Ackerman, Kurt D. MD, PhD; Heyman, Rock MD; Rabin, Bruce S. MD, PhD; Anderson, Barbara P. PhD; Houck, Patricia R. MSH; Frank, Ellen PhD; Baum, Andrew PhD
EDSS = Expanded Disability Status Scale;, LEDS = Life Events and Difficulties Schedule;, MS = multiple sclerosis.
A controversial issue in multiple sclerosis (MS) research concerns the extent to which psychological stress contributes to the development and progression of the disorder. Several studies have suggested that stress is a potent trigger for MS disease activity (1–4), but other studies either have failed to confirm this relationship (5) or have shown a protective role for stress (6, 7). This discrepancy may be the result of a number of research design problems, including infrequent monitoring of patients, subjective reporting bias, and lack of adequate controls. In the current study we addressed these issues in a longitudinal prospective study of patients with MS. A significant prospective association between stressful life events and MS exacerbations would suggest that stress plays a causal role in these episodes and would provide further insight into factors that govern the direction and extent of this relationship.
Twenty-three patients with relapsing-remitting MS participated in the study for 1 year. Given the relatively small sample size, only women were included. MS patients were recruited from the Multiple Sclerosis Clinic of the University of Pittsburgh Medical Center. They were informed that the study involved the exploration of factors associated with MS exacerbations, including drug and alcohol use, infections, depression, hormone and immune changes, and stressful life events. It was emphasized that individuals vary in their susceptibility to environmental and biological triggers and that the primary aim was to develop a risk profile for the development of MS exacerbations. All participants provided written informed consent under the guidelines of the University of Pittsburgh’s Institutional Review Board for Human Subjects Experimentation.
Participants were medically healthy except for the presence of MS. They all had clinically definite MS of the relapsing-remitting or secondary-progressive subtypes, according to Poser criteria (8). At entry into the study, participants were in remission and had not been treated with corticosteroids for at least 2 months. Because the great majority of MS patients are currently receiving disease-modifying therapy such as interferon-β or glatiramer acetate (copolymer), subjects were permitted to remain on these medications. However, subjects who altered their immunomodulatory regimen during the study were withdrawn at that time.
Assessment of Stressful Life Events
We used two methods to identify and characterize stressful life events. Each week participants completed the Psychiatric Epidemiologic Research Interview (9), a self-report scale of 102 potential life events. These questionnaires were reviewed with the subject every 4 weeks to gather additional details about the nature and timing of events. This information was then used to suggest additional areas for exploration during the Bedford College Life Events and Difficulties Schedule (LEDS) interview (10), performed at both the beginning and end of the study. The LEDS technique initially involves an extensive semistructured interview designed to probe a wide variety of potential stressors. The interviewer then compiles a narrative account of each endorsed event, which was rated by a consensus group using a “dictionary” of several thousand event examples provided by Brown and Harris. Short- and long-term threats for each event were rated on a 4-point scale, with a rating of 1 corresponding to the most severe threat. In the LEDS technique, short-term threat is defined as the threat experienced at the time of the event, whereas long-term threat reflects the subject’s experience 2 weeks after a life event. Representative short-term stressors for this cohort included the following: level 1, being physically assaulted; level 2, having a motor vehicle accident; level 3, finding out that a child is doing poorly in school; and level 4, starting a new job. Long-term threat would depend on how quickly the initial threat was resolved. For example, if the motor vehicle accident caused no health, financial, or interpersonal problems, it would be given a low long-term threat rating, whereas the same accident would be assigned a higher threat rating if the consequences were unresolved after 2 weeks.
The consensus panel was blind to physical symptoms associated with stressful events. Life events that were potentially related to MS disease activity (eg, losing a job after an MS attack) were excluded from analysis.
The combination of weekly questionnaires and periodic structured interviews provides a significant advantage over traditional methods of life events monitoring. Frequent self-report assessments allow the most accurate prospective information about the timing of life events but are limited in the life domains they monitor and may be strongly influenced by reporter bias. By combining this type of data with a structured interview, we were able to gather important information about the contextual nature of each event while maintaining accurate dating of even modestly stressful events.
Assessment of MS Disease Activity
MS patients were examined by a neurologist before the study to confirm their diagnosis and provide baseline disability ratings using the Kurtzke Expanded Disability Status Scale (EDSS) (11). On a weekly basis, subjects also completed a self-report MS symptom checklist (12). This questionnaire was reviewed with study personnel every 4 weeks. Neurologic data were collected before any discussion of life events to reduce the likelihood of reporter bias. Potential exacerbations were defined as the appearance of a new symptom or recurrence of previous symptoms lasting more than 48 hours in the absence of a fever. At the end of the study, the neurologist (who was unaware of stressful events) interviewed the patient and confirmed the presence and timing of MS exacerbations. Only exacerbations that were rated as very likely and that occurred after at least 30 days of remission were analyzed.
To determine whether life events were associated with MS exacerbations, two analytic strategies were used. First, a within-subject design was used to determine whether stressful life events were more likely to occur before exacerbations as compared with a control period. Second, a repeated event survival analysis was performed to determine whether more frequent life events increase the likelihood of developing an MS exacerbation. In the first analysis, each subject had one MS exacerbation and one control date randomly selected that was not within 6 weeks of the beginning of the study or the start or end of an exacerbation. The most recent life event before both dates was identified, and the timing from stressor to exacerbation or control date was calculated and compared using a paired t test. A chi-square test was then used to examine whether the source of the threat (eg, work, finances, or relationships) or the severity of the threat influenced its association with MS exacerbations.
In the second analysis, a repeated event survival analysis using the fixed-effect partial likelihood method (13) was performed using the time between exacerbations as the dependent variable and the rate of life events during that period as the covariate. This method is able to compensate for different numbers of data points between subjects and implicitly controls for stable covariates regardless of whether they are correlated with the measured covariates. Eligible exacerbations included those in which at least 8 weeks had passed since the start of the study or the previous exacerbation. Because the offset of MS exacerbations can be difficult to determine, an 8-week interval was chosen to ensure that exacerbations were distinct.
Average age was 39.4 years (range, 28–57). Eighty percent were married, 95% were white, and 87% had some degree of college education. Average length of MS was 7.9 years. Eighteen subjects had the relapsing-remitting subtype of MS, and five subjects had secondary-progressive MS. Baseline EDSS score averaged 3.0 (mild to moderate). Most subjects (21 of the 23) were premenopausal. Nine subjects were treated with serotonin selective reuptake inhibitor antidepressants throughout the study. One of these subjects was also receiving a benzodiazepine throughout the study period. Two additional subjects received a serotonin selective reuptake inhibitor during the first 5 months and then discontinued the medication. For these subjects, both exacerbations and control periods were randomized to the unmedicated portion of their participation.
Life Events and Exacerbations During the Study Period:
Consistent with their predominately relapsing-remitting diagnosis, there was no significant change in EDSS during the study period (3.0 vs. 3.1). Subjects averaged 2.6 exacerbations per year, lasting an average of 29 days. During the study period, 215 life events were recorded, with generally intermediate short-term stressor intensities: 8% level 1, 38% level 2, 39% level 3, and 15% level 4.
Overall, 85% of exacerbations were associated with one or more stressful life events in the prior 6 weeks. In addition, 49% of all life events (stressful or otherwise) were associated with subsequent exacerbations in a similar 6-week time frame. Potential triggering events were evenly distributed across all but the lowest short-term stressor intensities: 53% of level 1 events, 48% of level 2 events, and 63% of level 3 events were associated with exacerbations, compared with 16% of level 4 events (χ2(2) = 8.4, p < .01).
LEDS events are frequently classified as severe or nonsevere events, with severe events representing those directed at the subject with either level 1 or level 2 long-term threat. Fifty-six percent of severe events were associated with exacerbations, compared with 47% of nonsevere events. This mild drop-off in association for nonsevere events seems to be due to level 4 events because the linkage increased to 54% when level 4 events were excluded (χ2(1) = 0.8, NS for severe vs. nonsevere level 1 to 3 events). In addition to short- and long-term threat level, the source of the stressor also seemed to have little impact on the relationship between life events and subsequent exacerbations. Events with level 1 to 3 short-term threat in interpersonal, work, financial, health, and other domains were equally associated with exacerbations in the subsequent 6 weeks (67%, 60%, 69%, 55%, and 47%, respectively; χ2(4) = 2.8, NS).
The relationship between stressor and exacerbation was further examined using a within-subject case-control comparison, examining the time from the most recent stressor to a randomly selected exacerbation vs. a control date that was not within 6 weeks of an exacerbation. Because events with level 4 short-term intensity were frequently positive in nature and were not hypothesized to be triggers of MS exacerbations, they were excluded from this analysis. Thirty-six percent of control dates were preceded by a life event within 6 weeks, compared with 88% of selected exacerbations. The control dates averaged 32.8 ± 2.8 days from the most recent stressor, whereas the time from stressor to exacerbations was 14.0 ± 2.9 days (Fig. 1;t = 5.03, p < .0001). The subtype of MS did not seem to influence this relationship. Excluding the 5 subjects with secondary-progressive MS, subjects with relapsing-remitting MS had 14.0 ± 3.0 days from stressor to exacerbation, compared with 32.2 ± 3.5 days from stressor to control date (t = 4.93, p < .0001). There was insufficient power to separately analyze the subjects with secondary-progressive MS; however, they had a similar time from stressor to exacerbation (14.0 ± 7.2 days).
Using the fixed-effect partial likelihood method, we found that an increase in the rate of life events was associated with an increased likelihood of developing an exacerbation. The hazard ratio for life events was 13.18 (p < .05; 95% CI = 1.67–104.39) and describes the increase in relative risk of an exacerbation for a one-unit change in the rate of life events. The relationship between event rate and time between exacerbations is plotted in Figure 2, with 0 points on the x axis corresponding to exacerbations for which there were no preceding life events.
The results of this study suggest that stressful life events play an important role in triggering MS exacerbations. These results are consistent with the findings of several controlled studies, which have suggested a close relationship between life events and the development and progression of MS (1–4, 14). Our findings differ, however, in suggesting that stress rapidly precipitates MS exacerbations (with a mean of 14 days from stressor to exacerbation). Furthermore, a broad spectrum of stressors (ranging in severity from mild to severe threat and originating from a variety of sources) were equally associated with exacerbations. The relative sensitivity of MS to even modest stressors may account in part for previous negative findings. Many of these studies used retrospective reports of life events or examined stressors on a relatively infrequent basis (every 4–6 months). Modest stressors with relatively low long-term threat may be difficult to accurately assess using those techniques, yet they may still have important effects on the disease course of MS. In addition, if the error in dating these events exceeds 1 to 2 weeks, the effect of stress on MS exacerbations could be lost.
Our results do not explain the findings suggesting a protective role for stress. Studies showing a protective role for stress have generally focused on extreme stressors such as war and trauma, which represent a small proportion of the life events in our sample. A biphasic relationship between stress and MS disease activity may exist such that moderate stressors are associated with an increase in the production of inflammatory cytokines and subsequent disease activity, whereas extreme stressors produce high levels of glucocorticoid activity that may override other systems and suppress immune activity. This possibility is suggested by recent studies of experimental allergic encephalomyelitis, the animal model of MS, in which stressors such as foot shock delayed or diminished the severity of encephalomyelitis, whereas milder stressors increased the severity of the disease (reviewed in Ref. 15).
In this study, subjects averaged 1.6 severe events per year and 6.9 total events per year, excluding events directly attributable to MS disease activity. This rate is somewhat higher than that observed for control subjects (3.5 total events per year) (16) or depressed subjects in the year before their depression (1.0 severe events per year), but it is similar to that observed for depressed subjects during the period of their depression (2.0 severe events per year) (17). The higher rate of both severe and nonsevere events in patients with MS and other chronic conditions likely reflects the impact of their illness on a variety of life domains, such as finances, employment, and relationships, and suggests that these individuals may enter a deteriorating cycle of life events, illness episodes, and disability.
In naturalistic settings, life events do not occur as individual events but rather represent part of a person’s overall stress profile. To our knowledge, this is one of the first studies to examine the impact of stressor frequency on the development of MS exacerbations. The rapid decrease in the time between exacerbations as the frequency of life events increased suggests that there may be a cumulative effect of stressful life events on the propensity to develop MS exacerbations. The particular threshold for developing stress-related exacerbations may be influenced by a number of factors, including the presence of chronic difficulties, the duration of psychological and biological changes after a stressor, and the status of the neuroendocrine and immune systems at the time of the stressor.
Several limitations of this study must be noted. First, despite attempts to use objective criteria for both stressors and exacerbations, it is possible that the occurrence of stressful events increased the subject’s awareness of physical symptoms and thus their reporting of exacerbations. Similarly, although MS-related events were excluded from the analysis, subjects experiencing early symptoms of an MS exacerbation may be more likely to develop life events during the period before the official development of an exacerbation. For example, altered attention and concentration may precede more definitive signs of an exacerbation and may contribute to the loss of a job.
Some studies have attempted to overcome the bias associated with self-reported neurologic symptoms by using more conservative definitions of exacerbations, such as a one-point increase in EDSS score or the occurrence of new lesions on a magnetic resonance imaging scan. However, these restrictive definitions would eliminate the majority of clinical exacerbations experienced by MS patients. Furthermore, the EDSS is nonlinear, and subjects with more advanced MS would require a substantial increase in disability to generate a one-point change in the EDSS score.
Finally, the use of antidepressants and anxiolytics may have altered the stress response in some individuals. All subjects had similar medication regimens during both their selected exacerbation and control periods, thus limiting the impact of medication on the case-control analysis. It is possible, however, that the use of medication could influence the results of the survival analysis if individuals with differing rates of life events were exposed to different medications. We would hypothesize, however, that the psychotropic medications might buffer the relationship between stress and disease activity, thus diminishing the magnitude of the effects we observed.
In summary, this study contributes to a growing body of evidence that stressful life events are potent triggers of disease activity in women with relapsing-remitting MS. This relationship has strong clinical implications. MS exacerbations may be delayed or avoided by limiting the individual or cumulative effects of stressful life events. Furthermore, given the relatively short time frame between stressors and exacerbations, preventive strategies such as coping skills training and early intervention for symptoms of anxiety and depression may be more effective than waiting until the psychological impact of events has developed. Additional prospective studies are needed to examine the mechanism of this relationship and identify possible mediating and moderating factors. Once these relationships are understood, effective strategies may be designed to prevent or minimize stress-induced MS exacerbations.
The authors thank Angela Stover, BA, and Ruomei Liang, PhD, for their technical support. This research was supported by funds from National Institutes of Health Grants K01-MH01468, HL65112, and MHCRC-MH30915, and National Institutes of Health/National Center for Research Resources/General Clinical Research Center Grant M01-RR00056.
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