AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Chronic fatigue syndrome (CFS) is a disorder of unknown etiology that probably has an infectious basis. CFS is characterized by a state of chronic fatigue that persists for more than 6 months, has no clear cause, 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 persons. If the condition is accompanied by cognitive difficulties, the disease is termed CFS.

While the cause of CFS is unknown, it is probably an infectious disease with immunological manifestations. CFS has been excluded as a cause of EBV, although EBV infection may lead to a state of chronic fatigue. CFS is not synonymous with chronic EBV infection or chronic infectious mononucleosis.

With the exception of EBV, numerous viruses have been implicated as the cause of CFS, 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 contact with another infectious agent.

CFS was initially termed encephalomyalgia (also known as myalgic encephalomyelitis) because British clinicians noted that the essential clinical features of CFS included both an encephalitic component (manifesting as cognitive difficulties) and a skeletal muscle component (manifesting as chronic fatigue). The absence of cognitive dysfunction should exclude CFS as a potential diagnosis.

Because no direct tests aid in the diagnosis of CFS, the diagnosis is one of exclusion but 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 more than 6 months accompanied by cognitive dysfunction.

Pathophysiology

Because the immune system is up-regulated in CFS, the levels of antibodies to various previously encountered antigens are increased. Although increased titers do not indicate a causal relationship in CFS, the titers are nonetheless useful as laboratory clues, which, when taken together, are common in patients with CFS.

Because so many patients with a possible diagnosis of CFS are found to have high levels of immunoglobulin G (IgG) viral capsid antigen (VCA) EBV, this determination should be considered consistent with 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 have a decreased percentage of natural killer (NK) cells. Most patients with CFS have 2 of the 3 above-mentioned immunological perturbations.

Frequency

United States

CFS is common, but data are difficult to interpret since the various studies define CFS differently.

International

CFS appears to be less common overseas but probably exists worldwide.

Sex

CFS is more common in females than in males.

Age

This condition occurs most commonly in young to middle-aged adults.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

• Patients with chronic fatigue syndrome (CFS) present with prolonged fatigue of an indeterminate cause. If the source of the fatigue can be explained, the patient probably does not have CFS.
• Patients with CFS often report 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 caused by these infections experience fatigue during the acute illness, but the fatigue resolves as the patient recovers. In patients with CFS, the fatigue continues for 6 months or more after they have recovered from the acute infectious event.
• Patients with CFS are usually cardiac "A" intensive people from a personality standpoint. These patients are not malingerers, and they do not seek secondary gain. As a group, they typically 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 because of their inability to perform normal duties at home and at work, but they are not depressive individuals per se. Depressive individuals typically report longstanding depression (of several years’ duration), and they typically lack the cognitive dysfunction characteristic of individuals with CFS.
• Patients with CFS typically report problems with short-term memory but not long-term memory. They may also report verbal dyslexia that manifests as the inability to find or say a particular word during normal speech. This typically disturbs patients with CFS and may interfere with their occupation.
• Patients with CFS also typically report 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 report fatigue even after prolonged periods of rest or sleep. Patients with CFS do not recharge or arise refreshed after sleeping and rarely rarely have 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 manifests as otherwise unexplained fatigue.
• If the above conditions can be excluded, then the diagnosis of CFS may be considered.

Physical

• Signs of adrenal or thyroid disorders should also exclude a diagnosis of CFS, as the fatigue is explained by endocrinologic factors.
• Similarly, HIV infection and AIDS may also cause chronic fatigue.
• CFS should be diagnosed only after other causes of fatigue are excluded and the fatigue has lasted for at least 6 months. An absence of cognitive difficulties should also exclude a diagnosis of CFS.
• 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.
• Patients with CFS have small, moveable, painless lymph nodes that most commonly involve the neck, axillary region, and/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 common in patients with CFS. However, crimson crescents are not specific for CFS.
• A single lymph node that is very large, tender, or immobile suggests a diagnosis other than CFS. Similarly, generalized adenopathy suggests a diagnosis other than CFS.
• Trigger points, which suggest fibromyalgia, are absent in patients with CFS. CFS and fibromyalgia rarely coexist in the same patient.

Causes

• CFS may be caused by an infection due to a virus (except for EBV) or C pneumoniae.
• Many viruses have been studied as potential causal agents, including EBV, HHV-6, coxsackievirus B, spumaviruses, and even human T-cell leukemia virus strains; however, no definitive causal relationship has been determined.
• Patients with CFS are often referred to an infectious disease specialist because of elevated levels of IgG VCA EBV. Increased IgG titers to the VCA of EBV are common in the general population, regardless of whether the patient is fatigued. 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 infection is often the precipitating event that has triggered the patient's chronic fatigue state.
• Some investigators have suggested that C pneumoniae is the cause of CFS. In hospitals or commercial laboratories, immunoglobulin M (IgM) tests and IgG enzyme-linked immunosorbent assay (ELISA) are used to test for C pneumoniae. As with elevated EBV IgG VCA titers, many individuals in the healthy population have elevated IgG titers to C pneumoniae.
• Some patients with CFS are found to have elevated IgM C pneumoniae titers, indicating a recent C pneumoniae infection, and these patients are the most likely to respond to antichlamydial therapy. However, definitive proof supporting causality is lacking.^{1, 2}
• Some investigators studying the potential role of C pneumoniae in CFS believe that serum tests are insensitive and that a more sensitive test (eg, polymerase chain reaction [PCR]) should be used for evaluation. PCR for C pneumoniae is a very sensitive technique but, unfortunately, is available only in research centers.
• Candida albicans and other yeast infections do not cause CFS.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Chronic fatigue syndrome (CFS) must be differentiated from other disorders that have a fatigue component. CFS is typically easy to differentiate from other causes of CFS based on the presence of cognitive dysfunction, which is absent in almost all other fatigue-producing disorders. Possible differential diagnoses 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 be mistakenly taken as evidence for CFS. As mentioned above, EBV infection may precede CFS but does not cause CFS. Such patients do not present with the physical findings or abnormal laboratory findings that characterize CFS. Such patients also lack the cognitive dysfunction characteristic of CFS.

Lyme disease: CFS is readily differentiated from Lyme disease in various ways. Patients from areas with endemic Lyme disease may have elevated IgG Lyme titers. Few of these patients have neuroborreliosis, which is diagnosed based on measuring cerebrospinal fluid (CSF) and serum IgM and IgG Lyme titers simultaneously. CSF titers that are higher than serum titers indicate neuroborreliosis. Acute Lyme disease usually has 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 usually lack fatigue.

Fibromyalgia: Fibromyalgia does not cause cognitive defects, so it is readily differentiated from CFS. Furthermore, patients with CFS do not have trigger points, which are characteristic of fibromyalgia.

Other diseases may be ruled out based on history, physical, and/or laboratory findings.

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

Laboratory tests have two functions in chronic fatigue syndrome (CFS). First, tests are used to exclude other fatigue-causing diseases, and, second, they may be helpful diagnosing 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. An normal ESR or one that is in the upper reference range suggests another diagnosis.
• 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 percentage or their activity
• CFS laboratory abnormalities are not specific, but, taken together, the abnormalities provide a pattern of consistency with CFS in patients who have a cognitive dysfunction in whom other diseases have been excluded as a cause for their fatigue.
• 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 levels of serum transaminases, alkaline phosphatase, or lactic dehydrogenase should prompt a search for another explanation because these values are typically normal CFS.
• Serum protein electrophoresis is normal in patients with CFS but may be used to rule out other diseases that cause fatigue, including lymphoma and myeloma.
• Urinalysis findings are unremarkable in CFS.

Imaging Studies

• CT scanning or MRI of the brain is useful to rule out CNS disorders in patients with otherwise unexplained CNS symptomatology. Results of CT scans and MRI may be normal in patients with CFS.
• Findings of CNS imaging studies are not specific for CFS and are thus used to rule out alternative explanations rather than to diagnose CFS.
• Positron emission tomography (PET) scans show hypoperfusion in the frontoparietal/temporal region.

Other Tests

• Tilt-table testing became popular after a study showed that one of two large population groups with CFS 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.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

• Because most cases of chronic fatigue syndrome (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 specialists should perform a history and physical examination on patients with possible CFS.

Diet

• No special diet or vitamin supplements are effective.

Activity

• Rest (as needed)
• Moderate activity
• No exercise

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Trials of antiviral agents have been ineffective in relieving the symptoms of chronic fatigue syndrome (CFS). Various medications have been shown to be ineffective, including steroids, liver extract (eg, Kutapressin), chelation therapy, intravenous vitamin therapy, vitamin B-12 therapy, and intravenous or oral vitamin/mineral supplements. Antidepressants have little role in CFS.

Drug Category: Antibiotics

These agents are used in patients with elevated IgM C pneumoniae titers.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Prognosis

• Most cases of chronic fatigue syndrome (CFS) improve to some degree over time.

Patient Education

• Exacerbations are precipitated by stress, exercise, or lack of sleep.
• For excellent patient education resources, visit eMedicine's Mental Health and Behavior Center, Muscle Disorders Center, and Back, Ribs, Neck, and Head Center. Also, see eMedicine's patient education articles Chronic Fatigue Syndrome, Fibromyalgia, and Fatigue.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Be sure to rule out systemic disorders, particularly lymphoreticular malignancies, in patients who present with fatigue.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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Article Last Updated: Jul 16, 2008