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Chronic Fatigue Syndrome A Pamphlet for Physicians U.S. Department of Health and Human Services Public Health Service National Institutes of Health NIH Publication No. 92-484 May 1992 Table of Contents Introduction 1 Epidemiology 2 Historical Perspective 3 Clinical Picture 4 Evaluation of Patients 5 Immunologic Features 6 Neuropsychologic Features 7 Etiologic Theories 8 Patient Management 9 Conclusion 11 Appendix 12 Page 1 Chronic Fatigue Syndrome Introduction Chronic fatigue syndrome (CFS) is an illness characterized by debilitating fatigue and several flu-like symptoms such as pharyngitis, adenopathy, low-grade fever, myalgia, arthralgia, headache, difficulty concentrating, and exercise intolerance. These nonspecific symptoms can make the syndrome difficult to identify. Profound fatigue -- the earmark of the disorder -- usually comes on suddenly and persists or relapses throughout the course of the illness. But unlike the short-term fatigue and malaise that often accompanies an acute infection, by definition, CFS symptoms linger for at least 6 months, and often for years. Chronic fatigue is a common complaint in primary care practice. No evidence exists to suggest that most patients with chronic fatigue have CFS. Indeed, CFS is probably an uncommon cause of chronic fatigue. When evaluating patients with chronic fatigue of unknown origin, physicians can use the definition of CFS in the Appendix as a guide. This detailed definition was developed for research use under the leadership of the Centers for Disease Control. It was published in Annals of Internal Medicine in March 1988. Because the disease is still poorly understood, however, the outlined criteria should be considered provisional. Most investigators studying CFS believe that the syndrome has many possible causes. For example, various infectious agents often trigger the onset of CFS. Preliminary research also shows a variety of immunologic disturbances in some patients. No single pattern of disturbances appears consistently, however, and in general, patients are Page 2 not clinically immunocompromised: they do not develop opportunistic infections. In fact, the character, epidemiology, and prognosis of CFS is quite distinct from that of major immune deficiency disorders such as AIDS. Several different latent viruses also appear to be reactivated in some CFS patients, although reactivation has not been shown in all patients, and it is not clear that any of these viruses are causally related to CFS or its symptoms. Many patients with CFS also present with anxiety or depression. In summary, as with most chronic illness, CFS has both physical and psychiatric manifestations. Epidemiology Most cases of CFS are sporadic: the patient does not have a close contact who has developed a similar illness. Infrequently, however, close contacts, including family members, become ill with CFS at about the same time. During the past 60 years, several apparent epidemics of this illness affecting various communities or relatively large numbers of co-workers have been reported. Clusters of CFS cases are unusual, however, and it is not generally thought that people with CFS need to be isolated in any way. The clinical and laboratory findings of sporadic versus epidemic cases have yet to be compared. While the typical patient seeking medical care for CFS is a white woman in her thirties, patients of all ages (including the very young and very old), both sexes, many races, and all socioeconomic groups have been affected. CDC and NIAID-sponsored researchers have studies under way to try to estimate the prevalence of this disorder. Page 3 Historical Perspective Although interest in this illness has grown tremendously since the mid-1980's CFS does not appear to be a new disorder. It closely resembles neurasthenia or neurocirculatory asthenia, diagnoses commonly made in the late 19th and early 20th centuries. As stated earlier, small epidemics of a very similar illness (most often called myalgic encephalomyelitis, or ME) have been described in the medical literature for at least 60 years. Furthermore, case reports describing similar illnesses date back several centuries. These sporadic cases of fatigue syndromes have often been linked to bacterial, viral, or protozoal infections (for example, brucellosis and influenza). But fatigue syndromes also appear outside the setting of an infectious illness. Several recent studies indicate that the rheumatologic disorder called fibrositis or fibromyalgia, first ........................................................... Febricula, Vapors ################## Neurasthenia ####################### Da Costa's (Effort) Syndrome ################# Chronic Brucellosis ############ Hypoglycemia ############### Myalgic Encephalomyelitis, Epidemic Neuromyasthenia ############## Total Allergy Syndrome ############ Chronic Mononucleosis, Chronic EBV ############## Chronic Candidiasis ####### Postviral Fatigue Syndrome ###### Chronic Fatigue Syndrome ### |_________|_________|_________|________ 1800 1850 1900 1950 Timeline graph from 1800 to the present of other diseases with symptoms very similar to CFS. Page 4 described in the 19th century, is very similar to CFS. The average age of the patient with fibrositis is a bit older, however, and soft tissue pain is a more prominent symptom in this illness. In the early 1980's, several studies indicated that antibody levels to one virus, Epstein-Barr virus (EBV), were somewhat higher in patients with CFS than in healthy individuals. It is important to put this observation in context. EBV infection is extremely common: approximately 90 percent of American adults have been infected, and they harbor a lifelong infection thereafter. In most people the virus remains dormant. Antibody studies indicate that EBV may be reactivated - i.e., replicating itself - more often in patients with CFS than in healthy individuals. But the difference is not striking. Moreover, as mentioned earlier, evidence shows that several other viruses may also be reactivated in CFS. Therefore, investigators believe that there is no proof that EBV causes CFS, at least in most patients. Clinical Picture A hallmark of CFS is the sudden onset of the illness, typically with flu-like symptoms. In contrast to the usual flu-like illness, however, the symptoms of CFS do not fully resolve; they persist chronically, or wax and wane frequently, accompanied by debilitating fatigue and malaise. In a few cases, CFS seems to follow from a bout of classic acute infectious mononucleosis rather than from a nonspecific flu-like illness. In these cases, EBV - the cause of most cases of acute mononucleosis - may play a role in the pathogenesis of CFS. Clearly some CFS symptoms - headache, myalgia, sleep disorder, difficulty concentrating - could be secondary symptoms of a primary affective disorder. However, other symptoms such as pharyngitis, fever, Page 5 adenopathy, and arthralgias suggest a different underlying process. Many patients have a history of allergies years before the onset of CFS, and occasionally allergic symptoms worsen after these patients become ill. Allergies are so prevalent in CFS patients that it is important to differentiate those symptoms that are allergy-related and thus amenable to treatment. The course of CFS varies greatly, with symptoms lasting anywhere from many months to many years. Symptoms typical of CFS are often seen for short periods of time; but these symptoms must persist for at least 6 months, according to the current CDC definition, to entertain a diagnosis of CFS. Fortunately, CFS is not a progressive disease: usually the symptoms are most severe in the first year of illness. Systematic studies are under way to better define the prognosis. Evaluation of Patients The patient with the complaint of chronic fatigue that is interfering with his or her life must be taken seriously. CFS symptoms overlap with those of many well-recognized illnesses. For example, Lyme borreliosis, mild systemic lupus erythmatosus (SLE), and early or mild multiple sclerosis (MS) are among the numerous disorders that resemble CFS. A history of potential tick exposure, the typical Lyme rash (erythema chronicum migrans), and antibodies to the Lyme spirochete suggest the diagnosis of Lyme borreliosis. In both SLE and MS, debilitating chronic fatigue can be more prominent than rheumatologic or neurologic symptoms. Psychiatric illnesses that most resemble CFS include major depressive episode, panic disorder, generalized anxiety disorder, and somatization disorder. It remains unresolved whether Page 6 prior or current depressive episodes should exclude a diagnosis of CFS. Although infectious agents can trigger the syndrome, the diagnosis of CFS currently is one of exclusion. The Appendix lists several illnesses that must be considered and "ruled out" when first evaluating a patient with chronic fatigue. This list is a useful guide but should not be thought of as exhaustive. The patient's medical history -- particularly his or her potential epidemiologic exposures -- and physical examination will help determine the need for various laboratory tests. A reasonable initial laboratory workup would include a urinalysis, complete blood count and differential count, chemistry panel, thyroid function test (a TSH test may be sufficient), erythrocyte sedimentation rate, anti-nuclear antibodies, and rheumatoid factor. Significantly abnormal results on any of these tests should prompt consideration of alternative diagnoses. It is prudent for physicians today to also consider the possibility of infection with the human immunodeficiency virus. Subsequent workup should be guided by the clinical picture and may necessitate a chest X-ray, an electrocardiogram, an Ig level, a tuberculin skin test, and serum cortisol determinations, among other tests. Immunologic Features Many different immunologic findings have been described in patients with CFS, but no single immunologic disturbance has yet been identified as typical of the syndrome. Those disturbances observed include depressed natural killer (NK) cell activity, elevated viral antibody titers, and circulating immune complexes. These findings indicate general differences between patient populations Page 7 and control groups, but none is specific for CFS or abnormal in all CFS patients. Immunologic changes like these are often associated with infections and other stressful processes. Neuropsychologic Features As mentioned earlier, many patients with CFS also meet diagnostic criteria for depression or anxiety disorders at presentation. It remains unclear whether a higher than normal frequency of psychiatric disorders in this patient group also exists in the years prior to the onset of CFS. On the other hand, psychiatric evaluations fail to identify any psychiatric disorders in some patients. Because subtle psychiatric problems can be difficult to recognize, a consult with a psychiatrist or psychologist may benefit the evaluation of some patients. Many people with CFS have neurologic symptoms, including paresthesias, disequilibrium, and visual blurring. A few patients who are otherwise identical to the larger group have had more dramatic acute and transient neurologic events, such as primary seizures, periods of severe visual impairment, and periods of paresis. These few patients show no evidence of any well-recognized neurologic disorder such as MS. Patients with these more dramatic symptoms warrant a more intensive neurologic workup. One study found that people with CFS have a subtle deficiency of the steroid hormone cortisol. Because cortisol is a potent suppressor of immune responses, this finding provides an alternative explanation for some of the immune findings in the syndrome. Preliminary research indicates that some patients with CFS demonstrate punctate areas of high signal in the sub-cortical white matter on magnetic resonance imaging scans of the brain. Studies are under way to Page 8 determine if these abnormalities are found more frequently in people with CFS than in healthy individuals. For many patients, the cognitive impairment they experience is one of the most disconcerting symptoms. It is usually characterized as an inability to concentrate, unusual absent-mindedness, and difficulty with word finding. CFS patients do not exhibit gross dementia. Neuropsychological testing is being conducted to better define the presence, nature, and severity of cognitive impairment in patients with CFS. Etiologic Theories Several theories have been postulated as to the etiology of CFS. Most investigators currently believe that no single etiologic agent will prove to be the cause of all cases. Many investigators believe that the illness involves a constant antigenic challenge to the immune system and, as a consequence, a constant immunologic response to that challenge. One popular theory, which has experimental support, suggests that elevated levels of cytokines (e.g., interleukin-1, interleukin-2, various interferons) are generated by an immune system that is doing battle against antigens that it perceives to be foreign. The flu-like symptoms associated with many common infections are known to be caused by cytokines. Moreover, when these cytokines are administered for therapeutic purposes, such as the use of interleukin-2 or interferon in cancer therapy, many flu-like symptoms occur. Preliminary evidence suggests that several latent viruses may be actively replicating more often in CFS patients than in healthy control subjects. Antibody levels are higher in patients (indirect evidence of active infection); viral antigen is found more commonly; or there is direct evidence that the Page 9 virus is replicating in cells that it commonly infects, such as lymphocytes. Thus far, those viruses that show some evidence of more frequent active infection are several members of the herpesvirus family -- EBV, cytomegalovirus, herpes simplex viruses 1 and 2, and human herpesvirus 6 -- and of the enterovirus family -- coxsackievirus and echovirus. If subsequent studies confirm that several viruses are active more often in people with CFS than in healthy individuals, it will then need to be determined if this activity is a primary or secondary event. Because the viral agents thus far identified typically infect people in childhood, and since most patients with CFS are young adults, most investigators believe reactivation of these viruses is probably secondary to some immunologic disturbance. If viral activation is indeed a secondary event, it will need to be determined if it is merely an epiphenomenon, having nothing to do with the reason the patient feels sick, or whether the viral activation - even if secondary -- contributes to the symptoms. Patient Management CFS is debilitating in all patients, disabling in some, but apparently not progressive or fatal. The debility and disability stem from a combination of symptoms such as fatigue, arthralgias, or cognitive impairment, and in some patients from associated depression. The patients need both symptomatic treatment and emotional support. It should be noted, however, that some patients get better all by themselves. It is vitally important for the physician to be the patient's advocate. In the absence of any proven treatments, empiric therapies should be tried. At the same time, patients need to be kept from using exotic, untested remedies that may hurt them. Physicians also need to be on the lookout for other medical Page 10 problems, and to avoid the danger of interpreting every new sign or symptom as a manifestation of CFS. For many patients, it is important to slow the pace of their lives and to avoid situations that are physically or psychologically stressful. Counseling for both the patient and his or her family benefits their adjustment to this chronic illness. It is important for them to realize that no definitive diagnostic or therapeutic approaches exist. Neither has a specific nutritional program proved beneficial, though a balanced diet and rest enhance well-being. Some patients benefit from a graduated program of exercise. At a minimum, patients should be encouraged to maintain physical conditioning -- in some cases through a sustained program of physical therapy -- at whatever level of activity they can manage. Abrupt resumption of vigorous exercise should be avoided, however, because this can exacerbate symptoms. Symptomatic treatment can be quite helpful. Non-steroidal anti-inflammatory drugs may benefit the myalgias, arthralgias, headaches, or fever associated with the illness. Nonsedating antihistamines may help relieve any prominent allergic symptoms. Very few randomized, controlled clinical drug trials for CFS have been conducted. One such trial found the antiviral drug acyclovir to be no better than a placebo treatment. In fact, more than 40 percent of patients on placebo reported improvement. Several empiric therapies have been tried for CFS. Some investigators have administered intramuscular or intravenous gammaglobulin, particularly to those patients who, unlike most patients with CFS, have low levels of immunoglobulins. There are conflicting claims regarding the efficacy of this form of therapy -- one trial found some benefit, the other none. Page 11 Several empiric therapies have been tried for CFS. Because well-designed clinical trials have demonstrated the benefit of low doses of tricyclic antidepressant drugs in fibromyalgia (an illness similar to CFS), tricyclics are widely prescribed for CFS patients. Anecdotal experience with tricyclics has generally been positive. Some investigators believe that the tricyclics act by improving the quality of sleep. Other types of antidepressants have also been tried with some success. CFS patients often report that antidepressants exacerbate their fatigue, however, especially when given in therapeutic doses. It may be necessary to escalate doses very slowly and urge patience in detecting benefit, or to try the more activating antidepressants such as desipramine, fluoxetine, and MAO inhibitors. In brief, no strict recipe for treating CFS exists, and sometimes several different treatment approaches may have to be tried before the patient reports benefit. Both the physician and the patient need to be open to reasonable treatment alternatives and appreciate the difficulty in assessing their benefit in CFS. Conclusion A great deal of controversy and speculation surrounds CFS: Is it a single disorder or a heterogeneous mix of problems? What is its relationship to infections, the immune system, and mood disturbances? How can it best be treated? These and many more issues fuel the continuing broad debate, often leaving patients and their physicians frustrated. For now, physicians don't have all the answers. But in treating people with CFS, they can draw on practices that have always made medicine a valued art: exclude alternative problems, ameliorate symptoms, and offer guidance with compassion. Page 12 Appendix Research Case Criteria for the Chronic Fatigue Syndrome* A case of chronic fatigue syndrome must fulfill major criteria 1 and 2 and the following minor criteria: 6 or more of the 11 symptom criteria and 2 or more of the 3 physical criteria; or 8 or more of the 11 symptom criteria. Major Criteria 1. New onset of persistent or relapsing, debilitating fatigue or easy fatigability in a person who has no previous history of similar symptoms, that does not resolve with bedrest, and that is severe enough to reduce or impair average daily activity below 50% of the patient's premorbid activity level for a period of at least 6 months. 2. Other clinical conditions that may produce similar symptoms must be excluded by thorough evaluation, based on history, physical examination, and appropriate laboratory findings. These conditions include malignancy; autoimmune disease; localized infection (such as occult abscess); chronic or subacute bacterial disease (such as endocarditis, Lyme disease, or tuberculosis), fungal disease (such as histoplasmosis, blastomycosis, or coccidioidomycosis), and parasitic disease (such as toxoplasmosis, amebiasis, giardiasis, or helminthic infestation); disease related to human immunodeficiency virus (HIV) infection; chronic psychiatric disease, either newly diagnosed by history (such as endogenous depression; hysterical personality disorder; anxiety neurosis; schizophrenia; or chronic use of major tranquilizers, lithium, or antidepressive medications); chronic inflammatory disease (such *From Holmes GP, et al. Chronic fatigue syndrome: a working case definition. Ann. Intern. Med. 1988;108:387-9. Page 13 as sarcoidosis, Wegener's granulomatosis, or chronic hepatitis); neuromuscular disease (such as multiple sclerosis or myasthenia gravis); endocrine disease (such as hypothyroidism, Addison disease, Cushing syndrome, or diabetes mellitus); drug dependency or abuse (such as alcohol, controlled prescription drugs, or illicit drugs); side effects of chronic medication or other toxic agent (such as chemical solvent, pesticide, or heavy metal); or other known or defined chronic pulmonary, cardiac, gastrointestinal, hepatic, renal, or hematologic disease. Specific laboratory tests or clinical measurements are not required to satisfy the definition of the chronic fatigue syndrome, but the recommended evaluation includes serial weight measurements (weight change of more than 10% in the absence of dieting suggests other diagnoses); serial morning and afternoon temperature measurements; complete blood count and differential; serum electrolytes; glucose; creatinine, blood urea nitrogen; calcium, phosphorous; total bilirubin, alkaline phosphatase, serum aspartate aminotransferase; creatine phosphokinase or aldolase; urinalysis; posteroanterior and lateral chest roentgenograms; detailed personal and family psychiatric history; erythrocyte sedimentation rate; antinuclear antibody; thyroid-stimulating hormone level; HIV antibody measurement; and intermediate-strength purified protein derivative (PPD) skin test with controls. If any of the results from these tests are abnormal, the physician should search for other conditions that may cause such a result. If no such conditions are detected by a reasonable evaluation, this criterion is satisfied. Page 14 Minor criteria Symptom criteria To fulfill a symptom criterion, a symptom must have begun at or after the time of onset of increased fatigability, and must have persisted or recurred over a period of at least 6 months (individual symptoms may or may not have occurred simultaneously). Symptoms include: 1. Mild fever -- oral temperature between 37.6 degrees C and 38.6 degrees C, if measured by the patient -- or chills. (Note: oral temperatures of greater than 38.6 degrees C are less compatible with chronic fatigue syndrome and should prompt studies for other causes of illness.) 2. Sore throat. 3. Painful lymph nodes in the anterior or posterior cervical and axillary distribution. 4. Unexplained generalized muscle weakness. 5. Muscle discomfort or myalgia. 6. Prolonged (24 hours or greater) generalized fatigue after levels of exercise that would have been easily tolerated in the patient's premorbid state. 7. Generalized headaches (of a type, severity, or pattern that is different from headaches the patient may have had in the premorbid state). 8. Migratory arthralgia without joint swelling or redness. 9. Neuropsychologic complaints (one or more of the following: photophobia, transient visual scotomata, forgetfulness, excessive irritability, confusion, difficulty thinking, inability to concentrate, depression). 10. Sleep disturbance (hypersomnia or insomnia). 11. Description of the main symptom complex as initially developing over a few hours to a few days (this is not a true symptom, but may be considered as equivalent to the above symptoms in meeting the requirements of the case definition). Page 15 Physical Criteria Physical criteria must be documented by a physician on at least two occasions, at least 1 month apart. 1. Low-grade fever - oral temperature between 37.6 degrees C and 38.6 degrees C, or rectal temperature between 37.8 degrees C and 38.8 degrees C. (See note under Symptom Criterion 1.) 2. Nonexudative pharyngitis. 3. Palpable or tender anterior or posterior cervical axillary lymph nodes. (Note: lymph nodes greater than 2 cm in diameter suggest other causes. Further evaluation is warranted.) To receive a CFS information packet, contact: Office of Communications National Institute of Allergy and Infectious Diseases Building 31, Room 7A32 9000 Rockville Pike Bethesda, MD 20892 (301) 496-5717 National Institute of Allergy and Infectious Diseases NIH Publication No. 92-484 May 1992