Anthony Komaroff, MD: Hello. I’m Dr Anthony Komaroff, Professor of Medicine at Harvard Medical School in Boston, Massachusetts. I would like to welcome you to this Medscape CME/CE video lecture discussion titled, "Chronic Fatigue Syndrome: The Challenges in Primary Care."

With me today are Dr Lucinda Bateman, founder of the Fatigue Consultation Clinic and co-founder and executive director of the Organization for Fatigue and Fibromyalgia Education and Research in Salt Lake City, Utah, and Dr Charles W. Lapp, director of the Hunter-Hopkins Center and assistant consulting professor at Duke University Medical Center in Durham, North Carolina. Welcome to you both.

Anthony Komaroff, MD: Chronic fatigue syndrome (CFS) affects more than 1 million people in the United States. Clinical and laboratory scientists all over the world have been studying its causes, its effects on the body, its diagnosis, treatment, and prognosis. In the past several years there has been a lot of new information and some misinformation about CFS.

Our learning objectives today are to introduce you to the 1994 International Case Definition of CFS, to discuss the epidemiology of CFS, how to diagnose it in practice, the management options available in practice, when to refer to a specialist, what is known about the underlying causes, and what the prognosis is.

The case definition requires that a patient have severe fatigue that persists or relapses for more than 6 months, is of new or definite onset, is not substantially alleviated by rest, and results in substantial reduction in activities. In addition to severe chronic fatigue, the patient must also have present for more than 6 months, 4 or more of the symptoms listed on the accompanying slide. Finally, the patient must not have an active medical condition that could explain the chronic fatigue, or psychosis, melancholic depression, substance abuse, dementia, or an eating disorder.

The estimated prevalence of CFS is affected by the kind of study used, by the case definition used, and by whether the subjects are evaluated not only by history, but also by physical examination and laboratory testing which is considered a full evaluation. Using the 1994 International Case Definition and a full evaluation, the estimated prevalence in the United States among adults ranges from 1 to 4 per 1000 people. Prevalence is higher among women, minorities, and less well-educated people; thus the term "yuppie flu" that was used by some to define this syndrome is inaccurate. The prevalence in adolescents is less than 1 in 1000. Although the illness is seen in preadolescents, it appears to be rare; however, specific data addressing this are rare.

I’m going to turn now to Dr Bateman to discuss the differential diagnosis.

Lucinda Bateman, MD: Thank you. The diagnosis of CFS requires a careful work-up to exclude other known causes of the defining symptoms of fatigue, markedly reduced activity tolerance, neurocognitive complaints, unrefreshing sleep, and widespread or localized pain, including headaches and tender lymph nodes. There are many other common complaints depending on the patient which can include dizziness, arrhythmia, sensitivities, irritable bowel, and irritable bladder symptoms.

An essential work-up requires a thorough medical history, including a psychosocial history and a complete physical exam, as well as a structured mental health assessment.

There are basic screening laboratory tests that should be administered; these include a CBC with leukocyte differential, an expanded chemistry panel, thyroid studies, ESR or CRP as a marker of inflammation, and a urinalysis.

In individual patients, depending on the history and physical examination findings, it may be prudent to order additional blood work as clinically indicated. This may include screening for infectious agents or ordering additional autoimmune markers. Some patients may need vitamin D or vitamin B12 levels checked. Many patients may be experiencing alterations in hormone levels that can occur in midlife which should be checked, and some patients should be screened for celiac disease.

Patients should be up to date on [age-appropriate] preventive tests that screen for malignancies to look for beginning or end-stage malignancies that could be the cause of chronic fatigue.

Additional tests may be clinically indicated in any given patient to look for other diseases that can cause chronic fatigue. Some patients may need a brain MRI or a CT of the sinuses. Sleep studies may be indicated for patients with perpetually disturbed sleep, and cardiopulmonary tests may be indicated for patients who have exercise intolerance.

There are cases when the diagnosis of CFS is not appropriate, and there are exclusionary conditions listed as part of the case definition. The following conditions would exclude the diagnosis of chronic fatigue syndrome: treated or untreated medical conditions that would otherwise explain the symptoms, certain psychiatric conditions that cause altered perceptions of reality or profound fatigue, significant communication barriers, organic brain disorders, severe eating disorders, alcohol or other substance abuse problems, and severe obesity defined as a BMI greater than or equal to 45.

If no other important exclusionary conditions are found and patients meet the CFS case definition criteria, they should be diagnosed with CFS. If the criteria are not fully met but CFS is suspected, it would be appropriate to start clinical care and continue periodic reassessment until the diagnosis becomes clearer. It is possible to have CFS in combination with a comorbid condition that may be considered exclusionary based on the 1994 International Case Definition criteria because these were developed as research criteria. These issues may be clarified as more specific and sensitive biomarkers are developed from research for use in clinical practice.

Anthony Komaroff, MD: Thank you. Dr Lapp, can you please speak about the management of CFS?

Charles W. Lapp, MD: There are a number of articles that discuss the treatment of CFS, including a couple of meta-analyses that have concluded that there is insufficient evidence to support the use of many specific therapies for CFS. Two therapies that have shown success, though, in these articles are CBT and graded exercise therapy.

The goal of CBT is to help patients overcome difficulties by identifying and changing behaviors and emotional responses. CBT can help patients understand their limitations, pace themselves, and avoid pushing and crashing. CBT helps patients develop coping skills to lessen the anxiety, depression, grief, anger, and guilt that often accompany any kind of a chronic illness.

CBT, however, requires a skilled specialist, such as a psychologist, a social worker, or a trained nurse. The problem is that such specialists are often unavailable or difficult to find, so the practitioner is usually tasked with aiding the patient in adapting to the illness, developing coping mechanisms, and generating hope.

Exercise is a double-edged sword when it comes to CFS. It has been shown to be helpful, but too much exertion has been known to trigger flares or relapses of symptoms.

The rule here is to start slow and to move slowly with advancing the exercise regimen. You might begin with active stretching, for example, followed by some range-of-motion exercises, preferably with the patient lying down. If that is tolerated, then advance to aerobic activities, like Tai chi, yoga, walking, bicycling, maybe even pool therapy. To avoid flares of symptoms though, you have to encourage the patient to limit activity by either time—perhaps 5 minutes at a time—and by the number of repetitions. If the patient experiences excessive fatigue or he/she feels ill after exercising, then it is a good idea to reduce the number of repetitions that he/she is doing or the time that is spent on the exercise.

There is no known cause or cure for CFS. The standard of care today is to manage the symptoms. The 3 major symptoms to manage are insomnia, pain, and fatigue. I refer frequently to the symptom triangle or what I call the "CFS triangle." I use a triangle because the 3 symptoms are related to one another. For example, if you have pain, pain can interfere with sleep, and pain can also cause fatigue. One of my patients said the pain to her was "like rain on a snowman that melts you down." The symptoms are interrelated. Pain and sleep problems can be treated, but we don’t have really good treatments for fatigue. The idea is that if you can treat the pain or treat the sleep issues, then the fatigue will get better on its own.

One way to manage CFS is to look at 4 different pillars of management. The first is to educate the patient by providing information, brochures, or other forms of patient education. The second is to set goals for patients, to set realistic expectations, and define specific targets. Included in that is discussing follow-up. How much time are you going to spend at each follow-up visit, and how often are you going to schedule those follow-up visits? Also discussing pain management and disability issues is important. The third pillar is treatment. A general approach to treatment might be to address sleep, then pain, and then comorbid conditions. The last pillar is follow-up and monitoring of the patient. Most of us use a visual analog scale to do that and monitor key symptoms, such as pain, fatigue, sleep, or activity. Another option might be to record the patient's description of these parameters so that you have a written record of how the patient is doing.

Let’s talk about a couple of therapies. I will begin with sleep therapy, and specifically, I would like to discuss sleep habits or sleep hygiene. There are a couple of habits or aspects of sleep hygiene that I would like to emphasize. First, I encourage patients to go to bed when they are tired. It only causes anxiety to ask a patient to go to bed at a fixed time. Second, many patients will use the bed for computing, writing letters, watching TV, and reading books. Rather than making the bed the center of their life, I think it is better to use the bed only for sleeping. Also, I might recommend that patients keep to a sleep schedule by getting up at the same time every day.

With respect to medications, you might start with OTC medications, like melatonin, diphenhydramine, or the proprietary sleep aids. A second choice would be amitriptyline, cyclobenzaprine, or TCAs. The next step you might consider is using the nonbenzodiazepine hypnotic agents, like zaleplon, eszopiclone, and ramelteon, or the hypnotic agent, zolpidem. However, because these agents may be habit-forming and have adverse side effects, they would not be my first choice for sleep aids.

It is important to have a high index of suspicion for sleep problems, because up to 95% of our patients report that they have nonrestorative sleep. No matter how much they sleep, they never wake up refreshed. This is probably due to sleep disruption or a lack of deep sleep. Up to 62% of our patients with CFS can have a primary sleep disorder, like sleep apnea, periodic leg movements, or narcolepsy. It is important to keep a high index of suspicion, but remember that successful treatment of these classical sleep disorders will rarely reduce the fatigue from the nonrestorative sleep experienced by most patients with CFS.

Turning now to pain: Pain in CFS may include headaches, which we don’t have time to discuss in this activity, generalized myalgias, and joint or muscle pain. Fibromyalgia occurs in a majority of CFS cases, so treatments for fibromyalgia pain and pain in CFS frequently overlap. Starting with nonpharmacologic therapies, physical activity can be very helpful as long as it is modest. You can also prescribe the use of physical modalities such as cold or hot packs, topical liniments, a TENS unit, and EMS. Alternative and complementary therapies such as massage, acupuncture, and hot baths have been shown to be effective as well.

Many patients with CFS are sensitive to medications, so it is particularly important when you are using sedating medications to again go slow and start very low. You might want to start with nonsteroidal antiinflammatory drugs including COX-2 inhibitors, or acetaminophen, which may all be helpful for the joint discomfort and generalized myalgias; however, these may not help with fibromyalgia-type pain. A next step might be to use the tricyclic antidepressants such as amitriptyline and [the muscle relaxant] cyclobenzaprine again, because they help with both sleep and pain.

The FDA has approved 3 medications for the treatment of fibromyalgia which might be used for CFS pain as well. These include pregabalin, which is an antiepileptic drug, and 2 NSRIs, duloxetine and milnacipran. It is advisable to avoid opiates in most CFS patients, although many of our colleagues might use an opiate agonist/antagonist like tramadol. If an opiate is needed, it is probably a wise idea to refer the patient to a pain specialist.

Ideally, we should have a multidisciplinary approach; however, members of a multidisciplinary team may not be available in a single practice, so it is important for practitioners to develop their own team made up of providers in the community who understand and accept CFS. This team might include physical therapists or physiatrists who can provide a rehabilitation program, sleep specialists, pain specialists, cardiologists, neurologists, and maybe even an autonomic specialist to deal with the orthostatic intolerance that is so common in CFS patients.

Complementary and alternative medicine can be helpful and may involve the use of chiropractors, acupuncturists, neuromuscular specialists, or massage therapists. Finally psychologists and psychiatrists might be included in the multidisciplinary team. Don’t forget to refer patients to local support groups which can be very helpful for dealing with chronic illness and pain.

Anthony Komaroff, MD: I would like to ask both of you just what is involved in seeing a new patient with CFS. How much are you able to do on the first visit and then at subsequent visits?

Charles W. Lapp, MD: I think that the visits have to be broken up into small chunks, because that is the way clinical practices are today. Most practitioners like to have an approach: where do you start, and how do you handle the patient? I normally recommend that you look at the symptoms in the CFS triangle and maybe treat the sleep first and treat the pain second, and fatigue generally follows along after that. In subsequent visits, you can address the specific complaints the patient may have.

Anthony Komaroff, MD: So it is not going to happen in 1 magical visit.

Charles W. Lapp, MD: No, it is not.

Lucinda Bateman, MD: I would like to add that the diagnostic process and the treatment process are somewhat integrated. It really begins from the time the patient walks in the room. You take a look at what kind of diagnostic questions you want to ask, prioritize the symptoms, and start to work on symptom management including working on behavioral changes and prescribing pharmacologic treatments, while you are gradually completing your diagnostic work-up. Sometimes symptoms that don’t respond to treatment prompt more diagnostic work-up and that is a pathway you may go down for several months.

Anthony Komaroff, MD: As you have seen, CFS is defined exclusively by a set of symptoms reported by the patient. There are no regular physical examination abnormalities, no diagnostic laboratory tests. The question any clinician would ask then is: Is there any objective, biological evidence of abnormalities in patients with CFS compared to healthy control subjects or to subjects with other fatiguing illnesses, including depression?

I think the answer is yes. Multiple published studies have found that there are abnormalities of the brain and autonomic nervous system and chronic activation of the immune system as well as a genetic component, and oxidative stress and nitrosative stress and abnormalities in energy metabolism have been seen in patients with CFS. Finally, studies have shown that there is a possible role, in some cases, of infectious agents being the trigger or possibly perpetuator of the illness.

As for the brain studies that I have alluded to, there are obviously a lot of different ways of looking at the brain including MRI, SPECT, PET, studies of cognition, studies of the autonomic nervous system, sleep studies, and neuroendocrine studies. These all have identified abnormalities in patients with CFS compared to control populations.

Research studies have demonstrated several immunologic abnormalities in CFS. I want to emphasize that these are research studies, not studies that the practicing primary care physician should be ordering. Cytotoxic T cells that are activated and appear to be fighting some battle are seen more often in patients with CFS. Lymphocytes, called natural killer cells, have been shown to be functioning poorly in patients with CFS. There is an enzyme system in lymphocytes that is important in the antiviral response and that is turned on in CFS. Finally, proinflammatory cytokines are increased in CFS patients. Again these are results from research studies and not tests that I order in practice.

As for the genetics of CFS, several groups have found different prevalences of various class II human leukocyte antigens in CFS patients. Formal twin studies involving both identical twins and fraternal twins have shown that the heritability of CFS is about 51%, which is pretty high. Several gene variants that involve neuroendocrine responses have been associated with CFS.

Three different markers of oxidative stress have been shown to be different significantly different between patients with CFS and controls. This demonstrates that there is more oxidative stress in patients with CFS.

Why is this? We don’t know why, but 2 very common causes of oxidative stress are viral infection and the inflammatory response to viral infection.

My own view is that infectious agents probably can trigger and possibly perpetuate some cases of CFS, but there is no proof of that yet. Agents associated with CFS typically share 2 properties: (1) they cannot be fully eradicated by the immune system, and (2) they can infect the central nervous system. There is now solid evidence that CFS can follow a new infection and I will show you one example of this in a minute. Finally it is possible that in CFS, different infectious agents interact with one another to cause the symptoms.

A very important study in my view by Hickie and colleagues was organized by the CDC and published several years ago in 2006. Researchers from the CDC conducted it in a small rural community where virtually all of the medical care could be monitored. They followed 253 patients who had developed an acute infection with 1 of 3 different infectious agents and followed these patients very carefully over 12 months. The researchers demonstrated that CFS developed in 11% of these patients. The patients who were sicker at the beginning and the patients who were producing more proinflammatory cytokines at the beginning were the ones most likely to develop CFS months later. Interestingly, there was no connection between the premorbid psychiatric history of patients or their sociodemographic status and the likelihood of developing CFS.

The agents that have been linked potentially to CFS include Epstein-Barr virus; Coxiella burnetii, the cause of Q fever; Ross River virus; the bacterium that causes Lyme disease; parvovirus; enteroviruses; possibly Borna disease virus—although I think the evidence for that is not strong; and a virus called Human herpesvirus 6. Over the past 2 years there has been some excitement that retroviruses might cause CFS, but I think that most recent evidence is strongly against that theory.

Dr Bateman, please tell us about the prognosis of CFS.

Lucinda Bateman, MD: It is difficult to predict the prognosis of CFS due to a number of variations in the way it presents, including the age of onset, the nature of the onset of the disease, comorbid conditions, the clinical setting in which the patients are evaluated, and frankly a lack of robust longitudinal data. In general, complete recovery is rare, but improvement can occur.

In the 1990s, studies were mainly done in tertiary or specialty referral clinics. In those studies a range of 17% to 64% of adult patients with CFS did improve over a short, defined time period; 10% to 20% worsened, and less than 10% seemed to fully recover. The prognosis was a little better for children, with 50% to 94% of children showing definite improvement after 6 years.

In 2005, a review by Cairns and colleagues was published that looked at 14 adult CFS studies. The median full recovery rate in those studies was 5%. The median improvement during follow-up was less than 40%. Thus we see that CFS takes a substantial toll on adults who develop it.

A study [conducted from 1991 to 2009] by Rowe and colleagues looked at prognosis in 342 pediatric patients [who were initially referred to the CFS clinic at the Royal Children’s Hospital]. These patients were reassessed between 5 and 21 years after the onset of CFS. Sixty percent reported full recovery at 5 years, and 88% reported recovery at 12 years, although at least one-third of those patients monitored their workload to avoid relapse. The prognosis probably is somewhat better in the younger patients.

What factors are associated with prognosis? Well, we are not sure, but certain things are associated with worse prognosis. As you mentioned, greater baseline illness severity, longer illness duration, and the presence of comorbid psychiatric illnesses are associated with worse prognosis. It seems that studies from primary care settings have a better prognosis. Most studies and clinicians feel that specific therapies directed at the underlying mechanism(s) may significantly improve outcome and should offer hope for some patients with CFS.

Anthony Komaroff, MD: A question that I get asked by my colleagues often is: are you causing injury by giving people a diagnostic label to an illness whose cause we really don’t understand? Is it a good idea to tell people that they have this illness? What are your thoughts about that and do you hear similar concerns from your colleagues?

Charles W. Lapp, MD: When I diagnose CFS, I can see a sudden relief in the patient because now they finally have a diagnosis. Many patients have seen multiple doctors and have had multiple procedures trying to determine what they have, and it can be a tremendous relief when they finally have a diagnosis.

Lucinda Bateman, MD: I totally agree. I think it is very helpful to make a diagnosis and the diagnostic process can also be reassuring to the patients. All of the information is brought to a central place, their questions are answered, and then it’s a relief to have a context and a structure from which to work and move forward.

Anthony Komaroff, MD: Yes. I agree with both of you. I would say on occasion, I have seen a patient where I worried that maybe getting the label made him or her less functional. The patient now seemed not to be as active, as socially involved as they had been before being given the diagnosis of CFS. There is that threat, theoretically, from labeling. But most of the patients are so glad to hear a doctor say "I know what you have. I wish I knew what caused it, and I wish I had a perfect treatment. I don’t, but I will be able to help you with the symptoms of this illness."

Lucinda Bateman, MD: I have had patients become very depressed after receiving the diagnosis. I think they maintained hope when they didn’t have answers, and sometimes it’s very discouraging to be diagnosed with what may be a very chronic illness, particularly one that is stigmatized or misunderstood. Along with giving the diagnosis, it is very, very important to engage the patient in a process of setting goals and helping them stay optimistic and letting them know that we can improve many of their symptoms over time.

Anthony Komaroff, MD: Yes, I think that is a good point.

Charles W. Lapp, MD: Were you referring to illness behavior, Dr Komaroff? The concern that if someone gets a label like CFS, the patient starts behaving like he/she should be ill or starts trying to live up to the diagnosis.

Anthony Komaroff, MD: Yes.

Charles W. Lapp, MD: I suppose that is possible; however, I mostly see that when disability issues are involved. For example, when the insurance companies or to a lesser extent, Social Security, requires that the patient have a certain level of illness and is unable to work, so the patient tries to meet that goal. That is not a major problem in my estimation.

Anthony Komaroff, MD: In summary, CFS affects all ages, races, and socioeconomic groups. The few recommended tests are inexpensive. CBT, graded exercise therapy, and medications to treat sleep problems and pain are helpful, but are not curative. While a substantial fraction of patients develop depression after CFS starts, many patients have no past or current history of depression or other psychiatric disorders. Immune activation and abnormalities of the brain, autonomic nervous system, and energy metabolism have been found in these patients. And finally, complete recovery is unusual, but improvement is possible.

Thank you both for participating in this session, and thank you for joining us in this CME/CE spotlight presentation today. Please continue on to the post-test to obtain CME or CE credit for this program.