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Chronic fatigue syndrome

Highlights

Risk Factors

The CDC now estimates 1 million people have CFS. This may be the tip of the iceberg, since only an estimated 20% of persons with the disease have been diagnosed.

Stress has been identified as a possible trigger of CFS in people who are genetically at risk for the syndrome.

A phenomenon called central sensitization is now suspected to be the connection between fibromyalgia and CFS, which share many of the same features.

Causes

According to the CDC, the first credible evidence that CFS might have a biologic basis comes from 14 studies published in the April 2006 issue of Pharmacogenomics. Twenty researchers in different fields using the same data set independently linked CFS with genes involved with the hypothalamus-pituitary-adrenal axis and the sympathetic nervous system. These genes control the body's response to trauma, injury, and other stressful events.

Diagnosis

Although no definitive test for CFS has been identified, a variety of diagnostic tests are showing promise. One uses mass spectronomy to identify suspected biomarkers of CFS. Another is aimed at identifying gene sequences unique to people with CFS. One test has succeeded in identifying certain compounds in the urine of people with CFS; one has found antibodies to the Epstein-Barr virus as well as markers of oxidative stress; another has associated shrinking gray matter in the brain with CFS. It is hoped that one or more of these tests will prove useful in diagnosing this elusive disease.

Medications

Progress has been made in finding effective medications for CFS. Recent studies have verified the value of antidepressants, particularly SSRIs, D-ribose, and antibiotics, in reducing fatigue and other symptoms of CFS. Studies of a new drug made from dsRNA have shown it to be useful in improving the ability of people with CFS to exercise. This drug is now under FDA review.

Introduction

Chronic fatigue syndrome (CFS), sometimes called immune dysfunction syndrome or myalgic encephalomyelitis (in Europe), is not a new disorder. In the 19th century the term neurasthenia, or nervous exhaustion, was applied to symptoms resembling CFS. In the 1930s through the 1950s, outbreaks of disease marked by prolonged fatigue were reported in the United States and many other countries. Beginning in the early- to mid-1980s, interest in chronic fatigue syndrome was revived by reports in America and other countries of various outbreaks of long-term debilitating fatigue.

Fatigue that lasts for more than 6 months, impairs normal activities, and has no identifiable medical or psychological problems to account for it is referred to as unexplained chronic fatigue. In addition to fatigue, people may complain of other problems such as difficulty with memory or concentration, headaches, or sore muscles or joints.

The symptoms may be categorized as follows:

While the exact causes of CFS are not known, researchers think infection, genetics, hormonal imbalances, and chemical toxins play roles in different patients. Many experts believe there are different subtypes of CFS characterized by the following:

Risk Factors

In studies of large patient groups, 15 - 27% of people complain of long-term fatigue, but the majority can be explained by other medical or psychological problems. According to surveys, chronic fatigue syndrome (CFS) itself affects over four in every 1,000 Americans. It occurs in both sexes and at all ages and in all racial and ethnic groups. The CDC estimates 1 million people in the U.S. have the disease, but only 20% of people with CFS may be properly diagnosed. Nevertheless, the true prevalence of CFS is very difficult to determine, since an accurate diagnosis is difficult to obtain.

Age and Gender

Chronic fatigue is most often experienced by individuals 40 - 50 years old. Studies have found that four times the number of women than men have CFS, although women do not appear to have more severe symptoms than men with the disorder. Children and adolescents are not immune to its effects. Most studies indicate that girls are more likely to develop CFS than boys, although one study found the incidence of the syndrome to be equal.

Culture and Social Levels

Some studies report that CFS rates are highest in minority groups (African and Hispanic Americans), and people with lower levels of education and occupational status. Other studies found higher rates of CFS in Caucasian women than in women from other ethnic groups. However, this may reflect the greater socioeconomic ability of Caucasian women to seek treatment.

Depression and Psychological Factors

The link between psychological disorders and chronic fatigue syndrome is problematic because so many of the symptoms overlap. The rates of depression are very high in CFS patients. In one study, 27.4% of patients diagnosed with CFS alone also had a history of depression. (Depression rates were significantly higher in CFS patients who had other conditions, notably fibromyalgia and multiple chemical sensitivity.)

Studies also report that most children and adolescents with CFS suffer psychiatric disorders. Some evidence suggests that psychological factors during childhood may increase susceptibility for later CFS, although these factors are not consistent. For example, in a small 2003 survey, CFS patients tended to have mothers who were overprotective and depressed. In another small study, five out of 13 patients reported sexual or physical abuse during childhood. The bottom line is that studies have not found any consistent association between emotional or personality disorders and CFS to explain any causal role. Some may however, serve as a risk factor for CFS.

Depression, in any case, is very common in the general population. It affects up to one-fifth of all Americans at some point in their lives, and most depressed people feel fatigued.

Stress

There is some evidence that stress may be a trigger for CFS in people genetically at-risk for the disease. A long-term study of twins in Sweden, reported in 2006, found that higher emotional instability and self-reported stress were associated with higher risk of developing a CFS-type illness.

Conditions That Commonly Occur in CFS Patients

A number of conditions overlap or co-exist with chronic fatigue syndrome and have similar symptoms. In fact, in one study of patients with CFS only 38% of patients had a sole diagnosis. The others also had fibromyalgia, multiple chemical sensitivity, or both. It is not clear if these conditions or others are risk factors for CFS, are direct causes, have common causes, or have no relationship at all with CFS.

Fibromyalgia. Fibromyalgia causes prolonged fatigue and widespread muscle aches and is the disease most often confused with CFS. They also commonly appear together. In one study, for example, 37% of patients who met the criteria for CFS also had a co-diagnosis of fibromyalgia. In fact, many experts believe fibromyalgia is simply another variant of chronic fatigue syndrome or different manifestations of the same disease, with CFS patients experiencing severe fatigue while fibromyalgia patients experience more pain. There is a hypothesis that the connection may be found in central sensitization, which is known to cause fibromyalgia and may also cause CFS.

A characteristic feature of fibromyalgia is the existence of at least 11 distinct sites of deep muscle tenderness that hurt when touched firmly. The sites often include the following:

Some patients with CFS exhibit similar tender pressure points. Recurrent sore throat, headache, low fever, and depression are also common symptoms of fibromyalgia. Like CFS, fibromyalgia is chronic and not curable.

Multiple Chemical Sensitivity. Multiple chemical sensitivity (MCS) is a term now used to describe a condition in which certain chemicals can cause symptoms similar to CFS in some people. It has also been observed in people with CFS. Experts have come up with criteria to help recognize people with MCS.

Still, as with CFS and fibromyalgia, some experts are uncertain whether MCS is an actual medical condition or is psychologically based. In one study, for example, CFS patients who believed their problem was chemically triggered were exposed to either an active chemical or a placebo (an inactive substance). Both groups reported symptoms, including those exposed only to the placebo. It should be noted that everyone is exposed to many chemicals on a daily basis, and it is very difficult to determine if chemicals are responsible for specific symptoms.

Eating Disorders. Eating disorders, notably bulimia and anorexia, have been observed in patients with CFS. In one small study, CFS occurred after the development of the eating disorder. It is not clear if there was a causal relationship. The conditions often have over-lapping risk factors, although whether there is a causal relationship is unclear.

Work-Related Fatigue and Burn-Out. Many people who suffer burn-out or fatigue from employment have symptoms that are similar or even identical to CFS. One study of nurses, for example, found that those who were exposed to poor working conditions and threats of accidents faced a higher risk for CFS symptoms than those without these experiences. However, work-related CFS symptoms are usually of much shorter duration. It they persist, however, doctors should not rule out CFS.

Other Conditions that Commonly Co-exist With CFS. A number of other conditions also often co-exist with CFS and, in fact, occur at higher-than-average rates among CFS patients:

Causes

Theories abound about the causes of chronic fatigue syndrome. Indeed, no primary cause has been found that explains all cases of CFS, and no consistent biologic factors allow objective measures, such as blood tests or brain scans, to definitively diagnose the condition.

Overall, however, doctors are increasingly adopting the view that CFS probably denotes a disease category that includes a range of subtypes, in the same way that cancer is a broad term within which numerous specific forms occur. Mounting evidence suggests that different subtypes of CFS have different causes and manifestations, and that these various types require different treatment approaches.

Research on subgroups of CFS is underway, but is still in very early stages. To date, however, clinical experience and limited data suggest that subgroups of CFS may include the following:

Observations that disparate treatments work for select patients appear to support the idea that subtypes of CFS require distinct approaches. The existence of subgroups may also explain why CFS researchers are frequently unable to replicate their results in subsequent studies; patient selection in studies to date has not reflected such careful discrimination. Researchers are now, however, working to define the subgroups of CFS and identify which treatments are most effective for each.

It should be noted that while the subgroup theory is interesting, in some cases the differences among patient populations may also reflect stages of disease. For instance, in initial stages of the disease, many patients are extremely symptomatic and fit a particular psychological profile including alarm, denial, and anger. In contrast, patients in later phases of the disease typically have learned to cope better with their symptoms and have a degree of acceptance. Patients' mental and emotional status may have biological consequences that bear on their physical symptoms. Such a relationship is not yet documented in CFS patients, however, and remains subject to research.

Convergence of Factors. A number of experts believe that CFS develops from a convergence of conditions that may include the following:

For example, the majority of patients report some preceding moderate to serious physical illness (such as a chronic viral infection) or emotional event (like an episode of depression). Some experts theorize that such events, alone or in combination, may interact with certain neurologic and genetic abnormalities to trigger the event. Still, it is not clear what sequence of events actually leads to the fatigue and other prominent symptoms of this disorder. Nor is there any specific brain or nervous system abnormality that experts can point to with assurance. Research published in 2001 indicates that CFS is more common among identical twins (who share the same genes) than fraternal twins (who share only some genes). Inheritance, then, may play a role in roughly 30 - 50% of cases, similar to the influence thought to occur in depression or alcoholism, although specific genes have not yet been identified.

Sudden- and Gradual-Onset CFS. One interesting theory is that CFS can be categorized as either sudden- or gradual onset, with each subgroup having different causes. In over half of patients, the onset is sudden, while the remaining patients have a slow onset. Some experts believe that sudden-onset CFS may be triggered by a virus or neurologic abnormality, while gradual-onset CFS might have a psychological or other cause. Supporting this theory was a study that observed that MRI scans of the brains of CFS patients without an accompanying psychiatric problem showed small injuries suggesting either a viral infection or neurologic problem. Still other experts believe that in some cases, gradual-onset CFS may be traced to cognitive disorders that were present during childhood, but went unrecognized until symptoms advanced into adulthood.

Genetic Defects

New evidence suggests genes involved in the body's response to stress may play key roles in CFS. A series of 14 articles published in 2006 linked CFS with genes involved in the hypothalamic-pituitary-adrenal axis and the sympathetic nervous system. Julie Gerberding, MD, MPH, director of the Centers for Disease Control, called the research, "the first credible evidence of a biological basis for chronic fatigue syndrome." The researchers were able to locate a common variation of DNA sequences that predicted CFS with 76% accuracy. The genes control response to trauma, injury, and other stressful events. Nevertheless, the researchers were unable to find genetic markers of CFS or to determine how the genetic variations influenced symptoms.

In 2005, English researchers found that people with CFS are more likely than people without CFS to have human leukocyte antigen (HLA) class II alleles, variations that produce antibodies to certain immune factors. Another British study of people with CFS found alternations in 16 specific genes involved with immune function, communication between cells, and transfer of energy to cells.

Central Nervous System and Hormone Abnormalities

Another subgroup of CFS involves abnormalities in the central nervous system, particularly abnormal levels of certain chemicals regulated in the brain system known as the hypothalamus-pituitary-adrenal (HPA) axis. This system controls important functions, including sleep, response to stress, and depression. Of particular interest to researchers are the following chemicals and other factors controlled by the HPA axis:

Infections

Because most of the features of CFS resemble those of a lingering viral illness, many researchers have focused on the possibility that a virus or some other infectious agent causes the syndrome in some cases. There are three basic theories for infection-related causes of CFS:

Still, not all CFS patients show signs of infection. While experts have long been divided on whether infections play any role in this disorder, subtypes of viral-related and non-viral CFS may both exist.

Viruses. The theory that CFS has a viral cause is not based on hard evidence but on various observations that suggest an association, such as the following:

Evidence suggesting that some CFS cases may not be due to a virus:

Immune System Abnormalities

CFS has sometimes been referred to as the "chronic fatigue immune dysfunction syndrome." A number of studies have found many irregularities of the immune system. Some components appear to be overreactive, whereas others appear to be underreactive, but no consistent picture has emerged to explain CFS as a disease of the immune system. Again, the theory of subgroups may explain the significant heterogeneity among patients.

Allergies. Some, although not all, studies have reported that a majority of CFS patients have allergies to foods, pollen, metals (such as nickel or mercury), or other substances. One theory is that allergens, like viral infections, may trigger a cascade of immune abnormalities leading to CFS. (Most allergic people, in any case, do not have CFS.) Some research indicates that people with both allergies and emotional disorders, such as anxiety or depression, may be more vulnerable to the effects of the inflammatory response. This is a harmful overreaction of the immune system that can cause fatigue, joint aches, and fever as well as hormone and brain chemical disturbances.

One theory that may help tie in some of the various factors common to CFS suggests that allergies, stress, and infections may deplete a chemical in the body called adenosine triphosphate (ATP). This chemical stores energy in cells, and studies have reported a deficiency in many CFS patients. Supporting this theory was a study in which patients reported reduced CFS symptoms after they took a vitamin-like supplement called NADH, which increases ATP levels.

Autoimmune Abnormalities. The risk profile for chronic fatigue syndrome is similar to the risk profiles for a number of autoimmune diseases, such as lupus, rheumatoid arthritis, Sjögren's syndrome, and multiple sclerosis. These disorders also have early symptoms resembling CFS. Common to such diseases are the presence of high levels of autoantibodies, immune factors that mistakenly attack the patient's own cells. Studies are inconsistent, however, in reporting the presence of autoantibodies in CFS, and the disease is unlikely to be due to autoimmunity.

Overactive Immune System. Various studies have reported imbalances in various immune factors, importantly white blood cells called T cells, which serve as infection fighters in the immune system.

The result of some T-cell abnormalities is to produce an excess of inflammatory substances called cytokines, which has been observed in some CFS patients. Excess amounts of cytokines cause inflammation and damage in the cells of the body and play an important role in many chronic diseases. This activity also produces fatigue, muscle aches, and other symptoms of CFS. Nevertheless, not all studies have reported elevated cytokine levels in CFS patients.

Low Blood Pressure

Some studies have observed that a subgroup of patients who fit the strict criteria for chronic fatigue syndrome also has a condition known as neurally mediated hypotension (NMH). NMH causes a dramatic drop in blood pressure when standing up, even for as short a time as 10 minutes. Its immediate effect can be lightheadedness, nausea, and fainting. A less severe hypotension condition known as postural orthostatic tachycardia syndrome (POTS) is also associated with CFS. An estimated 30% of CFS patients may have POTS, and some experts believe that the key to understanding CFS will eventually be found in understanding orthostatic intolerance. To further confound the issue, different CFS patients display different types of orthostatic intolerances.

Some experts suggest that such events may be due to impaired blood flow in CFS patients, which might affect the leg and arm muscles. (This in turn might account for muscle fatigue in these patients.) Evidence suggests, however, that blood flow is not abnormal in CFS patients, with or without NMH.

In any case, not all CFS patients experience NMH or POTs. In fact, some studies have reported no higher incidence of NMH in chronic fatigue patients. More research is needed to determine how or if these conditions are associated.

Psychologic Factors

Psychological, personality, and social factors are strongly associated with chronic fatigue in most, but not all, patients. The complex relationship between physical and emotional factors has yet to be fully understood, however. Studies have not found any consistent association between emotional or personality disorders and CFS to explain a causal role. Psychological factors, then, are unlikely to be a primary cause of CFS. They may play a role in increasing susceptibility to onset or perpetuation of the disorder. Certainly, in many cases, CFS promotes psychological and social dysfunction.

Chemicals and Environmental Toxins

In another subgroup of patients, chronic fatigue and pain has been associated with exposure to various chemicals and environmental toxins, such as solvents, pesticides, or heavy metals (cadmium, mercury, or lead). Of note, some reports in Sweden have suggested that mercury found in dental preparations may trigger processes that might cause CFS in susceptible patients. However, most experts believe that dental amalgam is entirely safe. The most publicized example is Gulf War syndrome. Still, most people have been exposed to toxic chemicals at some point during their lives, and it is very difficult to determine specific chemicals that might be particularly dangerous. It is not clear, then, to what extent chemicals may cause CFS. A recently described condition called multiple chemical sensitivity may produce the same symptoms or even occur with CFS.

Diagnosis

It is very difficult to diagnose chronic fatigue syndrome. Even experts do not have a clear definition of what chronic fatigue actually is or what mechanisms in the brain or nervous system are responsible for it. The best diagnostic approach is to determine if the patient matches the criteria for CFS and to rule out other possible causes of symptoms.

Criteria for Chronic Fatigue Syndrome

The Centers for Disease Control define CFS as a distinct disorder with specific symptoms and physical signs after eliminating other identifiable causes of these symptoms and signs.

1. Four or more of the following symptoms must have been present for longer than 6 months:

  • Short-term memory loss or a severe inability to concentrate that affects work, school, or other normal activities
  • Sore throat
  • Swollen lymph nodes in the neck or armpits
  • Muscle pain
  • Pain in a number of joints without redness or swelling
  • Intense or changing patterns of headaches
  • Unrefreshing sleep
  • After any exertion, weariness that lasts for more than a day

2. The fatigue must be severe as indicated by the following:

  • Sleep or rest does not relieve it.
  • The fatigue is not the result of excessive work or exercise.
  • The fatigue substantially impairs a person's ability to function normally at home, at work, and in social occasions.
  • Even mild exercise often makes the symptoms, especially fatigue, much worse.

3. The fatigue must be a new, not lifelong, condition with a definite time of onset. Often, the condition first appears as a viral upper respiratory tract infection marked by some combination of fever, headache, muscle aches, sore throat, earache, congestion, runny nose, cough, diarrhea, and fatigue. Typically, the initial illness is no more severe than any cold or flu.

4. The symptoms must persist. In ordinary infections, symptoms go away after a few days, but in CFS, fatigue and other symptoms recur or continue for months to years. Many patients experience symptoms as recurring bouts of flu-like illness, with each attack lasting from hours to weeks.

Note: Other symptoms reported with CFS but not part of the criteria include intolerance to alcohol, irritable bowel syndrome, dry eyes and mouth, impaired circulation in the hands and feet, visual disturbances, and painful menstrual periods in women.

Personal and Medical History

A doctor should first take a careful personal and family medical history, which may include a psychological profile, as well as perform a thorough physical examination. Patients should be prepared to answer questions such as:

The doctor may also ask about any changes in weight or request a patient to monitor morning and afternoon body temperatures. The patient should report any drugs being taken, including vitamins and over-the-counter or herbal medications.

Laboratory Tests

Inexpensive tests, including thyroid and liver function tests, blood count, and sedimentation rate, are typically recommended to rule out specific conditions that can cause persistent fatigue. No blood, urine, or other laboratory test can specifically diagnose CFS. If any test is abnormal, it is not useful for diagnosing CFS specifically, and the doctor should look for other causes of these abnormalities.

That being said, research published in 2005 found that certain components in urine were unique in people with CFS, and may someday be considered biomarkers of the disease. Additionally, antibodies to Epstein-Barr virus and increased levels of isoprostanes, markers of oxidative stress, have been found in the blood of people with CFS.

Exercise Tests

Some experts recommend exercise tests. In general, CFS patients cannot exercise to the capacity of their peers. A 2003 study found that exercise capacity varied widely among patients who met the AMA guidelines for chronic fatigue syndrome. Therefore, exercise tests may help determine the severity of the condition. Some studies suggest that CFS patients have higher-than-normal ratings of perceived exertion (RPE), which describes the effort attributed to exercise. In a 2003 study, however, the perceptions of how hard they were exercising did not differ between CFS patients and their non-CFS peers. Interestingly, a 2005 Dutch study found the volume of gray matter in the brain to be markedly reduced in people with CFS. Such brain shrinkage has been linked to lower rates of physical activity in people with CFS.

Tilt Test for Neurally Mediated Hypotension

Simply measuring blood pressure will not identify CFS patients in whom the syndrome might be caused by neurally mediated hypotension (an abnormal drop in blood pressure). A tilt test, whereby the person lies on a table tilted upright at a 70-degree angle for a prolonged period, may confirm CFS caused by neurally mediated hypotension if the patient feels lightheaded, sick, and faint after several minutes.

Ruling Out Chronic Fatigue Syndrome

Among the many other common conditions that can lead to feelings of temporary exhaustion are the following:

In most of these cases, fatigue can be relieved with adequate rest. It is important to note that longstanding fatigue can be the harbinger of a serious medical or psychological problem. A number of more serious conditions may cause persistent fatigue and other symptoms of CFS and should be ruled out. Patients and doctors should not overlook these diseases, even if they have been previously treated, because they may not have completely resolved or may cause residual fatigue. Doctors can usually distinguish these diseases from CFS after a clinical evaluation and laboratory testing.

Infectious Mononucleosis and Epstein-Barr Virus. Infectious mononucleosis is marked by fatigue and swollen glands. It primarily affects adolescents and young adults. Some patients may have lingering fatigue that lasts for many months and blood tests that indicate a persistence of the Epstein-Barr virus (EBV), which causes mononucleosis.

In some people with CFS, there may be no direct link to Epstein-Barr virus. Many healthy persons without CFS have the same signs of low-level EBV infection, and, conversely, many patients with CFS show no signs of EBV infection. In others, however, the virus may play a role. Research published in 2005 shed new light on ways in which latent Epstein-Barr virus may cause immune problems and CFS-like symptoms.

Autoimmune Diseases. Some diseases, including systemic lupus erythematosus, multiple sclerosis, and rheumatoid arthritis, are caused by autoimmunity, a condition in which the person's immune system attacks the body's own tissues. The early symptoms of these conditions may mimic some of those that appear in CFS, such as muscle and joint pain and fatigue. These diseases, like CFS, also occur more often in women than in men. Autoimmune diseases evolve slowly, and even if a diagnosis of chronic fatigue syndrome is considered, doctors should keep track of any changes in symptoms over time in order to rule out these serious illnesses. It should also be noted that some experts are concerned that many patients who actually have CFS will be mistakenly diagnosed with these diseases, particularly multiple sclerosis, and subjected to unnecessary treatments.

Post-Lyme Syndrome. A delayed response or recurrence of previously treated Lyme disease (called post-Lyme syndrome) may be mistaken for chronic fatigue syndrome in people who live in areas where there are outbreaks. Although the two disorders are similar, one study found that CFS patients reported more flu-like syndromes and those with post-Lyme disease performed significantly worse on tests of mental functioning and motor control. If CFS patients are mistakenly diagnosed and treated for Lyme disease, they may take prolonged courses of antibiotics that can have serious side effects, ultimately doing more harm than good.

Psychosis and Severe Mental Disorders. The Centers for Disease Control (CDC), which set up the definitions in the US for research in chronic fatigue syndrome, recognize depression as one of the symptoms of CFS. However, the CDC rules out chronic fatigue syndrome as a diagnosis for anyone with a history of major depression or other severe psychiatric disorders, including bipolar disorder and schizophrenia. Depression or anxiety not associated with a psychosis or severe mental illness does not rule out CFS.

Symptoms of major depression include the following:

Major depression is likely to be the responsible condition in the presence of several of these symptoms and if there are no physical symptoms (such as sore throat, aches and pains, or fever). And the longer fatigue has continued without such physical symptoms, the more likely that the diagnosis is depression.

Of note, a persistent form of minor depression called dysthymia may be more difficult to differentiate from CFS and may actually account for a subset of CFS cases. Dysthymia is characterized by many of the same symptoms that occur in major depression but they are less intense and last much longer, at least two years. The symptoms of dysthymia have been described as a "veil of sadness" that covers most activities.

A 2001 study suggested that patients with depression and those with CFS differ in how they perceive their illnesses:

A number of patients who are diagnosed with CFS report having felt depressed before the onset of chronic fatigue. Many other CFS patients, however, felt alert and mentally sound before the onset of CFS symptoms. Many of these previously healthy patients become depressed and anxious because they feel so exhausted all the time. CFS may also lead to highly stressful socioeconomic situations, such as social isolation and poverty, that can contribute to and even cause emotional disorders in susceptible individuals, which in turn can worsen CFS.

Sleep Disturbances. Certain sleep disorders may cause persistent fatigue and be confused with CFS:

In addition, many patients with CFS suffer from sleep problems. A 2004 study found that over 80 percent of CFS patients experienced at least one type of sleep disorder. Non-restorative sleep and nighttime restlessness were the most common complaints.

Conditions that Cause Joint Pain, Muscle Aches, or Both. A number of illnesses cause one or more of CFS symptoms including arthritic symptoms, fever, and fatigue.

Other Diseases that Cause Joint Pain, Muscle Aches, or Both

Disease

Specific Subtypes

Osteoarthritis

Rheumatic Autoimmune Diseases

Rheumatoid arthritis, systemic vasculitis, systemic lupus erythematosus, scleroderma, Still's disease (also called juvenile rheumatoid arthritis), Behcet's disease

Infectious Arthritis

Lyme disease, septic arthritis, bacterial endocarditis, mycobacterial and fungal arthritis, viral arthritis

Postinfectious or Reactive Arthritis

Reiter syndrome (a disorder characterized by arthritis and inflammation in the eye and urinary tract), rheumatic fever, inflammatory bowel disease

Crystal Induced Arthritis

Gout and pseudogout

Fibromyalgia

Having fibromyalgia does not necessarily rule out accompanying CFS

Other Diseases

Hepatitis C, familial Mediterranean fever, cancers, AIDS, leukemia, bunions, Whipple's disease, dermatomyositis, Henoch-Schonlein purpura, Kawasaki's disease, erythema nodosum, erythema multiforme, pyoderma gangrenosum, pustular psoriasis

Severe Obesity. People who are severely obese often have symptoms of chronic fatigue because of the stress imposed by the weight. People who are obese are also at particular risk for sleep apnea, which can confuse the diagnosis.

Other Medical Conditions that Usually Rule Out CFS. Many diseases, both benign and serious, can fully explain prolonged or chronic fatigue, including hepatitis, anemia, hemochromatosis (a hereditary disease caused by iron overload) infections, various forms of cancer, neuromuscular diseases (such as myasthenia gravis), hypothyroidism, and diabetes.

Drugs and Alcohol. Fatigue is a side effect of many prescription and over-the-counter medications, such as antihistamines. In addition, dependency on or abuse of alcohol or illicit drugs may manifest as chronic fatigue. Medications should be considered as a possible cause of fatigue if an individual has recently started, stopped, or changed medicines. Withdrawal from caffeine can produce depression, fatigue, and headache.

Conditions That Do Not Rule Out Chronic Fatigue Syndrome

Many diagnosable conditions cause symptoms similar to CFS, but they can overlap. As such, their presence does not necessarily rule CFS out as a co-disorder. In fact, CFS patients appear to be at high risk for developing depression and additional health problems, particularly those with similar symptoms (for example, fibromyalgia, irritable bowel syndrome, chronic pelvic pain, chemical sensitivities, and temporomandibular disorder).

Some tests may be positive for one or more of these diseases. However, if the results are ambiguous or weak or if they have been treated successfully, CFS should not be ruled out if the patient still also meets the criteria for it.

Prognosis

The physical severity of chronic fatigue syndrome varies. Most commonly, patients with CFS report that they have trouble fulfilling both home and work responsibilities.

CFS sufferers typically work part-time. In extreme cases, patients are severely disabled and even bedridden. Such patients can do virtually nothing, including even light housework.

In a 2003 study, patients with either CFS or fibromyalgia were more likely to suffer losses of jobs, possessions, and support from friends and family than people suffering from other conditions that caused fatigue.

Mental Incapacity

Most patients say that while fatigue is the most incapacitating symptom, those of mental impairment, such as an inability to concentrate or memory loss, are the most distressing. The effects of CFS on mental functioning are complex, however. Some experts believe that the impaired mental functioning is due to depression, which is common in CFS patients.

Some studies indicate that although general intelligence is not impaired, CFS patients test lower in certain mental functions, particularly speed and efficiency in processing complex information, and that 40 - 60% suffer memory impairments. In such studies, this impaired mental function occurs regardless of the presence or absence of depression or other psychiatric disorders. A comparison study of patients with depression, CFS, and multiple sclerosis helped support a physical basis for CFS by finding that problems in mental functioning were consistent among MS and CFS patients, no matter how depressed they were. Problems in mental functioning among depressed patients varied, however, depending on the severity of the depression.

One study found that the mental impairment in CFS patients parallels the degree of their physical impairment, indicating that the disease process itself may exert a neurologic effect. A 2005 study found that people with CFS have to work harder to process information they hear, and they use more extensive regions of the brain, than people without the disease.

Long-Term Outlook in Adults

Because the illness remains elusive and poorly defined, and there are few objective measures for recovery, experts have found it difficult to determine the long-term course of the disease. Many patients are not covered by insurance or have difficulty finding good care, so available statistics may be incorrect. Bearing these factors in mind, some studies have reported that between 58 - 72% of patients who complain of chronic fatigue continue to experience it after a year. In one study, nearly 60% were still fatigued at 2 years. Even if patients get progressively worse, however, the disorder is not fatal.

Sudden or Gradual Onset. Some studies have observed that patients whose symptoms began abruptly following a severe viral illness recovered completely after 6 months to a year, whereas patients whose problems developed slowly and insidiously experienced symptoms for a longer period of time.

Severity of CFS. Many patients with moderate chronic fatigue have reported an increase in energy after a year or two. One small 1999 study observed that even after 4 years few patients with severe CFS had returned to their pre-illness state. It should be noted, however, that in another study, nearly all patients with severe CFS who were treated with a multidisciplinary rehabilitation program improved significantly and the gains were maintained for at least a year afterward.

Signs of Positive Outlook. According to one study, CFS patients who are more likely to experience improvement over time have the following positive signs:

Outlook in Children

Although children with symptoms of chronic fatigue have not been as rigorously studied as adults, limited evidence suggests that CFS can be significantly disabling in young people. Studies report that adolescents who meet the criterion for CFS also have greater anxiety, depression, and school absenteeism than their peers. Still, some studies indicate that children have a better prognosis than adults and that most will recover after 1 - 4 years. Several studies have indicated that cognitive-behavioral therapy is an effective treatment for adolescents with CFS.

Treatment

There is no proven or reliable cure for CFS, and no drug has been developed specifically for this disorder. Because CFS remains poorly understood, many patients have problems finding good care. Overall, the recommended strategy for treatment includes a combination of the following:

Patients with the best chance for improvement are those who remain as active as possible and who seek to have some control over the course of the disorder. Patients should seek physicians who are willing to consider the problem as a medical condition with psychiatric components. They should be very wary, however, if the physician recommends excessive and expensive treatments that may have serious adverse effects and that have no proven benefits. For patients with severe CFS that cannot be managed with lifestyle changes and standard medications, asking the physician about enrolling in any available clinical trials may be helpful.

Cognitive-Behavioral Therapy

CBT is designed to help patients regain a sense of control and is proving to have substantial benefits for some patients. Some experts believe that patients who are diagnosed with CFS should immediately be referred to therapists trained in cognitive-behavioral therapy. (Psychoanalysis and other interpersonal psychological therapies, which are concerned with subconscious thoughts and early childhood memories, are not generally helpful for the CFS patient.)

The Goals of Cognitive-Behavioral Therapy. The primary goals of cognitive-behavioral therapy (referred to below as just cognitive therapy) are to change any distorted perceptions that individuals have of the world and of themselves and to change their behavior accordingly. For CFS patients, this means learning to think differently about their fatigue and to improve their ability to deal with stressful situations and manage their disorder. Cognitive therapy is particularly helpful in defining and setting limits, behaviors that are extremely important for these patients.

The Procedure. Cognitive therapy may be expensive and not covered by insurance. It is usually performed over 6 - 20 sessions, each which last about an hour. Patients are also given homework, which usually includes keeping a diary and attempting tasks that they have avoided because of negative attitudes.

A typical cognitive therapy program may involve the following measures:

Using both self-observation and specific tasks, patients gradually shift their fixed ideas that they are helpless against the fatigue that dominates their lives to the perception that fatigue is only one negative and, to a degree, a manageable experience among many positive ones.

Success Rates. A 2001 review of CFS trials reported that, of all therapies available to CFS patients, only cognitive behavioral therapy (CBT) and graded exercise showed conclusive benefits. A 2005 study found that cognitive therapy is an effective treatment for adolescents with CFS. Patients who received CBT reported improvements in fatigue, functional status, and school attendance.

Not all studies support the benefits of cognitive therapy for CFS. It is important to note that different therapists may have different fundamental assumptions about CBT and may employ dissimilar techniques. For instance, some therapists believe that CFS is purely a psychological problem and that patients must reject the notion of physical causes, abandon all reliance on assistive devices, and participate in challenging exercise programs. In contrast, other therapists do not attempt to change patients' underlying beliefs at all, but instead focus on helping patients conserve energy and better cope with the limitations of their illness. When considering CBT, patients and their families must be aware of such important differences.

Regardless of whether specific organic causes of CFS are identified, the power of the mind to improve or oppose health problems is significant, and treatments that promote a positive outlook are beneficial for any disease.

Graded Exercise

A number of studies have suggested that a graded exercise program, in which patients perform increasingly more intense levels of exercise tailored to their individual abilities, has benefits for many patients with CFS. Exercise is best performed in combination with cognitive behavioral therapy.

The following are specific studies attesting to the benefits of graded exercise:

Other reports have found that 75% of CFS patients who were able to engage in exercise, particularly aerobic exercise, reported less fatigue and better daily functioning and fitness after a year. A 2004 review of clinical trials found that exercise therapy is beneficial for CFS, particularly when combined with patient education.

Some patient groups and experts contend that such studies use only patients with less severe conditions and do not apply to many CFS patients. Many patients have severe conditions and some are very incapacitated (such as being wheel-chair bound). These patients are unlikely to undergo even graded exercise. All CFS patients, in fact, have a lower exercise capacity than healthy individuals, and over-exercising can intensify symptoms. Some patients experience profound fatigue following even modest exercise. It is the primary factor in perpetuating the low-activity levels observed in these patients.

The following tips may be helpful for CFS patients when embarking on an exercise program:

Healthy Diet

Although there is no evidence to support any specific dietary factors in CFS, patients should be sure to maintain a healthy diet that includes:

Other Approaches For Managing Chronic Fatigue Syndrome

Stress Reduction Techniques. One panel of experts concluded that relaxation and stress-reduction techniques were helpful in managing chronic pain. They also can help relieve the stress associated with the disease. They are not useful, however, as the primary treatment for CFS. A number of relaxation techniques are available:

Light Therapy. Light therapy (phototherapy) has been used by some CFS patients. A 2002 study, however, reported no improvement in symptoms with its use. It may still help some patients with CFS whose symptoms have a seasonal variability that is similar to those of patients with seasonal affective disorder (SAD). Patients with SAD experience more depression during the winter, when the hours of sunlight decrease. With phototherapy, the patient sits a few feet away from a box-like device that emits very bright fluorescent light (4,000 lux) for about 30 minutes every day. It is best performed immediately after awakening in the morning.

Supportive Family and Groups. Strong, supportive relationships with family and friends are an important factor in the overall improvement of CFS patients. However, CFS patients should try not to impose unreasonable expectations on loved ones that cannot be met. Ongoing support groups with fellow patients may be very helpful. In a 2001 study, sharing experiences in a group therapy setting proved to be the most valuable component and one that improved patients' coping abilities.

Medications

No medications are specifically approved for the treatment of CFS. However, some may be useful for specific symptoms or in cases where CFS may have a specific cause. Doctors generally use combinations of drugs to accomplish specific goals, such as medication at night to improve sleep and medication in the morning to improve cognition and energy. Treatment is very individualized.

Mild Pain Relievers

Nonsteroidal Anti-Inflammatory Drugs (NSAIDs). Patients with CFS may find relief using NSAIDs. They are common pain relievers that reduce pain and swelling. Types include aspirin, ibuprofen (Motrin, Advil, Nuprin), and naproxen (Aleve, Naprosyn, Naprelan, Anaprox).

Although NSAIDs work well, long-term use can cause stomach problems, such as ulcers and bleeding. In April 2005, the FDA asked drug manufacturers of NSAIDs to include a warning label on their product that alerts users of an increased risk for cardiovascular events and gastrointestinal bleeding. Due to its proven cardiovascular benefits, aspirin was excluded from these labeling revisions.

NSAIDs can also increase blood pressure, particularly among people already being treated for hypertension. About 12 - 15% of elderly people take both an NSAID and an antihypertensive drug. Piroxicam, naproxen, and indomethacin appear to pose the greatest risk of high blood pressure. Sulindac has the smallest effect.

Other side effects of NSAIDs include dizziness, ringing in the ears, headaches, skin rashes, and possibly depression. Studies have appeared suggesting that high doses of NSAIDs can damage cartilage, and there have also been reports that NSAIDs can cause kidney damage. (The damage resolves once the patient stops using the drug. People with high blood pressure, severe circulation disorders, or kidney or liver problems, as well as people taking diuretics or oral hypoglycemics, must be closely monitored if they need to use NSAIDs on a long-term basis. Because NSAIDs reduce blood clotting, NSAID users scheduled for surgery should stop taking those drugs a week before the operation.

COX-2 Inhibitors (Coxibs). Coxibs block an inflammation-promoting enzyme called COX-2. This class of drugs was initially believed to work as well as traditional NSAIDs, but with less stomach problems. However, numerous reports of cardiovascular events, skin rashes, and other adverse effects prompted the FDA to re-evaluate the risks and benefits of the COX-2 drugs. Rofecoxib (Vioxx) and valdecoxib (Bextra) have been withdrawn from the U.S. market following reports of heart attacks in patients taking the drugs. Celecoxib (Celebrex) was still available at the time of this report, but labeled with strong warnings and a recommendation that it be prescribed at the lowest possible dose for the shortest duration possible. Patients should ask their doctor whether the drug is appropriate and safe for them.

Antidepressants

Because of the association between depression and CFS, antidepressants are often tried with varying degrees of success, depending on the type. Common side effects of many antidepressants include dry mouth, restlessness, reduced sexual drive, a slightly increased heart rate, and constipation. Virtually all antidepressants have complicated interactions with other drugs, and some are very serious.

Tricyclic Antidepressants. Antidepressants known as tricyclics may be particularly helpful for CFS patients. For example, the tricyclic amitriptyline (Elavil) is known to relieve many of the symptoms of CFS, including sleeplessness and low energy levels. They may provide benefits by promoting deep sleep and inhibiting pain pathways in the nervous system. Improvement in symptoms can take 3 - 4 weeks. Other tricyclics include doxepin (Sinequan), desipramine (Norpramin), nortriptyline (Pamelor), clomipramine (Anafranil), and imipramine (Tofranil, Janimine). These agents can have severe side effects, although patients with CFS normally respond to much lower doses than those used to treat people with depression. In fact, many CFS patients cannot tolerate the higher doses commonly used to treat the psychiatric disorder. Like all medications, tricyclics must be taken as directed. Overdose can be life-threatening.

Monoamine Oxidase Inhibitors (MAOIs). Monoamine oxidase inhibitors (MAOIs) block the enzyme monoamine oxidase, which has negative effects on many of the neurotransmitters that are important for well-being. In one study moclobemide, a newer MAOI, was associated with improved energy levels in CFS patients regardless of whether they are depressed or not. Other MAOIs are likely to have similar effects. The most serious side effect of MAOIs is severe hypertension, which can be brought on by eating certain foods having a high tyramine content. Such foods include aged cheeses, most red wines, sauerkraut, vermouth, chicken livers, dried meats and fish, canned figs, fava beans, and concentrated yeast products. They also have serious interactions with a number of medications and should not be taken by pregnant women.

Designer Antidepressants. Newer, so-called designer SSRIs, including bupropion (Wellbutrin), nefazodone (Serzone), or mirtazapine (Remeron), affect combinations of different neurotransmitters, and some may have moderate benefits for CFS patients. For example, in one study, nefazodone improved mood, fatigue, and sleep disturbances.

SSRIs. The popular antidepressants known as selective serotonin-reuptake inhibitors (SSRIs) may be helpful for the subgroup of CFS patients who experience significant depression. They include fluoxetine (Prozac), sertraline (Zoloft), and paroxetine (Paxil). Cymbalta (duloxetine) is a new antidepressant that is classified as a selective serotonin and norepinephrine reuptake inhibitor (SSNRI). Doctors are hopeful that it will be more effective because the drug targets two key neurotransmitters, serotonin and norepinephrine, in contrast to the SSRIs, which target only serotonin.

In a 2006 UK study of 275 CFS patients, those treated with antidepressants recovered faster than those who did not receive the medication. SSRIs were found to be more effective than tricyclic antidepressants, producing improvements that included a reduction in fatigue that were maintained at the 3-year followup.

Treatment of Neurally Mediated Hypotension

Treating NMH may be appropriate in the subgroup of CFS patients with this condition. In one study, 76% of patients diagnosed with and specifically treated for neurally mediated hypotension (NMH) experienced improvement within a month, and in 40% of these patients, chronic fatigue symptoms completely or nearly completely resolved. It should be stressed that increasing blood pressure can be very dangerous in individuals with existing normal or high blood pressure. No one should take measures to raise blood pressure without a clear diagnosis of NMH or without a doctor's approval.

Life Style Changes. For treating NHM, the doctor might first recommend non-medicinal measures:

Medications. If NMH does not improve with lifestyle measures, certain medications may be tried in combination or alone. A wide range of drugs normally used for other disorders have been used to treat NMH, but doctors have had difficulty adjusting them so that they would be effective for NMH without causing distressing side effects. Such medications include:

Other Drugs Being Investigated for CFS

Galantamine. Galantamine (Razadyne) is a cholinesterase inhibitor used to treat Alzheimer’s disease. A multicenter placebo-controlled trial of 434 patients with CFS tested various doses of galantamine during a 16-week study period. Results published in 2004 in the Journal of the American Medical Association clearly demonstrated that galantamine had no effect. This study was the largest CFS trial to date. Although the trial’s results were disappointing, its rigorous study design may serve as a model for future CFS trials.

Corticosteroids. Some evidence exists that patients with CFS may be deficient in cortisol, a steroid hormone. Studies testing the steroid drug hydrocortisone have reported increased energy and less fatigue in patients taking it. However, side effects, including insomnia, increased appetite, weight gain, and, more seriously, suppression of the adrenal gland, make this therapy unacceptable. One study reporting improvement with very low doses (5 - 10 mg daily) with only minor side effects may make this therapy feasible for some patients, but longer-term and larger studies are needed. Fludrocortisone (Florinef) is an oral steroid used for low blood pressure. This has been tested specifically on CFS subjects with NMH, but studies reported no benefits and side effects may be serious.

Psychostimulants. Psychostimulants may be helpful for a subgroup of patients with CFS who have cognitive problems such as difficulty concentrating, memory problems, and other attention deficit disorder (ADD)-like characteristics. Imbalances in norepinephrine and dopamine have been demonstrated in imaging studies of CFS patients, and are thought to be responsible for such symptoms. Although such imaging tests are not available to most patients, experts postulate that the benefit of psychostimulants offers proof that some CFS patients in fact have measurable chemical imbalances. It is not clear whether such imbalances may contribute to causing CFS, or whether the disease underlying CFS causes such changes in neurochemical structures in the brain.

Psychostimulants include Dexamphetamine, Adderal, Ritalin and Ritalin-like drugs such as Focalin, Concerta, Ritalin LA, and Metadate, as well as Strattera and Provigil.

Ampligen. The drug Ampligen is a form of genetic material called double-stranded (ds) RNA, which increases the body's defense against disease. In studies, Ampligen has been shown to improve exercise ability by increasing oxygen utilization. No serious adverse effects have been seen to date. Phase 3 studies are now complete, and the developer has applied for a New Drug Application from the FDA. At this time Ampligen must be administered intravenously twice per week.

D-ribose. D-ribose is another drug targeting cellular energy metabolism. It has been shown to increase cellular energy synthesis in heart and skeletal muscle. In a small study of 41 patients with CFS and or fibromyalgia, D-ribose caused significant improvement in energy, sleep, mental clarity, pain intensity, and well-being. Energy increased an average of 45% and well-being an average of 30%.

Antibiotics. Some patients with CFS exhibit a chronic state of immune activation. Azithromycin has been used to modulate the immune system. In one study, azithromycin reduced symptoms in 58 of 99 participants. Blood tests showed lower levels of plasma acetylcarnitine, likely reflecting lower levels of oxidative stress.

Alternative Remedies

Because of the difficulties in treating chronic fatigue syndrome, many patients seek alternative therapies. Some, such as acupuncture, yoga, and relaxation techniques, may be helpful and are not dangerous. No scientific evidence exists that vitamin and mineral supplements will relieve CFS, but taken in moderation, they are usually not harmful.

Herbal and Supplements. Popular herbal and dietary supplement remedies for CFS include coenzyme Q10, DHEA, ginseng, and acetylcarnitine. None have been rigorously tested. Some herbs, such as St. John’s wort, ginkgo, and comfrey, may cause serious side effects and drug interactions. [See Box: Herbs and Supplements.]

Herbs and Supplements

Herbal remedies and dietary supplements are not regulated by the FDA. This means that manufacturers and distributors do not need FDA approval to sell their products. In addition, any substance that can affect the body's chemistry can, like any drug, produce side effects that may be harmful. There have been a number of reported cases of serious and even lethal side effects from herbal products.

Some so-called natural remedies have been found to contain standard prescription medication. Of specific concern are studies suggesting that up to 30% of herbal patent remedies imported from China having been laced with potent pharmaceuticals, such as phenacetin and steroids. Most reported problems occur in herbal remedies imported from Asia, with one study reporting a significant percentage of such remedies containing toxic metals.

CFS patients should be wary of those that promise a cure or urge the purchase of expensive but useless and sometimes potentially dangerous treatments, such as the following:

  • St. John's Wort. One positive study concerned St. John's Wort, which is being investigated for mild depression. In the study, the herbal agent lessened fatigue in CFS patients, even in those who did not consider themselves to be depressed. Still, even St. John's Wort may have some serious side effects. This agent can interact with blood thinning medication. Of note, in a 2002 brand comparison only three products out of eight were within 10% of the active ingredient amounts claimed on their labels.
  • Melatonin. Some patients use melatonin, based on the association between CFS and possible sleep abnormalities. In a 2002 study, however, melatonin had no effect on symptoms.
  • Gingko. Although the risks for gingko appear to be low, there is an increased risk for bleeding at high doses and interaction with high doses of vitamin E anti-clotting medications. Commercial gingko preparations have also been reported to contain colchicine, an agent that can be harmful in pregnant women and people with kidney or liver problems. It should be further noted that some brands have no effect at all.
  • Comfrey. Comfrey is an herbal remedy used for a number of inflammatory problems. Recently, there is evidence that comfrey can be toxic to the liver and animal studies have reported a possible cancer risk. It is banned in Canada and other countries, but is widely available in the U.S.

Of particular note for CFS patients are products containing the ingredient Ma Huang, which contains the stimulants ephedrine and kola nut, a caffeine source. Serious adverse reactions, including seizures, psychosis, and several deaths, have been reported in people taking this supplement for increased energy or weight loss. Products that have only one of these ingredients appear not to have the same effect, but people should take so-called energy boosting supplements only with the knowledge and recommendation of their doctor.

Other alternative remedies with no proven benefit and possible toxic and dangerous effects include the following:

  • Hydrogen peroxide injection (can cause blood clots or strokes)
  • Megadoses of vitamins (which can be toxic and have shown no benefits)
  • High colonic enemas
  • Bee pollen (which can cause an allergic reaction)
  • Injections of liver extract
  • Superoxide dismutase (SOD)

Resources

References

Hickie I, Davenport T, Wakefield D, Vollmer-Conna U, Cameron B, Vernon SD, Reeves WC, Lloyd A; Dubbo Infection Outcomes Study Group. Post-infective and chronic fatigue syndromes preciptated by viral and non-viral pathogens: prospective cohort study. BMJ.2006;333(7568):575. Epub Sept 1.

Kerr JR, Christian P, Hodgetts A., Langford PR, Devanur LD, Petty R, Burke B, Sinclair LI, Richards SC, Montgomery J, McDermott C, Harrison TJ, Kellam P, Nutt DJ, Holgate ST. Current research priorities in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME): disease mechanisms, a diagnostic test and specific treatments. J Clin Pathol.2006;Aug 25 (Epub ahead of print).

Meeus M, Nijs J. Central sensitization: a biopsychosocial explanation for chronic widespread pain in patients with fibromyalgia and chronic fatigue syndrome. Clin Rheumatol.2006. Nov 18 (Epub ahead of print).

Kato K, Sullvan PF, Evengard B, Pedersen NL. Premorbid predictors of chronic fatigue. Arch Gen Psychiatry. 2006;63(11):1267-1272.

Vermeulen RC, Scholte HR. Azithromycin in Chronic Fatigue Syndrome (CFS), an analysis of clinical data. J Transl Med. 2006;4:34.

Teitelbaum JE, Johnson C, St Cyr J. The use of D-ribose in chronic fatigue syndrome and fibromyalgia: a pilot study. J Altern Complement Med. 2006;12(9):857-862.

Thomas MA, Smith AP. An investigation of the long-term benefits of antidepressant medication in the recovery of patients with chronic fatigue syndrome. Hum Psychopharmacol. 2006;21(8):503-509.

Hampton T. Researchers find genetic clues to chronic fatigue syndrome. JAMA. 2006;295(21):2466-2467.

Review Date: 1/4/2007
Reviewed By: Harvey Simon, MD, Editor-in-Chief, Associate Professor of Medicine, Harvard Medical School; Physician, Massachusetts General Hospital
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