INTRODUCTION
Multiple sclerosis (MS) is the most prevalent chronic inflammatory demyelinating disease of the central nervous system. Although its exact etiology remains unclear, MS is widely recognized as a multifactorial disorder resulting from complex interactions between genetic predisposition, immune dysregulation, and environmental influences [1]. Psychological stress has been increasingly investigated as a potential contributor to both the onset and progression of MS. Emerging evidence suggests that stress may influence immune function and disease acti-vity, with some studies reporting associations between stressful life events and increased risk of MS onset or relapse [1, 2].
Depression in the context of MS presents a complex diagnostic and therapeutic challenge, as several of its somatic and psychological symptoms – such as fatigue, cognitive impairment, and mood fluctuations – can overlap with or mimic depressive symptoms. This overlap complicates accurate diagnosis and may lead to underrecognition or misclassification. A recent meta-analysis found the overall prevalence of depression in people with MS to be around 27% [3]. Depression not only frequently co-occurs with MS but may also develop as a direct psychological response to the diagnosis, profoundly affecting patients’ mental health and overall quality of life [3]. Additionally, certain MS treatments – particularly interferon therapy – have been speculated to be connected to the onset or exacerbation of depressive symptoms [4]. Individuals with MS also face an elevated risk of suicide [5].
Systematic reviews and meta-analyses indicate a weak-to-modest effect of psychological stressors on the onset of MS. For example, a meta-analysis found that diagnosed stress disorders were associated with about a 1.87-fold increased risk of developing MS, but confidence intervals were wide, reflecting uncertainty [6]. Many studies on stress and the onset of MS have been retrospective and small, relying on self-reported stress or semi-structured interviews, which can introduce recall bias and limit causal inference [6].
The role of infectious agents in the pathogenesis MS remains an area of ongoing research. Both viral and bacterial infections are suspected to contribute to the development of the disease; however, conclusive evidence is still lacking [7]. Numerous studies have reported a strong association between Epstein-Barr virus (EBV) infection and an increased risk of MS [8]. A landmark longitudinal study showed that the risk of developing MS increases more than 30-fold following infection with EBV, and that the risk is minimal in individuals who remain EBV seronegative, suggesting that infection with tis virus is a necessary, though not sufficient, factor in the development of MS [8]. Similarly, genetic predisposition influences susceptibility to MS, but no single gene has been definitively identified as causative. Instead, the risk of developing MS appears to arise from complex interactions between multiple genetic variants and environmental triggers [9].
To the best of our knowledge, no prior studies have specifically investigated the relationship between MS, stressful life events, and childhood infections within a Polish population. This study aims to explore these associations by assessing the prevalence of depression, significant life stressors, and childhood infection history among patients with MS.
METHODS
This was a retrospective case-control study conducted between March 2014 and October 2015. The study protocol was approved by the Local Bioethics Committee at the Medical University of Gdańsk.
The study included two groups: a study group and a control group. The study group consisted of patients with MS, diagnosed according to the McDonald criteria, with a disease duration of at least two years. Participants were recruited from several sources: patients treated at Rehabilitation Centers for MS patients in Borne Sulinowo and Dąbek; inpatients and outpatients from the Provincial Specialist Hospital in Gdańsk; and individuals receiving home-based care, registered with the Gdańsk and Gdynia Chapters of the Polish Multiple Sclerosis Society.
Patients under 18 years of age were excluded from the analysis. Individuals with memory or cognitive dysfunction, as well as those with other focal inflammatory disorders, were also excluded.
The control group consisted of individuals without MS, recruited from the same communities as the MS patients (e.g., neighbors, coworkers), and matched for age and sex to ensure comparable sociodemographic characteristics.
After being informed about the purpose of the study, the nature of the tasks involved, and the method of completing them, each participant was asked to complete a set of questionnaires: the Beck Depression Inventory (BDI), the Recent Life Changes Questionnaire (RLCQ), and a survey developed specifically for the purposes of this study [10].
In the RLCQ, each life event was assigned a score by the original author, reflecting the level of stress it typi-cally induces. As a result, the total score represented the cumulative level of stress experienced in the past by MS patients and controls [11]. It consists of 5 sections concerning, respectively, health, work, home and family, personal problems, and financial situations – in the
6 months prior to diagnosis. Each section contains statements regarding events from the respective areas, and in the event that any of them have occurred it should be marked with a cross. Each situation is, by assumption, assigned a numerical value that characterizes the level of stress induced in the respondent. In this way, after summing-up the total number of points, it was possible to compare which group – study or control – had been more exposed to greater stress in the past. For the purposes of this study, only the comparison of the total overall results obtained by the respondents in the questionnaire was determined.
The custom survey used in this study consisted of 33 questions covering various areas: age, sex, place of origin and current residence, education, socioeconomic status, occupation, family medical history, blood type, past illnesses, history of infections, as well as information related to the diagnosis, course, and current symptoms of MS. Most participants completed the questionnaires independently, with only a few individuals (n = 8) requiring assistance. Participation in the study was voluntary and anonymous. All participants provided written informed consent prior to enrollment. The collected data were initially recorded on standardized forms and subsequently entered into an electronic database.
Statistical analyses
Statistical analyses were conducted using the STATA 12 software package. Continuous variables were described using arithmetic means and standard deviations (SD), while categorical variables were presented as percentages. The statistical significance of differences between groups for normally distributed variables was assessed using Student’s t-test or one-way ANOVA when comparing more than two groups. A p-value of less than 0.05 was considered statistically significant. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to assess the association between specific forms of MS and scores below the 50th percentile on selected scales. Both univariate and multivariate logistic regression analyses were performed to evaluate these relationships.
RESULTS
Sociodemographic characteristics of the study participants
The study included a total of 210 participants: 110 pa- tients (67 men and 43 women) and 100 controls (58 men and 42 women) (Table 1). The mean age was 50 years (range 18-67) in the MS group and 47 years (range 20-74) in the control group. There were no statistically significant differences in sociodemographic characteristics between the two groups, with the exception of occupational activity, which differed significantly (p < 0.001).
Table 1
Sociodemographic characteristics of multiple sclerosis (MS) patients and controls
Clinical characteristics
A more detailed analysis of the MS patient group revealed that participants were diagnosed with all clinical forms of the disease: relapsing-remitting (n = 36, 32.7%), secondary-progressive (n = 28, 25.5%), primary-progressive (n = 33, 30.0%), and progressive-relapsing (n = 8, 7.2%) (Table 2). In five cases (4.5%), the exact clinical form could not be determined.
Table 2
Characteristics of multiple sclerosis (MS) patients and prevalence of depression, stratified according to clinical type of MS
A total of 41 patients (37.3%) were receiving treatment with disease-modifying therapies, including interferon β-1b (n = 19), interferon beta-1a (n = 5), glatira-mer acetate (n = 10), mitoxantrone (n = 1), natalizumab (n = 4), and teriflunomide (n = 2). The remaining 69 patients (62.7%) had not received any disease-specific pharmacological treatment since their diagnosis.
Association between multiple sclerosis, depression, and severity of depression
Logistic regression analyses revealed that patients with MS were over three times more likely to be diagnosed with depression compared to controls (OR = 3.06, 95% CI: 1.64-5.70). When depression incidence was stratified by MS clinical subtype, it was highest among patients with primary-progressive MS and lowest in those with the relapsing-remitting and secondary-progressive forms (see Table 2). These differences in the prevalence of depression across MS subtypes were statistically significant.
As shown in Table 3, the study found that depression was significantly more prevalent and severe among patients with MS compared to the control group. Specifically, 53% of MS patients were identified as expe-riencing depression, in contrast to only 25% of controls, a diffe-rence that was statistically significant (p < 0.001). In terms of severity, a greater proportion of MS patients report- ed mild (34% vs. 19%), moderate (6% vs. 5%), and severe depression (18% vs. 3%), while a smaller proportion reported no depression at all (42% vs. 73%). These findings were supported by the mean scores on the BDI, which were significantly higher in the MS group (10.31 ± 7.44) than in the control group (6.72 ± 7.44), also with a p-value less than 0.001.
Table 3
The Beck Depression Inventory (BDI) and Recent Life Changes Questionnaire (RLCQ) scores, prevalence, and severity of depression in multiple sclerosis (MS) patients and controls
Association between multiple sclerosis and a history of stressful life events
The results from the RLCQ (Table 3) are noteworthy. Although the difference between groups was not statistically significant (p = 0.175), the mean score for MS patients was nearly twice as high as that of the controls (208.72 ± 225.69 vs. 139.1 ± 119.93). This suggests that, prior to their MS diagnosis, individuals with the condition experienced more frequent stressful life events in the 6 months prior to diagnosis across various domains – including health, work, home and family, personal and social life, and financial situations – compared to healthy controls.
History of childhood infections
Compared to the control group, significantly fewer MS patients reported a history of certain childhood infections, including strep throat, tonsillitis, pharyngitis, rubella, frequent common colds, and/or episodes of raised fever. However, there were no significant differences between the groups in the prevalence of chickenpox, tuberculosis, mumps, or measles (Table 4).
Table 4
Childhood medical histories of multiple sclerosis (MS) patients and controls
Results of logistic regression analysis
Logistic regression analysis confirmed that MS patients were less likely than controls to have a childhood history of strep throat, tonsillitis, pharyngitis, rubella, and frequent episodes of raised fever, as well as a lower likelihood of current cigarette smoking. Other variables – including sex, education, marital status, household income, history of smoking, and past or current alcohol consumption – were not significantly associated with MS status (Table 5).
Table 5
Odds ratios (OR) and their 95% confidence intervals (95% CI) for co-existence of multiple sclerosis with other study variables
Furthermore, logistic regression analyses revealed that MS was significantly associated with higher scores on the RLCQ, indicating greater exposure to stressful life events in the 6 months prior to diagnosis (Table 6).
Table 6
Odds ratios (OR) and their 95% confidence intervals (95% CI) for co-existence of multiple sclerosis with the Recent Life Changes Questionnaire (RLCQ) scores
| Raw OR | Adjusted OR | |||
|---|---|---|---|---|
| OR (95% CI) | p-value | OR (95% CI) | p-value | |
| RLCQ (points) | 1.002 (1.0006-1.0004) | 0.009 | 1.001 (1.00-1.003) | 0.05 |
| Age (years) | 1.022 (1.000-1.05) | 0.06 | 1.016 (1.00-1.04) | 0.186 |
DISCUSSION
Depression
Clinical depression is a serious and potentially life- threatening condition, diagnosed based on a defined set of symptoms that may appear at any stage of an illness. Clinical experience with patients diagnosed with MS indicates that approximately half experience a fully symptomatic episode of depression at least once during the course of the disease [12]. Statistical analysis clearly shows that individuals with MS are three times more likely to develop depression compared to the general population. In the study, depression was diagnosed in 58 out of 110 MS patients (53%), compared to only 25 individuals in the control group.
A meta-analysis reported a pooled prevalence of depression in patients with MS at 30.5% (95% CI: 26.3-
35.1%) [13]. Similarly, a survey conducted among members of the Multiple Sclerosis Association of King County found that 42% of 739 respondents screened with the Center for Epidemiologic Studies Depression Scale (CES-D) clinically significant depressive symptoms, with 29% showing moderate to severe depression. These findings, along with results from other studies [14, 15], suggest that the prevalence of depression among individuals with MS is notably high – even in comparison to those with other chronic illnesses. However, some authors caution that this prevalence may be overestimated due to the somatic symptoms commonly associated with MS, such as fatigue, which can be misinterpreted as indicators of depression [16].
Fatigue in MS patients is a pervasive, often overwhelming symptom characterized by a persistent sense of physical and mental exhaustion that is disproportionate to activity levels and not relieved by rest or sleep [17]. It affects up to 80-95% of people with MS and is consi-dered one of the most disabling and challenging “invisible” symptoms of the disease. MS fatigue shares several symptoms with depression, which can complicate diagnosis. Depression screening tools like BDI include somatic items (e.g., tiredness, sleep problems) that may be elevated due to MS fatigue rather than depression itself, potentially inflating depression scores in MS patients (see Limitations).
A recent Polish study investigated the level of happiness in individuals with MS compared to those with other neurological conditions. Analysis of data from 589 MS patients and 145 control participants revealed that individuals with MS reported significantly lower levels of happiness, particularly in the domains of life satisfaction and positive orientation. These findings suggest that diminished happiness may play a contributory role in the development of depression. The authors emphasized the importance of prioritizing psychological interventions that address these factors, especially for individuals with reduced well-being, including those living with MS [18].
Moreover, the clinical form of multiple sclerosis appears to be linked to the likelihood of co-occurring depression. Some studies have shown that, despite experiencing greater physical disability, individuals with primary-progressive MS are significantly less likely to suffer from depression compared to those with the secondary-progressive form [18]. It is worth noting that primary-progressive MS is typically associated with a lower burden of pathological lesions than other clinical subtypes [19].
In our study patients with relapsing-remitting and secondary-progressive MS, depression was diagnosed in 37.5% of individuals. In contrast, those with the primary- progressive form showed a significantly higher prevalence, with 76.7% affected by depression. Among patients with progressive-relapsing MS, 42.9% were diagnosed with depression.
The growing incidence of depression among patients with MS raises the question of whether individuals with this condition are at an increased risk of suicidal beha-vior [20]. The authors of a study on 29,617 Swedish MS patients analyzed the hazard ratio (HR) to determine the association of MS with suicide attempt and suicide death. The adjusted HR in MS patients was 2.18 for attempted suicide (95% CI: 1.97-2.43) and 1.87 for suicide death (95% CI: 1.53-2.30) compared with the general population [20]. Some evidence suggests that depression in patients with MS can be effectively treated with psychotherapy focused on developing active coping strategies (cognitive behavioral therapy – CBT), as well as with antidepressants [21].
Childhood infections
This study showed that patients with MS less often than healthy controls had a history of childhood infections. In countries with high standards of living, typically a decrease in the incidence of various infections is observed along with an increase in the risk of allergies, atopic diseases, chronic inflammatory and autoimmune conditions [22]. This phenomenon is explained by the co-called “hygiene hypothesis”, according to which an improvement of living conditions is associated with a decrease in environmental infectious burden and better hygienic standards. However, interactions with microorganisms exert a beneficial effect on immune function and health in general, whereas excessive hygiene may predispose to various diseases [23]. Patients with MS reported childhood infections significantly less often than the controls, which implies that they did not develop an adequate level of active immunity. However, these findings should be interpreted with care.
While the hygiene hypothesis is biologically plausible, direct evidence linking fewer childhood infections specifically to MS is limited. MS is a complex, multifactorial disease involving genetic, environmental, and infectious factors, and some infections – such as the EBV – are actually associated with increased risk of MS, complicating the hypothesis [9]. Epidemiological studies have shown inconsistent results, with some supporting and others contradicting the hygiene hypothesis [24]. These inconsistencies may stem from recall bias, confounding factors like socioeconomic status or healthcare access, and differences in study design [25]. To better understand the potential link, more mechanistic research, including animal studies and long-term cohort analyses, is needed to determine whether reduced microbial exposure truly contributes to MS development.
Relapse of MS was shown to be preceded by exposure to severe stress. In a study of 55 participants with relapsing-remitting MS, the probability of exacerbation in individuals with a history of unfavorable or stressful life events turned out to be 3.7-fold higher than in other patients [16]. Typically, exposure to a stressful life event is determined using the RLCQ created by R.H. Rahe [11].
Stressful life events
Stressful life events are increasingly recognized as contributing factors in both the development and progression of MS. Epidemiological studies, including large case-control analyses, suggest that major stressors – such as bereavement, serious illness in close relatives, or interpersonal conflicts – may raise the risk of developing MS by 17% to 30%, particularly if they occur within five years prior to disease onset [26]. Women may be more susceptible to stress-related MS risk than men, especially in the context of family-related stress. A meta-analysis indicated that diagnosed stress disorders nearly double the risk of MS. In individuals already diagnosed with MS, stress is also linked to higher rates of relapse, with some studies reporting hazard ratios up to 6.7 following multiple stressful events [6, 26]. Proposed mechanisms include immune dysregulation and disruption of the hypothalamic–pituitary–adrenal (HPA) axis. However, not all studies have found consistent results, due in part to variations in study design, stress assessment methods, and potential confounding factors, which complicate the attempt to arrive at definitive conclusions [27].
In our study, although the differences in the RLCQ scores did not reach the threshold of statistical significance, the scores of MS patients 6 months prior to the diagnosis were approximately two-fold higher than among patients in the control group; this implies that exposure to a stressful event might contribute to the activation of the disease. The association between MS and exposure to stressful events was documented in a study of 61 patients, divided into three groups based on their clinical status [28]. The first group included participants in whom MS symptoms persisted for no longer than 6 months, the second group included individuals with chronic symptoms present for more than 6 months, and the third group included patients in remission who remained asymptomatic for more than 6 months. All participants were asked to identify the stressors they had been exposed to in the 6 months preceding the survey. Individuals with exacerbation experienced stressful life events significantly more often than patients in the chronic phase. The argument for a relationship between exposure to stress and MS seems therefore reasonable and is widely accepted by patients with this condition; however, we still lack enough evidence to confirm this hypothesis.
LIMITATIONS
The retrospective design and the use of a specific Polish population sample may limit the generalizability of the findings to other populations or settings. As with many retrospective case-control studies, this study is subject to several limitations, including potential recall and selection biases, as well as the difficulties in exploring causality. The reliability and accuracy of self-reported information were difficult to verify, which may have introduced additional bias.
The retrospective nature of a study limits causal inference primarily because it looks backward in time, analyz-ing outcomes that have already occurred and then trying to identify causes. Our study was susceptible to confounding factors because the selection of participants was based on outcome status (MS diagnosis) rather than exposure status (depression, infections, stress). Thus, it is difficult to confirm that these factors preceded the onset of MS. For example, depression might have developed as a consequence of early MS symptoms rather than being a cause, limiting the drawing of causal conclusions. The observed associations (e.g., higher odds of depression in MS patients, lower odds of certain childhood infections) indicate correlation but do not prove causation. The retrospective design cannot definitively establish that depression or infections cause or protect against MS; alternative explanations such as reverse causation or confounding remain plausible.
Another main limitation of this study lies in the potential for recall bias. Participants reported past childhood infections and stressful life events through questionnaires, which rely on memory. This retrospective self-reporting can introduce inaccuracies, as individuals with MS might recall or report past events differently than controls, potentially biasing the associations observed. Individuals with MS may have been more likely to remember or overreport exposure to potential risk factors compared to controls.
For instance, a 2019 prospective observational study quantified recall bias in health-related quality of life (HRQoL) measurements among MS patients. It found that recall periods influenced reported HRQoL, with daily recall yielding more positive scores than weekly or monthly recall [29]. More generally, recall bias in MS studies arises because patients may have impaired memory or cognitive deficits, which can affect the accuracy of self-reported exposures or symptoms. This is supported by research on memory impairment in MS, which shows deficits in encoding and retrieval processes that could influence the reliability of recall [30].
Selecting controls from patients’ social circles can introduce several biases. Shared environments and beha-viors (e.g., stress, diet, infection exposure) may reduce exposure variability, potentially distorting associations with MS. This approach also risks non-independent exposure status, violating the assumption that controls should be selected independently of exposure. As a result, the exposure distribution in controls may not reflect the general population, leading to selection bias. Additionally, overmatching on social factors can obscure true differences in exposure, reducing the study’s power to detect associations [31].
The BDI includes items that assess somatic symptoms like fatigue, changes in sleep patterns, appetite changes, and physical tiredness. These symptoms are common both in depression and in chronic illnesses [32, 33]. Stu-dies have shown that in medically ill populations, the somatic dimension of the BDI contributes significantly to the total score, sometimes leading to an overdiagnosis or overestimation of the severity of the depression. The latter may coexist with both cognitive impairment and fatigue syndrome. In such cases, depression should be treated first since it can account for both dysfunctions. Therefore, a diagnosis of primary fatigue syndrome should not be made before addressing concomitant depressive disorder. Consequently, fatigue itself can represent a component of the depressive clinical syndrome.
Additionally, it is recommended to use adjusted cut-off scores or to analyze the cognitive-affective and somatic subscales of the BDI separately in chronic illness populations [34].
CONCLUSIONS
Individuals with MS are 3 times more likely to deve-lop depression than controls, which indicates the clinical relevance of the research. Patients with MS less often than healthy controls had a history of childhood infections, and had probably been exposed to a stressful life event. Patients with MS score higher on the RLCQ, which implies that, in the past, probably prior to being diagnosed with multiple sclerosis, they had been exposed to stressful events (both negative and positive ones).
