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Chronic fatigue syndrome - InDepth

An in-depth report on the causes, diagnosis, and treatment of chronic fatigue syndrome.

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Highlights

Chronic Fatigue Syndrome

Chronic fatigue syndrome (CFS) is a complicated and poorly understood disease that causes persistent and profound fatigue. CFS is also known as systemic exertional intolerance disease (SEID) or myalgic encephalomyelitis (ME/CFS). The causes of CFS are unknown.

Symptoms

Symptoms of CFS can come and go in cycles. People may feel better for a while, and then have a relapse. The main symptoms of CFS are:

• Severe fatigue that has lasted at least 6 months
• Worsening of symptoms after physical or mental activity or stress (postexertional malaise)
• Unrefreshing sleep

People with CFS may also experience many other symptoms, including problems with thinking and memory, worsening of symptoms when standing or sitting up, pain, and sensitivities to external stimuli.

Treatment

Treatment for CMS focuses on symptom relief. Cognitive behavioral therapy (CBT) and graded exercise therapy (GET) are two approaches that have been advocated for people with CFS and are supported by a few clinical studies. While these may work well for some patients, their appropriateness as a general indication in CFS has recently been under scrutiny. In 2017, the CDC decided to remove CBT and GET from the list of recommended therapeutic approaches for people with CFS/ME.

New Name and Diagnostic Criteria

In 2015, the Institute of Medicine (IOM) recommended systemic exertion intolerance disease (SEID) as the new name for CFS. The IOM's goal was to have the name reflect some of the disease's core symptoms, and to hopefully remove some of the stigma that surrounds this challenging condition.

Introduction

Chronic fatigue syndrome (CFS) is a serious and complex medical condition characterized by a cluster of systemic symptoms that affect physical and cognitive functioning. The hallmark symptom is persistent and profound fatigue, which often worsens after physical or mental exertion. This fatigue lasts for more than 6 months, impairs normal activities, and has no identifiable medical or psychological factors to account for it.

Fatigue is just one symptom of the condition. In addition to fatigue, people usually experience other problems such as unrefreshing sleep, difficulty with memory or concentration ("brain fog"), muscle and joint pain, and worsening of symptoms when in an upright position.

CFS is a serious condition that has a profound impact on the people who have it. Many people with CFS are forced to curtail or find new coping strategies to handle normal daily activities. About 1 in 4 people with CFS are so severely disabled that they cannot get out of bed or leave their home. Symptoms can come and go in cycles, and even when people feel better, they may experience a relapse triggered by exertion or an unknown cause.

CFS/ME

There are a number of challenges, confusions, and controversies surrounding CFS, including defining its possible causes, exact symptoms, diagnosis, and treatment. There is even disagreement about what to call the condition.

The term "myalgic encephalomyelitis" or "ME" is sometimes added to CFS, with the disease being abbreviated as ME/CFS or CFS/ME. However, some researchers believe that ME is not appropriate because it implies brain inflammation (encephalomyelitis) and muscle pain (myalgia), which are not its main symptoms.

Many people feel that the term CFS is not accurate either, because it contributes to belittling misunderstandings that undercut the serious nature of this condition. People with CFS are not lazy, neurotic, unmotivated, or suffering from the "yuppie flu." They struggle to live with a bewildering illness that is not completely understood by medical practitioners, much less the general public.

SEID

In 2015, the Institute of Medicine (IOM) proposed replacing ME/CFS with a new name: systemic exertion intolerance disease (SEID). The IOM's rationale for this name change is that SEID focuses on a core symptom of post-exertional malaise, which involves the entire body. The name also emphasizes that this condition is a "real" disease, not a psychological disorder.

However, the term SEID has not been universally embraced. Some people feel that it is still open to distortion and misrepresentation. Until experts agree upon the terminology, CFS may remain more commonly recognized as the name for this condition, and will be the term used in this report.

Causes

The exact causes of CFS are not known. Researchers think that infection, immune system problems, genetics, and the effects of stress on hormone production may play roles in different people. There may also be a genetic component. It is likely that CFS is due to a combination of factors rather than one single cause.

There is also no standard way that CFS develops. Some people have an abrupt onset of symptoms after an infectious disease or psychiatric problem. Other people experience a slowly progressive emergence of symptoms, and have no history of mental health issues.

It is not clear what sequence of events actually leads to the fatigue and other symptoms of this disorder. No primary cause has been found that explains all cases of CFS, and no blood tests or brain scans can definitively diagnose the condition.

Infections

Researchers have focused on the possibility that a virus or other type of infection may trigger CFS. Many people report having a flu-like illness or bacterial infection prior to developing CFS.

Possible viral causes include the Epstein-Barr virus (EBV) and herpesvirus type 6 (HHV-6). EBV is related to mononucleosis, which can cause severe fatigue. However, scientists have been unable to establish a causal link between EBV and CFS.

Researchers are also investigating whether CFS may be associated with the reactivation of a latent infection. Again, there is no conclusive evidence to support this theory.

Immune System Dysfunction

A number of studies have suggested that there may be problems of regulation of the immune system in people with CFS.

Researchers are investigating whether over- or under-activation of T cells, B cells, and natural killer (NK) cells, which help regulate the immune system, may play a role in CFS. It is not yet clear whether people with CFS have the autoantibodies (antibodies that attack the body's own tissues) found in people with autoimmune disorders. There is no indication at the current time to use immune system modulating therapies to treat CFS.

Allergies

Many people with CFS have allergies or sensitivities to foods, pollen, molds, metals (such as nickel or mercury), or other substances. One theory is that allergens, like viral infections, may trigger a cascade of immune abnormalities that lead to CFS. However, most people with allergies do not have CFS.

Central Nervous System Abnormalities

Abnormal levels of certain chemicals in the brain system known as the hypothalamus-pituitary-adrenal (HPA) axis have been proposed as a cause of CFS. This system controls important functions, including sleep, the stress response, and depression. Some people with CFS appear to have imbalances in hormones controlled by the HPA axis, such as cortisol.

Autonomic Nervous System Abnormalities

Researchers are investigating links between autonomic system dysfunction and CFS. The autonomic nervous system controls involuntary actions, including regulating blood pressure.

Some people who have CFS also have symptoms of a condition known as neurally mediated hypotension (NMH). NMH causes a dramatic drop in blood pressure when a person stands up, for even as few as 10 minutes. Its immediate effects can be light-headedness, nausea, and fainting.

A related condition experienced by some people with CFS is called postural orthostatic tachycardia syndrome (POTS). POTS causes a rapid increase in blood pressure when changing from a lying down to a standing up position.

Risk Factors

The Institute of Medicine estimates that up to 2.5 million Americans have CFS, but millions more may have the disease and not yet been diagnosed.

Age

CFS usually affects adults in their 30s, 40s, or 50s, but it can develop in people of all ages from children and adolescents to the elderly.

Gender

CFS is more common in women than men.

Family History

CFS sometimes occurs among members of the same family, which implies there may be a genetic link. CFS is not contagious.

Stress

There is some evidence that stress, or difficulty managing stress, may trigger CFS in people who are at risk for the disease because of genetic and other underlying factors. Stress may trigger the condition through its effects on the central nervous system, immune system, and neuroendocrine system (which is related to both nerves and hormones.)

Psychological Factors

Studies have not found any consistent association between psychological, emotional, or personality factors and CFS.

Overlapping Conditions

A number of conditions overlap or coexist with chronic fatigue syndrome and have similar symptoms. They include fibromyalgia, irritable bowel syndrome, and sleep disorders.

People with CFS often report extreme sensitivities and physical reactions to environmental chemicals, such as those found in perfumes, cigarette smoke, or paint fumes. There is controversy and disagreement surrounding "multiple chemical sensitivities" and whether these symptoms constitute a real disorder.

Symptoms

The main symptoms of CFS are:

• Severe fatigue that has lasted at least 6 months and that significantly impairs daily functioning. Feelings of flu-like exhaustion, heaviness in arms and legs, difficulties carrying out personal, social, and occupational tasks.
• Worsening of symptoms and function after exposure to physical or emotional stress (post-exertional malaise). Feeling completely drained or exhausted for more than 24 hours after physical or mental effort.
• Unrefreshing sleep or problems sleeping. Waking up feeling exhausted or difficulties falling or staying asleep.
• Problems with thinking, concentration, and memory (cognitive impairment). Sensation of "brain fog," challenges in multitasking or finding right words, memory lapses.
• Worsening of symptoms when assuming or maintaining an upright position (orthostatic intolerance). Feeling dizzy, lightheaded, or unbalanced when sitting or standing up for more than several minutes.

Other symptoms may include:

• Muscle pain
• Joint pain without redness or swelling
• Headaches that are new or different
• Sore throat that is frequent or recurring
• Sore lymph nodes in neck or under arms
• Stomach problems
• Sensitivity to substances found in food, medications, or chemicals

Additional symptoms that have been associated with CFS include abdominal bloating, urinary problems, alcohol intolerance, and sensitivity to light and loud noise.

Diagnosis

It is very difficult to diagnose chronic fatigue syndrome. Diagnosis focuses on symptom criteria, especially unexplained and profound fatigue that has lasted at least 6 months. The symptoms of CFS tend to come on suddenly in most individuals affected by the condition.

Personal and Medical History

The health care provider will take a careful personal and family medical history, and perform a thorough physical examination and psychological assessment. The provider will ask questions such as:

• When did the fatigue first begin?
• Does anything make it worse or better?
• Is it better at certain times of the day?
• Does physical or mental activity make it worse?
• What are your other symptoms?
• Has anyone else in your family experienced similar symptoms?
• Is your personal and professional life stressful?

The provider may also ask about any changes in weight or recent illnesses. You should tell your provider about any drugs you are taking, including over-the-counter medications, and vitamin, herbal, or dietary supplements. You may be asked to keep a diary for several weeks to record your activities and symptoms.

Laboratory Tests

No specific laboratory test can diagnose CFS. The following tests may be used to rule out other conditions that can cause persistent fatigue:

• Complete blood count (CBC)
• C-reactive protein
• Creatine kinase
• Erythrocyte sedimentation rate
• Liver function
• Fasting blood sugar (glucose)
• Serum calcium and magnesium
• Serum creatinine
• Thyroid function
• Urea and electrolytes
• Urine test for protein, blood, and glucose
• Tests for immune function

If any test is abnormal, it is not useful for diagnosing CFS specifically, and the provider should look for other possible causes suggested by the positive test (such as decreased thyroid function.)

Other Tests

Other tests for CFS may include:

• Exercise test to evaluate cardiopulmonary function.
• Tilt table test to evaluate orthostatic hypotension (low blood pressure when standing up.)
• MRI or other brain imaging test to evaluate signs of lesions associated with multiple sclerosis or other neurological conditions.

Ruling Out Other Conditions

Other conditions can mimic symptoms of CFS. They include:

• Fibromyalgia. A disorder that causes muscle pain and fatigue, is closely associated with CFS and often overlaps with it. Unlike CFS, fibromyalgia generally has specific pain trigger pains.
• Autoimmune diseases. Diseases such as systemic lupus erythematosus, Hashimoto's thyroiditis, multiple sclerosis, and rheumatoid arthritis, are caused by autoimmunity, a condition in which a person's immune system attacks the body's own tissues. The early symptoms of these conditions, such as muscle and joint pain and fatigue, may mimic CFS symptoms.
• Infectious diseases. Infections such as Lyme disease or HIV/AIDS can be identified with blood tests. Infectious mononucleosis causes fatigue and swollen glands. It primarily affects adolescents and young adults. Blood tests can detect the Epstein-Barr virus (EBV), which causes mononucleosis.
• Endocrine disorders. Endocrine disorders such as Addison disease or thyroid dysfunction can cause fatigue and muscle weakness.
• Sleep disorders. Sleep disorders such as obstructive sleep apnea and restless legs syndrome should be considered.
• Substance abuse and psychiatric disorders. Psychiatric conditions should also be ruled out. Fatigue is a side effect of many prescription and over-the-counter medications. In addition, dependence on or abuse of alcohol or illicit drugs may lead to chronic fatigue.

Treatment

CFS remains poorly understood and many people with the disease face challenges finding good care. It is important to recognize that there is no cure for CFS. As scientific understanding of the disease evolves, researchers hope to discover new treatments that address the disease systemically.

Current treatment focuses on relieving symptoms and helping people self-manage the condition.

You should work with your provider to develop a treatment plan that addresses your specific symptoms and concerns. It is best to begin treatment by focusing on the symptoms that cause you the most problems.

Treatment approaches by symptom may include.

Fatigue and postexertional malaise:

• Activity pacing
• Graded exercise program (may worsen fatigue)
• Cognitive behavioral therapy (CBT)

Sleep:

• Sleep hygiene techniques
• Activity pacing
• Medicines

Pain:

• Activity pacing
• CBT
• Nonprescription pain relievers
• Physical therapy

Emotional and Mental Health Problems:

• CBT
• Counseling
• Support groups
• Medicines

Non-Drug Treatments

People with CFS often experience post-exertional malaise after physical activity, which can last days to weeks. Creating an individualized plan balancing activity with appropriate periods of rest can help improve quality of life.

Activity Pacing (Adaptive Pacing Therapy)

Try to plan a daily schedule that allows you to spread out and accomplish a certain number of activities but also allows time for adequate rest. People with CFS often find that doing too much at once can worsen symptoms and exhaustion. A strategy that allows you to plan daily rest breaks, and find a rhythm that works for your energy level, will help you feel more in control.

When you begin activity pacing (also called adaptive pacing therapy), you may find it helpful to keep a diary that tracks your activities, rest, sleep, and symptoms so that you can identify patterns and set goals.

Activity pacing should involve:

• Balancing your time between activity, rest, and sleep
• Spreading out more challenging tasks throughout the day and week
• Breaking big tasks into smaller, more manageable ones
• Alternating types of activities (mental vs physical, gentle vs strenuous)
• Taking short frequent rest breaks throughout the day
• Slowly increasing your daily activities as you find you can do more

Cognitive-Behavioral Therapy

The goals of CBT include improving a person's ability to deal with stressful situations, and better manage their illness, as well as manage sleep problems and regulate activity levels.

CBT is and has been extensively used to manage CFS, however questions have been raised regarding its effectiveness. As a consequence, in 2017 the CDC has removed CBT from its list of recommended therapeutic approaches for CFS/ME.

Graded Exercise Therapy

Graded exercise therapy (GET) involves slowly increasing the duration and intensity of exercise over time. In general, people start with about 3 to 5 minutes of exercise, and then gradually increase activity over the course of several weeks.

GET does not work for all people with CFS and may worsen the condition in some. Some people experience profound fatigue after even mild or moderate exercise. Other people cannot exercise at all.

Due to concerns over its effectiveness, in 2017, the CDC has removed GET from its list of recommended treatment approaches for CFS/ME. Many specialists advise against pursuing aerobic exercise or any exercise that overly increases heart rate. Your provider may suggest that you wear a heart rate monitor while exercising. Recommended types of exercise include yoga, tai chi, and resistance and weight training.

People with CFS appear to have problems with aerobic metabolism, and must be careful not to exercise beyond their threshold. Over-exercise can worsen symptoms. For those who follow a GET approach, it is important to gradually build up to a level that is appropriate for you.

Sleep Hygiene

Sleep hygiene involves simple self-help measures and behavioral changes that can help improve sleep. These include:

• Establish a regular time for going to bed and getting up in the morning.
• Use the bed for sleep and sexual relations only, not for reading, watching television, or working.
• Do something quiet and relaxing in the 30 minutes before bedtime. Reading, meditating, or taking a warm bath are all appropriate activities.
• Keep the bedroom relatively cool and well ventilated.
• Eat light meals, and schedule dinner 4 to 5 hours before bedtime. A light snack before bedtime can help sleep, but a large meal may have the opposite effect.
• Spend at least 30 minutes in daylight every day. The best time is early in the day.
• Avoid fluids just before bedtime so that sleep is not disturbed by the need to urinate.
• Avoid stimulants such as caffeine or nicotine in the hours before sleep.
• Avoid alcohol in the hours before bedtime. While alcohol may help you fall asleep quickly, it can cause you to wake up in the middle of the night.
• If still awake after 15 to 20 minutes, go into another room, read or do a quiet activity using dim lighting until feeling very sleepy. (Do not watch television or use bright lights.)

Stress Management

Relaxation and stress-reduction techniques can be helpful. They include:

• Deep breathing exercises
• Massage therapy
• Meditation
• Muscle relaxation techniques
• Yoga and tai chi
• Acupuncture
• Biofeedback

Healthy Diet

There is no evidence that specific foods or restrictive diets influence CFS. It is best to take a commonsense approach to a healthy diet that includes:

• Plenty of fruits and vegetables.
• Limited saturated fats (found in animal products.)
• Limited sugars and starchy foods.
• Limited caffeine (people with CFS may turn to caffeine products to help improve energy, but caffeine will interfere with healthy sleep.)

Vitamins

Discuss with your provider whether you should take a multivitamin supplement. Your provider may recommend a specific vitamin supplement if you have deficiencies in vitamin D or vitamin B12. Only use the recommended dose for vitamins: megadoses can be dangerous.

Herbs and Dietary Supplements

Many people with CFS turn to herbal and so-called "natural" remedies but there is no scientific evidence that they are effective. Be wary of supplements advertised as "immune system boosters" because they may contain unlisted steroids or pharmaceutical products. If you choose herbal remedies, stick to safe and simple ones such as peppermint or ginger tea for stomach problems and relaxation.

Be aware that the FDA does not regulate herbal remedies or dietary supplements. The amounts of the active ingredients in these remedies may not always match what is claimed on the label. Be sure to let your provider know of any herbs or supplements you are taking. Some of these products may interact with medications.

Emotional Support

Strong, supportive relationships with family and friends are important. Attending support groups in which you share experiences with others who have CFS can be very helpful for sharing your concerns and strategies, and improving your coping abilities.

Medications

No medications are specifically approved to treat CFS. However, some medications may be useful for pain, sleep, or other symptoms. People with CFS are often very sensitive to drugs, so try to limit medication use as much as possible and use the lowest effective dose.

Pain Relievers

Nonsteroidal anti-inflammatory drugs (NSAIDs)

NSAIDs are common non-prescription pain relievers. They include aspirin, ibuprofen (Motrin, Advil), and naproxen (Aleve), and COX-2 inhibitors.

Daily use of NSAIDs can increase the risk for stomach bleeding and ulcers.

Talk to your provider before taking these medicines if you have kidney disease or heart disease. Your provider should be aware if you take these medicines on most days.

Sleep Medications

Nonprescription medications for sleep usually include the antihistamine diphenhydramine (Benadryl). Antihistamines can be effective when occasionally used, but in the long-term can cause problems with rebound insomnia.

Non-Benodiazepine Sedative Hypnotics

Are the preferred prescription medications for treating insomnia. They include zolpidem (Ambien), zaleplon (Sonata), and eszopiclone (Lunesta). Newer types of sedative hypnotics include ramelteon (Rozerem) and suvorexant (Belsomra).

It is important that your provider explain the risks of these drugs and the precautions you need to take. These drugs are usually prescribed for short-term use and should be taken at the lowest possible dose because they can affect next-day mental alertness and physical coordination. You should never use alcohol before taking these drugs. Long-term use of these drugs may cause problems with short-term memory.

Melatonin

A supplement that is a synthetic version of a hormone found in the body that is associated with regulating the circadian rhythms associated with sleep. Melatonin is a dietary supplement; therefore, it does not require FDA approval. There are no consistent standards on melatonin doses. General recommendations are to take 0.3 mg to 1 mg about 90 minutes before going to sleep. Taking higher doses may disrupt sleep and may cause daytime sleepiness, headaches, dizziness, nausea, and stomach cramps.

Other types of medications, such as tricyclic antidepressants or anticonvulsants, may be used to treat sleep problems, as well as pain.

Antidepressants

Tricyclic Antidepressants

Antidepressants known as tricyclics affect brain chemicals that are involved in managing pain. The tricyclic antidepressant amitriptyline (Elavil) is sometimes prescribed to treat pain and sleep problems associated with CFS. Other tricyclics include doxepin (Sinequan, generic), desipramine (Norpramin), nortriptyline (Pamelor), clomipramine (Anafranil), and imipramine (Tofranil).

Tricyclics for CFS pain and sleep management are given at lower doses than when used to treat depression.

Selective Serotonin-Reuptake Inhibitors (SSRIs), Selective Serotonin and Norepinephrine Reuptake Inhibitors (SNRI), and Seratonin Antagonist and Reuptake Inhibitors (SARI)

SSRIs may be helpful for people with CFS who experience significant depression. These drugs include fluoxetine (Prozac), sertraline (Zoloft), paroxetine (Paxil, Pexeva), citalopram (Celexa) and escitalopram (Lexapro).

Duloxetine (Cymbalta) and venlafaxine (Effexor) are antidepressants classified as SNRIs because they affect both neurotransmitters. SSRIs and SNRIs should not be taken with tricyclics, because the combination may cause dangerous side effects.

Trazodone (Desyrel)

A tetracyclic antidepressant that works as a SARI. Trazodone is often prescribed for sleep problems.

Other Drugs Being Investigated for CFS

Rituximab

Rituximab (Rituxan) is a biologic drug used to treat the autoimmune disease rheumatoid arthritis and certain cancers. The drug targets and blocks the activation of certain type of B cells. A small early-stage trial investigated rituximab's effectiveness in treating CFS. Results suggest that the drug may improve fatigue and other symptoms in some people with the disease. The results are preliminary and further study is needed before it can be determined if rituximab is likely to be helpful in treating CFS.

Rintatolimod

In 2016, Rintatolimod (Ampligen) an antiviral and immunomodulatory agent, was approved for the treatment of chronic fatigue syndrome in Argentina. It is also available now in Canada and Europe, but is still not approved for use in the United States. It is the only drug to receive an approval for the treatment of chronic fatigue syndrome anywhere in the world.

Resources

• National Institute of Allergy and Infectious Diseases -- www.niaid.nih.gov
• Centers for Disease Control and Prevention - Myalgic Encephalomyelitis/Chronic Fatigue Syndrome -- www.cdc.gov/me-cfs
• Solve ME/CFS Initiative -- solvecfs.org

Related Reports

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Review Date: 12/16/2019  

Reviewed By: Diane M. Horowitz, MD, Rheumatology and Internal Medicine, Northwell Health, Great Neck, NY. Review provided by VeriMed Healthcare Network. Also reviewed by David Zieve, MD, MHA, Medical Director, Brenda Conaway, Editorial Director, and the A.D.A.M. Editorial team.

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