Abstract
Introduction
Multiple sclerosis (MS) is a chronic, progressive, auto-immune disease that affects the central nervous system (Lutton et al., 2004). About 2.5 million people worldwide have MS, it is one of the most common neurological disorders and cause of disability of young adults (WHO, 2006). Although the etiology is unknown, MS is a complex disease that probably involves multiple genes and environmental factors. The most widely studied environmental factors include vitamin D deficiency (Munger et al., 2004), Epstein–Barr virus (Ascherio and Munger, 2010), and stress (Artemiadis et al., 2011).
Stress is the factor that has generated the most controversial results. Some studies report an association between stress and MS (Buljevac et al., 2003; Mohr et al., 2000; Warren et al., 1982) but others failed to find this association or only found a quasi-significant relationship (Gasperini et al., 1995; Riise et al., 2011). These disparate results can be explained by heterogeneity in study design (Artemiadis et al., 2011) as well as by the indirect way stress affects MS through other variables (Mohr et al., 2002). Factors proposed as potential moderators and mediators between stress and MS include stressor properties, environmental factors, and patients’ biological, social, and psychological characteristics (Mohr et al., 2002).
Some studies have reviewed articles published on the relationship between stress and MS. In 1999, the American Academy of Neurology found class II evidence both for and against an association between stress and the onset or exacerbation of MS, concluding that a relationship between MS and psychological stress was possible but data were insufficient for reasonable medical certainty (Goodin et al., 1999). In 2004, Mohr et al. analyzed 14 studies and found a consistent association between stressful life events and subsequent exacerbation in MS. Finally, in a recent systematic review, Artemiadis et al. (2011) found that 15 of 17 studies reported a significant stress–MS relationship; however, they pointed out that the heterogeneity in the measurement of stress precluded secure conclusions. Other authors highlight the need to identify factors that might modify the stress–MS association (Ackerman et al., 2002; Brown et al., 2006b). All these reviews focused on the quality and main results of the studies, but none examined the results in function of the way stress was measured or of potential moderators and mediators.
This study aims to review the evidence on the association between stress and MS, focusing on the methods used to evaluate whether stress affects MS and the role of potential moderator and mediator factors on this association. This knowledge can be useful for the design of future studies and for developing better interventions in MS patients.
Methods
Literature search
We searched the Web of Knowledge (MEDLINE and Web of Science), Scopus, and PsycINFO databases for relevant articles published from 1900 through December 2014. We searched for the terms
Selection criteria
We selected articles that met the following inclusion criteria: (1) published in international peer-reviewed academic journals (book chapters, abstracts of conference proceedings, and dissertations were excluded), (2) published in English or Spanish, (3) measuring psychosocial stress in everyday situations (induced stress studies were excluded), (4) evaluating MS onset, relapse rate during a period of time, or MS-related health status, and (5) observational and non-stress interventional studies in human subjects (stress-interventional and animal studies were excluded).
Two reviewers (L.B.B. and R.M.V.) independently selected articles and examined titles and abstracts to exclude those out-of-scopes. When the first two reviewers disagreed, three reviewers (L.B.B., R.M., and F.X.A.N.) reached a consensus about disagreements. Then, full papers were reviewed and selected for this study. All the processes were done following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statements (Moher et al., 2009).
The qualitative appraisal was based on Newcastle–Ottawa quality assessment scale recommended by the Cochrane Non-Randomized Studies Methods Working Group (Wells et al., 1999), following the adaptation for stress and MS made by Artemiadis et al. (2011).
Data extraction
We arranged papers into chronological order and extracted details on (1) source (authors, year, and country); (2) whether the study measured onset, relapse, or both; (3) design; (4) sample; (5) diagnostic criteria for MS, relapse, and health status; (6) study period; (7) qualitative assessment; (8) the instruments used to measure stress; (9) modifying factors considered; and (10) results regarding the relationship between stress and MS and influences of modifying factors.
Following Mohr et al. (2002), we classified modifying factors according to the following criteria: the nature of the stressor; the environmental context; and the patient’s biological, social, and psychological characteristics. We classified articles according to whether they evaluated disease onset or progression; however, we decided not to analyze disease type and process because the disease process cannot be controlled and almost all the papers reviewed dealt with remittent-recurrent or secondary-progressive clinical types.
Risk of bias
Our approach carries a risk of different biases. First, the selection process is susceptible to publication bias. Second, there is a risk of excluding papers using different terms to refer to the same concepts, for example, disseminated sclerosis instead of MS or anxiety instead of stress. Third, we may have missed other potential modifying factors because we only analyze factors included in studies that first focused on the relationship between MS and stress.
Results
Study selection
The initial database search provided 5030 records and we identified 11 records from other sources. After we removed duplicate studies and irrelevant titles, 336 unique and potentially relevant abstracts remained (Figure 1). After excluding out-of-scope records, we checked the full texts of 212 records. We excluded 189 articles because they did not meet the inclusion criteria: 5 (2.6%) were not published in English or Spanish; 122 (64.6%) did not measure psychosocial stress in everyday situations; 53 (28%) did not evaluate MS onset, relapse rate, or health status; 2 (1.1%) were stress-interventional studies; and 7 (3.7%) were animal studies. Thus, 23 studies were included.
Search and exclusion process.
Characteristics of the studies
Table 1 reports the main characteristics of the selected papers. When we grouped papers according to whether they evaluated the effects of stress on onset or progression, we found 9 papers evaluating the effects of stress on onset (Grant et al., 1989; Liu et al., 2009; Mei-Tal et al., 1970; Nielsen et al., 2014a, 2014b; Palumbo et al., 1998; Pratt, 1951; Riise et al., 2011; Warren et al., 1982) and 14 evaluating the effects on disease progression, of which 13 focused on relapses (Ackerman et al., 2002, 2003; Brown et al., 2006a, 2006b; Buljevac et al., 2003; Gasperini et al., 1995; Mitsonis et al., 2008, 2010; Mohr et al., 2000, 2002; Oveisgharan et al., 2014; Potagas et al., 2008; Warren et al., 1991) and 1 on health status (Schwartz et al., 1999).
Main characteristics of papers selected (sorted by onset/relapse in chronological order).
MS: multiple sclerosis; CNS: central nervous system; PNP: polyneuropathy;
Clinical criteria for relapses: 1. Unspecified. 2. Sudden appearance of a symptom typical of MS, which may have been new to participants or experienced during a previous relapse. Remission was defined as no symptoms in the previous 6 months. 3. New neurological symptom associated with a change of at least 1.0 point in EDSS which lasted more than 24 hours. 4. Increase of 1.0 point on the EDSS from the previous examination. 5. A worsening of existing symptoms or appearance of new symptoms, lasting more than 24 hours and after at least 30 days of improvement or stability not associated with fever. 6. Occurrence, recurrence, or worsening of symptom(s) of neurological dysfunction, associated with confirmatory change on neurological examination, lasted more than 48 hours, not associated with fever and occurred after at least 30 days of improvement or stability.
A wide variety of countries were represented, but nine (39%) were done in or in collaboration with the institutions in the United States.
Despite the broad range of years searched, all the papers selected were published after 1950. One paper was published in the 1950s, 1 in the 1970s, 2 in the 1980s, 4 in the 1990s, 10 in the 2000s, and 5 from 2010 to 2014.
The samples in the studies ranged from 23 to 170 participants with MS, with the exceptions of the three large cohort studies (Nielsen et al., 2014a, 2014b; Riise et al., 2011), which followed between 230,000 and 30 million people initially healthy participants. The control/comparison groups consisted of other individuals with MS in three studies (Gasperini et al., 1995; Mitsonis et al., 2010; Warren et al., 1991), of healthy individuals in three studies (Grant et al., 1989; Liu et al., 2009; Schwartz et al., 1999), and of individuals with other diseases in three studies: organic diseases of the central nervous system (Pratt, 1951), rheumatologic/neurologic diseases (Warren et al., 1982), and polyneuropathy (Palumbo et al., 1998).
Study design
Six of the nine studies examining the relationship between stress and the onset of MS were retrospective: one (Mei-Tal et al., 1970) was cross-sectional and five (Grant et al., 1989; Liu et al., 2009; Palumbo et al., 1998; Pratt, 1951; Warren et al., 1982) case–control; these studies focused on a period from 1 to 3 years before onset or on an unspecific period of time before onset (Mei-Tal et al., 1970; Pratt, 1951). Three prospective studies that examined the relationship between stress and the onset of MS were longitudinal, following a cohort of initially healthy people from 18 to 30 years (Nielsen et al., 2014a, 2014b; Riise et al., 2011).
The 14 studies examining the relationship between stress and progression of MS were all prospective; 12 of these were cohort studies (Ackerman et al., 2002, 2003; Brown et al., 2006a, 2006b; Buljevac et al., 2003; Mitsonis et al., 2008, 2010; Mohr et al., 2000, 2002; Oveisgharan et al., 2014; Potagas et al., 2008; Schwartz et al., 1999) and 2 were case–control studies (Gasperini et al., 1995; Warren et al., 1991). The duration of these studies ranged from 28 weeks to 8 years, but in most it was about 1 year.
Criteria for diagnosing MS and relapse
The criteria for the initial diagnosis of MS have evolved from those in Schumacher et al., (1965) publication, which were updated by Poser et al. (1983), and more recently by McDonald et al. (2001), last reviewed by Polman et al. (2011).
The criteria for diagnosing relapse varied widely. Whereas some articles used biological criteria (new lesions on gadolinium-enhanced magnetic resonance imaging (MRI)) to determine disease progression (Mohr et al., 2000, 2002), most studies used clinical criteria to define relapse, either changes in Expanded Disability Status Scale score (Gasperini et al., 1995; Mohr et al., 2000) or worsening or new symptoms (Ackerman et al., 2002, 2003; Brown et al., 2006a, 2006b; Buljevac et al., 2003; Mitsonis et al., 2008, 2010; Oveisgharan et al., 2014; Potagas et al., 2008; Warren et al., 1991), with some variation in the definition of these concepts. Nevertheless, the most commonly used clinical criteria describe relapse as a worsening of the existing symptoms or appearance of new ones lasting more than 24 hours (labeled clinical criteria 5 in Table 1) or more than 48 hours (labeled clinical criteria 6 in Table 1) after at least 30 days of improvement or stability not associated with fever.
Regarding relapse criteria, we observed that studies that used biological criteria (new gadolinium-enhanced lesions) or changes in Expanded Disability Status Scale found a positive but not significant association (odds ratio (OR) = 2.3, 95% confidence interval (CI) = 0.9–5.6) between stress and MS (Gasperini et al., 1995) or an association not sufficiently robust (OR = 1.64, 95% CI = 1.22–2.20) to predict clinical exacerbations (Mohr et al., 2000).
Methods used to evaluate stress and results: onset studies
Two studies (Mei-Tal et al., 1970; Pratt, 1951) used non-validated interviews; both found more emotional stress before onset (unspecific period of time), although in Pratt (1951) the difference was not significant (
Two other studies (Grant et al., 1989; Warren et al., 1982) used semi-structured interviews designed on the basis of previous information about stress; both showed a temporal relationship between greater emotional stress and MS. In the study by Grant et al. (1989), compared to matched controls without MS, more MS patients had experienced marked adversity in the year prior to onset of symptoms, (77% vs. 35% of controls;
Two studies (Palumbo et al., 1998; Riise et al., 2011) used ad hoc questionnaires to determine the amount of stress. Palumbo et al. (1998) observed a nonsignificant trend toward more stressful events in MS patients than in patients with polyneuropathy (24.6% vs. 14.8%) in the year before onset. Riise et al. (2011) observed no effect of stress on MS development in 30 years’ follow-up of a large cohort of initially healthy subjects.
One study used a rating scale of stressful events. Liu et al. (2009) found significant differences (
Finally, two studies (Nielsen et al., 2014a, 2014b) used data about specific stressful events from the National Multiple Sclerosis Registry and observed little evidence for a causal association between major stressful events and MS risk. Only parental divorce in childhood increased modestly the risk of MS (Nielsen et al., 2014b).
Methods used to evaluate stress and results: progression studies
Progression studies can be classified into two categories: those that evaluated the stress patients experienced in a period of time before a relapse retrospectively after the relapse occurred (Gasperini et al., 1995; Warren et al., 1991) and those that evaluated stress systematically before the relapse occurred (Ackerman et al., 2002, 2003; Brown et al., 2006a, 2006b; Buljevac et al., 2003; Mitsonis et al., 2008, 2010; Mohr et al., 2000, 2002; Oveisgharan et al., 2014; Potagas et al., 2008; Schwartz et al., 1999).
In the first category, Warren et al. (1991) used a questionnaire and different scales and observed a significant positive relationship between stress and MS exacerbation: patients scoring 5 or above in Goldberg and Hillier’s General Health Questionnaire-28 (Goldberg and Hillier, 1979) had a relative risk (RR) of exacerbation of 3.1 (95% CI). In contrast, Gasperini et al. (1995) used a structured interview to determine whether patients had undergone a single stressful event and found no differences between MS patients who had relapsed and those who had not, although cumulated stressful events were associated with a nonsignificantly higher risk of MS relapse (OR = 2.3, 95% CI = 0.9–5.6).
In the second category, eight studies used different combinations of questionnaires, scales, and interviews. Mohr et al. (2000, 2002) used different scales to evaluate stressful events and hassles monthly, considering the 8 weeks after every stressful event a period at risk for relapse; these studies found that
Schwartz et al. (1999) using a self-reported stressful event scale every 6 months also found a bidirectional relationship between stress and MS exacerbation, in which MS progressed after stress and stress increased after MS exacerbations in a vicious cycle. More than one stressful event increased the risk of disease progression (OR = 1.13,
Finally, four studies (Buljevac et al., 2003; Mitsonis et al., 2008, 2010; Potagas et al., 2008) used self-reported diaries. All these studies showed increased risk for exacerbation during the 4 weeks after a stressful event. Buljevac et al. (2003) found that one or more stressful events were associated with a 2-fold risk of relapse (RR = 2.2, 95% CI = 1.2–4.0,
Moderating and mediating factors: evaluation and results
All but 2 of the 23 studies took into account potential modifying factors of the relationship between stress and MS (Table 2). We classified these factors into three main categories: stressor properties, individual characteristics, and environmental factors.
Stress measuring instruments, moderator factors and results.
MS: multiple sclerosis; SLE: stressful life event, which produces emotional tension, different from everyday life; LEDS: Life Events and Difficulties Schedule; DSM-IV:
Stressors properties
Thirteen studies analyzed stressor properties such as type, duration, severity, valence, source, and frequency. Among the different stressor properties, type and source (for example, work stress) were the least significant (Ackerman et al., 2002; Grant et al., 1989; Mei-Tal et al., 1970; Mitsonis et al., 2008). However, Mohr et al. (2000) observed that only the type of stressor referred to as “Conflict and disruption in routine” was associated with new gadolinium-enhanced lesions. The duration of exposure to a stressor was more important. Stressors associated with relapses were mainly sustained and protracted or long-term stressors (versus acute stressors), lasting more than 48 hours (Ackerman et al., 2002; Brown et al., 2006a; Grant et al., 1989; Mei-Tal et al., 1970). With regard to severity of the stressor, most studies found a stronger association with MS relapses for intermediate-to-severe intensity stressors (Ackerman et al., 2002; Grant et al., 1989; Warren et al., 1991). Finally, frequency was important; in general, studies found that cumulated stress or the presence of various stressful events increased the risk of relapse compared with a single stressful event (Brown et al., 2006a; Gasperini et al., 1995; Mitsonis et al., 2008; Oveisgharan et al., 2014; Potagas et al., 2008; Schwartz et al., 1999).
Patients’ characteristics
Eight studies evaluated the impact of different patient characteristics on the stress–MS relationship. Seven considered psychosocial factors such as premorbid personality (Pratt, 1951), coping style (Brown et al., 2006b; Mohr et al., 2002; Warren et al., 1982, 1991), and mental health symptoms (anxiety, depression, optimism) (Brown et al., 2006b; Liu et al., 2009; Potagas et al., 2008). Only one study (Ackerman et al., 2003) evaluated biological factors (cardiovascular reactivity, resting heart rate, and blood pressure).
Personality did not seem to affect disease progression (Pratt, 1951), but other psychosocial factors differed significantly between MS patients and controls (Liu et al., 2009), including a trend toward worse mental health in MS patients. In a recent study by Potagas et al. (2008), a Hamilton Rating Scale for Anxiety (Hamilton, 1959) score ⩾18 was associated with a hazard rate of 2.9 (95% CI = 1.3–6.4,
There seems to be modest evidence that coping style affects MS; Mohr et al. (2002) found greater use of distraction had a protective effect against MS (OR = 0.69, 95% CI = 0.49–0.98,
Finally, Ackerman et al. (2003) found that higher cardiovascular reactivity to an acute stressor and higher baseline heart rate were significantly correlated with greater relapse rate (
Environmental factors
Six studies examined environmental factors such as early life stress (Nielsen et al., 2014b; Riise et al., 2011; Warren et al., 1982), social support (Brown et al., 2006b; Palumbo et al., 1998), or escitalopram intake (Mitsonis et al., 2010).
Regarding the early life stress, Riise et al. (2011) found a nonsignificant trend toward developing MS in women who had been forced into sexual activity several times during childhood (OR = 1.51, 95% CI = 0.90–2.55) or adolescence (OR = 1.25, 95% CI = 0.70–2.23). However, Nielsen et al. (2014b) found that persons exposed to parental divorce in childhood were at 13 percent increased risk of developing MS (RR = 1.13, 95% CI = 1.04–1.023).
Finally, social support and intake of escitalopram seem to decrease the stress–relapse relationship. Liu et al. (2009) found a negative correlation between social support and negative emotions, suggesting that MS patients lacked the ability to use social support. Mitsonis et al. (2010) studied the effects of escitalopram on stress-related relapses in a randomized controlled trial, finding that patients in the control group (no intake) had a risk of relapse 2.9 times higher than those in the experimental group (receiving escitalopram) (hazard ratio (HR) = 2.9, 95% CI = 1.7–5.9,
Discussion
To elucidate the relationship between stress and MS and moderating and mediating factors that might influence this relationship, we analyzed the results of 23 studies in function of the methods they used to evaluate stress. We classified studies into two main categories: those that analyzed the effect of stress on the onset of MS and those that analyzed the effect of stress on the progression of MS. Studies focused on onset used a retrospective design with interviews being the main instrument to assess stress. In these studies, semi-structured interviews and scales were the instruments that showed more significant associations with the onset of MS. Studies focused on progression were mostly prospective and evaluated stress systematically prior to exacerbations using a combination of interviews, questionnaires, scales, and self-reported diaries. Almost all these studies showed a significant positive relationship between stress and progression, and self-reported diaries yielded the most consistent results. The potential moderating and mediating factors with the most consistent effect on the stress–MS relationship were the duration, severity, and frequency of the stressor; anxiety, cardiovascular reactivity, and heart rate; and social support and escitalopram intake.
As previous reviews (Artemiadis et al., 2011; Mohr et al., 2004) pointed out, one of the main problems in evaluating the evidence for the relationship between stress and MS is the wide variety of methods used to measure stress. Moreover, different studies not only used different combinations of several stress-measuring instruments but also different study designs, temporal frameworks between stress and disease (onset or progression), and different criteria to evaluate disease onset and progression.
The studies that evaluated disease onset with a prospective design or ad hoc questionnaires failed to show a significant relationship between stress and disease onset. Only studies using interviews with a retrospective design or questionnaires and scales in a case–control design showed a significant relationship, although this approach cannot establish a causal link. To firmly confirm or rule out whether stress is a risk factor for MS onset, prospective studies that frequently assess stressors are required.
Most studies evaluating disease progression assessed stress prospectively before the changes in disease progression became evident. Almost all these studies showed a positive relationship, regardless of the instruments used or the temporal framework considered as the period “at risk” (from 4 to 8 weeks). However, the studies that used self-reported diaries or weekly assessment (Ackerman et al., 2002, 2003; Buljevac et al., 2003; Mitsonis et al., 2008, 2010; Potagas et al., 2008) had more consistent results. Another important element for obtaining consistent results is the criteria used to measure relapse. As mentioned by Mohr and Pelletier (2006), after a stressful life event, the changes in MS manifest in the following order: first, MRI brain lesions, second, clinical symptoms or relapses, and third, the changes in the Expanded Disability Status Scale. Therefore, studies using the Expanded Disability Status Scale to evaluate MS progression after stress would probably show less progression because the scores often do not change until long after patients notice worsening symptoms or several relapses have occurred. Thus, biological or clinical criteria, or a combination of the two, are likely to provide more accurate results in early stages. In addition, since stress can affect disease without causing relapse, but only worsening symptoms, it seems necessary to add periodic functionality assessment to evaluate different categories of health status.
The relationship between stress and disease is modulated by several factors. The characteristics of the stressors have been the most widely studied. Although one study (not included in the systematic review) found that psychosocial and occupational stress were linked to a disease worsening (Strenge, 2001), overall the typology and source of stress do not apparently moderate the stress–MS relationship. In contrast, stressor duration, severity, and frequency have consistently been identified as modifying factors.
Chronic stress, defined as exposure to a stressor for more than 48 hours, had a greater effect on MS than acute stress (Ackerman et al., 2002; Brown et al., 2006a, 2006b; Grant et al., 1989; Mei-Tal et al., 1970). However, the studies reviewed often categorized duration differently. For example, for Ackerman et al. (2002), long-term stressors were those lasting at least 15 days, but for Brown et al. (2006a, 2006b), long-term stressors were those lasting more than 6 months. The effect of chronic stress on MS could be explained by alterations in the stress-response systems of the hypothalamic–pituitary–adrenal axis and autonomic nervous system (for a review, see Gold et al., 2005).
Stressor severity is also important. Intermediate and severe stressors have shown the most consistent associations with disease progression. However, these results seem applicable only to everyday or common stress; in extremely stressing situations, such as war, relapse rate can decrease (Nisipeanu and Korczyn, 1993). The frequency of exposure to stress is also positively associated with disease progression: an increase in the number of stressful events is associated with an increase in the likelihood of relapse. The reason why stressor duration, severity, and frequency consistently modify the effects of stress on MS but source and typology do not is that the former directly determine the amount of stress, whereas the latter depend on personal assessment.
Many studies have also explored the potential modifying role of patients’ individual characteristics on the effects of stress on MS. The most important factors identified are anxiety, cardiovascular reactivity, and heart rate, all of which are related to autonomic reactivity. The autonomic nervous system is one of the stress-response systems and could be involved in MS pathogenesis and progression (Gold et al., 2005). Future studies should take biological measures of stress into account, so they can analyze biological correlates of stressful situations. Biofeedback technology has been widely used to reduce stress and anxiety and might help teach people which emotional states cause greater activation of biological stress-response systems. In a recent review, Biondi and Valentini (2014) concluded that biofeedback therapies are able to produce somatic peripheral changes (neuroendocrine and neurovegetative systems).
Another patient factor that has been analyzed is coping style; however, the results for this factor have been contradictory. Whereas Mohr et al. (2002) found modest support for a moderating effect of coping style, Warren et al. (1982, 1991) found no significant differences between MS patients and control group but a tendency to use a more emotion-focused coping style in MS patients experiencing exacerbations compared to patients in remission. Brown et al. (2006b) found that only coping responses using social support had a modifying effect on stress. Other studies (not included in the systematic review) showed limited support for the stress-buffering effects of coping (Pakenham, 1999) and a tendency for people with MS, especially men, to be less likely than the general population to adopt coping styles related to problem-solving and seeking social support (McCabe et al., 2004). More research is needed to elucidate the effects of coping on stress.
Finally, the environmental factors escitalopram intake and social support decrease the effect of stress on MS (Brown et al., 2006b; Mitsonis et al., 2010). Escitalopram reduces the stress-dependent relapse rate in MS patients (Mitsonis et al., 2010). Escitalopram regulates serotonin reuptake and blunts autonomic reactivity, resulting in lower emotional reactivity to stressful situations (Fabre and Hamon, 2003). The efficacy of escitalopram in reducing the relapse rate in Mitsonis et al. (2010) clinical trial opens new directions for the study of MS. It could be interesting to study whether disease progression is linked to genetic factors related to serotonin transporters due to that serotoninergic neurotransmission in MS patients is altered in limbic and paralimbic regions as well as in the frontal cortex (Hesse et al., 2014).
Social support can attenuate responses to stress or threatening situations by reducing neural activity in regions that respond to basic survival threats while increasing activity in regions that process safety signals (Eisenberger, 2013). Other studies in MS patients have found that social support may moderate the impact of negative life events and have a positive effect on quality of life (Costa et al., 2012) and that it is a predictor of perceived health status (Krokavcova et al., 2008).
Although our systematic review showed little evidence for early life stress as a moderating factor, a recent case–control study (Spitzer et al., 2012) found that MS patients had more traumatic experiences in childhood and adolescence than healthy people. Moreover, patients with early life stress showed a higher relapse rate than those without. Early life stress can cause neuroendocrine alterations that remain into adulthood, increasing susceptibility to certain diseases (Panzer, 2008) and increasing the prevalence of severe psychological disorders (Alvarez et al., 2011) that predispose to inadequate coping in stressful situations. More prospective studies are needed to better understand the effect of early life stress in MS.
Our study has both strengths and limitations. To our knowledge, this is the first review of studies analyzing the relationship between stress and MS that takes into account how stress was evaluated and moderators of the stress–MS relationship. Although the first article included in our review dates from 1950, we searched three important databases compiling publications from 1900 to the present in an attempt to summarize all the evidence accumulated since Charcot first described MS in 1877. Moreover, we took into account English and Spanish languages, more comprehensive search than other papers. However, relatively few studies met the inclusion criteria. We did not include stress-intervention or animal studies, although these studies could surely contribute important data about the stress–MS relationship. Almost all the studies took at least one moderating factor into consideration; however, the wide variety of factors considered meant that few studies considered the same factors, precluding strong conclusions about the impact of most moderating and mediating factors. Almost all the studies reviewed were done in women, so despite the higher prevalence of MS in women, the results extracted may not be generalizable to the entire population.
Conclusion
The effect of stress on the onset of MS remains unclear. More prospective studies evaluating stress systematically are needed to better understand this effect. In stress progression studies, instruments and designs based on self-evaluation and subjective measures have shown more consistent results than objective ones or instruments based on standard stressors. This means that patients’ subjective appraisal of the stress could be an important predictor of MS relapse and onset. Also, the criteria used to evaluate disease progression are important in the evaluation of results. The greatest amplifying or buffering effects on stress come from factors directly related to the amount of stress and autonomicnervous system reactivity. Future studies should clarify the biological mechanisms involved: combining self-reported measures with biofeedback technology and genetic evaluation can improve our knowledge about the relationships between stress and MS. We also strongly recommend including moderating factors in studies on the effects of stress on MS; this approach can provide information that might be useful for treating patients, since some factors such as anxiety and coping styles are potentially modifiable.