, about half are boys and half girls.

CFS occurs both in isolated cases and large-scale outbreaks. In a number of documented cases several people in a building or large numbers of people in a community came down with the disease essentially simultaneously, suggesting that it is (in at least some cases) partly due to an infectious agent. Blood relatives of people who have CFS appear to be more predisposed.

Disease associations
Some diseases show a considerable overlap with CFS, and it may be hard to distinguish between them. People with fibromyalgia have muscle pain and sleep disturbances. Those with multiple chemical sensitivities (MCS) are sensitive to chemicals and have sleep disturbances. Many veterans with Gulf War syndrome (GWS) have symptoms almost identical to CFS. Post-polio syndrome also bears a strong and remarkable resemblance to CFS. Some researchers maintain these disorders are all expressions of a general, yet undefined, syndrome with protean symptoms.

Other disorders with known causes and treatments that may produce CFS-like symptoms are Lyme disease, gluten intolerance (celiac disease and related disorders), and vitamin B12 deficiency. There may also be correlation with polycystic ovary syndrome (PCOS). Thyroid disorders, anemia, and diabetes can present similar symptoms, and must be ruled out. Psychiatric disorders, especially depression, can appear to cause similar symptoms as well, and patients must be carefully screened to determine whether depression is co-morbid with, causing, or being caused by CFS or another syndrome.

Co-morbidity
Many CFS patients will also have, or appear to have, other medical problems or related diagnoses. Fibromyalgia will occur in a large percentage of CFS patients between onset and the second year, and some researchers suggest that 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. As previously mentioned, many CFS sufferers also experience symptoms of IBS, temporomandibular joint pain (as in TMJ), headache including migraines, and other forms of myalgia. Clinical depression and anxiety are also commonly co-morbid.

Proposed etiologies and corresponding treatments
The cause of CFS is unknown, although a large number of causes have been proposed, and several proposed causes have very vocal and partisan advocates.

As there is no one identifiable cause or falsifiable diagnosis for CFS, there is also no one treatment protocol or "magic bullet". Due to the multi-systemic nature of the illness, and others like it, an emerging branch of medical science called psychoneuroimmunology is exploring how all the various theories fit together.

The treatments that are proposed and often attempted for CFS are as varied as the suggested causes, and can generally be classified either according to the cause that they presume, or the symptom they propose to treat. Unfortunately, since CFS symptoms tend to vary over time, it is very easy for someone to become convinced that a particular treatment has helped them (or not), regardless of its true effectiveness. Alternative medicine is often proposed for CFS, especially when conventional treatments are too toxic or otherwise poorly tolerated, or simply fail to relieve symptoms. Alternative treatments may also be more affordable or accessible to patients with limited funds or health care coverage.