Chronic Fatigue Syndrome (CFS) Research Review

Chronic Fatigue Syndrome (CFS) Research Review updated 16/2/00

Chronic fatigue syndrome (CFS) was first defined in 1988 by the U.S. Centers for Disease Control (CDC)¹ as an illness of at least six months duration which begins suddenly with flu-like symptoms, causes a minimum of 50% reduction in activity, and cannot be explained by alternate medical or psychiatric diagnoses.

Since that time, research has tried to solve the mysteries of CFS. — Such as what causes it, how many people have it, how can we treat it. There is a long way to go — there is still no laboratory marker or universal treatment for CFS — but progress is being made.

Diagnosis

In 1994, the CDC revised its CFS case definition.² Because there is no simple laboratory test that can identify CFS, a physician must exclude other possible causes of the symptoms before diagnosing a patient with CFS.

To meet the definition for CFS, a person must have clinically evaluated, unexplained persistent or relapsing chronic fatigue that is of new or definite onset (i.e., not lifelong), is not the result of ongoing exertion, is not substantially alleviated by rest and results in substantial reduction in previous levels of occupational, educational, social or personal activities. In addition, the person must have at least four of the following symptoms: substantial impairment in short-term memory or concentration; sore throat; tender lymph nodes; muscle pain; multi-joint pain without swelling or redness; headaches of a new type, pattern, or severity; unrefreshing sleep; and post-exertional malaise lasting more than 24 hours.²

Epidemiology

Of every 100,000 Americans, 422 have CFS, and only 10% who meet the definition have been diagnosed ³ It is most common in women (522 cases per 100,000) and minorities, especially Latinos (726 cases per 100,000), but people in all race, age and socioeconomic groups get CFS. Improvement is uncommon, with only 4% of patients recovering and 39% showing some symptom improvement after four years.⁴

Viral Triggers

Because most cases of CFS begin with a flu- or mono-like illness, many viruses, bacteria and toxins have been studied as possible causes of CFS. Most —the most notable being the Epstein-Barr virus — have been excluded because of their relative commonness in the general population and the inability to link any pathogen to all cases CFS. Two pathogens now being studied closely in CFS are the human herpesvirus-6 (HHV-6)^5-9 and Chlamydia pneumoniae.¹⁰ Of particular interest, both have also been linked to multiple sclerosis, an illness that shares many clinical features with CFS. Even so, there is still much debate in scientific circles over whether either of these agents — or any pathogenic agent — will emerge as the only cause of CFS. Current thinking is that there may ultimately be found several triggers of the CFS pathophysiology in genetically, environmentally, or otherwise susceptible individuals ¹¹

Immune Dysregulation

Immune system abnormalities have been found in CFS patients, although none has emerged as a diagnostic marker. The most common findings are diminished natural killer cell function,¹² generalized immune system upregulation,¹³ and dysfunction in the 2-5 A synthetase RNase L antiviral pathway.^14-18

RNase L fights infection by degrading viral RNA. Temple University researchers have found that CFS patients have a novel low molecular weight (37kDa) form of this enzyme and low levels of normal RNase L (8OkDa). Studies are underway to determine if the unique RNase L is present in other diseases and whether it might serve as a marker for CFS. Another new finding of interest is the discovery of autoantibodies to lamin B-1, a component of the cellular structure, which has led to increased speculation that CFS may be an autoimmune disease. ^19-20

Dysautonomia

In 1995, Johns Hopkins researchers reported that up to 95% of CFS patients have neurally mediated hypotension, a condition in which the blood pressure falls when it should rise. ²¹ This has become a dynamic area of CFS research and scientists are actively debating the nature of this and other forms of orthostatic intolerance. ^21-26 Recent studies have focused on three possible keys to understanding orthostatic intolerance in CFS: low blood volume,²⁴ abnormal sympathetic tone,²⁵ and neurological dysfunction. One research group has proposed that the orthostatic intolerance in the most severely ill patients may be caused by low circulating blood volume, while in less ill patients orthostatic intolerance may be related to neurological dysfunction.²⁶

Brain Abnormalities

Abnormalities on brain scans have been reported by several research groups.^27-31 Bright signals in the white matter on MRI have been found in about half of CFS patients. Abnormalities on SPECT scans are more striking, and appear to correlate with clinical status.^27-28 CFS patients show SPECT brain perfusion deficiencies most commonly in the lateral frontal and temporal cortexes and basal ganglia.^27-28 Neuropsychological testing has been helpful in quantifying the disabling cognitive problems patients report^.32-37 Research has shown that the memory and concentration deficits are independent of any depression experienced by CFS patients^32-33and physical and/or mental exertion worsens these symptoms for several days afterward.³⁴

Endocrine Dysfunction

Researchers at the National Institutes of Health attempted to treat low circulating cortisol, which has been found in CFSpatients,^38-39 with hydrocortisone. While two-thirds of treated patients saw symptomatic improvement over the course of the study researchers concluded that hydrocortisone was not an advisable treatment for CFS because of the high risk of adrenal suppression while on this therapy.³⁹

Scientists in the UK have found that CFS patients' with low cortisol have abnormally small adrenal glands.⁴⁰ In CFS patients the adrenal glands are half the size of normal, while in depression they are enlarged up to 70%.

References
1. Holmes, et al: Chronic fatigue syndrome: A working case definition. AnnIntMed 1988;108:387-89.
2. oFukuda, et al.: The CFS: A comprehensive approach to its definition and study. Am IntMedW^, 121:953-59.
3. Jason, et al-: A community-based study of chronic fatigue syndrome. Arch IntMed 1999,159:2129-37.
4. Hill, et al.: Natural history of severe chronic fatigue syndrome. Arch Phys Med Rehab 1999;80:1090-94.
5. Knox, et al.: Persistent active human herpesvirus 6 (HHV-6) infections in patients with CFS. Presented 10/11/98, AACFS Biennial Research Conference, Cambridge, MA.
6. Ablashi, et al.: Increased activation of HHV-6, but not HHV-7 or HHV-8 in CFS patients. Presented 10/11/98, AACFS Biennial Research Conference, Cambridge, MA.
7. DeLuca, et al.: HHV-6 and HHV-7 in CFS. JClinMicro 1995;33:1660-61.
8. Yalcin, et al.: Prevalence of HHV-6 variants A and B in patients with CFS. Microbiol Immunol 1994;38:587-90.
9. Sairenji, et al.: Antibody responses to Epstein-Barr virus, HHV-6 and HHV-7 in patients with CFS. Intervirology 1995 ;3 8:269-73.
10. Mitchell, William M.: Personal correspondence, 9/25/96.
11. Klimas, et al.: Immunologic abnormalities in CFS. J Clin Microbiol 1990:25:1403-10.
12. Komaroff: A 56-year old woman with CFS. JAMA 1997,278:1179-85.
13. Landay, et al.: Chronic fatigue syndrome: clinical condition associated with immune activation. Lancet 1991,338:707-12.
14. Suhadolnik, et al.: Biochemical evidence for a novel low molecular weight 2-5A dependent RNase L in CFS. J Interferes Cytokine Res 1997,17:377-85.
15. Lebleu, et al.: A 2-5A binding polypeptide of 37 kDa as a potential biochemical marker for CFS. JInterferon Cytokine Res 1997,17(S2):S47.
16. Horvath, et al.: Biochemical evidence for a RNase L enzyme dysfunction in individuals with CFS. JInterferon Cytokine Res 1997,17(S2):S104.
17. Suhadolnik, et al.: Biochemical dysregulation of the 2-5A/RNase L antiviral pathway in CFS. Presented 10/11/98, AACFS Biennial Research Conference, Cambridge, MA
18. DeMeirleir K, et al: A 37 kDa 2-5A binding protein as potential biomarker for chronic fatigue syndrome. Am JMed 2000,108:99-105.
19. Mikecz, et al.: High frequency of autoantibodies to insoluble cellular antigens in patients with CFS. Arth Rheum 1997,40:295-30.
20. oTan, et al: Development of an assay to quantitate autoantibodies to lamin Bl in CFS. Presented 10/10/98, AACFS Biennial Research Conference, Cambridge, MA.
21. Bou-Houlaigah, et al.: The relationship between neurally mediated hypotension and the C^S.JAMA 1995,274:961-67.
22. Freeman, Komaroff: Does the CFS involve the autonomic nervous system? Am J Med 1997;102:357-64.
23. Stewart, et al:. Orthostatic intolerance in adolescent CFS. Pediatrics 1999,103:116-21.
24. Streeten, Bell: Circulating blood volume in CFS. JCFS 1998;4:3-11.
25. Furlan, et al.: Chronic orthostatic intolerance: A disorder with discordant cardiac and vascular sympathetic control. Circulation 11/17/98:2154-59.
26. Peckerman, et al.: CFS severity is related to reduced stroke volume and diminished blood pressure responses to mental stress. Presented 10/11/98, AACFS Biennial Research Conference, Cambridge, MA.
27. Schwartz, et al.: Detection of intracranial abnormalities in patients with CFS: comparison of MR imaging and SPECT. Am JRot 1994;162:935-41.
28. Schwartz, et al.: SPECT imaging of the brain: comparison of findings in patients with CFS, AIDS dementia complex, and major unipolar depression. Am J Rot 1994:162:943-51.
29. Mena, Villanueva-Meyer: study of cerebral perfusion by NeuroSPECT in patients with CFS. In: Hyde, et al., eds.: The clinical and scientific basis ofmyalgic encephalomyelitis/CFS. Ottawa: Nightingale Research Foundation, 1992:432-39.
30. Lange, et al.: Neuroimaging in CFS. Am JMed 1998;105(3A):50S-53S.
31. Tirelli, et al.: Brain positron emission tomography (PET) in CFS: preliminary data. Am J Med 1998;105(3A):54S-58S.
32. oChristodoulou, et al.: The relationship between neuropsychological impairment and functional disability in patients with CFS. J Neurol Neurosurg Psychiatry 1998:64:431-34.
33. DeLuca, et al.: Cognitive functioning is impaired in patients with CFS devoid of psychiatric disease. JNeurol Neurosurg Psychiatry 1997 Feb;62(2):151-5.
34. DeLuca, Schmaling: Neurocognitive testing in CFS. JCFS 1995:1:21-26.
35. LaManca, et al.: Influence of exhaustive treadmill testing on cognitive functioning in CYS.AmJMed 1998,105(3A):59S-65S.
36. DeLuca, Johnson: Neuropsychological impairments in CFS, multiple sclerosis and depression. JNeurol Neurosurg Psych 1995:58:38-43.
37. Grafman, et al.: Analysis of neuropsychological function in patients with CFS. J Neurol Neurosurg Psychiatry 1993:56:684-89.
38. Demitrack, et al.: Evidence for impaired activation of the hypothalamic-adrenal-pituitary axis in patients with CFS. JClin Endocrin Metab 1991:73:1224-34.
39. McKenzie, et al.: Low-dose hydrocortisone for treatment of CFS. JAMA 1998,280:1061-66.
40. Scott, et al.: Small adrenal glands in chronic fatigue syndrome: a preliminary computer tomography study. Psychoneuroendocrinology 1999:24:759-68.

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