Childhood Trauma in Multiple Sclerosis: A Case-Control Study
Spitzer, Carsten MD; Bouchain, Miriam; Winkler, Liza Y. MD; Wingenfeld, Katja PhD; Gold, Stefan M. PhD; Grabe, Hans Joergen MD; Barnow, Sven PhD; Otte, Christian MD; Heesen, Christoph MD
From the Department of Psychosomatic Medicine and Psychotherapy (C.S., K.W.), University Medical Center Hamburg-Eppendorf and Schön Klinik Hamburg-Eilbek; and Institute of Neuroimmunology and Clinical MS Research and Department of Neurology (M.B., L.Y.W., S.M.G., C.H.), University Medical Center Hamburg-Eppendorf, Hamburg; Department of Psychiatry and Psychotherapy (K.W., C.O.), Campus Benjamin Franklin, Charité-Universitätsmedizin Berlin, Berlin; Department of Psychiatry and Psychotherapy (H.J.G.), Ernst-Moritz-Arndt-University, Greifswald; and Institute of Psychology (S.B.), Ruprecht-Karls University, Heidelberg, Germany.
Address correspondence and reprint requests to Carsten Spitzer, MD, Department of Psychosomatic Medicine and Psychotherapy, University Medical Center Hamburg-Eppendorf and Schön Klinik Hamburg-Eilbek, Martinistr. 52, 20246 Hamburg, Germany. E-mail: email@example.com
The Study of Health in Pomerania is part of the Community Medicine Research net of the University of Greifswald, Germany, which is funded by the Federal Ministry of Education and Research (Grant nos. 01ZZ9603, 01ZZ0103, and 01ZZ0403), the Ministry of Cultural Affairs, and the Social Ministry of the Federal State of Mecklenburg-West Pomerania. This work was also partly funded by the German Research Foundation (GR 1912/5-1).
Received for publication January 18, 2011; revision received October 11, 2011.
Objective: To investigate the association between childhood trauma and multiple sclerosis (MS) by comparing histories of child abuse and neglect between patients with MS and adults from the general population in a cross-sectional case-control study. Previous research has demonstrated a connection between MS and a variety of emotional stressors, but childhood trauma, which is known to have long-lasting negative consequences for physical health decades into adulthood, has not been studied.
Methods: The self-reported Childhood Trauma Questionnaire for the assessment of emotional, physical, and sexual abuse and emotional and physical neglect was administered to 234 patients with definite MS and 885 adults from the general population.
Results: After adjusting for sociodemographic factors and current depression, patients with MS scored significantly higher in all Childhood Trauma Questionnaire subscales apart from physical abuse and neglect than adults from the general population. Adjusted odds ratios for these types of childhood trauma were higher in the MS group than in controls, ranging from 2.0 for emotional neglect (95% confidence interval = 1.3–3.2) to 3.4 for emotional abuse (95% confidence interval = 2.0–5.7). Although childhood trauma was not associated with the degree of current MS-related disability, patients with MS with histories of physical and/or sexual abuse had significantly higher relapse rates than patients without early-life stress.
Conclusions: Our findings suggest an association between childhood trauma and MS in this cross-sectional study. Larger prospective longitudinal studies are needed to clarify the relationship between early-life stress and the risk for MS in genetically susceptible individuals.
Abbreviations: MS = multiple sclerosis; SDMT = Symbol Digit Modalities Test; CTQ = Childhood Trauma Questionnaire; EDSS = Expanded Disability Status Scale
Multiple sclerosis (MS) is a demyelinating inflammatory and degenerative condition of the central nervous system affecting the brain and spinal cord by destroying the myelin sheath and neurons, resulting in plaques or scars at the damaged sites. Although the symptoms of MS vary considerably, common symptoms include limb weakness, poor balance, and cerebellar symptoms, as well as sensory symptoms, loss of vision, or diminished bladder or bowel control based on the location of lesions. Neuropsychiatric symptoms such as fatigue, depression, and cognitive deficits are common and less well understood. The disease is characterized by a relapsing-remitting or chronic progressive course, frequently leading to severe disability (1). Although its etiology is not known, there is mounting evidence that both genetic susceptibility and environmental factors may play a role (2–5). Among the environmental factors, psychological or emotional stress has been linked to MS since the 19th century (6), and most patients with MS believe that stressful events can cause or contribute to their exacerbations (7). In line with this notion, numerous prospective studies have consistently shown an association between stressful life events and subsequent exacerbations (8,9). Moreover, emotional stress was reported to be related to the development of MS in several case-control studies (10,11). A recent longitudinal study (12) based on the follow-up of nationwide and population-based cohorts investigated whether the death of a child increased the risk of MS in bereaved parents. Parents exposed to this well-defined stressor had a significantly elevated risk to develop MS compared with parents without child loss, and this risk increased with the length of the follow-up period (12).
These findings suggest that severe stress is a likely candidate in the complex pathogenesis of MS and that some of its devastating effects may only be seen in the long term. One of the most extreme forms of traumatic stress is childhood trauma, which is known to have long-lasting negative consequences for both mental and physical health decades into adulthood (13–15). However, child maltreatment defined by the World Health Organization as “all forms of physical and/or emotional ill-treatment, sexual abuse, neglect or negligent treatment or commercial or other exploitation, resulting in actual or potential harm to the child’s health, survival, development or dignity” (16) has not yet been investigated in MS. This is surprising for several reasons. First, previous studies have suggested that adverse childhood experiences are related to a number of chronic somatic diseases involving inflammatory processes, particularly cardiovascular disease and asthma (15,17,18). Second, childhood trauma was found to increase the likelihood of hospitalization with a diagnosed autoimmune disease such as MS decades into adulthood (19). Finally, previous research has indicated that traumatic stress in general and childhood adversities in particular are independently related to a proinflammatory state in later life (20,21). This proinflammatory state may contribute to and sustain the central nervous system–confined inflammatory processes characteristic of MS (1,4,5).
Taking these findings and considerations into account, the objective of our study was two-fold: a) to investigate the association between childhood trauma and MS by comparing histories of child abuse and neglect between patients with MS and individuals from the general population in a case-control design and b) to relate childhood trauma to traditional end points in MS research, that is, age at symptom manifestation, relapse rate, disease progression, and neurologic impairment as assessed by measures of MS-related disability.
Procedure and Participants
The MS sample was recruited at the Multiple Sclerosis Outpatient Clinic of the University Medical Center Hamburg-Eppendorf. Because we intended to obtain a representative sample of patients with MS with different disease courses and levels of impairment, we chose the following as inclusion criteria: definite MS according to the revised McDonald criteria (22,23), age between 18 and 50 years, and lack of severe cognitive impairment as assessed by the Symbol Digit Modalities Test (SDMT; see in the next section). All patients with definite MS who attended the outpatient clinic in 2009 and met the age criteria were invited to participate and sent the self-report measure for the assessment of childhood trauma. At their outpatient visits, all patients underwent a thorough neurologic examination including standardized clinical tests (see the next section for details). We also recorded disease-related variables such as age at first symptom manifestation (MS onset) and relapse rate through the whole disease course as derived from patient report and medical charts archived in the clinical database of the MS center (see the next section for details). Post hoc, we had to exclude six patients because of severe cognitive impairment. Of the 334 eligible patients, 34 (10.0%) refused to participate, and 66 (19.4%) did not respond to our invitation letter, resulting in 234 participants (70.1%) of the eligible cohort. Excluded patients did not differ from the investigated cohort with respect to age, sex, age at MS onset, relapse rate, or neurologic impairment (results not presented).
The control subjects from the general population participated in the “Life-Events and Gene-Environment Interaction in Depression” study (24) representing a cross-sectional investigation nested in a community-based cohort study, the Study of Health in Pomerania in North East Germany (25). For this study, which was approved by the local institutional review board and conforms to the principles of the Declaration of Helsinki, we only included individuals not older than 50 years and without cognitive impairment (assessed by clinical psychologists). For both patients with MS and control subjects, we recorded age, sex, and educational level as proxy measures for the socioeconomic status (26). Corresponding to the German school system, educational level was categorized into less than 10 years (extended elementary school = 0), 10 to 11 years (junior high school = 1), and more than 11 years (secondary and high school = 2). All participants gave written informed consent.
The Childhood Trauma Questionnaire (CTQ) was used for the self-report of child maltreatment (27). It is a brief, reliable, and valid screening device for histories of childhood trauma including emotional, sexual, and physical abuse and emotional and physical neglect. It consists of 28 items about adverse childhood experiences that are rated on a 5-point Likert scale, with higher scores indicating a higher degree of childhood maltreatment. In addition to a dimensional scoring procedure, the manual provides threshold scores to determine the severity of abuse and neglect (none = 0, low = 1, moderate = 2, and severe to extreme = 3). Dichotomized variables (0 and 1 as absent versus 2 and 3 as present) were created for each trauma type. In line with previous research (28), severe abuse was defined in case participants who reported physical and/or sexual abuse. In independent studies, the CTQ was reported to have good reliability and validity. In addition, the five-factor model (i.e., the five subscales reflecting the different types of childhood trauma) was empirically confirmed (27,29). The psychometric properties of the German version of the CTQ were found to be similar to the original (30).
For the patients with MS, to minimize the burden of questionnaire items, current depression was estimated by a validated two-item depression screening tool (31). The questions are “During the past two weeks, have you often been bothered by feeling down, depressed, or hopeless?” and “During the past two weeks, have you often been bothered by little interest or pleasure in doing things?” A mean of 3 or higher on a 5-point Likert scale ranging from “not at all” (scored as 1) to “extremely” (scored as 5) was used as conservative estimate for current depression. In the control group from the general population, current (i.e., in the last 2 weeks) depression was measured by the Beck Depression Inventory II, which is a 21-item self-report questionnaire with high reliability and validity (32). For general population samples, the optimal cutoff score is considered to be 17 or higher (33). Current depression was used as a binary covariate (absent versus present) in subsequent analyses.
To assess neurologic impairment in the MS sample, the Expanded Disability Status Scale (EDSS) (34) was applied as the criterion standard measure to assess disability in MS. The EDSS is based on a neurologic examination and integrates neurologic functions from different domains into a sum score ranging from 0 (no impairment) to 10 (death due to MS). EDSS scores of 1.0 to 4.5 refer to people with MS who are ambulatory. In the range from 4 to 7, the score is biased toward ambulation impairment, and neuropsychiatric symptoms are poorly represented. In addition, our study used parts of the Multiple Sclerosis Functional Composite (35) assessment. This instrument adds objective measures to the EDSS in the domains of hand function, walking, and information processing. We performed the Nine-Hole Peg Test (dominant hand), a standardized test of upper extremity function. In this test, the patient picks up nine pegs, places them into holes in a plastic block, and removes them again as quickly as possible; the time required to complete this task is recorded. In addition, we performed the 25-Foot Timed Walking Test as an objective measure of lower extremity function. The oral version of the SDMT (36) was used as an objective screening measure of processing speed and attention. In this test, nine different symbols are numbered from 1 to 9, and the patient has to call out the corresponding numbers to a series of symbols presented to him/her on a sheet of paper as quickly as possible. The number of correct responses within 90 seconds is recorded. The SDMT has repeatedly been recommended as a sensitive cognitive screening device in MS research (37,38). Results of the SDMT are given as standard deviations (SDs) from an age- and education-matched healthy norm population; a value less than −2.5 is indicative of substantial cognitive impairment.
MS-related end points, that is, MS onset and relapse rates, were taken from medical charts and patient reports in retrospect. At the clinic, patients were asked about the date of diagnosis, the date of their first symptoms, and the number of relapses that they had experienced since disease onset. Whenever available, these data were confirmed by checking medical charts on record in our clinical database. If there was disagreement between patient self-report and medical charts, the data obtained from the charts were used. Moreover, we checked archived versions of letters to the patients’ primary care physician or treating neurologist from other treating hospitals in the past and letters sent from the university hospital after each visit. In addition to relapse rate, we used a simple progression index, which can be calculated by dividing EDSS scores by years of disease duration.
The data analyses were computed using the SPSS (version 18.0; SPSS Inc., Chicago, Illinois). Patients with MS and control group participants were compared by analyses of variance for continuous variables and χ2 test for categorical variables. Because both groups differed with respect to age, sex, educational level, and current depression, these variables were taken into account as potential confounders in subsequent analyses. We also calculated effect sizes (Cohen d) when possible. To determine the relationship between childhood trauma and MS, we performed logistic regression analyses with the different types of childhood trauma as dependent variables and health status (MS versus control group) as independent variables. We report odds ratios with the corresponding 95% confidence interval (CI). To assess the association between childhood trauma and MS-related end points, multiple regression analyses were run with MS-related outcomes as dependent variables controlling for age, sex, educational level, current depression, and course of MS. Significance level was set at p < .05.
The sociodemographic and clinical data of the patients with MS and the control group from the general population are presented in Table 1. Both samples differed with respect to sex, age, educational level, and current depression.
As depicted in Table 2, current depression was significantly associated with all types of self-reported childhood maltreatment with two exceptions in the MS sample (physical and sexual abuse).
Dimensional CTQ scores were significantly higher in the MS sample compared with the general population (apart from the subscale physical abuse). Significant differences remained for emotional abuse, sexual abuse, emotional neglect, and the total score when age, sex, educational level, and current depression were accounted for (cf. Table 3). Effect sizes (Cohen d) for these comparisons ranged between 0.13 (physical abuse) to 0.61 (emotional abuse). Using the categorical scoring method of the CTQ revealed a similar pattern: patients with MS reported significantly more exposure to all types of childhood trauma apart from physical abuse than the control subjects from the general population. Adjusting for age, sex, educational level, and current depression, patients with MS still were more likely to report emotional abuse, sexual abuse, emotional neglect, and severe abuse (i.e., physical and/or sexual abuse) with increases in this likelihood ranging between two-fold for emotional neglect to 3.4-fold for emotional abuse (cf. Table 4). In sex-specific analyses, we found an almost identical pattern. In women, dimensional scores and categorical CTQ data revealed that emotional abuse, sexual abuse, and emotional neglect were associated with MS. In male patients with MS, dimensional scores for and categorical rates of emotional abuse and neglect were significantly higher than those in participants of the control group, but sexual abuse was not (data not presented).
In patients with MS with either a relapsing-remitting (n = 164) or a secondary progressive course (n = 53), multiple linear regression analyses with MS-related outcomes as dependent variables indicated that childhood trauma was not associated with age at MS onset, disease progression, or the degree of current MS-related disability as assessed by EDSS, Nine-Hole Peg Test, 25-Foot Timed Walking Test, or SDMT (data not presented). However, physical abuse and emotional neglect were associated with higher relapse rate (β = 0.22, p = .033 and β = −0.31, p = .048, respectively). There were no differences between patients with MS with and without severe abuse regarding age at MS onset and functional impairment. The mean relapse rate of 0.89 (SD = 0.68) of participants reporting severe abuse was significantly higher than the mean relapse rate of 0.62 (SD = 0.54) found in those without histories of severe abuse (F = 5.4, p = .022, d = 0.44). Because of the low numbers of participants with a primary progressive course (n = 17), they were excluded from these analyses.
To the best of our knowledge, this is the first study investigating the association between all types of childhood trauma and MS. Our main finding is that patients with MS reported significantly more childhood maltreatment than adults from the general population except physical abuse and neglect. This pattern emerged using both the dimensional and the categorical scoring method of the CTQ and remained significant when age, sex, education, and current depression were accounted for. Consideration of these potentially confounding covariates is important because sociodemographic factors are differentially associated with adverse childhood experiences (13–15). In addition, adult retrospective reports of childhood trauma may be biased by current mood, particularly depression, which is frequent in patients with MS and may lead to mood-congruent memory distortions (39,40). Emotional maltreatment was more closely associated with MS than the other types of childhood trauma: the odds of having been emotionally abused was more than three-fold higher in patients with MS relative to adults from the general population (odds ratio = 3.4, 95% CI = 2.0–5.7), and the odds of emotional neglect was 2.0 (95% CI = 1.3–3.2). This finding is in keeping with recent evidence suggesting that different types of childhood trauma may predict different outcomes (41–43). Particularly, emotional abuse was found to have a significant and independent effect on adult health, and there is evidence that emotional maltreatment additionally accentuates the adverse effects of other forms of abuse and neglect, which are closely interrelated and often co-occur (41,43). In general, our findings are in line with previous research indicating that traumatic experiences in childhood negatively affect physical health in adulthood (13–15). This seems to be particularly true for conditions involving inflammatory processes such as asthma and cardiovascular and autoimmune diseases (17–19).
Among patients with MS, there were no relevant associations among childhood trauma, MS-related variables, current neurologic impairment, and disease progression as assessed by standard instruments. However, we found that patients with MS reporting severe abuse (i.e., physical and/or sexual abuse) had higher relapse rates than those without histories of severe abuse, possibly suggesting that traumatic stress in childhood may contribute to the disease course in later life. However, considering that determination of relapses was mainly derived from patients’ reports and could not be based on clear-cut definitions in concert with neurologic assessment, which is a typical shortcoming of retrospective studies, we are in need of longitudinal investigations to clarify this issue.
In sum, our data indicate that emotional and sexual childhood trauma may increase the risk of developing MS but are not related to disease course and severity (with the exception of a weak association with relapse rate). Such dissociation between disease incidence and disease severity has been reported for several well-established risk factors. For example, women have a two- to three-fold higher risk of developing MS (44), but men were reported to have a shorter time to and a younger age for conversion from relapsing-remitting to secondary progressive MS (45). Thus, being female confers a higher risk of developing MS, but the disease in males seems to be more aggressive once established. There is also evidence for a functional dichotomy between risk genes involved in MS susceptibility and those affecting the clinical phenotype (46). Conversely, other factors such as pregnancy strongly affect disease activity (47) but have no impact on disability progression (48). Thus, it is not uncommon for one factor to be linked to risk of developing MS but not to markers of disease severity in established disease or vice versa. Our finding that childhood trauma may more strongly be associated with MS susceptibility than disease progression could provide some indication that biologic mechanisms involved in pathogenesis versus progression are differentially affected by this stressor.
Potential pathways by which childhood trauma might be linked to MS have, to date, not been studied, but an effect of trauma on neuroendocrine-immune networks is a likely candidate. The nervous, endocrine, and immune systems are anatomically and functionally interconnected (49), and disturbances in the communication among these systems may play a role in MS pathogenesis (50). Interestingly, animal studies have shown that neonatal exposure to high levels of glucocorticoids (51) and early-life stressors such as maternal deprivation (52) can “prime” the immune system and lead to increased susceptibility for MS-like disease during adulthood, possibly by a lasting interference with neuroendocrine responses to inflammatory stimuli (51). In line with this notion, previous research indicated that traumatic stress in general and childhood adversities in particular are independently related to a proinflammatory state later in life (20,21). Taken together, there is indirect evidence that childhood trauma may increase the risk for MS in genetically susceptible individuals through its lasting effects on neuroendocrine-immune networks, but the exact mechanisms remain to be elucidated.
Although our study has some major strengths, for example, the assessment of childhood trauma with a psychometrically sound measure, the exclusion of individuals with cognitive impairment, and the use of a control group from the general population, some limitations merit discussion. First, because our investigation was cross-sectional, the reported associations do not allow any definite causal inferences. However, considering that the CTQ inquires about adverse events in childhood and given that the mean age at MS onset was 29.2 (SD = 7.8) years, it is very likely that the traumatic childhood experiences antedated MS onset in almost all cases. Nevertheless, we cannot rule out reverse causation, that is, patients with MS are more likely to endorse items of childhood trauma. Because humans seek explanations, a phenomenon called “effort after meaning,” it may be that patients with MS misattribute their illness to childhood maltreatment (53) particularly because effort after meaning was shown to bias memory (54).
Second, being aware of the delicate issue of asking about childhood trauma in an MS cohort, we aimed to minimize questionnaire items leading to just two screening questions for depression, which we only could compare with Beck Depression Inventory II scores of the control group. Although this drawback may compromise the validity of our results, we consider this methodological issue to be minor for several reasons. In our patients with MS, the estimate for current depression was 21.4%, similar to the 12-month prevalence of 15% to 26% reported for independent MS samples (31,55). Likewise, the 8.2% current depression rate in the control group is similar to the 4-week prevalence of 5.6% reported for unipolar depression in the German general population (56). Moreover, empirical evidence suggests that recall biases due to mood-congruent memory distortions is of minor relevance (40). Although these considerations strongly suggest that our results reflect “true” associations, we are in need of replication and prospective studies to confirm this.
Third, because we included patients with MS referred to a university department (i.e., a tertiary care setting), it remains unknown if our results can be generalized to other MS samples, for example, in primary care settings. However, the sample composition was very close to other cohort study data (57–59). In addition, the frequencies of abuse and neglect reported by our control group were very similar to those found in an independent and representative German general population study (60). Finally, some MS-related variables, that is, onset, disease duration, and relapse rate, cannot be considered highly precise data because of inherent assessment problems of retrospective studies, which can only be overcome by prospective investigations with objective criteria of worsened disability in reference to a baseline (61). However, these tools may miss numerous relapses because of insensitivity to so-called hidden symptoms, for example, fatigue. Because the numbers of relapses were taken mainly derived from patients’ reports independent of the CTQ results, we do not think that this inherent weakness in determining relapse rates biased study results.
Despite these caveats possibly limiting the generalizability of our results, we suggest that emotional childhood trauma may play a role in the complex pathogenesis of MS. Although the potential mechanisms underlying the association of MS and traumatic stress have not yet been adequately tested among patients with MS, research in this area is likely to contribute to and expand on the theory of developmental origins of adult disease and health (62). Because adverse experiences in childhood are common and MS is a chronic and often debilitating condition, future studies are warranted that focus on the impact of traumatic stress on adult chronic diseases such as MS.
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childhood trauma; multiple sclerosis; case-control study; neurobiological alterations
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