Chronic fatigue syndrome

Letters to the Editor

David H. Collier, MD Lela A. Lee, MD Department of Medicine Denver Health Medical Center Departments of Dermatology and Medicine University of Colorado Health Sciences Center Denver, Colorado 1. Kohler PF, Percy J, Campion WM, Smyth CJ. Hereditary angioedema and “familial” lupus erythematosus in identical twin boys. Am J Med. 1974;56:406 – 411. 2. Agnello V. Lupus diseases associated with hereditary and acquired deficiencies of complement. Springer Semin Immunopath. 1986;9:161–178. 3. Brickman CM, Tsokos GC, Balow JE, et al. Immunoregulatory disorders associated with hereditary angioedema. I. Clinical manifestations of autoimmune disease. J Allergy Clin Immunol. 1986;77:749 –757. 4. Donaldson VH, Hess EV, McAdams AJ. Lupus-erythematosus-like disease in three unrelated women with hereditary angioneurotic edema. Ann Intern Med. 1977;86:312– 313. 5. Hochberg MC. The epidemiology of systemic lupus erythematosus. In: Wallace DJ, Hahn BH, eds. Dubois’ Lupus Erythematosus. Baltimore, Md: Williams & Wilkins; 1997:49 – 65. 6. Agnello V. Association of systemic lupus erythematosus and SLE-like syndromes with hereditary and acquired complement deficiency states. Arthritis Rheum. 1978;21: 5146 –5152. 7. Arnett FC, Reveille JD. Genetics of systemic lupus erythematosus. Rheum Dis Clin North Am. 1992;18:865– 891.

CHRONIC FATIGUE SYNDROME To the Editor: Our clinical experience and research in chronic fatigue syndrome has led us to conclusions different from those presented in the article by De Meirleir et al (1) and the accompanying editorials (2,3). In our Psychosomatic Rehabilitation Center, located a few miles from Dr. De Meirleir’s clinic in Brussels, we have seen more than 1,500 patients with chronic fatigue syndrome during the past 5 years, and about 50 of

them had already undergone a “diagnostic” RNase-L test. Throughout the years, we have developed serious doubts about the validity of this test and its discriminative value. For example, some patients with a “positive” test had a history of psychiatric problems, including premorbid depression, while others who attributed their symptoms to a previous viral infection had a “negative” test. The test results failed to predict therapeutic outcomes in patients who followed our comprehensive rehabilitation program. Moreover, we witnessed the potentially detrimental psychological and physical effects of the test: patients with typical symptoms of chronic fatigue syndrome but a negative test often felt confused, fearing the stigma of a psychiatric or— even worse—imaginary illness, and some of those with a positive test— convinced that their illness was “proven”— entered medicolegal disability claims that clearly reinforced their passive-regressive tendencies and hampered attempts at rehabilitation. Given our experience, we disagree with Dr. Komaroff’s editorial (2) in its support of the opposition between “real” (ie, organic, testable) and “imaginary” symptoms. In our view, all symptoms, including psychological or psychiatric distress, have a “real” (neuro)-biological basis, although often not yet clinically testable. Furthermore, we think that mainstream medicine should pay more attention to, and try to integrate, the growing body of psychoneuroendocrinological/immunological research, which suggests, for example, that chronic stress may influence susceptibility to infections (4) and make it more likely that pain becomes a chronic problem (5). On the other hand, we believe that a pure cognitive-behavioral model of chronic fatigue syndrome, which—as rightly stated by Dr. Manu (3)— has proven its therapeutic value, is not free from this duality either: the model focuses on physical avoidance behavior and the somatic attribution August 15, 2000

of symptoms based on an unknown, but most likely psychological or psychiatric, illness. We have recently found empirical support for the pivotal effect of chronic stress in chronic fatigue syndrome (6,7). Our results, which are in accordance with the pathophysiological hypothesis of hypothalamic-pituitary-adrenal axis disturbances (8), make a strong plea for abandoning the fruitless debate about biological versus psychological explanations of chronic fatigue syndrome. A biopsychosocial approach, taking account of predisposing developmental and personality factors, precipitating physical and psychological stresses, cognitive-behavioral and sociocultural maintaining mechanisms, and mediating psychoneuroendocrinological/immunological interactions, should direct our clinical work and future research on chronic fatigue syndrome. Such a multidimensional approach seems to be most promising, not only for understanding these patients’ suffering, but also for designing multimodal rehabilitation programs by which their helplessness may be converted into adequate coping. Boudewijn Van Houdenhove, MD Stefaan Vanthuyne, MD Eddy Neerinckx, PhD Universitaire Ziekenhuizen K.U. Leuven Leuven, Belgium 1. De Meirleir K, Bisbal C, Campine I, et al. A 37 kDA 2–5A binding protein as a potential biochemical marker for chronic fatigue syndrome. Am J Med. 2000;108:99 –105. 2. Komaroff AL. The biology of chronic fatigue syndrome. Am J Med. 2000;108:169 – 171. 3. Manu P. Chronic fatigue syndrome: the fundamentals still apply. Am J Med. 2000; 108:172–173. 4. Grant I. Caregiving may be hazardous to your health. Psychosom Med. 1999 61:420 – 423. 5. Loeser JD, Melzack R. Pain: an overview. Lancet. 1999;353:1607–1609. 6. Van Houdenhove B, Neerinckx E. Victimization in fibromyalgia and chronic fatigue

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Letters to the Editor syndrome in tertiary care: a controlled study on prevalence and characteristics. Psychosom Med. 2000;62:109. 7. Neerinckx E, Van Houdenhove B, Vingerhoets A. Daily hassles reported by chronic fatigue and fibromyalgia syndrome patients in tertiary care: a qualitative and quantitative analysis. Psychosom Med. 2000;62:148. 8. Demitrack MA, Crofford LJ. Evidence for and pathophysiological implications of hypothalamo-pituitary-adrenal axis dysregulation in fibromyalgia and chronic fatigue syndrome. Ann NY Acad Med. 1998; 840:684 – 697.

The Reply: The first paragraph of the letter by Van Houdenhoven et al (1) is unrelated to the article in the Journal, so we will refrain from comment. Moreover, the statements about the 50 patients have not been published in the scientific literature. Some patients with chronic fatigue syndrome, as well as many healthy persons, have experienced severe burdening life events and chronic stress. These experiences should not preclude a diagnosis of chronic fatigue syndrome in patients who fulfill the Centers for Disease Control criteria. Indeed, the definitions of the syndrome by Fukuda et al (2) and Schluederberg et al (3) state that patients with a psychiatric history should not be excluded from the working definition of chronic fatigue syndrome. It is clear that stress can influence the course of disease adversely, as in cancer for example, but do we treat stress instead of the biological correlates in cancer patients? In chronic diseases, coping strategies and psychological support are certainly very important. Although comprehensive rehabilitation programs are beneficial for most chronically ill patients, they do not solve the underlying problem nor do they deal with the cause of disease. The long-term outcome of comprehensive rehabilitation programs for patients with chronic fatigue syndrome remains unproven. The authors assume that RNase-L dysfunction is inherently associated 258

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with a preceding viral infection. However, our observations suggest that while RNase-L may have an effect on chronic fatigue syndrome, they do not suggest that viruses, or a specific immune dysregulation, cause the syndrome. Chronic fatigue syndrome is probably a multifactorial syndrome that involves many dysregulations. Hypothalamic - pituitary-adrenal axis disturbances do not fully explain the clinical picture of chronic fatigue syndrome. Many other central and peripheral hormonal systems (eg, the antidiuretic hormone and renin-angiotensin systems) can be abnormal in these patients. Perhaps there is a defective intracellular response to hormonal stimulation in target cells in these patients. The statements on the etiological role of stress are based only on observational data. Identifying potential biological markers for chronic fatigue syndrome reminds us of the importance of demonstrating that stress-reduction therapies are effective in randomized controlled trials. Kenny De Meirleir, MD, PhD Pascale De Becker, PT Department of Human Physiology and Medicine Vrije Universiteit Brussel Brussels, Belgium 1. De Meirleir K, Bisbal C, Campine I, et al. A 37 kda 2–5A binding protein as a potential biochemical marker for chronic fatigue syndrome. Am J Med. 2000;108:99 –105. 2. Fukuda K, Strauss SE, Hickie I, et al, and the International Chronic Fatigue Syndrome Study Group. The chronic fatigue syndrome. A comprehensive approach to its definition and study. Ann Intern Med. 1994;121:953–959. 3. Schluederberg A, Straus SE, Peterson P, et al. Chronic fatigue syndrome research. Definition and medical outcome assessment. Ann Intern Med. 1992;117:325–331.

The Reply: Doctor Van Houdenhove and colleagues misunderstand my position. Since the beginning of our studies of chronic fatigue syndrome more than a decade ago, I have said that “with

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the chronic fatigue syndrome . . . it may be more productive to avoid the kind of ‘mind-body’ dualism that has characterized much past thinking about the pathogenesis of illness” (1). Moreover, in recent reviews (2,3), I have highlighted the possible effect of stress in making people vulnerable to this illness and the substantial evidence that hypothalamic dysfunction may be the mediator of such stress. Indeed, in the editorial that Dr. Van Houdenhove refers to, I cited a few of the most persuasive studies demonstrating hypothalamic dysfunction in patients with chronic fatigue syndrome. Van Houdenhove and colleagues would have to concede, however, that many patients with chronic fatigue syndrome do not report unusual stressors in the months before the onset of their illness and do not have evidence of hypothalamic dysfunction. Available data do not support the hypothesis that stress leading to hypothalamic dysfunction explains all cases of chronic fatigue syndrome. It must be more complicated than that. I agree with Van Houdenhove and colleagues that “all symptoms . . . have a ‘real’ (neuro)-biological basis,” although that is a difficult proposition to prove. I also agree that the central nervous system and immune system communicate with one another. Indeed, it is plausible that the “immunological” phenomenon reported by DeMeirleir and colleagues is secondary to a primary process in the central nervous system. In summary, the main point of my editorial was that there are objective, measurable, biological perturbations in many patients with chronic fatigue syndrome. In the face of that evidence, the suggestion that these patients are “imagining” their symptoms is unwarranted. The suffering of patients with chronic fatigue syndrome has a real, biological basis— just as Van Houdenhove and colleagues argue—and biologically ori-