Self reported stressful life events and exacerbations in multiple sclerosis:prospective study
BMJ 2003; 327 doi: https://doi.org/10.1136/bmj.327.7416.646 (Published 18 September 2003) Cite this as: BMJ 2003;327:646All rapid responses
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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="the" cyclic="cyclic" biochemical="biochemical" reaction="reaction" patterns="patterns" found="found" in="in" our="our" study="study" may="may" be="be" indicators="indicators" of="of" adaptive="adaptive" response="response" to="to" psychosocial="psychosocial" stressors.="stressors." specifically="specifically" stressors="stressors" have="have" caused="caused" deviations="deviations" from="from" normal="normal" functioning="functioning" leading="leading" an="an" activation="activation" counter-regulating="counter-regulating" mechanisms="mechanisms" feed-back="feed-back" loops="loops" re-establish="re-establish" systemic="systemic" equilibrium.="equilibrium." p="p"/> 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
Competing interests: No competing interests
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
Competing interests: No competing interests
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
Competing interests: No competing interests
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
Competing interests: No competing interests
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
Competing interests: No competing interests
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
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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,
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9 Filippi M, Rocca MA, Martino G, Horsfield MA, Comi G. Magnetization
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10 Goodkin DE, Rooney WD, Sloan R, Bacchetti P, Gee L, Vermathen M et
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11 Pollak Y, Ovadia H, Goshen I, Gurevich R, Monsa K, Avitsur R et
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13 Nisipeanu P,.Korczyn AD. Psychological stress as risk factor for
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14 Sibley WA. Risk factors in multiple sclerosis. In Raine CS,
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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.
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Competing interests:
None declared
Competing interests: No competing interests