Help! I Have a Patient with Chronic Fatigue Syndrome
Author: Rebekah Wang-Cheng, MD, Associate Professor of Medicine, Medical College of Wisconsin, Milwaukee, WI.
Peer Reviewer: Catherine Bacheller, MD, Associate Program Director, Internal Medicine Residency Program, Kettering Hospital, Kettering, OH.
Editor’s NoteChronic fatigue syndrome (CFS) is a baffling, poorly understood illness that often results in frustration for the patient and the primary care physician. This article reviews the literature to date regarding postulated etiology, epidemiology, treatment (including unproven remedies touted by various practioners), and prognosis. Most importantly, it discusses a practical approach to management aimed at frontline physicians who do not have the luxury of a "multidisciplinary CFS clinic."
Since the initial recognition of an illness of fairly abrupt onset characterized by chronic fatigue in the early 1980s, controversy has persisted over what CFS is. Is it a true disease with demonstrable pathology, a syndrome, a psychological problem, or a cluster of illnesses? Is CFS a result of immune dysfunction, or do the immune system abnormalities follow as a result of the CFS? For a while in the late 1980s, patients and the popular press referred to CFS as "Chronic Fatigue Immune Dysfunction Syndrome." While it is true that various immune system abnormalities, such as elevated antibody titers to human herpesvirus 6 and cytomegalovirus, decreased numbers and function of natural killer cells, increased cytokine levels, and elevated levels of immune complexes and IgG, have been demonstrated in some patients,1 identification of these abnormal immune tests has still not yielded a clue as to the etiologic trigger.
Flu-like symptoms, which are often pronounced at the onset of illness, prompted researchers to investigate a viral etiology. Initially, enthusiasm was generated by the possibility that the Epstein-Barr virus was the agent responsible for a chronic mononucleosus picture, and physicians began to order antibodies to EB nuclear antigen and other EB titers hoping to confirm the diagnosis for a worried patient. Clusters of patients with CFS in certain geographic locations also seemed to a point to an infectious etiology. Eventually the EB virus connection proved not to be true, and to date, no viral entity has been discovered as a cause.
The search continues, but CFS does appear to overlap with several distinct clinical problems, particularly fibromyalgia. (See Table 1.) Buchwald collected data on 90 patients, 30 each with CFS, fibromyalgia, and multiple chemical sensitivities, and found similar demographic characteristics and symptoms among all groups.2 Seventy percent of the patients with fibromyalgia also met the criteria for CFS.
A structured psychiatric interview was conducted with 60 CFS patients to detect previously unrecognized psychiatric morbidity.3 These CFS patients were significantly more likely to have somatization disorder (P < 0.001) than control patients who had fatigue as a chief complaint but who did not meet the criteria for CFS.
The co-existence of CFS with fibromyalgia, somatization, and depression only adds to the confusion. How are these disorders related? Is some central neurobiologic process involved in the pathogenesis of all of them? The old chicken-egg theory surfaces. Does the patient develop depression because of the chronic fatigue or vice versa?
These overlapping diagnoses may also complicate treatment and prognosis. In a given patient, which of these problems predominates? Does the patient really have only somatization disorder, but he/she has latched on to the label of CFS because it is more acceptable or even trendy? The diagnosis of CFS is one of exclusion and should be considered only after other causes, including psychiatric, have been reasonably investigated. Unfortunately, patients who develop a psychiatric diagnosis after onset of CFS appear to have poorer outcomes.
JF is 42-year-old white, divorced, college English professor who developed a sore throat with some associated myalgias and low-grade fever in the spring from which he recovered in a few days. He was an avid runner and biker and prided himself on how well he took care of himself. After the viral infection, he found himself unable to run his usual five miles a day. In fact, he became quite fatigued with minimal physical exertion. Thinking that this would pass after a few weeks, he didn’t worry until he also noticed that he had great difficulty concentrating on his writing. His focus and alertness were gone. In addition, he began experiencing insomnia and was only sleeping about five hours a night. When he awoke feeling unrefreshed, he was also quite stiff and sore all over. About every few weeks, his throat would get scratchy, and he feared that he was getting another sore throat. These symptoms persisted throughout the summer, and he described only two days when he felt "back to normal." He came to see me in the fall to find out "what is going on." The overwhelming fatigue troubled him the most, but compounding the situation was recent onset of depression after the break-up of a two-year relationship.
Is his a characteristic case of CFS?
Fatigue is a common symptom, reported by about 20% of patients presenting to the doctor. The vast majority of these patients will not turn out to have CFS. In a consecutive sample of 135 patients with six months or more of debilitating fatigue, only six patients met the criteria for CFS.4 Estimates of prevalence of CFS in the general population vary according to how strict a case definition is applied, from a low of 7.6 per 100,0005 to as high as 267 cases per 100,000.6
Patients tend to be white, young, middle-class, previously healthy adults. They also tend to be well-educated, with 58.7% of 223 CFS cases being college graduates vs. 22.6% in the general population group in a Boston study.7 JF fits this profile and that of many of the few dozen CFS patients I’ve treated. For the most part, they are well-read, employed, hard-working individuals who can remember almost to the day when their lives changed. He is only atypical by being male since women comprise a majority of the sufferersup to 77% at most referral centers.
Buchwald discovered very few gender differences in 288 women and 60 men with CFS.8 Women had a higher frequency of tender or enlarged lymph nodes (60% vs 33%; P < 0.01) and fibromyalgia (36% vs 12%; P < 0.001). Men more often had pharyngeal inflammations (42% vs 22%; P < 0.001). JF also had frequent episodes of pharyngitis, one of which was culture-proven Group A streptococcus.
Attempts have been made to identify possible triggers of CFS. MacDonald et al recently published a case-control study of 47 CFS cases, 35 women and 12 men.9 Median duration of illness was 54.3 months at the time of the interview. Although this was a small sample, it provides interesting information that warrants further investigation. They found that women with CFS were much more likely to be nulliparous than controls (51% vs 31%; matched odds ratio = 8.0.) Nulliparity was also found to be a cofactor in another earlier case-control study.10
Another surprising and intriguing cofactor discovered by MacDonald was exercise. Regular exercise prior to the onset of CFS was present in 67% of cases vs. 40% of controls (matched odds ratio = 3.4). As with JF, many of my CFS patients were not only healthy but were more physically active than the general population prior to the onset of their illness. This often makes the fatigue and inability to exercise even more frustrating for them.
Physician-diagnosed depression before the CFS was not different between cases and controls, but the development of depression subsequent to the diagnosis of CFS was significantly more common than in controls during the same time-frame. JF did not have a premorbid history of depression or other psychiatric disorders. From an emotional standpoint, he had handled the fatigue relatively well for several months, but when his girlfriend left him, he became clinically depressed and realized he needed more help.
Does JF meet the criteria for CFS?
In 1987, the Centers for Disease Control developed a clinical case definition that would make it easier for clinicians and researchers to have some uniformity. Two major criteria included fatigue severe enough to reduce activity below 50% for six months and the exclusion of other conditions. There were also minor criteria involving symptoms and physical findings.
These criteria were modified by the International Chronic Fatigue Syndrome Study group in 1994.11 In addition to the major criterion of clinically evaluated, unexplained, persistent fatigue of new or definite onset, a list of eight symptoms was also delineated. (See Table 2.) Please note that physical signs, such as fever or adenopathy, are not necessary for diagnosis. Table 3 provides a list of steps to be included in the initial evaluation of a CFS patient.
When JF saw me in the fall, he had been continuously fatigued for more than six months without medical explanation. He had been forced to reduce his teaching schedule and had stopped exercising completely. He related four of the eight symptoms listed in the diagnostic criteria: impaired concentration, sore throat, unrefreshing sleep, and post-exertional malaise.
A thorough history, including social history and any previous testing and treatments, is important in the initial evaluation. A formal mental status exam is also important if the patient’s history or affect warrant it. You might want to consider a structured psychiatric survey instrument like the PRIME-MD or Beck Depression Inventory. Patients who have a history of prior psychiatric illness may require formal evaluation by a psychiatrist.
Although the physical exam is unlikely to yield positive findings to help with the diagnosis, be sure to perform a fairly comprehensive exam with special attention to the throat and the detection of any lymphadenopathy.
For the majority of patients, obtaining a CBC, serum chemistries, TSH, and sedimentation rate are more than adequate for excluding common causes of fatigue.
JF’s blood tests were all within normal limits. Since he lived in Wisconsin and had gone camping, a Lyme titer was also obtained and was negative. He had read about the tilt table test in the newspaper and wondered if he should be tested. I discussed the fact that even if the test was positive, I would not choose to prescribe the medication until more studies had been done, thereby convincing him not to spend the time and money at this point.
Although there are many associated abnormalities of unknown significance (see Table 4), I do not recommend obtaining any of these as screening tests since they do not aid in making the diagnosis, are not predictive of prognosis, and are not helpful in planning treatment. Some of these tests are expensive and not readily obtainable. I will list them below for interest sake and because some patients may be aware of these tests and have questions about them.
Associated Abnormal Findings of Unknown Significance
Miscellaneous blood tests. Blood tests of 579 CFS patients from chronic fatigue clinics in Boston and Seattle were compared with 147 blood donors who denied chronic fatigue.12 CFS cases were much more likely to have circulating immune complexes, atypical lymphocytosis, elevated alkaline phosphatase, and elevated total cholesterol than the controls. Antinuclear antibodies (ANA > 1:40) were detected in 15% of CFS cases and 0% of controls.
The authors conclude that these positive laboratory findings suggest a biological process that may contribute to the symptoms of CFS, but the tests alone are not sensitive or specific enough to be viewed as markers for CFS.
Brain imaging. Magnetic resonance imaging (MRI) abnormalities have been noted by researchers.
High signal intensity foci were seen in 113 of 144 patients (78%) but in only 10 of 47 matched healthy controls (21%) studied in Reno.1 The subcortical white matter was affected most often, and in some patients there was a relationship between the affected anatomic area and the clinical presentation. When the MRI studies were repeated in several cases, the abnormal areas persisted even after symptom resolution.
In a much smaller study comparing 15 CFS patients to 15 age-matched controls,13 the CFS patients had significantly more defects of the cerebral cortex on single-photon emission computed tomography (SPECT) scans than controls (7.31 vs 0.43; P < 0.001). The authors also performed MRI scans on these patients and found that the SPECT abnormalities appeared to correlate with clinical status, whereas MRI changes were irreversible.
Disordered sleep. Formal sleep studies were performed on 12 patients with CFS to determine if sleep pattern abnormalities might contribute to daytime fatigue.14 Patients with CFS spent more time in bed than controls (544 minutes vs 465 minutes; P < 0.001) but slept less efficiently (90% vs 96%; P < 0.05) and spent more time awake after initially going to sleep (31.9 minutes vs 16.6 minutes; P < 0.05). Seven of the 12 patients had sleep disorders, mainly an inability to maintain sleep, and these seven patients showed greater functional impairment than the remaining five patients.
Disordered sleep is also characteristic of patients with fibromyalgia or major depression. It is interesting to note the overlap of both of these illnesses with CFS, all of which have sleeping difficulty in common. Further research should help clarify the causal role of sleep, if any, in the development and symptomatology of CFS.
Abnormal response to upright tilt. Some researchers at Johns Hopkins had observed that patients with neurally mediated syncope develop prolonged fatigue following syncopal episodes. They hypothesized that patients with CFS might actually have treatable neurally mediated hypotension. In testing a sample of 23 patients who satisfied the criteria for CFS, they found an abnormal response to upright tilt in 22 of the 23 patients vs. only four of 14 controls (P < 0.001).15
Patients were advised to increase their dietary salt intake and were offered treatment with fludrocortisone 0.1 mg daily. With some patients the fludrocortisone dose was adjusted or fludrocortisone was supplemented or replaced by a beta-blocker or dispyramide. Of the 19 patients who accepted medication, nine reported complete or nearly complete resolution of all symptoms within one month of beginning treatment.
Often CFS patients who read in the lay press about such dramatic responses are eager to be tested or try a new therapy. While these results are intriguing, caution should be exercised. This was a very small study that was not randomized or placebo-controlled. In addition, follow-up of only five weeks is much too early to determine long-term beneficial effects.
Reassure the patient. Although no definitive treatment or cure is available for CFS, the physician can help the patient in several practical ways. (See Table 5.) The most important first step is to establish the diagnosis for the patient. Many times these patients have been worrying privately for several months that either they have some serious illness like undiagnosed cancer, or that they are doomed to a poor quality of life thereafter, or that they are going crazy. Knowing that CFS is a disorder with distinct criteria and that they are not alone in experiencing many of the associated symptoms is often a great relief. It is essential to inform the patient that although there is no specific treatment, you will continue to work with them in searching for appropriate therapies that will improve their ability to function .
Review the patient’s lifestyle. Upon review of the patient’s lifestyle, inevitably you will find areas where small changes can result in improved well-being. In addition to a dietary history, I also inquire about caffeine, alcohol, and tobacco. This is an opportune time to educate the patient about the effects of these addictive substances and dietary fat on the immune system and make recommendations for changes.
JF tried to eat a prudent diet, although since being divorced a few years earlier he had been eating out more and using more frozen, prepared foods. Although he rarely drank alcohol and did not smoke, he had increased his caffeine intake greatly to try to become more energized and was consuming a few pots of coffee and three or four cans of soda per day. He agreed to cut down gradually on the caffeine.
Finding the fine line between adequate exercise and overexertion is not easy. Patients sometimes report that even minimal exercise, such as walking a few blocks, may send them to bed for several days because of pain and/or exhaustion. On the other hand, no exercise leads to further deconditioning. Sisto et al studied the aerobic power of 21 women with CFS by measuring treadmill performance, VO2max, and heart rate.16 They found that compared to normal controls, the CFS women had low normal fitness levels with no indication of cardiopulmonary abnormality. Most importantly, none of the women reported a major exacerbation in fatigue or other symptoms four days after the maximal exercise testing.
JF, who had been very active prior to the development of CFS, was essentially engaging in no physical activity. I encouraged him to gradually begin with walking and stationary biking at home to levels that did not land him in bed on the following day.
Sleep disturbance is a frequent complaint particularly in patients who have fibromyalgia as well. Educating the patient about sleep hygiene (regular hours for sleep, avoidance of caffeine, not eating or reading in bed) and the judicious use of sedating antidepressants when necessary may help restore regular sleeping patterns. Some patients need to be gently reminded that too much daytime napping will interfere with nighttime sleep.
After reducing his caffeine intake to one cup of coffee in the morning, JF found that he was able to fall asleep more easily, but was still awakening too early. Low doses of Trazodone (25-50 mg) taken at bedtime resulted in longer and deeper sleep.
Prescribe symptomatic treatment. If appropriate, you may prescribe an antidepressant for improved sleep, associated depression, analgesic augmentation, or simply as an empiric trial. The use of antidepressants is discussed in detail in the following section. Nonsteroidal antiinflammatory drugs (NSAIDs) are often very helpful for joint pain and headache.
Refer as needed. Most large cities now have support groups for patients with CFS. There is a national association that has local chapters in most states. Our state organization also publishes a quarterly newsletter and brings in national experts to speak from time to time.
You may refer some patients for psychiatric consultation or other ancillary services, such as physical therapy. The patient will need your guidance regarding use of other health care servicesboth traditional and nontraditional onesbecause it is so easy for them to become caught up in various methods that are touted as "cures." More than with most patients, we must remember to first protect the patient from harm.
JF was very insightful and recognized that the loss of his significant other was also affecting his ability to sleep, concentrate on work, and cope with his CFS. He was open to referral for brief psychotherapy and found it to be beneficial.
Regularly monitor the patient. Continue to regularly monitor the patient for progress and any other medical problems. I find that frequent short visits, every 2-3 months, help avert any rapid declines in functioning or progression of a mild sore throat into a protracted illness. This reassures the patient of your commitment to work with them and not abandon them even though both you and the patient will be frustrated at times with the rate of improvement. Regular visits also reduce the number of phone calls you will receive about the latest news flash relating to CFS seen or heard by patients. The office visit provides an opportunity to discuss these media reports.
Cognitive behavior therapy (CBT) has been helpful in disorders such as chronic pain and irritable bowel syndrome. It involves goal setting, education about the illness, relaxation training, the evaluation of the social context, and potential reinforcers of disability, cognitive restructuring, and graduated exposure to avoided activities. In a controlled British trial at an infectious disease clinic in which 30 CFS patients were randomized to usual care and 30 CFS patients received usual care plus CBT, 73% of the CBT patients had attained normal functioning at 12 months vs. 27% of the medical care alone (P < 0.0001).17
While this specialized treatment, which requires experienced therapists to work with the patient during many sessions over several months, is usually not available to most clinicians, most of us do have access to good physical therapists or exercise specialists. They can design an individualized graduated exercise program to help reduce deconditioning.
Pharmacologic Treatment for Symptomatic Relief
Antidepressants. Although antidepressants have been widely used for treatment of CFS, there have been no large, randomized controlled studies documenting efficacy. Their use has good rationale, since many CFS patients, as has been mentioned earlier, also suffer from depression and/or fibromyalgia. When 455 CFS patients were followed up an average of 1.5 years after diagnosis, the most frequently mentioned beneficial form of treatment was antidepressants, noted by 28% of the group.17 The older tricyclics may not be tolerated as well because of anticholinergic and sedative properties.
Selective serotonin reuptake inhibitors (SSRIs), a new class of antidepressants released in the past decade, have been rapidly gaining favor as the drugs of choice. There are currently four drugs in this class: fluoxetine (Prozac), paroxetine (Paxil), sertraline (Zoloft), and fluvoxamine (Luvox). Sertraline, when given to 79 CFS patients in an uncontrolled pilot study at a 50 mg daily dose, reduced symptoms of fatigue, myalgia, sleep disturbance, and depression.18 SSRIs may also be preferred for their ease of administration (most are long-acting, once-a-day) and lack of lethal potential. They are also relatively free of serious side-effects, although gastrointestinal effects such as diarrhea and anorgasmia can be troublesome for patients. For the patient who has significant difficulty with insomnia or with pain, I prefer paroxetine which tends to be mildly sedating, and advise the patient to take it at bedtime. Fluoxetine, because of its activating properties, works well with patients who complain of marked lack of energy. Patients also note an improvement in cognitive functioning, especially concentrating ability, with fluoxetine (Prozac).
JF was willing to give Prozac a short trial. He was desperate to feel better and return to a full teaching load, so I started him on 20 mg of Prozac a day. After about two weeks he noted improvement in his energy level and ability to focus. Fortunately, he did not note any side effects. With his renewed energy, sometimes he attempted to overdo the exercise and quickly learned not to push himself too much, lest he become overtired.
NSAIDs. For symptomatic myalgias/arthralgias and headache, the NSAIDs are effective. Patients can also take acetaminophen or aspirin, but the longer-acting NSAIDs, like nabumetone, seem to provide more consistent relief. Of course, the NSAIDs do not have any direct effect on fatigue, but by lessening the pain, they enable the patient to be more physically active. As with any chronic pain condition, narcotics should be avoided, because of the potential for dependence.
Vitamins/supplements. Patients are understandably anxious to get well and return to premorbid functioning and are hopeful that somewhere a cure is available, perhaps in the form of a supplement. There are plenty of entrepreneurs who have the answer, the ingredient that is missing from their diets. These range from barley green to blue-green algae to selenium. While most of these supplements are probably innocuous, I do not recommend them for several reasonsthe high cost, the lack of quality-control, and the false hopes they raise. On the other hand, I do not forbid my patients from taking them and request that they keep me informed of exactly what they are ingesting.
Therapies of Questionable Benefit
Because CFS patients have been frustrated by the seeming lack of answers in conventional medicine, and because they are willing to try almost anything to feel better, they can be an easy prey for fringe therapies. I have listed many of these in Table 6, although I will not discuss each of them in detail.
Miscellaneous Medications. Because of purported infectious etiology, antibiotics, antiviral, and antifungal agents have all been tried with varying reports of effect. A double-blind, placebo-controlled study with acyclovir showed no benefit over placebo.20
Immunotherapies. Most of these therapies have been used primarily on an experimental basis or by practitioners of alternative medicine. High-dose immunoglobulin has been administered intravenously or intramuscularly in a few studies with mixed results.21-23 Although Lloyd noted a positive treatment response in 10 of 23 (43%) patients vs. three of 26 (12%) placebo recipients, the sample size is too small to draw conclusions.22
Poly (I) Poly (C12U) is a double-stranded RNA preparation thought to have both antiviral and immunomodulatory properties. When administered in multi-center, placebo-controlled study to CFS patients, subjects receiving the Poly (I) Poly (C12U) showed a significant improvement in exercise and quality of life.24
Injectable porcine liver extract containing folic acid and B12 was similar to placebo in an early study.25 The liver extract is now marketed commercially under the name of Kutapressin (Schwarz Pharma, Mequon, Wisconsin), and there are anecdotal reports of patient response.
It has been suggested that patients with CFS have cell membrane changes consistent with chronically elevated utilization of essential fatty acids. The hypothesis entertained is that changes in essential fatty acids and their metabolites are a physiologic response to excessive or prolonged stress. Based on this belief, Gray treated CFS patients with dietary essential fatty acid modulation in combination with titrated mental and physical activity and psychotherapy and found 24 of 29 patients showing improvement in three months.26 Behan and Behan also reported an 85% response rate in patients treated with a mixture of fish oil and evening primrose seed oil in a 15-week randomized, placebo-controlled study.27
Miscellaneous. A variety of self-help books are on the market promoting various supplements, like royal jelly or megavitamins and minerals. Exclusion diets, in particular the chronic Candidiasis diet, which eliminates yeast and sugar from the diet, are popular. None of these diets are substantiated by clinical research, and, when evaluated from a nutritional standpoint, they are found lacking.28
CFS is a chronic illness whose natural history is still unclear, but, in general, 40-60% of patients improve in varying degrees about 1-3 years after diagnosis. (See Table 7.) One needs to remember that the patient may still be ill for several years, since the mean duration of illness prior to diagnosis was 52.6 months in 407 patients.29
The University of Washington CFS Clinic surveyed 216 patients with chronic fatigue and 226 with CFS an average of 1.5 years after an initial evaluation.18 Although some improvement was noted by 61% of CFS patients vs. 28% of the chronic fatigue patients, 40% of the CFS patients were still unable to work at all. Current dysthymia was the only predictor of less improvement.
In an Australian outcomes study of 103 patients, the two predictors of poor outcome were the assignment of a psychiatric diagnosis at a follow-up evaluation and a strong belief of the patient that a physical disease explained all the symptoms.30 Although 65 patients reported improvement, only six had no symptoms. Factors that did not predict outcome included age, duration of illness, cell-mediated immunity, neuroticism, and the presence of premorbid psychiatric diagnoses.
A year after my initial evaluation of JF, he remains on Prozac 40 mg per day, a higher dose than initially. He continues to teach full-time, but has learned to "pace" himself, knowing that if he overextends himself he is prone to upper respiratory tract infections and return of disabling fatigue for days. He is no longer running long distances, but does engage in light exercise three times a week. Occasionally he wonders if he will ever return to his baseline, but he is pleased to be functioning much better than he was a year ago. His depression over his lost relationship was short-lived, and he does not have any psychiatric disturbance. He continues to keep up with research on CFS and hopes that someday more answers will be discovered.
Chronic fatigue syndrome is a condition that often strikes young, healthy individuals rather abruptly, resulting in significant physical and social disability. Although the etiology is still undetermined and there is overlap with fibromyalgia, depression, and somatization, standardized criteria are available to help the clinician make the diagnosis. While no specific treatments are uniformly efficacious in CFS, simple improvements in lifestyle, such as diet and exercise, coupled with antidepressant medication, have restored a modicum of functioning for many patients. Most of the other pharmacologic or dietary interventions need further investigation before being recommended to patients. As primary care clinicians, we can monitor the progress of CFS patients, reassure them of our support, and encourage them that slightly over half of them will improve within a few years after diagnosis.
Resources
A. American Association for Chronic Fatigue Syndrome; Box 895; Olney, MD 20830
B. Roger Burns edits the CFS-NEWS electronic newsletter: [email protected]. He also has a discussion group for physicians on the Internet: [email protected].
References
1. Buchwald D, Cheney PR, Peterson DL, et al. A chronic illness characterized by fatigue, neurologic and immunologic disorders, and active human herpesvirus type 6 infection. Ann Intern Med 1992;116:103-113.
2. Buchwald D, Garrity D. Comparison of patients with chronic fatigue syndrome, fibromyalgia, and multiple chemical sensitivities. Arch Intern Med 1994;154:2049-2053.
3. Lane TJ, Manu P, Matthews DA. Depression and somatization in the chronic fatigue syndrome. Am J Med 1991;91:335-344.
4. Manu P, Lane TJ, Matthews DA. The frequency of the chronic fatigue syndrome in patients with symptoms of persistent fatigue. Ann Intern Med 1988;109:554-556.
5. Levine PH. Summary and perspective: epidemiology of chronic fatigue syndrome. Clin Infect Dis 1994;18 S57-60.
6. Buchwald D, Umali P, Umali J, et al. Chronic fatigue and the chronic fatigue syndrome: prevalence in a Pacific northwest health care system. Ann Intern Med 1995;123:81-88.
7. Komaroff AL, Fagioli LR, Doolittle TH, et al. Health status in patients with chronic fatigue syndrome and in general population and disease comparison groups. Am J Med 1996;101:281-290.
8. Buchwald D, Pearlman T, Kith P, Schmaling K. Gender differences in patients with chronic fatigue syndrome. J Gen Intern Med 1994;9:397-401.
9. MacDonald KL, Osterholm MT, LeDell KH, et al. A case-control study to assess possible triggers and cofactors in chronic fatigue syndrome. Am J Med 1996;100:548-554.
10. Khan AS, Heneine WM, Chapman LE, et al. Assessment of a retrovirus sequence and other possible risk factors for the chronic fatigue syndrome in adults. Ann Intern Med 1993;118: 241-245.
11. Fukuda K, Straus SE, Hickie I, et al. The chronic fatigue syndrome: a comprehensive approach to its definition and study. Ann Intern Med 1994;121:953-959.
12. Bates DW, Buchwald D, Lee J, et al. Clinical laboratory test findings in patients with chronic fatigue syndrome. Arch Intern Med 1995;155:97-103.
13. Schwartz RB, Grada BM, Komaroff AL, et al. Detection of intracranial abnormalities in patients with chronic fatigue syndrome: comparison of MR Imaging and SPECT. Am J Radiol 1994;162:935-941.
14. Morris R, Sharpe M, Sharpley AL, et al. Abnormalities of sleep in patients with the chronic fatigue syndrome. BMJ 1993; 306:1161-1164.
15. Bou-Holaigah I, Rowe PC, Kan J, Calkins H. The relationship between neurally mediated hypotension and the chronic fatigue syndrome. JAMA 1995;274:961-967.
16. Sisto SA, LaManca J, Cordero DL, et al. Metabolic and cardiovascular effects of a progressive exercise test in patients with chronic fatigue syndrome. Am J Med 1996;100:634-640.
17. Sharpe M, Hawton K, Simkin S, et al. Cognitive behavior therapy for the chronic fatigue syndrome: a randomized controlled trial. BMJ 1996;6:312:22-26.
18. Bombardier CH, Buchwald D. Outcome and prognosis of patients with chronic fatigue vs chronic fatigue syndrome. Arch Intern Med 1995;155:2105-2110.
19. Behan PO, Haniffah AG, Doogan DP, Loudon A. A pilot study of sertraline for the treatment of chronic fatigue syndrome. Clin Infect Dis 1994;18 (Suppl 1):S111.
20. Straus SD, Dale JK, Tobi M, et al. Acyclovir treatment of the chronic fatigue syndrome. Lack of efficacy in a placebo-controlled trial. N Engl J Med 1988;26:1692-1698.
21. Peterson PK, Shepard J, Macres M, et al. A controlled trial of intravenous immunoglobulin G in chronic fatigue syndrome. Am J Med 1990;89:554-560.
22. Lloyd A, Hickie I, Wakefield D, et al. A double-blind, placebo-controlled trial of intravenous immunoglobulin therapy in patients with chronic fatigue syndrome. Am J Med 1990;89: 561-568.
23. Dubois RE. Gamma globulin therapy for chronic mononucleosis syndrome. AIDS Res 1986:S191-S195.
24. Strayer DR, Carter WA, Brodsky, et al. A controlled clinical trial with a specifically configured RNA drug, poly (I:) poly (C12 U), in chronic fatigue syndrome. Clin Infect Dis 1994;18 (Suppl 1): S88-95.
25. Kaslow JE, Rucker L, Onishi R. Liver extract-folic acid-cyancobalmin versus placebo for chronic fatigue syndrome. Arch Intern Med 1989;149:2501-2503.
26. Gray JB, Martinovic AM. Eicosanoids and essential fatty acid modulation in chronic disease and the chronic fatigue syndrome. Med Hypotheses 1994;43:31-42.
27. Behan PO, Behan WMH. essential fatty acids in the treatment of postviral fatigue syndrome. In Horrobin DR, ed. Omega-6 Essential Fatty Acids: Pathophysiology and Roles in Clinical Medicine. New York: Wiley-Liss, 1990:270-282.
28. Morris DH, Stare FJ. Unproven diet therapies in the treatment of the chronic fatigue syndrome. Arch Fam Med 1993;2:181-186.
29. Klonoff DC. Chronic fatigue syndrome. Clin Infect Dis 1992; 15:812-823.
30. Wilson A, Hickie I, Lloyd A. Longitudinal study of outcome of chronic fatigue syndrome. BMJ 1994;308:756-759.
Physician CME Questions
17. What is the etiologic agent in chronic fatigue syndrome?
a. Epstein-Barr virus
b. Cytomegalovirus
c. Human herpesvirus 6
d. Unknown
18. Which of the following diagnoses shares many of the characteristics of CFS?
a. Lyme disease
b. fibromyalgia
c. allergic rhinitis
d. congestive heart failure
19. Which of the following symptom is not part of the diagnostic criteria for CFS?
a. fever
b. sore throat
c. impaired memory or concentration
d. muscle pain
20. Which class of antidepressants are probably the drugs of choice for CFS patients?
a. tricyclics
b. monoamine oxidase inhibitors
c. heterocyclics
d. selective serotonin reuptake inhibitors
21. Which of the following factors is a predictor of poor outcome?
a. psychiatric diagnosis at follow-up
b. premorbid psychiatric diagnosis
c. duration of illness
d. age
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