Date sent:      	Fri, 25 May 2001

Journal of the Amarican Medical Association (JAMA)
Vol 285, No 20, pp 2557-2559
May 23/30 2001

URL:    http://jama.ama-assn.org/pi/                                (JAMA archive)
        http://jama.ama-assn.org/issues/v285n20/rfull/jct00014.html (html version)
        http://jama.ama-assn.org/issues/v285n20/rpdf/jct00014.pdf    (pdf version)

[Linking Evidence and Experience]


Chronic Fatigue Syndrome
------------------------

Benjamin H. Natelson, MD

Author Affiliations: Chronic Fatigue Syndrome Cooperative Research Center,
  Department of Neurosciences, University of Medicine and Dentistry of New
  Jersey-New Jersey Medical School, Newark; and Veterans Affairs Medical Center, East
  Orange, NJ.
Corresponding Author and Reprints: Benjamin H. Natelson, MD, Fatigue Research
  Center, New Jersey Medical School, 88 Ross St, East Orange, NJ 07018 (e-mail:
  bhn@njneuromed.org).
Contempo Updates Section Editors: Stephen J. Lurie, MD, PhD, Senior Editor;
  Alice T. D. Hughes, MD, Fishbein Fellow.

--------------------------------------------------------------------------------

Chronic fatigue syndrome (CFS), like fibromyalgia and multiple chemical
sensitivity, comprises a number of poorly understood signs and symptoms, and
whether a patient receives the diagnosis for one or another of these symptom
clusters may depend on the specialty of the physician making the diagnosis.1
Patients with CFS also often fulfill case definitions for these other
illnesses.1 This overlap suggests that these "functional somatic illnesses"
may be variants of one another.2 However, this does not necessarily mean that
these syndromes share the same pathobiological processes or causes. For
example, patients with fibromyalgia have been found to have elevated levels of
substance P in spinal fluid3 and reduced pain thresholds, while patients with
CFS have not.4 Similarly, the fatigue reported by patients with fibromyalgia
may be secondary to chronic sleep disruption because of pain, while fatigue
may be primary in CFS.

The case definitions for CFS5, 6 reflect the observation that the severe
fatigue and influenza-like symptoms, which often begin suddenly, were
initially thought to represent an underlying viral infection. Thus, the
diagnosis requires at least 6 months of new-onset symptoms of fatigue
accompanied by infectious, rheumatological, and neuropsychiatric symptoms, and
which cannot be explained by other medical diagnoses. In the United States,
CFS has a prevalence of 0.52% in women and 0.29% in men.7 Patients with CFS
may experience severe disability; one study reported that patients with CFS
have lower self-reported functional status than a group of similar patients
with congestive heart failure.8 In this article, I review the evidence for
several proposed hypotheses about the etiology of CFS.


Viral and Immunological Factors

The initial hypothesis that CFS represents a form of chronic Epstein-Barr
virus (EBV) infection was abandoned when it was found that elevated EBV
titers, which reflect prior infection, are not uncommon in healthy people
without CFS.9 Similarly, there are no convincing data that other infectious
agents are associated with CFS. On the other hand, acute infections can evolve
into CFS and an influenza-like onset of CFS is more common in the winter than
in other seasons.10 A postviral syndrome that appears similar to CFS is not
uncommon following infectious mononucleosis11 and severe viral infection,12
but persistence of an infectious agent in CFS has not been demonstrated.

Another hypothesis proposes that acute infection may lead to CFS via sustained
immunological activation or dysregulation, rather than through persistent
infection. Although a number of studies have found some form of immune
activation in patients with CFS, these results have been inconsistent.13
Rather than causing CFS, such changes may reflect other consequences of CFS,
such as inactivity, disturbed sleep, and chronic stress. For instance, 1 study
found no evidence of immunological dysfunction in a group of patients with CFS
who had been matched with a control group that was equally sedentary.14
Despite this negative result, some data do support an underlying immunological
problem.15 For instance, some patients with CFS have a dysregulated 2,5
ribonuclease-L antiviral defense pathway16 and treatment with an immune active
agent, mismatched RNA, may reduce disability.17


Psychiatric and Social Factors

A different set of hypotheses proposes that CFS may reflect depression or
other psychiatric illness. Patients with CFS and major depression, however,
appear to have different profiles from patients with only major depression.
Patients with CFS have less self-reproach and more somatic symptoms than do
depressed patients,18 less personality disturbance,19 and different
immunological profiles.20 They are also more likely to display down-regulation
of the pituitary-adrenal axis21 rather than the up-regulation that often
occurs in depression.

Another explanation for CFS is that it is a form of somatization disorder,
which may be diagnosed in patients with many years of multiple system
complaints without an obvious organic basis. However, this diagnosis is
subject to the bias of the examiner. Clinicians who do not believe that CFS
has an organic basis are more likely to diagnose somatization disorder among
such patients even if they do not meet Diagnostic and Statistical Manual of
Mental Disorders, Fourth Edition criteria for somatization disorder. In fact,
as few as 5% of patients with CFS may meet these strict criteria for
somatization disorder.22 This implies, for instance, that a physician could
appropriately diagnose somatization disorder in a patient with lifelong
multisystem symptoms, but not in the more common case of a previously
asymptomatic patient who complains of persisting and debilitating systemic
symptoms following an acute influenza-like illness.

Another study23 used factor analysis of self-reported symptoms to define CFS
and found approximately that one fourth of patients with CFS reported a large
number of symptoms and had a high probability of also having other major
psychiatric disorders. The remaining patients had both fewer symptoms and less
psychopathology. These and similar results have led to suggestions that the
case definition for CFS be changed to include only patients with relatively
few somatic symptoms.24 Although this strategy would exclude patients who
endorse multiple somatic symptoms, it is not known whether it would also
exclude patients with somatization disorder or CFS.

Regardless of the diagnostic label, many patients with CFS have psychiatric
comorbidity. Clinical experience suggests that treating comorbid psychiatric
conditions may relieve these psychiatric symptoms, but does not alter the
somatic symptoms; nonetheless, patients with CFS who receive antidepressants
for at least 6 months have reduced costs in medical care.25

Wessely et al26 have described a "cognitive behavioral" model that emphasizes
the importance of psychological factors in influencing recovery from CFS. They
argue that personality factors can interact with illness triggers and
subsequent deconditioning to affect the duration of illness. Thus, patients
with a tendency to have mood problems or to amplify somatic sensations might
become worried about activity-related symptoms following a viral illness and
thus further reduce their activity. In terms of beliefs about illness, the
prognosis is less favorable when patients make catastrophic statements about
their condition or attribute their illness solely to physical factors, such as
viral infection, rather than to stress or psychological factors.26

If beliefs, attributions, and fears are important in maintaining a state of
chronic fatigue, then treatments aimed at altering these thought processes
should improve the health of patients with CFS. Sharpe et al27 and Deale et
al28 have reported that cognitive behavioral therapy (CBT) led to improved
clinical outcomes in patients with CFS.

While these results support the role of beliefs in maintaining illness in CFS,
this does not mean that CFS is necessarily psychological in origin. For
instance, CBT can improve the symptoms of patients with other chronic diseases
such as rheumatoid arthritis.29 Furthermore, CBT is not always effective in
treating CFS30, 31 and its efficacy may be greater in treating patients who
are at a relatively low functional level because of a possible "ceiling
effect" for high-functioning patients.32 Thus, while some patients may have
cognitive and behavioral factors that impede recovery, this is not necessarily
true for every patient with CFS.


Orthostatic Intolerance

Although an initial study using tilt testing found that a majority of patients
with CFS developed delayed orthostatic hypotension that could be reversed with
fludrocortisone, beta -blockade, or disopyramide,33 a subsequent
placebo-controlled trial did not find a therapeutic effect of
fludrocortisone.34 Furthermore, 2 controlled studies found no difference in
orthostatic intolerance between unmedicated patients with CFS and sedentary
healthy control subjects.35, 36 One of these studies35 found that patients
with CFS had lower cardiac stroke volumes, even in baseline conditions.
Whether this finding might indicate covert cardiac dysfunction37 or reduced
blood volume38 remains unknown.

Although tilt testing is not a sensitive way to diagnose orthostatic
intolerance in CFS, it may be reasonable to monitor heart rate and blood
pressure after 5 minutes of supine rest and then every minute for 5 to 10
minutes of standing, as some patients may show a dramatic postural tachycardia
or other orthostatic change within this brief time frame.39, 40 If either
change is present, it may be reasonable to observe if treatment with beta
-blockade, an alpha -agonist, or intravascular volume expansion relieves the
patient's fatigue symptoms. Tilt table testing may be a better diagnostic tool
for adolescents than for adults. A recent controlled study found that 11- to
19-year-old patients with CFS were highly sensitive to orthostatic
challenge.41


Covert Encephalopathy

Patients with CFS appear to have significant cognitive abnormalities42 and
those without psychiatric comorbidity may have the greatest degree of
cognitive dysfunction.43 The degree of cognitive abnormality in such patients
also appears to be directly related to the amount of impairment in functional
status.44 A follow-up study found that among patients with CFS and no
psychiatric codiagnosis, 66% had abnormalities on a magnetic resonance image
of the brain vs 30% of the patients with CFS and a psychiatric codiagnosis,
and vs 22% of those in the control group.45 The abnormalities were generally
subtle and the most common finding was small T2-weighted lesions in the
frontal lobes.

These abnormalities appeared to have functional significance in that the
patients with these abnormalities reported significantly poorer physical
functioning on the Medical Outcomes Study Short-Form 36 Health Status Survey,
a common disability assessment tool.46 As a whole, these studies suggest that
some patients with CFS, principally those without concurrent psychopathology,
may have subtle encephalopathy.


Future Directions

Advances in understanding CFS are impeded by at least 3 factors. First,
researchers tend to test their favorite theories and rarely perform
confirmatory studies. Second, studies often compare data from inactive
patients to healthy subjects who might be extremely active and thus
differences between groups could reflect activity level or fitness rather than
underlying disease. Finally, patients with CFS are a heterogeneous group with
frequent comorbid diagnoses (eg, depression, fibromyalgia, irritable bowel
syndrome) whose presence could alter study outcomes. Use of stratification
strategies to control for such comorbid conditions would address the inherent
heterogeneity of such samples47 and would help to isolate possible organic
etiologies in subgroups of patients with CFS symptoms.


Funding/Support:

This work was supported by National Institutes of Health Center grant AI32246.


References


 1. Buchwald D, Garrity D.
    Comparison of patients with chronic fatigue syndrome, fibromyalgia, and
    multiple chemical sensitivities. Arch Intern Med. 1994;154:2049-2053.
 2. Wessely S, Nimnuan C, Sharpe M. Functional somatic syndromes: one or many?
    Lancet. 1999;354:936-939.
 3. Russell IJ, Orr MD, Littman B, et al. Elevated cerebrospinal fluid levels of
    substance P in patients with the fibromyalgia syndrome. Arthritis Rheum.
    1994;37:1593-1601.
 4. Evengard B, Nilsson CG, Lindh G, et al. Chronic fatigue syndrome differs from
    fibromyalgia: no evidence for elevated substance P levels in cerebrospinal
    fluid of patients with chronic fatigue syndrome. Pain. 1998;78:153-155.
 5. Holmes GP, Kaplan JE, Gantz NM, et al. Chronic fatigue syndrome: a working
    case definition. Ann Intern Med. 1988;108:387-389.
 6. Fukuda K, Straus SE, Hickie I, et al. The chronic fatigue syndrome: a
    comprehensive approach to its definition and study. Ann Intern Med. 1994;
    121:953-959.
 7. Jason LA, Richman JA, Rademaker AW, et al. A community-based study of chronic
    fatigue syndrome. Arch Intern Med. 1999;159:2129-2137.
 8. Komaroff AL, Fagioli LR, Doolittle TH, et al. Health status in patients with
    chronic fatigue syndrome and in general population and disease comparison
    groups. Am J Med. 1996;101:281-290.
 9. Gold D, Bowden R, Sixbey J, et al. Chronic fatigue: a prospective clinical
    and virologic study. JAMA. 1990;264:48-53.
10. Zhang Q, Natelson BH, Ottenweller JE, et al. Chronic fatigue syndrome
    beginning suddenly occurs seasonally over the year. Chronobiol Int.
    2000;17:95-99.
11. White PD, Thomas JM, Amess J, et al. Incidence, risk and prognosis of acute
    and chronic fatigue syndromes and psychiatric disorders after glandular fever. Br
    J Psychiatry. 1998;173:475-481.
12. Hotopf M, Noah N, Wessely S. Chronic fatigue and minor psychiatric morbidity
    after viral meningitis: a controlled study. J Neurol Neurosurg Psychiatry.
    1996;60:504-509.
13. Strober W. Immunological function in chronic fatigue syndrome. In: Straus S,
    ed. Chronic Fatigue Syndrome. New York, NY: Marcel Dekker Inc; 1994:207-237. 14.
Zhang Q, Zhou X, Denny T, et al. Changes in immune parameters in Gulf War
    veterans but not in civilians with chronic fatigue syndrome. Clin Diagn Lab
    Immunol. 1999;6:6-13.
15. Von Mikecz A, Konstantinov K, Buchwald DS, Gerace L, Tan EM. High frequency
    of autoantibodies to insoluble cellular antigens in patients with chronic
    fatigue syndrome. Arthritis Rheum. 1997;40:295-305.
16. DeMeirleir K, Bisbal C, Campine I, et al. A 37 kDa 25A binding protein as a
    potential biochemical marker for chronic fatigue syndrome. Am J Med. 2000;
    108:99-105.
17. Strayer DR, Carter WA, Brodsky I, et al. A controlled clinical trial with a
    specifically configured RNA drug, poly(I) poly(C12U), in chronic fatigue
    syndrome. Clin Infect Dis. 1994;18(suppl 1):S88-S95.
18. Johnson SK, DeLuca J, Natelson BH. Depression in fatiguing illness: comparing
    patients with chronic fatigue syndrome, multiple sclerosis and depression.
    J Affect Disord. 1996;39:21-30.
19. Johnson SK, DeLuca J, Natelson BH. Personality dimensions in the chronic
    fatigue syndrome: a comparison with multiple sclerosis and depression.
    J Psychiatr Res. 1996;30:9-20.
20. Natelson BH, Denny T, Zhou XD, et al. Is depression associated with immune
    activation? J Affect Disord. 1999;53:179-184.
21. Scott LV, Dinan TG. The neuroendocrinology of chronic fatigue syndrome: focus
    on the hypothalamic-pituitary adrenal axis. Funct Neurol. 1999;14:3-11.
22. Johnson SK, DeLuca J, Natelson BH. Assessing somatization disorder in the
    chronic fatigue syndrome. Psychosom Med. 1996;58:50-57.
23. Hickie I, Lloyd A, Hadzi-Pavlovic D, Parker G, Bird K, Wakefield D. Can
    chronic fatigue syndrome be defined by distinct clinical features? Psychol
    Med. 1995;25:925-935.
24. Katon W, Russo J. Chronic fatigue syndrome criteria: a critique of the
    requirement for multiple physical complaints. Arch Intern Med. 1992;152:1604-
    1609.
25. Thompson D, Hylan TR, McMullen W, Romeis ME, Buesching D, Oster G.
    Predictors of a medical-offset effect among patients receiving antidepressant
    therapy. Am J Psychiatry. 1998;155:824-827.
26. Wessely S, Hotopf M, Sharpe M. Chronic Fatigue and Its Syndromes. London,
    England: Oxford University Press; 1998.
27. Sharpe M, Hawton K, Simkin S, et al. Cognitive behaviour therapy for the
    chronic fatigue syndrome: a randomised controlled trial. BMJ. 1996;312:22-26. 28.
Deale A, Chalder T, Marks I, Wessely S. Cognitive behavior therapy for chronic
    fatigue syndrome: a randomized controlled trial. Am J Psychiatry. 1997;154:
    408-414.
29. Parker JC, Iverson GL, Smarr KL, Stucky-Ropp RC. Cognitive-behavioral
    approaches to pain management in rheumatoid arthritis. Arthritis Care Res.
    1993;6:207-212.
30. Lloyd AR, Hickie I, Brockman A, et al. Immunologic and psychologic therapy for
    patients with chronic fatigue syndrome: a double-blind, placebo controlled
    trial. Am J Med. 1993;94:197-203.
31. Friedberg F, Krupp LB. A comparison of cognitive behavioral treatment for
    chronic fatigue syndrome and primary depression. Clin Infect Dis. 1994;18(suppl
    1):S105-S110.
32. Friedberg F. A subgroup analysis of cognitive behavioral treatment studies.
    J Chronic Fatigue Syndr. 2000;5:149-159.
33. Bou-Holaigah I, Rowe PC, Kan J, Calkins H. The relationship between neurally
    mediated hypotension and the chronic fatigue syndrome. JAMA. 1995;274:961-967.
34. Rowe PC, Calkins H, DeBusk K, et al. Fludrocortisone acetate to treat neurally
    mediated hypotension in chronic fatigue syndrome: a randomized controlled
    trial. JAMA. 2001;285:52-59.
35. LaManca JJ, Peckerman A, Walker J, et al. Cardiovascular response during
    head-up tilt in chronic fatigue syndrome. Clin Physiol. 1999;19:111-120.
36. Poole J, Herrell R, Ashton S, Goldberg J, Buchwald D. Results of isoproterenol
    tilt table testing in monozygotic twins discordant for chronic fatigue
    syndrome. Arch Intern Med. 2000;160:3461-3468.
37. Lerner AM, Goldstein J, Chang C, et al. Cardiac involvement in patients with
    chronic fatigue syndrome as documented with Holter and biopsy data in
    Birmingham, Michigan, 1991-1993. Infect Dis Clin Pract. 1997;6:327-333.
38. Streeten DHP, Bell DS. Circulating blood volume in chronic fatigue syndrome.
   J Chronic Fatigue Syndr. 1998;4:3-11.
39. Schondorf R, Benoit J, Wein T, Phaneuf D. Orthostatic intolerance in the
    chronic fatigue syndrome. J Auton Nerv Syst. 1999;75:192-201.
40. Streeten DHP, Anderson GH. The role of delayed orthostatic hypotension in the
    pathogenesis of chronic fatigue. Clin Auton Res. 1998;8:119-124.
41. Stewart JM, Gewitz MH, Weldon A, Arlievsky N, Li K, Munoz J. Orthostatic
    intolerance in adolescent chronic fatigue syndrome. Pediatrics. 1999;103:
    116-121.
42. DeLuca J, Johnson SK, Beldowicz D, Natelson BH. Neuropsychological
    impairments in chronic fatigue syndrome, multiple sclerosis, and depression. J
    Neurol Neurosurg Psychiatry. 1995;58:38-43.
43. DeLuca J, Johnson SK, Ellis SP, Natelson BH. Cognitive functioning is impaired
    in chronic fatigue syndrome patients devoid of psychiatric disease. J Neurol
    Neurosurg Psychiatry. 1997;62:151-155.
44. Christodoulou C, DeLuca J, Lange C, et al. Relation between neuropsychological
    impairment and functional disability in patients with chronic fatigue
    syndrome. J Neurol Neurosurg Psychiatry. 1998;64:431-434.
45. Lange G, DeLuca J, Maldjian JA, Lee HJ, Tiersky LA, Natelson BH. Brain MRI
    abnormalities exist in a subset of patients with chronic fatigue syndrome.
    J Neurol Sci. 1999;171:3-7.
46. Cook DB, Lange G, DeLuca J, Natelson BH. Relationship of brain MRI
    abnormalities and physical functional status in CFS. Int J Neurosci. 2001;
    107:1-6.
47. Natelson BH. Facing and Fighting Fatigue: A Practical Approach. New Haven,
    Conn: Yale University Press; 1998.

--------
(c) 2001 American Medical Association