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The Chronic Fatigue Syndrome: A Comprehensive Approach to Its Definition and Study

Keiji Fukuda, MD, MPH; Stephen E. Straus, MD; Ian Hickie, MD, FRANZCP; Michael C. Sharpe, MRCP, MRC Psych; James G. Dobbins, PhD; Anthony Komaroff, MD, International Chronic Fatigue Syndrome Study Group.
[+] Article, Author, and Disclosure Information

From the Centers for Disease Control and Prevention, Atlanta, Georgia; the National Institutes of Health, Bethesda, Maryland; Prince Henry Hospital and University of New South Wales, Sydney, Australia; University of Oxford and Warneford Hospital, Oxford, United Kingdom; and Brigham and Women's Hospital and Harvard University, Boston, Massachusetts. Requests for Reprints: Keiji Fukuda, MD, MPH, Mailstop A15, Division of Viral and Rickettsial Diseases, National Center for Infectious Diseases, Centers for Disease Control and Prevention, 1600 Clifton Road, Atlanta, GA 30333. Acknowledgments: The authors thank Carla Arpino, Judy Basso, Lyria Boast, Janet K. Dale, Karen Ezrine, Marya Grambs, K. Kimberly Kenney, Teruo Kitani, David Klonoff, Dorothy Knight, Gerhard R.F. Krueger, Hirohiko Kuratsune, Gudrun Lindh, Lars Lindquist, Lisa Livens, Alison Mawle, David McCluskey, John O'Connor, Orvalene Prewitt, Bonnie Randall, Karen B. Schmaling, Scott Schmid, John Stewart, Lars Wahlstrom, Denis Wakefield, and Andrew Wilson.

Copyright ©2004 by the American College of Physicians

Ann Intern Med. 1994;121(12):953-959. doi:10.7326/0003-4819-121-12-199412150-00009
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The complexities of the chronic fatigue syndrome and the methodologic problems associated with its study indicate the need for a comprehensive, systematic, and integrated approach to the evaluation, classification, and study of persons with this condition and other fatiguing illnesses. We propose a conceptual framework and a set of guidelines that provide such an approach. Our guidelines include recommendations for the clinical evaluation of fatigued persons, a revised case definition of the chronic fatigue syndrome, and a strategy for subgrouping fatigued persons in formal investigations.

*For a listing of members of the Study Group, see Appendix.


Grahic Jump Location
Figure 1.
A conceptual framework of abnormally fatigued populations, including those with the chronic fatigue syndrome (CFS) and overlapping disorders.
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Figure 2.
Evaluation and classification of unexplained chronic fatigue.

ALT = alanine aminotransferase; BUN = blood urea nitrogen; CBC = complete blood count; ESR = erythrocyte sedimentation rate; PO4 = phosphorus; TSH = thyroid-stimulating hormone; UA = urinalysis.

Grahic Jump Location




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Submit a Comment/Letter
Thiamine anti-metabolites Cause chronic fatigue
Posted on January 23, 2009
Joseph W Arabasz
No Affiliation
Conflict of Interest: None Declared

To Drs. Fukuda, Straus, Hickie, Sharpe, Dobbins, Komaroff, ICFSSGroup, and Editors at AIM:

In reviewing the Center for Disease Control (CDC) Web Site regarding the Chronic Fatigue Syndrome (CFS) and your December 15, 1994 Article, I found some unusual disparities with a modern day workup for that disease. Perhaps it is time to revisit the Diagnostic Criteria for the CFS and its Idiopathic counterpart.

Specifically, I happen to disagree with the opinion that Primary Care Physicians (most likely referring to General Practitioners, Family Practice Physicians, and those Specialists who partake of either of those Clinical Practices) shouldn't obtain a Laboratory Data Base when working up the patients complaint of chronic fatigue. As you are aware, circumstances and serum levels, etc could possibly be altered with time. I would think that obtaining lab values of Thiamine and Niacin would be most important when gotten early, if the Patient is deficient of either of those essential nutrients. Most Patients don't have more than a week's vacation available to them. Delaying a workup for their fatigue would be ill advised. We are all aware that significant deficiencies of Thiamine and/or Niacin cause severe fatigue and dementia.

A second comment on the AIM CFS Article of December 15, 1994 would be that, while there are recommendations for the measurement of about a dozen lab tests, the Thiamine anti-metabolites, oxythiamine, pyrithiamine (aka neopyrithiamine), amprolium, etc, aren't mentioned at all. Laboratory values should be made for their presence or absence with all Thiamine serum measurements. As has been noted, referring to bacteria, most likely after the Publishing of this AIM Article on the CFS, "pyrithiamine pyrophosphate has been shown to bind and activate the thiamin pyrophosphate (TPP) riboswitch, causing the cell to cease the synthesis and import of TPP. Because pyrithiamine pyrophosphate does not substitute for TPP as a coenzyme, the cell dies (1)."

Oxythiamine, which blocks that essential Vitamine B1 Pathway without reducing the serum Thiamine level, must also be sought for or measured. While oxythiamine supposedly doesn't enter through the Blood Brain Barrier (BBB), it therefore causes a milder disease of fatigue without other Neurologic symptoms, as compared to pyrithiamine. However, if the BBB had been previously disrupted with etoh, or a previous exposure to pyrithiamine, then oxythiamine would enter the Cerebral Spinal Fluid (CSF).

And thirdly, I would tend to disagree with the some of the content of the paragraphs titled, "Conditions That Explain Chronic Fatigue" and "Conditions That Do Not Adequately Explain Chronic Fatigue". I don't think that any previously diagnosed medical condition of a psychological nature should pre-empt a proper metabolic workup for the CFS, especially regarding Thiamine and Niacin deficiencies. As noted in the very next paragraph, "Conditions That Do Not Adequately Explain Chronic Fatigue." The comment is made that "the following conditions do not exclude a patient from the diagnosis of unexplained chronic fatigue (1) and is defined primarily by symptoms that cannot be confirmed by diagnostic laboratory tests, including fibromyalgia, anxiety disorders, somatoforms disorders, nonpsychotic or nonmelancholic depression, neurasthenia, and multiple chemical sensitivity disorder."

Note that almost all psychological diagnoses cannot be confirmed by diagnositic laboratory tests. Their possibly erroneous presence shouldn't prevent a proper workup for the CFS. I think it is time to reconsider the Diagnostic Criteria for the CFS, the Workup of which must include measurements of the synthetic Thiamine anti-metabolites that cause fatigue. The same can be said of Niacin, at the very least. Since the blockage of the Thiamine Pathway by its anti-metabolites are competitive inhibitions, then an appropriately administered pharmacological dose of that essential B Vitamin would overcome the block. This adds credence to the comment made by Dr Adelle Davis RD PhD in her 1968 Text, "Let's Get Well," that "once an increased Minimum Daily Requirement (MDR) occurs for a particular Nutrient, it seldom ever returns to normal."

Please note that the unusual practice which seems to be in Vogue with some specialties nowadays to diagnose grammar school children with a psychological illness, would then, according to the Article's criteria, prevent a workup for the CFS later in life. I would suggest that the whole matter of the diagnostic criteria for the CFS be discussed again openly by all of the Medical Community.


1 Riboswitches as antibacterial drug targets, Nature Biotechnology - 24, 1558 - 1564 (2006)< http://en.wikipedia.org/wiki/Riboswitch >

Conflict of Interest:

None declared

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