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The need for more information on the complex relationship between psychological and somatic factors in multiple sclerosis

http://bmj.bmjjournals.com/cgi/eletters/328/7442/731

9 April 2004
BMJ
Christian Schubert - Medical Doctor, Psychologist, Clin. Dep. of Med. Psychology and Psychotherapy, Medical University, A-6020 Innsbruck, Austria,
Willi Geser, Dietmar Fuchs

Dear Editor,

With great interest we read the thorough meta-analysis by Mohr et al. (1) on the association between stressful life events and exacerbation in multiple sclerosis (MS). The main finding from 14 group studies (case control, longitudinal) was a clinically meaningful, significant positive correlation between psychosocial stress and MS disease activity. Nevertheless, there were also heterogeneous results, e.g. the study by Nisipeanu and Korczyn (2) contradicted this main finding.

Nisipeanu and Korczyn (2) demonstrated that MS patients exposed to the threat of missile attacks during the first Gulf War showed significantly fewer MS exacerbations during the war and the following 2 months compared to the preceding 2 years. Mohr et al. (1) ascribed this inconsistency in their meta-analysis to the fact that different types of stressors may have different effects on MS disease activity. Moreover, the pathophysiological mechanisms leading to a decrease in MS activity during and following traumatic stress were attributed to the anti-inflammatory potency of cortisol.

We believe that such inconsistencies in psychosomatic research can better be understood by considering the complex relationship between psychosocial stressors and somatic reactions. We are currently investigating the impact of everyday incidents on the dynamic course of various biochemical parameters in patients with systemic lupus erythematosus (SLE), another autoimmune disease. For this purpose, we have developed an "integrative" research approach based on the assumption that time-series data should not be aggregated across individuals when psychosomatic dynamics are analysed (3).

In order to attain time-series long enough to allow the statistical control of serial dependencies (e.g. trends and cycles), patients collect their entire urine over a period of at least 50 days, in 12-hour intervals, for the analysis of cortisol (RIA) and neopterin (HPLC), a cellular immune parameter and indicator of SLE disease activity (4). Additionally, patients fill out questionnaires and take notes on daily incidents on a 12-hour basis. Each week, they are clinically examined and thoroughly interviewed to discuss the past week's incidents. Then, using various time-series analysis techniques (e.g. ARIMA modelling, cross- correlational analysis), it is possible to determine which variable - psychological or biochemical - precedes another and to identify the temporal lags and complex reaction patterns.

To date, two women with SLE have been investigated using this approach. Both patients showed complex biochemical patterns in response to everyday stressors. Specifically, psychosocial stressors were initially followed by an increase in urine cortisol up to 24 hours later and then by a decrease after a total of 36 hours. Urine neopterin, in these patients, decreased 36 hours later and then increased after a total of 60 hours (3, 5). Moreover, preliminary findings on two healthy women showed that psychosocial stressors were initially followed by a decrease in urine cortisol 12 to 24 hours later and then by an increase after a total of 72 to 84 hours. Urine neopterin increased after 12 hours and then decreased after a total of 48 hours.

Our findings suggest that cortisol and neopterin clinical indicators of both SLE and MS disease activity (6) tend to react to psychosocial stressors in a biphasic or cyclic manner rather than in a monophasic manner. Cyclic responses may be indicators of complex regulatory mechanisms, e.g. feedback mechanisms. Thus, it would hardly be surprising if psychosocial stressors were also shown to be associated with cyclic biochemical fluctuations in MS patients, or even in disease activity. An initial decrease and subsequent increase in MS disease activity over a period of months following traumatic stress might be another explanation for Nisipeanu and Korczyn's findings (2).

Our research suggests that aggregating fluctuating processes across individuals a typical procedure in conventional group studies may result in false or non identified correlations. We agree with the recommendations for future stress research made by Mohr et al. (1). These recommendations could be expanded to include both the personal meaning of stressors and the dynamic interdependencies between psychosocial stressors and illness-associated parameters. This would provide a more accurate understanding of the complex nature of psychosomatic phenomena in future studies.

Christian Schubert, Willi Geser, Dietmar Fuchs Clinical Department of Medical Psychology and Psychotherapy, Innsbruck Medical University, Institute of Psychology, University of Innsbruck, and Institute of Medical Chemistry and Biochemistry, Innsbruck Medical University, Austria Christian.Schubert@uibk.ac.at

References:

1. Mohr DC, Hart SL, Julian L, Cox D, Pelletier D. Association between stressful life events and exacerbation in multiple sclerosis: a meta-analysis. BMJ, doi:10.1136/bmj.38041.724421.55 (published 19 March 2004).

2. Nisipeanu P, Korczyn AD. Psychological stress as a risk factor for exacerbations in multiple sclerosis. Neurology 1993; 43:1311-2.

3. Schubert C, Lampe A, Geser W, Noisternig B, Fuchs D, König P, Chamson E, Schüßler G. Daily psychosocial stressors and cyclic response patterns in urine cortisol and neopterin in a patient with systemic lupus erythematosus. Psychoneuroendocrinology 2003; 28:459-73.

4. Fuchs D, Weiss G, Wachter H. Neopterin, biochemistry and clinical use as a marker for cellular immune reactions. Int Arch Allergy Immunol 1993; 101:1-6.

5. Schubert C, Geser W, Noisternig B, König P, Rumpold G, Lampe A. Stressful life events and skin diseases: an additional perspective from research on psychosomatic dynamics in systemic lupus erythematosus. Psychother Psychosom 2002; 71:123-4.

6. Giovannoni G, Lai M, Kidd D, Thorpe JW, Miller DH, Thompson AJ, Keir G, Feldmann M, Thompson EJ. Daily urinary neopterin excretion as an immunological marker of disease activity in multiple sclerosis. Brain 1997; 120:1-13.

Competing interests: None declared
 

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