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Chronic Fatigue Syndrome Last Updated: May 2, 2006 |
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| Synonyms and related keywords: chronic fatigue syndrome, encephalomyalgia, CFS, fatigue, chronic fatigue, idiopathic fatigue, viral infection, Chlamydia pneumoniae, C pneumoniae, Epstein-Barr virus, EBV infection
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AUTHOR INFORMATION
| Section 1 of 10   |
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| Author: Burke A Cunha, MD, MACP, Professor of Medicine, State University of New York at Stony Brook School of Medicine; Chief, Infectious Disease Division, Winthrop-University Hospital |
| Burke A Cunha, MD, MACP, is a member of the following medical societies:
American College of Chest Physicians,
American College of Physicians, and
Infectious Diseases Society of America |
| Editor(s): Wesley W Emmons, MD, FACP, Assistant Professor, Department of Medicine, Thomas Jefferson University; Consulting Staff, Infectious Diseases Section, Department of Internal Medicine, Christiana Care, Newark, DE; Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine;
Thomas M Kerkering, MD, Professor of Medicine & Microbiology, Department of Internal Medicine, Division of Infectious Disease, Brody School of Medicine at East Carolina University;
Eleftherios Mylonakis, MD, PhD, Assistant Professor of Medicine, Harvard Medical School, Clinical Assistant in Medicine, Division of Infectious Disease, Massachusetts General Hospital;
and Michael E Zevitz, MD, Assistant Professor of Medicine, Finch University of the Health Sciences, The Chicago Medical School; Consulting Staff, Private Practice |
Disclosure
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INTRODUCTION
| Section 2 of 10   |
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Background: Chronic fatigue syndrome (CFS) is a disorder of unknown etiology, which probably has an infectious basis. CFS is a state of chronic fatigue, which exists without other explanation, for a year or more, and is accompanied by cognitive difficulties.
Various unrelated infectious diseases (eg, pneumonia, Epstein-Barr virus [EBV] infection, diarrhea, upper respiratory tract infections) appear to lead to a state of prolonged fatigue in some patients. If the condition is accompanied by cognitive difficulties, the disease is termed CFS.
While the cause of CFS is unknown, the disease probably is an infectious disease with immunological manifestations. CFS is not caused by EBV, one of the viruses that may lead to a state of chronic fatigue. EBV definitely has not been shown to cause CFS, and CFS is not synonymous with chronic EBV or chronic infectious mononucleosis.
One or more viruses have been implicated as the cause of CFS, excluding EBV, but no causal relationship between any virus and CFS has been proven. Some have suggested that Chlamydia pneumoniae is the infectious agent responsible for CFS, which may become activated following prior contact with another infectious disease agent.
CFS initially was termed encephalomyalgia because it was appreciated, particularly by British clinicians, that the essential clinical features of CFS included both an encephalitic component (as manifested by cognitive difficulties) and a skeletal muscle component (as manifested by chronic fatigue). Patients without cognitive dysfunction should not be considered to have CFS.
Because no direct tests aid in the diagnosis of CFS, the disease is a diagnosis of exclusion, but one that meets certain clinical criteria, which are further supported by certain nonspecific tests. The diagnosis of CFS also rests on historical criteria, ie, otherwise unexplained fatigue for a period equal to or longer than 1 year accompanied by cognitive dysfunction. Pathophysiology: Because the immune system is up-regulated in CFS, antibody titers to various previously encountered antigens are increased. While increased titers do not indicate a causal relationship in CFS, nevertheless, the titers are useful as laboratory clues, which, when taken together, occur regularly in patients with CFS.
Because so many patients with a possible diagnosis of CFS present with an elevated immunoglobulin G (IgG) viral capsid antigen (VCA) EBV titer, this determination should be considered consistent but not diagnostic of CFS. Most patients with CFS demonstrate elevated IgG, coxsackievirus B, human herpes virus 6 (HHV-6), and/or C pneumoniae titers. Patients with CFS also commonly show a decrease in the percent of natural killer (NK) cells. Most patients with CFS have 2 of the 3 above-mentioned immunological perturbations.
Hypoperfusion of frontoparietal areas of the brain is responsible for cognitive abnormalities in CFS. Frequency:
- In the US: CFS affects tens of thousands of individuals.
- Internationally: CFS appears to be less common overseas but probably exists worldwide.
Sex: This condition occurs more commonly in females than in males.
Age: This condition occurs most commonly in young to middle-aged adults.
History: - Patients with CFS present with prolonged, otherwise unexplained fatigue. If another explanation exists for the fatigue, the patient probably does not have CFS.
- Patients with CFS often give a history of an antecedent infection that precipitated the prolonged state of fatigue and followed the initial illness. The patient may have a history of EBV infectious mononucleosis, cytomegalovirus (CMV) infectious mononucleosis, pneumonia, diarrhea, or upper respiratory tract infection. Patients with acute disease from these infections have fatigue during the acute illness, but the fatigue resolves as the patient recovers. In patients with CFS, the fatigue continues for a year or more after they have recovered from the acute infectious event.
- Patients usually are cardiac "A" intensive people from a personality standpoint. These patients are not malingerers, and they do not seek secondary gain. As a group, they want a fully functioning life restored, and they become frustrated by their inability to perform their work and home tasks because of their prolonged fatigue and cognitive dysfunction.
- Patients with CFS may be depressed secondarily because of their inability to perform normal duties at home and at work, but they are not depressive individuals per se. Depressive individuals give a history of being depressed for many years, and they lack the cognitive dysfunction characteristic of individuals with CFS.
- The typical complaint of patients with CFS is that they have problems with short-term memory but not long-term memory. Patients with CFS may complain of verbal dyslexia manifested by the inability to find or say a particular word during normal speech. The inability to find the word or delay in getting the word out is very disturbing to patients with CFS and may interfere with their occupation.
- Patients with CFS also typically complain of postexertional fatigue, being excessively tired after doing relatively normal tasks that they have done for years previous to their CFS without any particular problem. Patients also complain of fatigue even after prolonged periods of rest or sleep. Patients with CFS do not recharge or arise refreshed after sleeping. Patients with CFS do not complain of sore throats or fevers.
- The diagnosis of CFS depends on eliminating other causes of chronic persistent fatigue. Many patients have lifestyles that would make anyone feel fatigue on a long-term basis. This may be related to job, family, or home stress. Patients with malignancy should be excluded because fatigue often accompanies neoplastic disease.
- Many patients with fatigue but not CFS have a supratentorial component to the illness, and psychosomatic illness often is manifested as otherwise unexplained fatigue.
- If the above conditions can be excluded, then the diagnosis of CFS may be entertained.
Physical: - Patients with signs of adrenal or thyroid disorders also should be eliminated from consideration of CFS because they have an endocrinologic explanation for their fatigue.
- Similarly, patients with signs of human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS) also have a reason for chronic fatigue.
- CFS should be diagnosed only after other causes of fatigue are excluded and the fatigue has lasted for at least 1 year. CFS may be excluded as a diagnostic consideration from patients with prolonged fatigue if they do not have cognitive difficulties.
- The physical examination often reveals no abnormalities, but left axillary node involvement and/or crimson crescents are the most consistent findings during a physical examination.
- The lymph nodes in CFS are small, moveable, and not tender and most commonly involve the neck, axillary region, or inguinal region.
- In the oropharynx, purple/crimson discoloration of both anterior tonsillar pilars in the absence of pharyngitis is a frequent marker in patients with CFS. The cause of crimson crescents is not known, but they are observed frequently in patients with CFS. Patients with other disorders also may have crimson crescents.
- A single lymph node that is very large, tender, or immovable suggests a diagnosis other than CFS. Similarly, generalized adenopathy suggests a diagnosis other than CFS.
- Trigger points are not present in CFS. Trigger points indicate fibromyalgia but not CFS. CFS and fibromyalgia rarely coexist in the same patient.
Causes: - CFS probably is caused by an infection due to a virus and/or C pneumoniae infection.
- Many viruses have been studied as potential causal agents, including EBV, HHV-6, coxsackievirus B, spumaviruses, and even human T-cell leukemia virus strains.
- Patients with CFS often are referred to an infectious disease consultant because of elevated IgG VCA EBV titers. Increased IgG titers to the VCA of EBV are common in the general population, regardless of whether the patient is fatigued or not. An increased IgG VCA EBV titer indicates past exposure to EBV but does not indicate acute disease or explain the patient's chronic fatigue state. EBV often is the precipitating event that has triggered the patient's chronic fatigue state.
- Some investigators have suggested that C pneumoniae is the cause of CFS. Tests for C pneumoniae that are available in hospital or commercial laboratories are done by immunoglobulin M (IgM) and IgG enzyme-linked immunosorbent assay (ELISA) determinations. As with elevated EBV IgG VCA titers, many individuals in the healthy population have elevated IgG titers to C pneumoniae.
- Some patients with CFS have evidence of acute or recent infection by C pneumoniae, as evidenced by an elevated IgM C pneumoniae titer, and these patients are the most likely to respond to antichlamydial therapy.
- Investigators studying the potential role of C pneumoniae in CFS believe that serum tests are insensitive, and the only way to determine if some patients have CFS due to C pneumoniae is to diagnose the presence of the organism using sensitive tests, including polymerase chain reaction (PCR). PCR for C pneumoniae is a very sensitive technique but, unfortunately, is available only in research centers.
- Candida albicans or yeast infections do not cause CFS.
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DIFFERENTIALS
| Section 4 of 10 |
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Fibromyalgia
Hypothyroidism
Lyme Disease
Other Problems to be Considered:
CFS must be differentiated from other disorders that have a fatigue component. CFS usually is easily differentiated from other causes of CFS by the presence of cognitive dysfunction, which is absent in almost all other fatigue-producing disorders. Possible differentials include the following:
Adrenal insufficiency
Malignancy
AIDS
Liver disease
Renal disease
Psychosomatic illness: Patients with psychosomatic disorders may have elevated IgG VCA EBV titers, which may mislead them and their physicians to believe they have CFS. As mentioned, EBV may precede CFS, but it does not cause CFS. Such patients do not manifest the physical findings or abnormal laboratory tests that are part of the diagnosis of CFS. Such patients also do not have the cognitive dysfunction that is typical for a patient with CFS.
Lyme disease: CFS may be readily differentiated from Lyme disease in various ways. Patients from endemic areas may have elevated IgG Lyme titers. Few of these patients have neuroborreliosis, which must be diagnosed by doing simultaneous cerebrospinal fluid (CSF) and serum IgM and IgG Lyme titers. If the CSF titers are higher than those simultaneously obtained from the serum, then the patient has neuroborreliosis. Most patients with acute Lyme disease have a neurologic component, but chronic neuroborreliosis is distinctly uncommon. Patients with chronic neuroborreliosis do not have the same cognitive defects as patients with CFS (see History), and fatigue usually is not present.
Fibromyalgia: Fibromyalgia may be readily differentiated from CFS because no cognitive defects occur in fibromyalgia. Furthermore, patients with CFS do not have trigger points, which are characteristic of patients with fibromyalgia.
Other diseases may be ruled out by history, physical, or laboratory tests. |
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Lab Studies:
- Laboratory tests have 2 functions in CFS. First, tests are used to exclude other fatigue-causing diseases, and second, they may be helpful in making the diagnosis of CFS.
- The most consistent laboratory abnormality in patients with CFS is an extremely low erythrocyte sedimentation rate (ESR), which approaches zero. Typically, patients with CFS have an ESR of 0-3 mm/h. If the ESR is elevated or even in the high-normal range, another diagnosis is suggested.
- Thyroid, adrenal, and liver function tests are useful in excluding disorders that may have a fatigue component.
- Most patients with CFS usually have 2 or 3 of the following abnormalities:
- Elevated IgM/IgG coxsackievirus B titer
- Elevated IgM/IgG HHV-6 titer
- Elevated IgM/IgG C pneumoniae titer
- Decreased NK cells, either the percent or their activity
- CFS laboratory abnormalities are not specific, but taken together, the abnormalities provide a pattern of normalities consistent with CFS in those patients who have a cognitive dysfunction, if other diseases with fatigue are excluded.
- The WBC count in patients with CFS is normal. Leukopenia, leukocytosis, or an abnormal cell differential count indicates a diagnosis other than CFS, and another cause should be pursued to explain these findings.
- Results of liver function tests are within the reference range in patients with CFS.
- Increased serum transaminases, alkaline phosphatase, or lactic dehydrogenase should prompt a search for another explanation because the results of these tests are not abnormal in CFS.
- Results of serum protein electrophoresis are normal in patients with CFS but may be used to rule out other diseases that cause fatigue, including lymphoma and myeloma.
- Urinalysis is unremarkable in CFS.
Imaging Studies:
- CT scans or an MRI of the brain is useful to rule out CNS disorders in patients with otherwise unexplained CNS symptomatology. Results of CT scans and MRI are normal in patients with CFS.
- Single-photon emission computed tomography and/or positron emission tomography scans show hypoperfusion in the frontoparietal/temporal region, which is the anatomical substrate for CFS cognitive abnormalities.
Other Tests:
- Tilt-table testing became popular after a study showed, in 2 large population groups with CFS, that 1 group had a minimal degree of relative adrenal insufficiency. The study showed that the groups could be differentiated as large groups, but that the overlap was such that in the individual case, tilt-table testing was not helpful. This author has not found a tilt-table test useful and has recommended that practitioners abandon this practice because, in some patients, the test has precipitated cardiovascular problems and has questionable diagnostic utility.
- Extensive immunological testing is not indicated in patients with CFS because it is neither diagnostic nor specific for CFS. Similarly, RBC magnesium levels and allergy testing, particularly serological tests for Candida, are of no value.
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TREATMENT
| Section 6 of 10 |
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Medical Care: - Because most cases of CFS may be based on a viral infection, no uniformly effective therapy exists for CFS.
- In patients with elevated C pneumoniae levels, particularly increased IgM titers, antichlamydial therapy may be effective.
Consultations: - Infectious disease consultants should perform a history and physical examination on patients with possible CFS.
Diet: - No special diet or vitamin supplements are effective.
Activity:
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MEDICATION
| Section 7 of 10 |
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Trials of antiviral agents have been ineffective in relieving the symptoms of CFS. Various medications have not been shown to be effective, including steroids, liver extract (eg, Kutapressin), chelation therapy, intravenous vitamin therapy, vitamin B-12 therapy, and intravenous or oral vitamin/mineral supplements.
Only 2 therapeutic modalities are helpful in some, but not all, patients. Patients without elevated IgM Chlamydia titers may benefit from an empiric trial of beta-carotene using 50,000 U/d for 3 weeks only. Beta-carotene should be discontinued after this time, whether it has helped the patient or not. Carotenemia may result if therapy is continued beyond 3 weeks because beta-carotene is a provitamin A lipid soluble vitamin that accumulates in the liver. If the patient has improved on beta-carotene therapy, the effect persists for months after the 3-week therapy. If the patient responds, another 3-week course of beta-carotene therapy may be given 6 months after the initial 3-week course.
Patients with elevated IgM C pneumoniae titers often benefit from an empiric course of doxycycline. Doxycycline may be given for a 2- or 3-week period orally with food. In patients responding to doxycycline, the response is prompt and dramatic and the therapeutic effect (ie, restoration of energy or decrease in cognitive impairment) persists long after doxycycline therapy has been discontinued.
Drug Category: Antibiotics -- For use in patients with elevated IgM C pneumoniae titers. Drug Name
| Doxycycline (Vibramycin, Doryx) -- Second-generation tetracycline. Much more active than tetracycline against many pathogens. Different adverse-effect profile and pharmacokinetics compared to tetracycline. Inhibits bacterial growth, possibly blocking dissociation of peptidyl t-RNA from ribosomes, causing RNA-dependent protein synthesis to arrest. |
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| Adult Dose | 100-200 mg PO bid q12h |
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| Pediatric Dose | >12 years: Administer as in adults |
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| Contraindications | Documented hypersensitivity; severe hepatic dysfunction, children <8 y |
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| Interactions | None reported |
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| Pregnancy |
X - Contraindicated in pregnancy |
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| Precautions | Photosensitivity may occur with prolonged exposure to sunlight or tanning equipment; reduce dose in renal impairment; consider drug serum level determinations in prolonged therapy; tetracycline use during tooth development (last half of pregnancy through 8 y) can cause permanent discoloration of teeth; Fanconilike syndrome may occur with outdated tetracyclines |
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FOLLOW-UP
| Section 8 of 10 |
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Prognosis:
- Most cases improve to some degree over time.
Patient Education:
- Exacerbations are precipitated by stress, exercise, or lack of sleep.
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MISCELLANEOUS
| Section 9 of 10 |
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Medical/Legal Pitfalls:
- Be sure to rule out systemic disorders, particularly lymphoreticular malignancies, for patients presenting with fatigue.
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BIBLIOGRAPHY
| Section 10 of 10 |
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