The Role of Laboratory Tests in Diagnosis of Chronic Fatigue Syndrome

By Charles W. Lapp, MD
Hunter-Hopkins Center
Duke University

Current diagnosis of chronic fatigue syndrome (CFS) is based primarily on whether or not the patient's symptoms fit the case definition of the condition established by the Centers for Disease Control and Prevention (CDC). So laboratory testing in the person suspected of having CFS should be conducted for two reasons: to exclude other plausible causes for the patient's symptoms and to identify disorders that are con-current or that may contribute to poor health.

The authors of the 1994 CDC criteria for CFS closely studied the tests most helpful in excluding other causes of chronic fatigue and settled on the battery shown below¹.

Unfortunately, there is no one diagnostic test that can be recommended at this time, although research is underway (see "RNase L: Hope for a biomarker"). Some studies have actually demonstrated the futility of performing more extensive studies in making the diagnosis of chronic fatigue syndrome².

Of course, if disorders with overlapping symptoms are suspected, then specific studies should be obtained to confirm or rule out those diagnoses. For example, a person with suspected systemic lupus erythematosis should have antibody and complement studies performed, and a person suspected of multiple sclerosis should have an MRI, lumbar puncture or measurement of evoked potentials.

It is beyond the scope of this article to discuss the differential diagnosis of chronic fatigue syndrome in detail, but the chart below provides a list of diagnoses that have many features in common with CFS, and these should be excluded by history, examination and appropriate testing.

In the past, many researchers tested for immune status, infectious agents and disorders of the endocrine or central nervous systems. However, with experience we have learned that it is no longer necessary to perform such studies unless the patient is clearly informed of the investigational nature of the tests, the testing is done as part of a protocol-based research study or the diagnosis is in question.

We know, for example, that the hypothalamic-pituitary-adrenal axis is suppressed in CFS³, which leads to low 24-hour cortisol levels, flat ACTH response curve, and even low growth hormone (somatomedin, IGF-1) levels. Numerous studies have demonstrated punctate T2 weighted lesions within the cerebral convexities of CFS patients^4,5, and SPECT scanning has repeatedly demonstrated a pathological decrease of blood flow in the cerebrum and mid-brain⁶. We also know that the immune system is characteristically up-regulated in CFS, but that natural killer cell activity is typically low. As a result, latent pathogens may not be fully suppressed, and serology for herpes viruses (like the Epstein Barr virus), chlamydia species or mycoplasma, for example, may show reactivation or positivity more commonly in persons with CFS than in the general population.

So, aside from the exclusionary tests mentioned above, what should you order when CFS is suspected? I personally tend to order an antinuclear antibody (ANA), a Lyme serology (ELISA with a reflex Western Blot for borderline or positive tests), tilt table testing for dysautonomias and polysomnography.

The first two should be strongly considered if there is any suggestion of frank arthritis or the patient has frequented a Lyme-endemic area. The tests are relatively inexpensive and lupus and Lyme disease so closely mimic CFS and are so imminently treatable that the diagnoses should not be missed for the sake of conserving resources.

The downside, however, is that borderline ANA and Lyme ELISA tests are not uncommon in CFS⁷, and such indeterminate results may trigger both anxiety and more indiscriminate testing.

Tilt table testing is used to demonstrate the dysautonomia that occurs in up to 96% of persons with CFS⁸, including neurally mediated hypotension, symptomatic orthostatic tachycardia and milder forms of orthostatic intolerance. These dysautonomias are treatable, and appropriate therapy can significantly reduce the symptoms of CFS. Unfortunately, one cannot clinically predict who will or will not have a positive test, nor can one predict the type of dysautonomia⁹, so virtually all patients can benefit from the study.

Tilt table testing is relatively expensive and must be performed properly at centers with empathy and good understanding of the orthostatic intolerance seen in CFS⁸. Therefore, this procedure may not be available to all patients.

There is a high incidence of sleep apnea and other sleep disorders occurring in conjunction with CFS. The recognition and management of such sleep disorders can markedly improve symptoms and prevent secondary complications, such as weight gain, hypertension and even stroke. Patients at high risk (history of snoring, apneic periods, gasping awake, obesity and hypertension, short neck and/or retrognathism) should be strongly considered for sleep monitoring.

While they are admittedly less accurate than inpatient studies, home sleep monitoring studies can be quite helpful in ruling out sleep apena-they are less expensive, much less intrusive and frequently available from sleep centers. The clinician will have to rely on a history from the patient or family if restless legs, periodic leg movements or myoclonus are suspected, however, because home monitoring generally does not include any muscle monitoring¹¹.

References

1. Fukuda K et al. The chronic fatigue syndrome: a comprehensive approach to its definition and study. Annals of Int Med.1994; 121(12):953-59.
2. Lane TJ, Matthews DA, Manu P. The low yield of physical examinations and laboratory investigations of patients with chronic fatigue. Am J Med Sci.1990;299:313-18.
3. Demitrack MA et al. Evidence for impaired activation of hypothalamic-pituitary-adrenal axis in patients with chronic fatigue syndrome. J Clin Endocrinol Metab.1991;73:1224-34.
4. Buchwald D et al. A chronic illness characterized by fatigue, neurologic and immunologic disorders, and active human herpesvirus type 6 infection. Ann Intern Med.1992:116 (2):103-13.
5. Schwartz RB et al. Detection of intracranial abnormalities in patients with chronic fatigue syndrome: comparison of MR imaging and SPECT. Am J Roentgenology.1994;162:935-41.
6. Schwartz RB et al. SPECT imaging of the brain: comparison of findings in patients with chronic fatigue syndrome, AIDS dementia complex, and major unipolar depression. Am J Roentgenology.1994;162:943-51.
7. Bates DW et al. Clinical laboratory test findings in patients with chronic fatigue syndrome. Arch Int Med.1995;155:97-103.
8. Bou-Holaigah I et al. The relationship between neurally mediated hypotension and the chronic fatigue syndrome. JAMA.1995;274:961-67.
9. Personal communication with Dr. Peter Rowe at Johns Hopkins University, Baltimore, Md.
10. Buchwald D et al. Sleep disorders in patients with chronic fatigue syndrome. Clin Infect Dis.1994;18 (1):568-72.
11. Victor LD. Obstructive sleep apnea. Am Fam Phys.1999;60 (8):2279-86.

Dr. Lapp practices internal medicine at the Hunter-Hopkins Center in Charlotte, North Carolina. He is also a Clinical Associate Professor of Family and Community Medicine at Duke University.