Chronic Fatigue Syndrome (CFS) Differential Diagnoses

Updated: May 19, 2017
  • Author: Burke A Cunha, MD; Chief Editor: Michael Stuart Bronze, MD  more...
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Diagnostic Considerations

Chronic fatigue syndrome (CFS) is, in large measure, a diagnosis of exclusion. The key diagnostic task is to differentiate it from other disorders that also have a fatigue component. CFS may be distinguished from other causes of fatigue on the basis of the presence of cognitive dysfunction, which is absent in almost all other fatigue-producing disorders. Once a specific cause of fatigue has been diagnosed, CFS is excluded by definition.

Careful perusal of the Centers for Disease Control and Prevention (CDC) criteria indicates that essentially any chronic illness that produces extensive disability in a setting of persistent fatigue may be included in the differential diagnosis. Conditions that can cause fatigue include the following:

  • Chronic heart disease
  • Psychiatric illnesses
  • Thyroid disease
  • Connective tissue diseases
  • Chronic anemia
  • Neoplastic disease
  • Chronic infections (eg, AIDS)
  • Endocrine diseases (eg, Addison disease)
  • Inflammatory bowel disease
  • Drug abuse
  • Liver disease
  • Renal disease

Patients with psychosomatic disorders may have elevated titers of immunoglobulin G (IgG) to Epstein-Barr virus (EBV) viral capsid antigen (VCA), which may be incorrectly interpreted as evidence for CFS. EBV infection may precede CFS, but it 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.

CFS is readily differentiated from Lyme disease. Patients from areas with endemic Lyme disease may have elevated IgG Lyme titers. Few have neuroborreliosis, which is diagnosed by simultaneously measuring cerebrospinal fluid and serum IgM and IgG Lyme titers. CSF IgM titers that are higher than serum IgM titers indicate neuroborreliosis (if the patient has not been treated with antibiotics). Acute Lyme disease usually has a neurologic component.

Because fibromyalgia does not cause cognitive defects, it is readily differentiated from CFS. Furthermore, patients with CFS do not have the trigger points that are characteristic of fibromyalgia.

It is especially important to rule out systemic disorders, particularly lymphoreticular malignancies, in patients who present with fatigue. Other diseases may be ruled out on the basis of the history, physical examination, or laboratory findings. These other potential causes of fatigue sometimes must be reinvestigated several times.

Differential Diagnoses