10 October 2003
Ian Galea, Yori Gidron and Tracey A. Newman
The front page of the British Medical Journal (20th September 2003) carries the title: "Relapse in multiple sclerosis: stressful life events increase exacerbations". This is an impression which is highly prevalent amongst patients with multiple sclerosis (MS) as well as doctors. Whether it is true or not remains to be proven. Buljevac et al are to be commended on their efforts to identify potential factors associated with relapse in MS (1). In their latest contribution, they present evidence that psychological stress is associated with a doubling in risk of relapse during the ensuing four weeks (2). There are two issues that need to be highlighted. First, this study has limitations, some of which are clearly acknowledged by the authors. Secondly, even if this association is proven to be correct, it does not equate to causality.
Stress was monitored by patient self-reporting on a diary every Sunday, such diaries being collected every eight weeks by the investigators. The most critical limitation of the study is recall bias. Patients having a relapse and filling their diary on Sunday morning are more likely to recall stressful events during the previous weeks as compared to patients who have not had one. A relapse at the time of annotation provides a stimulus to look backwards and try and identify a trigger. Patients experiencing a relapse might have felt a need to explain why it occurred. There is evidence from other pathologies like myocardial infarction that patients commonly attribute their illnesses to psychological factors (3). Given that the diaries were collected every eight weeks, there is always the possibility that patients failed to annotate regularly every Sunday and were instead prompted to fill in their diaries by a relapse, just before appointments or by other circumstantial events. The authors say that they found no evidence of this, though it is not clear how this was or could be definitively established.
Only the windows of three and four weeks after a stressful life event showed a significantly increased risk of exacerbation, while the two and five weeks windows did not. It is interesting to note that the average duration of a stressful event as noted in the diaries was 2.8 weeks. It is not clear whether the "high risk" window was considered to start from the onset or the termination of a stressful life event. In the former case, the termination of the stressful event would be in the week just before the relapse, strengthening the possibility of interference by recall bias.
MS relapse is known to be associated with anxiety, depression and emotional disturbances (4,5). Thus another intrinsic limitation in the study is that the relapse itself is likely to induce negative moods and thus, to alter the patient's perception and recall of events in the previous weeks, secondary to negative affect. This would especially be true in the case of patients with a personality trait of high negative affect (6). Also, it has been noted by Rabins et al that MS patients with cerebral lesions display an enhanced perception of stress compared with patients whose lesions are confined to the spinal cord (7). In this respect it would have been interesting to assess affect with a validated tool on each Sunday and look for correlations between affect and reporting of psychological stress in preceding weeks. A suitable example of such a tool is the PANAS (positive affect negative affect score) which is not time-consuming and is easily self-administered (8).
The association between psychological stress and relapse does not necessarily imply causality. It is important to keep in mind the alternative hypothesis that psychological stress and neurological relapse are different temporally disseminated manifestations of the same underlying disease process. It has been shown that magnetization transfer changes precede the traditional radiological signs accompanying clinically overt neurological relapse by up to 3 months (9,10). Sub-clinical reversible cognitive changes have been observed to accompany relapses (5). There is evidence from an established animal model of multiple sclerosis, experimental allergic encephalomyelitis, that behavioural changes precede motor deficits (11). Thus it is reasonable to suspect that an appreciable number of negative life events could well have occurred as a result of subtle changes in cognition or behaviour preceding an overt clinical relapse. Indeed, several groups have reported the presence of an association between relapse and mild-to-moderate stressful life events (eg job stress, marital conflict) which disappears with major negative life events (eg death in the family) (12-14). The major difference between these two categories of life events is that events in the first category might well occur secondary to changes in daily life management, unlike events in the second category, which are beyond control of the patient. Thus some of the perceived stressful life events become unconventional symptoms of the underlying disease process, on a par with neurological relapse. A more compelling argument for an independent (and perhaps causal) relationship between stressful events and relapse would be made if a holistic indicator of baseline disease severity (such as the Multiple Sclerosis Functional Composite) is included in multivariate analysis of future studies. This situation bears resemblance to a previous study investigating the effect of the psychological response of breast cancer patients on their survival, where adjustment for disease severity led to no effect or strengthening of the observed associations between hopelessness/helplessness or depression and survival (15).
There is evidence that the immunological consequences of stressors depends on their nature: chronic versus acute (16-18) and major versus minor (12-14,19,20). It would thus be interesting to examine the data after dichotomizing stressors on the basis of such characteristics. There is a potential risk that combining all stressors together might not adequately reflect the true relation between stress and relapse.
The association between stress and MS is hard to define given the complexities outlined above. Yet the efforts of Buljevac et al (2003) are welcomed. Their study is an apt reminder of the psychological morbidity accompanying even the early stages of MS, which is eminently neglected by health professionals. On the other hand, this study's impact on the understanding of the pathogenesis of a relapse needs to be assessed with caution. Despite the difficulties of this research there are valuable research tools in the field of psychoneuroimmunology that would provide more objective indicators of stress. Although the human mind, common to both patients and their doctors, is biased towards seeking a cause for every effect, we must resist the temptation to jump into conclusions prematurely. The case supporting a role of stress in precipitating a relapse in multiple sclerosis is far from proven.
Research Assistant & Honorary Specialist Registrar
CNS Inflammation Group, University of Southampton, SO16 7PX Wessex Neurosciences Centre, Southampton General Hospital, SO16 6YD
School of Psychology, University of Southampton, SO17 1BJ
Tracey A Newman
Post Doctoral Scientist
CNS Inflammation Group, University of Southampton, SO16 7PX
1 Buljevac D, Flach HZ, Hop WC, Hijdra D, Laman JD, Savelkoul HF et al. Prospective study on the relationship between infections and multiple sclerosis exacerbations. Brain 2002;125:952-60.
2 Buljevac D, Hop WC, Reedeker W, Janssens AC, van der Meche FG, van Doorn PA et al. Self reported stressful life events and exacerbations in multiple sclerosis: prospective study. BMJ 2003;327:646.
3 Billing E, Bar-On D, Rehnqvist N. Causal attribution by patients, their spouses and the physicians in relation to patient outcome after a first myocardial infarction: subjective and objective outcome. Cardiology 1997;88:367-72.
4 Di Legge S, Piattella MC, Pozzilli C, Pantano P, Caramia F, Pestalozza IF et al. Longitudinal evaluation of depression and anxiety in patients with clinically isolated syndrome at high risk of developing early multiple sclerosis. Mult.Scler. 2003;9:302-6.
5 Foong J, Rozewicz L, Quaghebeur G, Thompson AJ, Miller DH, Ron MA. Neuropsychological deficits in multiple sclerosis after acute relapse. J Neurol Neurosurg Psychiatry 1998;64:529-32.
6 Watson D,.Pennebaker JW. Health complaints, stress, and distress: exploring the central role of negative affectivity. Psychol.Rev 1989;96:234-54.
7 Rabins PV, Brooks BR, O'Donnell P, Pearlson GD, Moberg P, Jubelt B et al. Structural brain correlates of emotional disorder in multiple sclerosis. Brain 1986;109 ( Pt 4):585-97.
8 Watson D, Clark LA, Tellegen A. Development and validation of brief measures of positive and negative affect: the PANAS scales. J Pers.Soc Psychol. 1988;54:1063-70.
9 Filippi M, Rocca MA, Martino G, Horsfield MA, Comi G. Magnetization transfer changes in the normal appearing white matter precede the appearance of enhancing lesions in patients with multiple sclerosis. Ann Neurol 1998;43:809-14.
10 Goodkin DE, Rooney WD, Sloan R, Bacchetti P, Gee L, Vermathen M et al. A serial study of new MS lesions and the white matter from which they arise. Neurology 1998;51:1689-97.
11 Pollak Y, Ovadia H, Goshen I, Gurevich R, Monsa K, Avitsur R et al. Behavioral aspects of experimental autoimmune encephalomyelitis. J Neuroimmunol 2000;104:31-6.
12 Mohr DC, Goodkin DE, Bacchetti P, Boudewyn AC, Huang L, Marrietta P et al. Psychological stress and the subsequent appearance of new brain MRI lesions in MS. Neurology 2000;55:55-61.
13 Nisipeanu P,.Korczyn AD. Psychological stress as risk factor for exacerbations in multiple sclerosis. Neurology 1993;43:1311-2.
14 Sibley WA. Risk factors in multiple sclerosis. In Raine CS, McFarland H.F., Toutellotte WW, eds. Multiple sclerosis: clinical and pathogenetic basis, pp 141-8. London: Chapman & Hall, 1997.
15 Watson M, Haviland JS, Greer S, Davidson J, Bliss JM. Influence of psychological response on survival in breast cancer: a population-based cohort study. Lancet 1999;354:1331-6.
16 Cohen S, Frank E, Doyle WJ, Skoner DP, Rabin BS, Gwaltney JM, Jr. Types of stressors that increase susceptibility to the common cold in healthy adults. Health Psychol. 1998;17:214-23.
17 Dhabhar FS, Satoskar AR, Bluethmann H, David JR, McEwen BS. Stress -induced enhancement of skin immune function: A role for gamma interferon. Proc Natl Acad Sci U S A 2000;97:2846-51.
18 Stefanski V,.Engler H. Effects of acute and chronic social stress on blood cellular immunity in rats. Physiol Behav. 1998;64:733-41.
19 Potter PT,.Zautra AJ. Stressful life events' effects on rheumatoid arthritis disease activity. J Consult Clin Psychol. 1997;65:319-23.
20 Walker JG, Littlejohn GO, McMurray NE, Cutolo M. Stress system response and rheumatoid arthritis: a multilevel approach. Rheumatology.(Oxford) 1999;38:1050-7.
Competing interests: None declared
Copyright © 2003, BMJ