Association between stressful life events and exacerbation in multiple sclerosis: a meta-analysis
BMJ 2004; 328 doi: https://doi.org/10.1136/bmj.38041.724421.55 (Published 25 March 2004) Cite this as: BMJ 2004;328:731
All rapid responses
When Gasperini and colleagues reported their study of risk factors preceding exacerbation in multiple sclerosis (reference 23 in this meta-analysis), they wrote: ‘No significant differences were found between cases and controls for a single stressful life circumstance; cumulated stressful events were associated with a higher risk for subsequent exacerbation but this did not reach significance.’
However, the forest plot here suggests that the same study has been interpreted as finding that stress does significantly increase the risk of exacerbation, d= 0.42 (95% CI 0.13 to 0.71).
Although the calculations of effect size for this meta-analysis were carried out a long time ago, I’m hoping that it will still be possible to check them. It would be helpful to have this apparent anomaly resolved and, if an error has occurred, to know how much it affects the average effect size.
Competing interests: No competing interests
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
Competing interests: No competing interests
Re: Association between stressful life events and exacerbation in multiple sclerosis: a meta-analysis
I'd like to thank Christopher Martyn for his interest in our paper. Unfortunately, all of the records for this paper, published in 2004, were left at the San Francisco VA Hospital, where I was employed at the time. Being a federal facility, I was not allowed to take data with me. However, looking at the Gasparini paper, I would think that what we did was compared the stressful life events in the the MS cases (22/89) and controls (12/89) only, since we were not interested in non-stress events like infectious diseases, etc. A rough estimate of that proportion comes to d=.42.
Competing interests: No competing interests