Rapid Responses to:

PAPERS: D Buljevac, W C J Hop, W Reedeker, A C J W Janssens, F G A van der Meché, P A van Doorn, and R Q Hintzen Self reported stressful life events and exacerbations in multiple sclerosis: prospective study BMJ 2003; 327: 646 [Abstract] [Full text]

Rapid Responses: Submit a response to this article

Rapid Responses published:

More evidence for the negative relationship between stress and health.

Stephen J Palmer   (20 September 2003)

Cover image has been shown upside down

Sudhir Kumar   (21 September 2003)

Stress and MS: cause-effect shown but dose-effect and mechanisms need further studies

Sudhir Kumar   (22 September 2003)

Inconsequential research

David Barnes   (25 September 2003)

Influence of everyday stressors on biochemical dynamics in systemic lupus erythematosus

Christian Schubert, Willi Geser, Dietmar Fuchs   (30 September 2003)

Stressful life events increase exacerbations in multiple sclerosis: far from proven

IAN GALEA, Ian Galea, Yori Gidron and Tracey A. Newman   (10 October 2003)

More evidence for the negative relationship between stress and health. 20 September 2003
Stephen J Palmer, Director:Centre for Stress Management; Vis. Prof. of Work Based Learning & Stress Management, NCWBLP SE3 7DH Send response to journal: Re: More evidence for the negative relationship between stress and health.	This is one more paper that highlights the negative relationship between stress and health. Eventually it will be difficult for the sceptics to deny the link. Perhaps clients suffering from MS would benefit from some form of stress management programme showing them how to respond less negatively to stressors. Possibly a broad spectrum multimodal cognitive-behavioural approach could be used, focusing on a range of techniques as not all clients respond to cognitive reappraisal interventions. Competing interests:   None declared
Cover image has been shown upside down 21 September 2003
Sudhir Kumar, Consultant Neurologist, Department of Neurological Sciences Christian Medical College Hospital, Vellore, India-632004 Send response to journal: Re: Cover image has been shown upside down	Sir, The cover picture (September 20 issue) shows a T2W FLAIR axial image of brain of a patient with multiple sclerosis. The image has been put upside down (front has become back and vice versa)- therefore, frontal lobe has been shown to be posterior to parietal lobe whereas the reality is just the opposite. Could you please verify whether what I am saying is correct? If it is so, please rectify it. Regards, Dr. Sudhir Kumar Consultant Neurologist, CMC Hospital, Vellore, India-632004 Competing interests:   None declared
Stress and MS: cause-effect shown but dose-effect and mechanisms need further studies 22 September 2003
Sudhir Kumar, Consultant Neurologist, Department of Neurological Sciences Christian Medical College Hospital, Vellore, India-632004 Send response to journal: Re: Stress and MS: cause-effect shown but dose-effect and mechanisms need further studies	Sir, I read with interest the recent paper by Buljevac et al (1). They conclude that stressful life events (SLEs) lead to a twofold increase in the relapse of multiple sclerosis (MS) episodes. I would like to make certain comments. In the study, additional visits were planned after infection or ‘exacerbation’. Ideally, these visits should have been planned within a week of SLEs in order to study its effect on relapse rate of MS. As the authors point out, the diaries may have been filled immediately before the scheduled appointments. Therefore, data regarding SLEs may be ‘retrospective’ in this prospective study. 50 out of 110 eligible patients did not complete the study (37 did not take part and 13 dropped out). This is rather unfortunate as only 55% of patients were available for final analysis. If more had taken part, results may have been different. Patients were asked to write about the stressful events in a diary. However, it is known that writing about the stressful experiences causes a significant symptom reduction of medical diseases such as asthma or rheumatoid arthritis (2). Therefore, effects of stress on MS may have been reduced by the study protocol. Three observations in this study point towards the fact that stress may not be a significant factor in causing relapse in MS: 1)Authors found that stress-related effects were seen three weeks after SLEs and there was no significant effect at two/four/five weeks. This is rather peculiar as effects of stress on immune system start within 24 hours and last for much longer duration. In a previous study, the occurrence of temporal arteritis and/or polymyalgia rheumatica was significantly higher after stress within the past ‘two years’ (3). Similarly, a significant number of patients with psoriasis reported SLEs within ‘three months’ of onset of illness (4). 2)Stress was not related to the third episode of exacerbation (whereas infection was related to the third episode of exacerbation), 3)Multiple stressors (as compared to single stressor) did not increase the risk of relapse or exacerbation. The mechanisms involved in mediating the effects of stress on brain are not fully known. On one hand, stress lowers immunity and leads to an increase in infections. On the other hand, stress causes an increase in the incidence of autoimmune disorders. Dual effects of stress may be related to the type of SLEs and the period they last for. Stress lasting for a shorter or longer duration may have varying effects on immunity. In conclusion, there is convincing evidence today that stress leads to an increase in relapse rate of MS. However, there is a need to compare the effects of 1) different types of stress, and 2) stress of varying duration. We also need to follow up the patients for much longer duration as the effects of stress are long lasting. Additionally, biochemical markers of inflammation such as oligoclonal bands may be measured in cerebrospinal fluid following SLEs. References 1.Buljevac D, Hop WCJ, Reedeker W, Janssens ACJW, van der Meché FGA, van Doorn PA, Hintzen RQ. Self reported stressful life events and exacerbations in multiple sclerosis: prospective study. BMJ 2003; 327:646- 49. 2.Smyth JM, Stone AA, Hurewitz A, Kaell A. Effects of writing about stressful experiences on symptom reduction in patients with asthma or rheumatoid arthritis: a randomized trial. JAMA. 1999; 281: 1304-9. 3.Cenac A, Sparfel A, Amiel-Lebigre F, Cleuziou A, Pennec Y, Le Goff P, et al. Effect of stressful life events on clinical development of temporal arteritis and/or polymyalgia rheumatica. Presse Med. 2002; 31: 873-9. 4.Devrimci-Ozguven H, Kundakci TN, Kumbasar H, Boyvat A. The depression, anxiety, life satisfaction and affective expression levels in psoriasis patients. J Eur Acad Dermatol Venereol. 2000; 14: 267-71. Competing interests:   None declared
Inconsequential research 25 September 2003
David Barnes, semiretired Herts SG12 8RE Send response to journal: Re: Inconsequential research	Again the research work the BMJ reports about MS is as useful as the inconsequential report on midwives which appeared last week. These reports must be valuable in that they affect conduct or they shouldn‘t be published at all. We are now told that stress is likely to cause relapse, but I seem to remember this was being taught in 1966. What stress is, if it has a physical existence at all, and how the pharmacology operates to exacerbate the condition remains obscure if it alters neurones and oligodendrocytes. The heresy of an autoimmune aetiology still appears in this account. Oh for some research which matters. Competing interests:   None declared
Influence of everyday stressors on biochemical dynamics in systemic lupus erythematosus 30 September 2003
Christian Schubert, Medical doctor, psychologist Dep. of Med. Psychology and Psychotherapy, University Hospital Innsbruck, A-6020 Innsbruck, Austria, Willi Geser, Dietmar Fuchs Send response to journal: Re: Influence of everyday stressors on biochemical dynamics in systemic lupus erythematosus	Dear Editor, With great interest we read the article by Buljevac et al. (1) in which the influence of severe life events (major stressors) on the disease activity of multiple sclerosis (MS) was investigated. The study's approach goes beyond conventional study designs in that it applies both frequent prospective sampling and self reports (diaries) of exposure to emotional stress in order to consider temporal aspects as well as the personal relevance of life events. A further refinement of this approach using a more differentiated measurement of life events might lead to an even better understanding of the relationship between psychosocial stress and disease activity in MS. Stressful events, for example, may be anticipated by patients, thus resulting in an increase in disease activity before the actual event occurs; events can also be difficult to cope with, leading to a specific temporal delay in somatic effects. Such events, however, may relate to personally meaningful themes and conflicts that patients do not want to or cannot easily speak or write about. Consequently, identifying life events can be a difficult task. Self reports tend not to cover the full range of events and, therefore, should be supplemented by interviews (2). In our research, we apply a differentiated approach to psychosocial data. Using an "integrative" design, we are currently investigating the influence of everyday stressors (minor stressors) on the dynamic course of endocrinological and immunological parameters in patients with systemic lupus erythematosus (SLE), another autoimmune disease. A woman with SLE collected her entire urine during 56 consecutive days, in 12-hour intervals. The urine samples were analyzed for the stress hormone cortisol (RIA) and the immune marker neopterin (HPLC) (3). Neopterin is released by macrophages during cell-mediated (Th1-type) immune response and has been identified as a reliable indicator of disease activity in SLE as it is in MS (4, 5). In parallel, the patient answered questionnaires and took notes on daily incidents, both in 12-hour intervals. Once a week, the patient was clinically examined and interviewed to discuss the past week's incidents. At the end of the study period, all daily incidents were independently rated according to various criteria (e.g. stress intensity, anticipation, thematic content and personal meaning), and the interdependencies between psychosocial, psychological and biochemical time -series were statistically determined using ARIMA modeling and cross- correlational analyses. Statistical analyses showed that everyday stressors were associated with cyclic response patterns in both urine cortisol and urine neopterin. Specifically, whenever the patient anticipated a "moderately stressful" incident, urine cortisol initially increased 24 hours before the incident and then decreased 12 hours before the incident. In turn, "moderately stressful" incidents not anticipated by the patient were associated first with an increase in urine cortisol 24 hours following the incident and then by a decrease in urine cortisol after a total of 36 hours. Furthermore, "emotionally painful" incidents associated with one specific theme, the patient's extramarital relationship, were associated with an initial decrease in urine neopterin 36 hours later and then with an increase after a total of 60 hours (all p <0.05). The cyclic biochemical reaction patterns found in our study may be indicators of adaptive response to psychosocial stressors. Specifically, stressors may have caused deviations from normal biochemical functioning, leading to an activation of counter-regulating mechanisms (feed-back loops) to re-establish systemic equilibrium. In summary, our study shows that even minor incidents such as everyday stressors can lead to alterations in disease-associated parameters in SLE, and we conjecture that major stressors such as severe life events can trigger serious clinical SLE exacerbations as it has been demonstrated to be the case in MS (1). These interrelationships could be of special relevance in several diseases with immunopathogenetic background. Christian Schubert, Willi Geser, Dietmar Fuchs Department of Medical Psychology and Psychotherapy, Institute of Psychology, and Institute of Medical Chemistry and Biochemistry, University of Innsbruck, Austria Christian.Schubert@uibk.ac.at References: 1. Buljevac D, Hop WCJ, Reedeker W, Janssens ACJW, van der Meché FGA, van Doorn PA, Hintzen RQ. Self reported stressful life events and exacerbations in multiple sclerosis: prospective study. BMJ 2003; 327:646- 49. 2. Brown GW, Harris TO. Life events and illness. New York: Guilford Press. 1989, pp. 3-45. 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. 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
Stressful life events increase exacerbations in multiple sclerosis: far from proven 10 October 2003
IAN GALEA, Research Assistant CNS Inflammation Group, School of Biological Sciences, University of Southampton, SO16 1PX, UK, Ian Galea, Yori Gidron and Tracey A. Newman Send response to journal: Re: Stressful life events increase exacerbations in multiple sclerosis: far from proven	EDITOR - 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. Ian Galea Research Assistant & Honorary Specialist Registrar CNS Inflammation Group, University of Southampton, SO16 7PX Wessex Neurosciences Centre, Southampton General Hospital, SO16 6YD Yori Gidron Senior Lecturer 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