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Putting chronic fatigue syndrome's myths to bed

A new campaign aims to raise awareness of a condition that many say doesn't exist

From the May ACP Observer, copyright © 2007 by the American College of Physicians.

By Jessica Berthold

Respected researchers say it's a condition that can be as disabling as AIDS or multiple sclerosis. Its prevalence is greater than that of ovarian cancer, lung cancer or lupus. And yet, nearly 20 years after chronic fatigue syndrome was officially recognized as a legitimate medical condition, many internists still doubt whether it truly exists.

The CDC is trying to change that. Spurred by 15 years of research, the agency kicked off a campaign in November to raise awareness about how to spot and treat the disease, which brings exhaustion, aches and pain, and is diagnosed in only 16% of the 1 million Americans who have it. "This is a disease that is very difficult to diagnose and very difficult to understand and treat," said CDC Director Julie Gerberding, MD. "(It) has been shrouded in a lot of mystery and controversy."

Lucinda Bateman, MD, counsels Kathy Jensen about chronic fatigue syndrome.


Lucinda Bateman, MD, counsels Kathy Jensen about chronic fatigue syndrome.



Lucinda Bateman, MD, has no doubt that chronic fatigue syndrome is real. A general internist and founder of a fatigue consultation clinic in Salt Lake City, Utah, Dr. Bateman became acutely aware of CFS in the mid-1980s when she tried to determine why her once-healthy, happy sister seemed to be getting viral infection after infection without improving.

"When I left for medical school in 1983 she was fine, and when I returned four years later, she had developed chronic fatigue syndrome-though it didn't have a name at the time," Dr. Bateman said. "I was an eager young internist doing my internship and residency, and I started reading and attending conferences to figure out how to help her."

Dr. Bateman soon became known for her expertise, and physicians referred more and more CFS patients to her. A year after opening her specialty clinic in 2000, Dr. Bateman's sister died of complications from non-Hodgkin's lymphoma at age 50.

"I think that having chronic fatigue syndrome for 10-15 years may have increased her risk of developing the illness that killed her. We know that diagnosing and treating CFS early leads to better outcomes," Dr. Bateman said. "That is why people need to recognize, research and diagnose this disease, and stop arguing about whether it's real or not."

Diagnosis of exclusion

Nailing down the diagnosis of CFS is a long, frustrating process for both patient and physician, internists said. There is no diagnostic test or laboratory marker for CFS, so physicians must rule out other potential causes, like thyroid or neurological disorders, before they confirm the diagnosis. Since the main symptoms of CFS—fatigue, pain, headaches—are common to many other illnesses, the exclusion process means repeat visits, a lot of lab work, and a lot of time.

"Most patients don't come in as the classic case, where they developed a mononucleosis-like illness and then it progressed. They just come in and say they haven't been feeling well for months or years," said Julie Brady, MD, a general internist in Colorado Springs, Colo. who currently has four CFS patients. "A diagnosis can take anywhere from three to six months."

The criteria for CFS, according to the International Chronic Fatigue Syndrome Study Group Case Definition, include medically unexplained fatigue of at least six months that's not the result of other disease or conditions. The fatigue continues despite rest, and leads to a significant reduction in social, personal, educational and job-related activities. At least four of several characteristic symptoms—like sore throat, muscle pain, joint pain, headache and memory impairment—must be present concurrently.

Questionnaires that can help identify and monitor CFS patients include the MOS SF-36, the CDC Symptom Inventory, the Multidimensional Fatigue Inventory, the McGill Pain Score, and the Sleep Answer Questionnaire. Most of these assessment tools are available through the Web site of the CFIDS Association of America.

According to the CDC, clinical evaluation of patients with fatigue requires:

  • a detailed patient history, including review of medications that may cause fatigue,
  • a thorough physical examination,
  • a mental status screening, and
  • a minimum battery of lab tests. Recommended tests include urinalysis, thyroid function and C-reactive protein (see sidebar for a complete list of tests).

Adding to the difficulty of pinning down CFS is the fact that the disease's clinical course and the severity of symptoms tend to vary considerably by patient. Symptoms often wax and wane, with patients remitting and relapsing repeatedly. CFS patients also often have co-morbid conditions. Fibromyalgia is the most common; other typical ones include depression, irritable bowel syndrome, and interstitial cystitis. Patients with Gulf War syndrome also often meet criteria for CFS, or go on to develop CFS, according to a June 2005 study in the Annals of Internal Medicine.

In some cases, co-morbidities arise because people wait several years to see a doctor for CFS and develop other problems in the meantime, said Suzanne Vernon, PhD, team leader of the CDC's molecular epidemiology program and a chronic fatigue expert.

"By the time people are seen, they have been sick for a long time, so not only do they have chronic fatigue syndrome, they have depression; their blood pressure has gone crazy; they have orthostatic instability," Dr. Vernon said. "It becomes a cascade of events."

Dr. Bateman, the fatigue clinic founder, said she understands why such a tricky diagnostic process might make internists hesitant to embrace CFS.

"Internists are the most rigid about meeting diagnostic criteria, and that's good, but it can marginalize patients with atypical presentations," Dr. Bateman said. "Still, general internal medicine should be the home for management of these illnesses, because we know how to manage chronic illness and multiple problems."

A tough sell for some

Lawrence Edwards, MD, professor of rheumatology at the University of Florida in Gainesville, said he often encounters patients with persistent pain and fatigue. But he doesn't diagnose them with CFS.

"To view it as a separate disease process rather than one that is associated with other medical problems or depression is beyond what we know scientifically," Dr. Edwards said. "I think there are a lot of ways to treat fatigue without raising it to the level of a disease process."

Several internists, who asked not to be named, expressed similar views. A commonly stated belief was that chronic fatigue syndrome is a catch-all term for another condition that hasn't been properly diagnosed—like a sleep disorder or clinical depression. Yet recent research on chronic fatigue syndrome patients indicates otherwise, according to Anthony L. Komaroff, FACP, a Harvard Medical School professor of medicine and CFS expert.

"There is a huge [body of] literature that demonstrates measurable biological differences in these patients compared to healthy people of the same age and gender, or compared to depressed people or people with other fatiguing organic illnesses like multiple sclerosis and lupus," Dr. Komaroff said. "Indeed, the CDC's research uncovering such biological differences was one of the reasons it decided to initiate a public education campaign. I think most practicing doctors aren't aware of this literature."

More than 4,000 published studies show that patients with CFS have underlying biological abnormalities, many of them centering on brain hormones and the autonomic nervous system, Dr. Komaroff said. In terms of clinical application, he identified three research areas as the most promising or cutting-edge:

  • Evidence that the immune system is chronically activated, and that pro-inflammatory cytokine production is increased. "This has therapeutic implications because there are a number of biologic pharmaceuticals that counter the activation of the immune system and the effect of the production of pro-inflammatory cytokines," he said.
  • Evidence that there is something wrong with energy metabolism and the oxidative electron transport chain in mitochondria.
  • Evidence that CFS develops following several different kinds of infections, and that people with genetic vulnerability are most likely to get CFS when infected with certain kinds of infectious agents.

Genetics is an especially promising frontier in CFS research, Dr. Vernon said, pointing to 14 papers published in the April 2006 issue of the journal Pharmacogenomics which discussed findings from a CDC study in Wichita, Kan. from 1997-2001. Among other findings, researchers found that CFS is linked to five mutations in three genes that relate to the body's ability to handle stressors. Research from the CDC and other investigators also has shown gene activation patterns that reflect a chronically activated immune system and aberrant energy metabolism.

The next step is for researchers to use these findings to develop diagnostic tests, and to determine which gene activity profiles respond best to certain treatments, said Nancy Klimas, MD, a professor of medicine and the director of the Gulf War Illness and Chronic Fatigue Syndrome Research Center at the University of Miami and Miami Veterans Administration Medical Center.

"The first set of diagnostic tests will be focused on identifying subgroups of chronic fatigue patients by specific biomarkers. That could happen within two to three years," Dr. Klimas said. "As for treatment interventions for specific subgroups, five years isn't an unreasonable goal."

Case-by-case treatment

For now, internists are treating patients by managing symptoms, improving coping skills, managing physical activities, and sometimes, using medication. Because the disease manifests differently in each patient, one of the first steps is to determine which symptoms are bothering a patient most, Dr. Brady said.

"It really depends on the patient and what his or her major concern is. Is it sleep, is it low energy, is it that they hurt all over? Find the major thing and start there," she said.

Often, a patient's dominant symptom will change, added Dr. Bateman, which is why she re-evaluates patients each month using visual analogue scales and pain diagrams. "We try to prioritize what's going on-what's worse right now," Dr. Bateman said.

Research coordinator Ali Allen, RN, (left) administers Ampligen, an experimental drug for chronic fatigue that is undergoing phase III trials. Patient Pauline Gill watches.


Research coordinator Ali Allen, RN, (left) administers Ampligen, an experimental drug for chronic fatigue that is undergoing phase III trials. Patient Pauline Gill watches.



Unrefreshing sleep is a common symptom and may exacerbate others, so it's a good idea to treat it early, the CDC recommends. Internists should review patients' sleep patterns and suggest they avoid daytime naps, large meals before bedtime and caffeine or alcohol in the evening, as well as limiting time in bed to eight hours and restricting bedroom activities to sleep and sex.

Paradoxically, one of the very things that can make a CFS patient feel worse—exercise—can help her feel better if done in moderation. Again, the prescription varies by patient: "I figure out what a patient is already doing, or likes to do, and slowly increase the amount. It depends a lot on where the muscle pain is," Dr. Brady said.

Since postexertional malaise is a defining symptom of CFS, doctors should avoid telling patients to exercise without setting up parameters, said Kathleen Andries, ACP Member, a general internist in St. Joseph, Mich.

"There are compulsive personalities who, when you tell them to exercise, will go out and walk for miles and miles. You need to specify starting out slowly, perhaps with walking five to 10 minutes a couple times a week," Dr. Andries said.

The more specific the instruction, the better, Dr. Bateman agreed. She usually starts her patients out with several weeks of stretching, relaxation and breathing exercises that are done supine or seated rather than standing. Patients may then do strength training, either with light stretch bands, very low weights, or no equipment, in sessions of 30-60 seconds with rest times in between. (The CDC recommends patients observe a ratio of one minute of exercise to three minutes of rest.)

If possible, a patient might eventually try some brief, low-intensity aerobic activity, like walking to the corner and back. "Start with only a slight increment more than current daily activities demand," Dr. Bateman said. Activities should be kept at such a level that there will be no malaise the following day, and there should be rest days between exercise days, she added.

Doctors need to carefully monitor patients, move gradually, and recognize that exercise might not work for everyone. "Pushing too hard physically can cause a relapse into illness," Dr. Komaroff said.

Though the CDC advises trying treatments like exercise first, medication can also help with certain symptoms. Anti-depressants may work for those with co-morbid depression, and may in fact help other CFS patients as well. SSRIs are usually tolerated best, and should be chosen based on side-effect profile.

Non-steroidal medications can work to treat pain, Dr. Komaroff noted, while some tricyclic antidepressants can bring restorative sleep as well as address pain. "Amitriptyline, which is rarely used now for depression because there are better tricyclics, SSRIs, and other drugs, seems to help with the illness. A dose of 10mg at bedtime typically produces more hours of deep sleep each night—a tiny dose compared to amounts normally used for depression. And the effects are evident in the first few days, whereas antidepressant effects take weeks" Dr. Komaroff said.

Dr. Brady said her patients have had success with the psychostimulant modafinil (Provigil), because it increases energy while letting people sleep, as well as with antidepressants. "Cymbalta (duloxetine hydrochloride) is a good choice because it helps with muscle pain and also has norepinephrine, so that provides a stimulating effect. Effexor (venlafaxine) works, as well," Dr. Brady said.

Internists should be aware, however, that a drug that relieves one symptom can aggravate another. A stimulant prescribed for cognition difficulties can exacerbate restless sleep, and sleep medications may cause daytime sedation, Dr. Bateman noted. The CDC advises starting at low doses—like 5-10 milligrams of a tricyclic antidepressant—and increasing slowly, since many CFS patients are particularly sensitive to medication.

Patients often seek relief from alternative remedies, like herbal supplements, hydrotherapy or acupuncture. These can work, and physicians should keep an open mind, the CDC advises; they should always ask patients if they are trying such remedies before prescribing new treatments. Counseling, particularly cognitive behavioral therapy, helps some patients cope with the illness and function better; support groups can, too.

Internists should help patients identify any lifestyle factors—like working too much—that might exacerbate symptoms. Dr. Andries usually enlists the support of a patient's loved ones. "Often they have another insight into situational factors," she said. "And having family members involved can encourage a patient to stick to treatment better."

According to the CDC, 40%-60% of CFS sufferers report that they eventually recover from the disease, either partially or fully. For those who don't, learning to accept and adapt to the illness is a worthwhile goal, said Dr. Bateman.

"When you give people good, attentive medical care, they adjust to the illness. They are still limited in their ability to function, but they function much, much better, and they don't have secondary mood issues," Dr. Bateman said. "A supportive physician goes a long way."

More research on how to diagnose and treat chronic fatigue syndrome is available on the ACP's PIER module and at the CDC's Web site.

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CDC debunks CFS myths

One of the most common and inaccurate stereotypes about chronic fatigue syndrome patients "is that this is a bunch of hysterical, upper-class professional white women who are seeing physicians and have mass hysteria," said Dr. Williams Reeves, CDC chief of the chronic viral disease branch, at an April 2007 media briefing. According to CDC research, facts about chronic fatigue syndrome include:

  • At least 1 million Americans have CFS.
  • Less than 20% of Americans with CFS have been diagnosed.
  • CFS affects four times as many women as men.
  • CFS is most prevalent among adults age 40-59.
  • In the U.S., CFS is at least as common among Hispanics and African-Americans as whites.
  • CFS appears to be more common in lower-income than affluent individuals.
  • CFS results in $9 billion in lost productivity in the U.S. annually.
  • CFS results in $20,000 annually in lost wages and income per family.

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Exclude other diseases before CFS

The CDC recommends the following laboratory screening tests be done to exclude other diseases before a diagnosis of chronic fatigue syndrome is made:

  • urinalysis
  • total protein
  • glucose
  • C-reactive protein
  • phosphorus
  • electrolyte
  • complete blood count with leukocyte differential
  • alkaline phosphatase
  • creatinine
  • blood urea nitrogen
  • albumin
  • ANA and rheumatoid factor
  • globulin
  • calcium
  • alanine aminotransferase (ALT) or aspartate transaminase serum level (AST)
  • thyroid function tests (TSH and Free T4)

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Make the differential diagnosis

Chronic fatigue can be a prominent feature in many organic disorders, which should be considered as alternative diagnoses to CFS. Successful treatment of a fatiguing condition doesn't exclude CFS in patients who remain symptomatic and meet diagnostic criteria, however. Other disorders include:

  • occult malignancy
  • autoimmune disease
  • endocrine disease
  • organ failure: cardiac, respiratory, or renal
  • multiple sclerosis
  • myasthenia gravis
  • Parkinson's disease
  • myositis
  • chronic active hepatitis (B or C)
  • Lyme disease
  • HIV
  • nocturnal asthma
  • alcohol abuse/overuse
  • heavy metal poisoning
  • irradiation
  • narcolepsy
  • obstructive sleep apnea

Chronic fatigue is also a common complaint with many psychiatric disorders, which may exist as co-morbid conditions with CFS. Physicians should make a psychiatric diagnosis as an alternative or in addition to CFS, depending on how the condition explains the pattern and development of symptoms. These disorders include:

  • major depression
  • dysthymia
  • generalized anxiety disorder
  • panic disorder
  • agoraphobia
  • hypochondriasis
  • somatization disorder
  • conversion disorder

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