Myalgic Encephalomyelitis - Chronic Fatigue Syndrome

Chronic Fatigue Syndrome

Chronic fatigue syndrome (also called myalgic encephalomyelitis in England) does not appear to be new. In the 19th century there were various reports of neurasthenia, or nervous exhaustion. 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. Over six million patient visits are made each year because of fatigue, although only a very small percentage of these can be attributed to chronic fatigue syndrome.

If no identifiable medical or psychological problems account for fatigue that has lasted for more than six months and impairs normal activities, experts define the condition as unexplained chronic fatigue. A group of experts have developed criteria for further differentiating this unexplained fatigue as either chronic fatigue syndrome (CFS) or idiopathic chronic fatigue. (Idiopathic simply means that the cause is not known.) Chronic fatigue syndrome is diagnosed in people meeting the following criteria: If these criteria are not met, then the condition is considered to be idiopathic chronic fatigue.

  • Four or more of the following symptoms must have been present for longer than six months:
    1. short-term memory loss or a severe inability to concentrate that affects work, school, or other normal activities
    2. sore throat
    3. swollen lymph nodes in the neck or armpits
    4. muscle pain
    5. pain without redness or swelling in a number of joints
    6. intense or changing patterns of headaches
    7. unrefreshing sleep
    8. after any exertion, weariness that lasts for more than a day
  • The fatigue must be severe: Sleep or rest does not relieve it; the fatigue is not the result of excessive work or exercise; and 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.
  • The fatigue must be a new -- not lifelong -- condition with a definite time of onset. For instance, many patients with chronic fatigue report having had a flu-like illness that triggered the symptoms. (In one study, 20% reported chronic fatigue following a flu.) 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.
  • 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.

Who Gets Chronic Fatigue Syndrome

In studies of large patient groups, between 15% and 27% of people complain of long-term fatigue, but the majority of these cases are explained by other medical or psychological problems. According to a survey conducted by the Centers for Disease Control and prevention, chronic fatigue syndrome is a serious public health concern affecting about three in every 1000 Americans. This disorder occurs in both sexes and all racial and ethnic groups, but is most common in Caucasian women. In fact, among white women, it is more prevalent than lung cancer, breast cancer, and high blood pressure. Some studies indicate that women with gynecologic problems such as irregular menstrual cycles may face an even higher risk than others. There appears to be no difference in severity in symptoms between men and women who already have CFS. Chronic fatigue is most often experienced by patients 20 to 50 years old. One study of two boroughs reported that .07% of children had symptoms of chronic fatigue, with most occurring in one borough. Most studies indicate that girls are more apt to develop CFS than boys, although one found the incidence of the syndrome to be equal. Chronic fatigue syndrome is also more often reported in people who are well educated. Such people, however, are more likely to seek medical help, be aware of chronic fatigue syndrome as a specific disorder, and have health insurance. One study has indicated that the problem is more widespread and that the disease is under-diagnosed in lower-income and some ethnic groups. One study of nurses found that those who were exposed to poor working conditions and threats of accidents faced a higher risk for CFS symptoms, indicating that people in very stressful jobs may be at risk.

What Causes Chronic Fatigue Syndrome

Theories abound about the causes of chronic fatigue syndrome. Many physicians still doubt that CFS is an actual disease but believe rather that it is a component of a psychological disorder or a symptom of other problems, similar to anemia and high blood pressure. Indeed, no primary cause has been found that explains all cases of CFS, and a number of experts believe that it develops from a combination of factors including brain abnormalities, a hyper-reactive immune system, and a viral or other infectious agent. Still, although all of these elements appear to be at work in many cases of CFS, it is not yet clear what sequence of events actually leads to the fatigue and other prominent symptoms of this disorder. Other conditions that have been posited as causes for certain CFS cases include hypotension, hyperventilation, and defective muscle tissue.

Central Nervous System and Hormone Abnormalities

Abnormalities in the central nervous system, including pinpoint spots of brain inflammation and abnormal levels of certain hormones have been reported in a number of patients with CFS, but similar findings have also been found in those without the illness. Of particular interest to researchers are possible abnormalities in the brain system known as the hypothalamus-pituitary-adrenal axis, which controls important functions, including sleep, response to stress, and depression. A number of studies on CFS patients have observed deficiencies in cortisol levels, a stress hormone produced in the hypothalamus. Cortisol is a powerful suppressor of the immune system. One central hypothesis for CFS suggests that after a person with cortisol deficiency is exposed to a viral infection or some other physical or emotional stress, the immune system over responds and causes symptoms typical of chronic fatigue syndrome. (Unfortunately, drug trials that replace cortisol have only reported modest improvement in symptoms. One small but well-conducted study, in fact, reported elevated levels of cortisol in the saliva of CFS patients.) Other researchers have observed that men with CFS had high levels of serotonin, a neurotransmitter (chemical messenger in the brain); such elevated levels in the brain are associated with fatigue. If these hormonal imbalances prove to be typical of CFS patients, the low levels of cortisol and high levels of serotonin may help distinguish CFS from major depression, in which an opposite relationship of these hormone levels occurs. Yet another study reported that deficiencies in dopamine -- another important neurotransmitter -- may underlie CFS.


In many instances, chronic fatigue syndrome starts suddenly with a flu-like condition. 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 the U.S. outbreaks of CFS occurring within the same household, workplace, and community have been reported but most have not been confirmed by the Centers for Disease Control. A large British study of people with both diagnosed CFS and idiopathic chronic fatigue also found no evidence of infection as a direct cause of either condition but previous infections may play some role. Most cases of CFS occur sporadically, cropping up individually without appearing to be contagious, and there is no consistent evidence that CFS is spread through casual contact, such as shaking hands or coughing, or by intimate sexual contact. Well-designed studies of patients who met strict criteria for chronic fatigue syndrome and of patients with idiopathic chronic fatigue have also not found an increased incidence of any infections, including Lyme disease, candida ("yeast infection"), herpesvirus type 6 (HHV-6), human T cell lymphotropic (HTLVs), Epstein-Barr, measles, coxsackie B, cytomegalovirus, or parvovirus. Some researchers are suggesting that changes in normally harmless bacteria found in the intestine may play a role in the development of CFS symptoms. Another theory referred to as "hit and run" suggests that chronic fatigue syndrome might be the result of a virus or bacteria that infects the body, causes immune abnormalities, and is then eliminated. It leaves behind a damaged immune system, however, that continues to cause flu-like symptoms even in the absence of the virus. Other theories posit that immune system or neurologic abnormalities cause a reactivation of a viral or bacterial infection that had presumably resolved.

Immune System Abnormalities

CFS has been referred to as the "chronic fatigue immune dysfunction syndrome", because some studies have found many irregularities of the immune system, in which some components appear to be overreactive, whereas others appear to be underreactive. Researchers have detected a number of immune abnormalities in CFS patients, but no consistent or major abnormality that could indicate a primary cause.

Allergies and Contributing Factors. Allergies are the only consistent immune system abnormality among CFS patients. Researchers continue to report that between 55% and 80% of CFS patients have allergies to food, pollen, or other substances, which in turn appear to make the CFS symptoms worse. Most allergic people, however, do not have CFS. Some research indicates that in some cases people with both allergies and emotional disorders, such as anxiety or depression, are more vulnerable to the effects of the inflammatory response, which is triggered by allergens. This response produces a number of immune factors, importantly cytokines -- powerful factors that can cause fatigue, joint aches, and fever and which can also affect the hypothalamus-pituitary-adrenal system in the brain. Another recent study found a similar relationship between depression, allergies and low back pain.

A theory that may help tie in the various conditions associated with CFS suggests that a combination of factors, including allergies, stress, and infections, may impair metabolic function by depleting adenosine triphosphate (ATp). This enzyme stores energy in cells, and low levels are common in CFS patients. One study showing symptom improvement using a coenzyme called NADH that increased ATp levels lends support to this theory.

Other Immune Abnormalities. The risk profile for chronic fatigue syndrome, i.e., being female, Caucasian, and well-educated, is also the risk profile for autoimmune diseases, such as systemic lupus erythematosus, rheumatoid arthritis, Sjogren's syndrome, and multiple sclerosis, which also have early symptoms resembling CFS. Common to such diseases are the presence of high levels of autoantibodies -- antibodies that attack the patient's own cells. Some studies are finding high levels of autoantibodies directed against substances in cell nuclei in CFS patients. Others have found low levels of certain antibodies. Some patients, particularly those with severe CFS symptoms, have increased numbers of infection-fighting white blood cells known as CD8 killer T cells, which launch attacks on invading viruses and other disease-causing microorganisms. However, these same people have lower-than-normal numbers of another type of white blood cell, known as the suppressor T cell, which helps to shut down the immune response once the invading organisms have been killed. The immune system then becomes persistently overactive and produces fatigue, muscle aches, and other symptoms of CFS. Other studies have indicated lower amounts of so-called natural killer cells in many CFS patients, which might make them more susceptible to viruses.


Studies are now finding that some people who fit the strict criteria for chronic fatigue syndrome may also have a condition known as neurally mediated hypotension (NMH). One recent study, for example, reported that 25 out of 26 adolescents with CFS experienced NMH. In another small study of patients who met the criteria for CFS, 96% showed signs of NMH compared to only 29% of the comparison group. NMH causes a dramatic drop in blood pressure when standing up, even for as short a time as ten minutes. It is the result of an abnormality in the central nervous system that signals the heart to slow down and lower blood pressure when a person stands up; blood pools in the feet and legs before circulating back up to the heart, sometimes causing light-headedness, nausea, and fainting. NMH can explain many of the symptoms of chronic fatigue, although the blood pressure condition is most likely lifelong and chronic fatigue usually occurs in midlife. Some experts believe that in CFS patients, a virus or infection may cause injury to the central nervous system that results in the hypotension abnormality. This could help explain why so many patients report a viral infection before developing chronic fatigue syndrome. A less severe condition known as postural orthostatic tachycardia syndrome (pOTS) is also associated with CFS. Major studies need to be done and the results repeated with larger patient groups before they can be applied to the majority of CFS patients.

Other Theories

patients with CFS sometimes complain that they feel so weak that it seems as if their muscles are no longer working properly. It has been proposed that a defect in skeletal muscle could be the cause of the fatigue. However, physical, chemical, and metabolic studies have not found any consistent pattern of abnormalities in the muscles of these patients. Another theory to account for some cases of chronic fatigue syndrome is hyperventilation -- the tendency to "over-breathe", which can be caused by many conditions, including asthma, hyperthyroidism, infections, and anxiety disorder. Chronic hyperventilation may cause an imbalance in oxygen and carbon dioxide, which can produce chest pain, faintness, numbness in the fingers and toes, and motor impairment. In one study, although a significant number of CFS patients experienced hyperventilation, there were no differences in CFS symptoms between patients with hyperventilation and patients who did not experience it. Hyperventilation is very unlikely to be a cause of many instances of chronic fatigue. One study found that after CFS patients exercise, they exhibit slight abnormalities in the activity of the vagus nerves on the heart; the vagus nerves run down each side of the neck and end at the intestines and affect many bodily functions.

Causes of Chronic Fatigue-Like Symptoms after the Gulf War

Gulf War veterans have been intensively studied because of a high percentage reporting CFS symptoms. One major study reported that 45% of Gulf War veterans met the overall criteria for chronic fatigue syndrome, with 6% having severe cases. Women veterans had three times the risk as men. Interestingly 15% of the noncombat personnel -- representing the general population -- reported the same problems although the cases in general were less severe than in the veterans. Because such symptoms have occurred in other veteran groups, some experts suspect that post-traumatic stress syndrome may be responsible for the symptoms in some cases. After finding that stress weakens the blood-brain barrier, some experts believe that, in extremely stressful situations such as the Gulf War, this weakened barrier may allow agents, such as small viruses, to pass into the brain causing damage and triggering CFS symptoms. Whether uncovering the causes of the syndrome in Gulf War soldiers can be applied to civilian cases of CFS, however, is not known. More than a dozen different illnesses have been detected in over 70,000 soldiers examined for this problem. Some researchers identified an unusual bacteria-like organism known as Mycoplasma fermentans in nearly half the veterans who suffered from Gulf War syndrome, and one scientist speculated that it might have been developed for biological warfare. Some researchers suspect that the symptoms were caused by an experimental vaccine that contained a substance called squalene. High levels of antibodies to this compound have been found in the blood of veterans with CFS symptoms. An investigation is underway. Still other studies have found that up to 20,000 troops may have been exposed to low levels of the nerve gas sarin. Other possible causes among these veterans include multiple immunizations, oil well fires, and sleep apnea. One study reported that the incidence of hospitalization and death was no higher in these veterans than in soldiers who had not been stationed in the persian Gulf, but this only proves that the symptoms are not fatal or severe enough to send a patient to the hospital. The study does not disprove the condition itself.

How Is Chronic Fatigue Syndrome Diagnosed

A physician 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 certain questions. When did the fatigue first begin Does anything make it worse or better Is it better at certain times of the day Does physical activity make it worse Are there any other symptoms Has anyone else in the family ever complained of fatigue Is your personal and professional life stressful The physician 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.

In most cases of chronic fatigue syndrome, laboratory tests tend to be normal or if they are abnormal (such as high cholesterol levels, which tend to be common in patients with CFS), they are not useful for diagnosing chronic fatigue syndrome specifically. Inexpensive tests, including thyroid and liver function tests, blood count, and sedimentation rate, are recommended to rule out other conditions but none can diagnose CFS. psychological profile testing may be suggested. Since many insurance policies do not cover this testing, the patient may want to determine the cost beforehand (usually less than $200).

Simply measuring blood pressure will not identify CFS patients whose condition might be caused by neurally mediated hypotension (an abnormal drop in blood pressure). A tilt test, whereby an individual 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.

In academic centers where CFS is studied, a series of tests may be performed to measure immune function. Such testing is controversial, because it is expensive and difficult to interpret. Of interest are certain proteins called CFSUM1 that are found in higher levels in the urine of CFS patients with severe symptoms. Some experts are hoping that this or other markers may reveal a biologic basis for CFS and also establish a method for diagnosing it.

Conditions That Rule Out Chronic Fatigue Syndrome

Depression, infections, pregnancy, extreme exercise, sleep disorders, and excessive stress -- these and many other common conditions can lead to feelings of exhaustion. In many instances, fatigue can be relieved with adequate rest. It is important to note that because fatigue can be the harbinger of a serious medical or psychological problem, anyone who experiences unexplained fatigue longer than one month should see a physician.

Epstein-Barr Virus. Epstein-Barr virus (EBV) causes infectious mononucleosis, which is marked by fatigue and swollen glands; it primarily affects adolescents and young adults. In the early to mid-1980s, what is now called chronic fatigue syndrome was often thought to be chronic Epstein-Barr virus infection, because some patients who suffered from a bout of apparent mononucleosis had lingering fatigue that persisted for many months and a persistent low-level EBV infection, indicated by virus particles circulating in the blood. However, researchers subsequently noted that many healthy persons without CFS had the same signs of low-level EBV infection and that other individuals with CFS showed no signs of EBV infection. Because of these and other findings, researchers generally do not believe there is any direct link between Epstein-Barr virus infection and CFS.

Long-Term Autoimmune Diseases. Some diseases are caused by autoimmunity, a condition in which the person's immune system attacks the body's own tissues. Such diseases include systemic lupus erythematosus, multiple sclerosis, Sjogren's syndrome, and rheumatoid arthritis. The early symptoms of these conditions may mimic some of those that appear in CFS, such as muscle and joint pain and fatigue. They also occur more often in women than in men. These diseases evolve slowly, and even if a diagnosis of chronic fatigue syndrome is considered, physicians should keep track of any changes in symptoms over time in order to rule out these serious illnesses.

post-Lyme Syndrome. A delayed response or recurrence of previously treated Lyme disease (called post-Lyme syndrome) may be mistaken for chronic fatigue syndrome. 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.

Other Medical Conditions. Many diseases, both benign and serious, can fully explain prolonged or chronic fatigue, including hepatitis, anemia, infections, various forms of cancer, neuromuscular diseases (such as myasthenia gravis), hypothyroidism, and diabetes. In addition, a number of illnesses also cause arthritic symptoms and fever (see Table, below). patients and physicians should also not overlook other diseases that have been previously treated, but which may not have completely resolved or may cause residual fatigue, including cancer or hepatitis. physicians can usually distinguish these diseases from CFS after a clinical evaluation and laboratory testing.

psychosis and Severe Mental Disorders. The Centers for Disease Control, which set up the definitions in the U.S. for research in chronic fatigue syndrome, recognize depression as one of the symptoms of CFS, but rule 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.

Sleep Disturbances. A common sleep disorder that can cause daytime fatigue without the patient being aware of the problem is sleep apnea, a breathing disorder often marked by loud snoring and thrashing in bed. A person may not realize the problem exists unless it is brought to his or her attention by a sleeping partner or observer. Other sleep disorders that cause daytime fatigue include insomnia and restless legs syndrome. Narcolepsy is a peculiar and rare disorder in which a person suddenly falls asleep without any previous signs of fatigue.

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 medications. Withdrawal from caffeine can produce depression, fatigue, and headache.

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.

Diseases Which Cause Fever with Joint and Muscle pain

  • Infectious Arthritis. Lyme disease, septic arthritis, bacterial endocarditis, mycobacterial and fungal arthritis, viral arthritis.
  • postinfectious or Reactive Arthritis. Enteric infection, Reiter's syndrome, rheumatic fever, inflammatory bowel disease.
  • Rheumatoid Arthritis and Still's Disease (Juvenile Rheumatoid Arthritis)
  • Systemic Rheumatic Illness. Systemic vasculitis, systemic lupus erythematosus
  • Crystal Induced Arthritis. Gout and pseudogout
  • Other Diseases. Familial Mediterranean fever, cancers, sarcoidosis, AIDS, leukemia, Whipple's disease, dermatomyositis, Behcet's disease, Henoch-Schonlein purpura, Kawasaki's disease, erythema nodosum, erythema multiforme, pyoderma gangrenosum, pustular psoriasis, Sjogren's syndrome.

Data from The New England Journal of Medicine, March 17, 1994. polyarthritis and fever, Robert S. pinals, M.D.

Conditions That Accompany and Not Rule Out Chronic Fatigue Syndrome

Many conditions that can account for extreme fatigue can be identified or diagnosed but may not necessarily rule out the additional presence of chronic fatigue syndrome.

Fibromyalgia. Fibromyalgia causes prolonged fatigue and widespread muscle aches. A characteristic feature is the existence of at least 10 distinct sites of deep muscle tenderness that hurt when touched firmly; the sites include the side of the neck, the top of the shoulder blade, the outside of the upper buttock and hip joint, and the inside of the knee. 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; some, but not all, experts believe it is simply another variant of chronic fatigue syndrome, and one compared fibromyalgia to chronic fatigue as the same relationship as a migraine to a headache.

Exposure to Chemicals or Toxins. Exposure to various chemicals and environmental toxins -- such as solvents, pesticides, or heavy metals (cadmium, mercury, or lead, for example) can cause fatigue and other symptoms of CFS, including psychological changes. Identifying such exposure, however, does not rule out the possibility of chronic fatigue syndrome.

Depression or Anxiety Disorders. A number of physicians believe that chronic fatigue is not a physical illness but can be attributed to emotional disorders. The link between psychological disorders and chronic fatigue syndrome is problematic because so many of the symptoms overlap with each other and also can occur as symptoms in other disorders. Fatigue, listlessness, poor concentration, memory deficits, agitation, and sleep disorders can all be manifestations of depression and anxiety. Stressful events -- such as surgery, a significant illness or injury, the birth of a child, divorce, the death of a loved one, or other serious emotional trauma -- further complicate the picture, because even everyday stress can contribute to fatigue and may play a role in lowering the body's resistance to infection. Certain screening tests, particularly one called Short-Form General Health Survey (SF-36), are fairly accurate in differentiating people who have major depression from those with chronic fatigue. Depression is very common, affecting up to a fifth of all Americans at some point in their lives, and most depressed people feel fatigued. Unlike ordinary periods of sadness, an episode of depression can last many months. Symptoms of depression include (1) a depressed mood everyday, (2) significant weight gain or loss (of 10% or more of an individual's typical body weight), (3) insomnia or excessive sleeping, (4) restlessness or a sense of being slowed down, (5) low energy daily, (6) worthless or inappropriately guilty feelings, (7) an inability to concentrate or to make decisions, and (8) suicidal thoughts. The presence of several of these symptoms suggests depression, rather than chronic fatigue, particularly if physical symptoms, such as sore throat, aches and pains, or fever, are not also present. The longer fatigue has continued without these other symptoms, the more likely the diagnosis is depression and not chronic fatigue syndrome. Depression is not necessarily present in CFS, however. Although many patients who are diagnosed with CFS report feeling depressed before the onset of chronic fatigue, many feel alert and well before experiencing chronic fatigue. Depression in people with CFS is usually a reaction to the disease. They are discouraged, but not hopeless and wish to enjoy life, not avoid it. Many of these previously healthy patients get depressed and anxious because they feel so exhausted all the time after coming down with the syndrome.

Fatigue Following Adequately Treated Disorders. If a physician can verify that a disease has been treated adequately and yet symptoms of chronic fatigue persist, then CFS or idiopathic chronic fatigue cannot be ruled out. If hypothyroidism, for example, is treated by replacement thyroid hormone, and if fatigue and other relevant symptoms continue after normal levels of thyroid have been reached, then an additional diagnosis of CFS is still possible.

Weak Results from Laboratory Tests. Some tests for diseases that cause the same symptoms as CFS or idiopathic chronic fatigue may be ambiguous or weak. In such cases, unexplained chronic fatigue should not be ruled out.

How Serious Is Chronic Fatigue Syndrome
Severity of Symptoms

The severity of chronic fatigue syndrome varies. In extreme cases, patients are bedridden and can do virtually nothing, including even light housework. More often, CFS sufferers can work at least part-time. Most commonly, patients with CFS report that they have trouble fulfilling both home and work responsibilities. Studies may under-report the severity of the condition because severely disabled patients may have difficulty getting to and from the clinical study site and would not be able to participate. The problem is compounded by some medical centers that do not accommodate the disabled CFS patients with the same consideration or resources (e.g., wheelchairs, beds) that would be given patients with more recognized disorders, such as multiple sclerosis.

Most patients say that while fatigue is the most incapacitating symptom, those of mental impairment, such as an inability to concentrate, are the most distressing. 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. In such studies, this impaired mental function occurs regardless of the presence or absence of depression or other psychiatric disorders. 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. Some studies indicate that there is very little measurable difference in memory, information processing, and concentration between CFS patients and those without the disorder and that the perceived differences are due to emotional problems. It has been suggested, however, that such results are due to the tests being performed in an doctor's office or clinical setting, which often do not accurately reflect the burden that daily tasks place on severely fatigued patients and which result in little spare capacity for attention or mental flexibility.

Long-Term Outlook

Because the illness has been undefined and there are few objective measures for recovery, experts have found it difficult to determine the long-term outlook of CFS. Some physicians have observed that patients whose symptoms began abruptly following a severe viral illness recovered completely after six months to a year, whereas patients whose problems developed slowly and insidiously experienced symptoms for a longer period of time. One recent study found that when patients with severe CFS were treated with a multidisciplinary rehabilitation program, nearly all improved significantly and the gains were maintained for at least a year afterward. Many patients with less severe chronic fatigue have reported turning a corner after a year or two and slowly regaining energy despite some setbacks along the way. Some patients get progressively worse, but the disorder is not fatal. Although children with symptoms of chronic fatigue have not been rigorously studied, some studies indicate that children generally have a better prognosis than adults and recover after one to four years in up to 95% of cases.

How Is Chronic Fatigue Syndrome Treated

There is no proven or reliable cure for CFS; studies have found that 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.

Lifestyle Changes

Exercise. Some patients experience profound fatigue following even modest exercise, and it is the primary factor in the low-activity levels in these patients. A recent study found, however, that 75% of patients who were able to engage in exercise, particularly aerobic exercise, reported improvement in fatigue, normal functioning, and fitness after a year. It is necessary to go slowly, however, to prevent relapse. patients should gradually increase activity level keeping within limits and avoiding over-exertion. An incremental program of activity, beginning with as little as three to five minutes of moderate exercise a day, is suggested, although capacity varies greatly among CFS sufferers. The goal is to increase activity by about 20% every two to three weeks. Setbacks will occur, but patients should not become discouraged. Rather, they should experiment with various forms of physical activity that suit their available energy levels. Some patients report great benefits from Tai chi chuan, an Eastern form of meditation and exercise.

Diet. Chronic fatigue syndrome patients should maintain a healthy diet low in animal fat and high in fiber, with plenty of fresh fruits and vegetables. Some fats may be beneficial, however. One study found that 85% of patients with CFS experienced improved symptoms using black current and fish oils. (Another study, however did not confirm these results.) These oils contain a polyunsaturated fatty acid known as gamma linolenic acid, which seems to block the release of cytokines and prostaglandins -- substances that play major destructive roles in inflammatory diseases. (Olive oil may have similar benefits and, in any case, there is no downside in using it in cooking.) For those with demonstrated low blood pressure, increasing the amount of salt in the diet may be helpful.

Stress Reduction Techniques. A number of relaxation techniques are available, including deep breathing exercises, muscle relaxation techniques, meditation, hypnosis, biofeedback, and massage therapy. One panel of experts concluded that a number of 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.

personal Relationships. Strong, supportive, relationships with family and friends may be an important factor in the overall improvement of CFS patients.

Cognitive Therapy

Cognitive therapy is proving to have substantial benefits for enhancing patients' beliefs in their own abilities for dealing with stressful situations and managing their disorder. The primary goal of cognitive therapy is to change the distorted perceptions that patients have of the world and of themselves; for CFS patients, this means learning to think differently about their fatigue. Cognitive therapy is particularly helpful in defining and setting limits -- behaviors that are extremely important for these patients. One study found that patients who felt the least control over symptoms reported more severe and chronic fatigue. Using specific tasks and self-observation, 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. Cognitive therapy may be expensive and not covered by insurance, although it is usually of short duration -- typically six to 20 one-hour sessions, plus homework, which usually includes attempting a task that the patient has avoided because of negative thinking.

Homework also may include keeping an energy diary, which can be a key component of CFS cognitive therapy. The diary serves as a general guide for setting limits and planning activities. The patient uses the diary to track any factors, such as a job or a relationship, that may be making the fatigue worse or better. It is also used to track the times of day when energy levels are at their highest and lowest peaks and adjust schedules accordingly. For instance, the patient may plan low-energy times for taking a nap and high-energy times for planning important activities. Developing fairly rigid daily routines around probable energy spurts or drops may help establish a more predictable pattern. It should be noted, however, that energy levels will most likely never be entirely predictable; patients must also be prepared to adapt to energy variations. Flexibility is important. Instead of a long nap, for instance, patients may need between five to 10 minutes rest periods every hour or more, during which time relaxation or meditation methods are useful. Cognitive therapy teaches patients how to prioritize their responsibilities, dropping some of the less critical tasks or delegating them to others. Limits should be designed to keep both mental and physical stress within a manageable framework so that patients do not get discouraged by forcing themselves into situations in which they are likely to fail. As part of the therapeutic process, patients learn to adapt even to impaired concentration, a common CFS problem. For example, the patient learns to choose activities that are appealing, that will focus attention, and will help increase alertness. CFS patients are taught to request instructions that are given as concise simple statements and to keep external distractions, such as music or talking, to a minimum.

In one study comparing patients receiving standard treatment with those receiving the same treatment plus cognitive therapy, 73% of the cognitive group were spending less time in bed and functionally normally after a year, as opposed to only 27% of those who received standard therapy. In another study, 70% of patients improved significantly after six months of cognitive therapy, compared to 19% who used only relaxation techniques. Not all studies support the benefits of cognitive therapy; the skill of the therapist is very important in its success. psychoanalysis and other interpersonal psychological therapies, which are concerned with subconscious thoughts and early childhood memories, are not generally helpful for the patient with chronic fatigue syndrome. It is important to note that even if chronic fatigue syndrome proves to have a specific organic cause, 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.

Antidepressant and Antianxiety Drugs

The antidepressant amitriptyline (Elavil) is known to relieve many of the symptoms of CFS, including sleeplessness and low energy levels. patients with CFS normally respond to much lower doses than those used to treat people with other disorders, and, in fact, many CFS patients cannot tolerate the higher doses commonly used to treat depression. Improvement in symptoms can take three to four weeks. Many researchers report that other antidepressant medications have also helped, including doxepin (Sinequan), desipramine (Norpramin), nortriptyline (pamelor), clomipramine (Anafranil), and imipramine (Tofranil, Janimine). (popular antidepressants known as selective serotonin-reuptake inhibitors (SSRIs), such as fluoxetine (prozac), sertraline (Zoloft), and paroxetine (paxil), appear to have little value for CFS beyond treating any accompanying depression.) It often takes several weeks for tricyclics to produce benefits. Common side effects of many antidepressants include dry mouth, restlessness, a slightly increased heart rate, and constipation. If anxiety is also a problem, an anxiety-relieving drug, such as alprazolam (Xanax), may be prescribed, although anti-anxiety drugs can become addictive if used for prolonged periods and are not usually recommended.

pain Relievers

If muscle aches or pains persist, nonsteroidal anti-inflammatory drugs (NSAIDs), such as aspirin or ibuprofen (Advil, Motrin), or acetaminophen (Tylenol) may help. Because chronic fatigue syndrome can cause on-going joint pain, some patients may abuse over the counter medications. It is important to note that NSAIDs can cause bleeding, and excessive use of acetaminophen has been associated with liver or kidney damage and even death. Those with ulcers should not take NSAIDs without a physician recommendation. If joint pain is not relieved with nonprescription painkillers, local injections of lidocaine (an anesthetic to relieve pain) may be administered. Deep massage, hot and cold applications, topical anesthetics, stretching, acupuncture, and chiropractic treatment may also help minimize symptoms.

Treatment of Neurally Mediated Hypotension

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. For treating NHM, the physician might first recommend nonmedicinal measures, such as increasing salt content in the diet. Caffeinated beverages may be helpful. patients are instructed to perform exercises before getting out of bed that flex the feet so that the blood moves up toward the head. They are encouraged to avoid excessive activity after meals. They should not use medications that reduce blood pressure. Special support garments may help to prevent circulating blood from pooling in the lower part of the body and to return it to the heart. If the condition does not improve, certain medications may be tried in combination or alone. Midodrine (proAmatine) is a drug that increases smooth muscle tone and blood pressure and reduces symptoms of NMH. Adverse effects include itching, numbness, and tingling, but the drug is well tolerated. A wide range of drugs normally used for other disorders have been used to treat NMH, but physicians have had difficulty adjusting them so that they would be effective for NMH without causing distressing side effects. Such medications include fludrocortisone (an oral steroid), phenylpropanolamine or ephedrine (decongestants), indomethacin or ibuprofen (nonsteroidal anti-inflammatory drugs or NSAIDs), disopyramide (an anti-arrhythmic drug), beta-blockers (drugs normally used to prevent hypertension), and recombinant erythropoietin epoetin alfa (used to increase red blood cells). It should be stressed that no one should take measures to raise blood pressure without a clear diagnosis of NMH or without a physician's approval, since increasing blood pressure can be very dangerous in individuals with existing normal or high blood pressure. There is also no clear evidence yet that NMH is a major cause of chronic fatigue syndrome.

Treatment for Low Stress Hormones

Some evidence exists the 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, increase appetite and weight gain, and -- more seriously -- suppression of the adrenal gland -- make this therapy unacceptable. A recent study reporting improvement with very low doses (5 mg to 10 mg daily) with only minor side effects may make this therapy feasible for some patients, but longer-term and larger studies are needed.

Antiviral Medications

The antiviral drug, polyl:polyC12U (Ampligen) is one of the most studied anti-CFS drugs at this time. In an analysis of studies, after 24 weeks of Ampligen therapy patients had a 31% improvement in CFS symptoms compared to a 10% improvement in patients on placebo. patients taking Ampligen progressed from needing daily assistance of normal activities to needing assistance only once a week. However, there has been some controversy concerning the 25-year old drug, which has been studied without success for many cancers and for AIDS.

Experimental Treatments

A natural agent called nicotinamide adenine dinucleotide, or NADH (Enada), is also in trials. This substance triggers adenosine triphosphate (ATp) an enzyme found in every cell that is necessary for conversion of food into energy. In one well-conducted small study about 30% of patients reported feeling better and having more energy after taking NADH compared to 8% who took a placebo. Although the study was small, these results showed promise. Although there is some indication that CFS patients may have low magnesium levels, there has been no proven benefit for magnesium sulfate. Because chronic fatigue syndrome still has not been clearly defined as a specific disorder, patients should approach any experimental treatment cautiously and seek more than one opinion before embarking on such programs.


The use of phototherapy may be effective treatment for 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 winter than summer months. With phototherapy is the patient sits a few feet away from a box-like device that emits very bright fluorescent light (10,000 lux) for about 30 minutes every day. It is best performed immediately after wakening in the morning.

Alternative Therapies

Because of the difficulties in treating chronic fatigue syndrome, many patients seek alternative therapies. Some, such as acupuncture and relaxation techniques, may be helpful and are not dangerous. But everyone should be wary of those who promise a cure or urge the purchase of expensive but useless and potentially dangerous treatments, such as hydrogen peroxide injections (which can cause blood clots or strokes), megadoses of vitamins (which can be toxic), high colonic enemas, and bee pollen (which can cause an allergic reaction). No scientific evidence exists that vitamin and mineral supplements will relieve CFS, but taken in moderation, they are usually not harmful. It should be noted, however, that megadoses of vitamins can be toxic. A number of herbal medicines have been used for chronic fatigue syndrome; none have been proven to have any benefit, and some can be harmful. Injections of liver extract, folic acid, and vitamin B12 have shown no benefit, nor have supplements of vitamin B15 (also called pangamic acid) or superoxide dismutase (SOD). It is extremely important for patients to realize that herbal medicine has as many potential side effects and toxic reactions as standard drug therapy; in fact, the dangers increase because no standards exist for safe or effective dosages. Of particular note is the product Nature's Nutrition Formula One; it includes 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 physician.

Recent Literature

  • Cognitive-Behavioral Therapy. Harvard Men's Health Watch, April, 1998
  • Chronic multisymptom illness affecting air force veterans of the Gulf War. JAMA 9/16/98, Vol. 280.
  • NADH shows promise in study. CFIDS Chronicle, January/February 1998
  • patients improve with glutathione. CFIDS Chronicle, January/February 1998
  • Tai chi chuan: a pathway of hope. CFIDS Chronicle, March April 1998

Well-Connected Board of Editors

  • Harvey Simon, M.D., Editor-in-Chief
    Massachusetts Institute of Technology; physician, Massachusetts General Hospital
  • Masha J. Etkin, M.D., Gynecology
    Harvard Medical School; physician, Massachusetts General Hospital
  • John E. Godine, M.D., ph.D., Metabolism
    Harvard Medical School; Associate physician, Massachusetts General Hospital
  • Daniel Heller, M.D., pediatrics
    Harvard Medical School; Associate pediatrician, Massachusetts General Hospital; Active Staff, Children's Hospital
  • Irene Kuter, M.D., D. phil., Oncology
    Harvard Medical School; Assistant physician, Massachusetts General Hospital
  • paul C. Shellito, M.D., Surgery
    Harvard Medical School; Associate Visiting Surgeon, Massachusetts General Hospital
  • Theodore A. Stern, M.D., psychiatry
    Harvard Medical School; psychiatrist and Chief, psychiatric Consultation Service, Massachusetts General Hospital

Carol peckham, Editorial Director

Cynthia Chevins, publisher

Copyright * 1999 Nidus Information Services, Inc. Well-Connected Report: Chronic Fatigue Syndrome. June 1999. (Online) Well-Connected

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