Contributing factors to health‐related quality of life in multiple sclerosis

Abstract Background Health‐related quality of life (HRQoL) is lower in people with multiple sclerosis (PwMS) compared to the healthy population, psychological symptoms accompanying multiple sclerosis (MS) have a serious impact on the HRQoL of PwMS. Data regarding the subject, however, remain conflicting. Objectives To evaluate the patients' sociodemographic attributes, education, fatigue, depression, and cognitive impairment level of impact on the HRQoL for the whole cohort as well as comparing the sexes. Materials and Methods Three hundred and twenty‐two relapse‐remitting MS patients filled out the Fatigue Impact Scale (FIS), Beck Depression Inventory (BDI), MS Quality of Life‐54 (MSQoL‐54) questionnaires, cognitive impairment were identified using Brief International Cognitive Assessment for MS (BICAMS) test. The patients' data were acquired from our clinic's MS registry or from patients' files. Results Depression and fatigue were found to have the most ubiquitous and robust effect on the overall and any given subdivision of the HRQoL composite. Other factors had a slight effect on some of the subscales when the whole cohort was evaluated. When the genders were compared, differences were found on 10 domains. Conclusion Psychopathological symptoms have a more powerful influence on the HRQoL of MS patients than physical impairment, also these symptoms influence men's and women's HRQoL with different power. This invokes the need for complex and personalized care in the treatment of PwMS. Ours is the first study to show a difference between the sexes in this regard.

their everyday lifestyle. As expected, several studies have shown the health-related quality of life (HRQoL) to be affected in PwMS compared with the general population. However, when compared to other autoimmune conditions (namely rheumatoid arthritis and inflammatory bowel disease), PwMS have the lowest perceived HRQoL (Rudick, Miller, Clough, Gragg, & Farmer, 1992). Various factors have been identified over the years by several authors to have an influence on the HRQoL. Lower household income, higher EDSS score, lower score on the 9-hole-peg test, weaker coping capacity, and a more debilitating, more progressive disease course have been all linked to a lower HRQoL, and lower HRQoL has been shown to foreshadow worse survival in PwMS (Ruet et al., 2013;Lanzillo et al., 2016;Kurtzke, 1983;Solaro, Gamberini, & Masuccio, 2018).
In the past two decades, it was revealed that most PwMS have cognitive and psychological symptoms as well as physical ones and that these symptoms can develop at any stage of the disease (Glanz et al., 2007;Amato et al., 2012). The lifetime prevalence of depression in PwMS is about 50%; 43%-70% suffer from cognitive impairment (CI) and fatigue turned out to be the most common symptom of the disease, with a prevalence rate over 90% (Ben Ari Shevil, Johansson, Ytterberg, & von Bergstrom, 2014;Chiaravalloti & DeLuca, 2008). In recent years, several evaluations concluded that these psychological symptoms have a serious impact on the HRQoL independently from the patients' physical state. CI was shown to be one of the most crucial factors in patients becoming unemployed and leading to several other serious burdens (Langdon, 2011). Fatigue and depression were both shown to be individual factors that heavily worsen the HRQoL of PwMS in almost all domains of life (Benedict et al., 2005). Furthermore, some comprehensive assessments indicated that these psychological aspects of the disease play a greater role in determining the HRQoL of PwMS than physical state and other (clinical, social, and demographic) characteristics (Benedict et al., 2005).
While the merit of the above-mentioned studies is unquestionable, the independent contribution of various cognitive dysfunction and clinical disability to the quality of life is only rarely investigated.
Thus, the aims of our study were to: 1. Explore the effect of the sociodemographic and clinical aspects (age, education, sex, and disease duration), as well as the psychological aspects (fatigue, depression, and CI) of MS on the patients' HRQoL.

To determine the most important contributor(s) to MS patients'
HRQoL.
3. To further explore the potential differences between the sexes, considering that there are known differences between man and women regarding prognosis and symptoms.

| Participants and data collection
We have involved a total of 322 patients in the present study.
The patients were recruited from the MS outpatient clinic of the  (2011), (c) relapsing-remitting (RRMS-not active, treated patients) or clinically isolated syndrome (CIS-not active, not treated) disease course, (d) age 18 years or older, (e) native language was Hungarian, (f) the patients were in remission and did not receive steroid therapy for at least 30 days previous to the evaluation, (g) an Expanded Disability Status Scale (EDSS) score between 0 and 6.5. Exclusion criteria were: (a) any substance use, which may interfere with cognitive abilities or psychometric testing, (b) history of chronic alcoholism, (c) any concomitant or previous physical or psychiatric disorder other than MS that could affect the results of cognitive and/or psychiatric testing, or could affect the patients' mood with the exception of depression, (d) any neurological disorder other than MS that could influence the result of the administered psychometric tests, (e) primary-progressive (PPMS) or secondary progressive (SPMS) disease course.
The sociodemographic and clinical data of the enrolled patients were acquired from the multiple sclerosis registry of the Department of Neurology of the University of Szeged if available . For patients who were not yet in the database or were recruited from one of the other MS outpatient clinics, the data were obtained from the patient documentation delivered by the patient's attending physician.

| Physical disability
Physical disability was measured by the EDSS score (Kurtzke, 1983).
In each case, the score was determined by the patient's respective neurologist specialist at the time of enrollment. (BICAMS) test, which is a rapidly administered screening tool with high sensitivity and specificity for the detection of cognitive impairment in MS patients (Sandi et al., 2015). It consists of three subtests, namely the orally administered version of the Symbol Digit Modalities Test (SDMT), the first 5 immediate recall trial of the California Verbal Learning Test-II (CVLT-II), and the first 3 immediate recall trial of the Brief Visuospatial Memory Test-Revised (BVMT-R; Langdon et al., 2012). We considered a patient cognitively impaired if he/she had abnormal scores on at least one of the three tests administered, a criterion proposed by Dusankova et al. in 2012(Dusankova, Kalincik, Havrdova, & Benedict, 2012. A score on a given test was considered abnormal if it fell outside of the predefined normal values of said test.

| Mood
The patients' mood was evaluated by the Beck Depression Inventory II (BDI-II) questionnaire validated for Hungarian (Beck, Steer, & Brown, 1996). A patient was considered having depressive symptoms if scored at least 13 points on the test, which is in accordance with the standard cutoff point for this test (Beck et al., 1996).

| Fatigue
Fatigue was assessed by the use of the Hungarian version of the Fatigue Impact Scale (FIS) questionnaire (Losonczi et al., 2011). It consists of 40 items, each of which is scored from 0 (indicating no problem) to 4 (indicating a severe problem), providing a final scoring scale from 0 to 160. The three internal subscales of the survey examine the physical, the social, and the cognitive aspects of fatigue separately. Scoring higher means fatigue is more significantly affecting a patient's life. For example, someone with a score of 80 is affected by fatigue more than someone with a score of 20. As there is no well-established cutoff score for this test, we considered a patient to have been burdened by fatigue if one scored at least 40 points on the FIS questionnaire.

| Health-Related Quality of Life
Of the many tools available to measure HRQoL in MS, we used the MSQoL-54 questionnaire's Hungarian validated version (Fuvesi et al., 2008). This tool was specifically designed for patients suffering from MS by expanding the SF-36 survey. The questionnaire consists of 36 general questions and 18 MS specific ones, in total conceiving a 54-item instrument that contains 12 internal subscales, two singleitem measures along with two additional summary scores. We used the MSQoL-54 survey because it is a very detailed questionnaire; its basis, the SF-36 survey is widely used in healthy individuals as well, its results are independent of the assessed population and the expanded questionnaire is very sensitive to problems presenting in patients with MS.

| Statistical analysis
The most common approach to identify the impact of certain variables on an independent variable is the various forms of multivariate regressions. However, this approach might be misleading especially in those circumstances when predictors are not independent. This is especially true for the to be examined clinical and cognitive disability. Hence, in order to determine a given variable's impact on the evaluated subscale of HRQoL, we utilized the model-free, partial least squares regression (PLS) analysis. PLS successively extracts latent (Toth et al., 2017) variables from the dependent variables and the predictors in such a way that covariance between the factors and loadings is maximized. With this approach, PLS reduces the dimensionality of the data by providing a weighted linear combination of X variables to form orthogonal components that predict the dependent variable. In our analysis, the dependent variables were the subscales of the MSQoL-54 questionnaire and the preditors were the scores describing the clinical and cognitive disability. The statistical inference on the significance of the latent variable was carried out by permutation tests on the singular values of the decomposition (5,000 permutations). We regarded the parameter to have an impact on the given subscale if the variable importance of projection (VIP) score was ≥1 (Wold, Johansson, & Cocchi, 1994). The greater the score, the more important a given variable is to the model. Variables with VIP scores <1 are less important and are usually good candidates to be omitted from the model. To evaluate any differences regarding clinical and sociodemographic variables, we used one-way ANOVA and Fisher's exact test.
Regarding the comparison of the sexes, we only found a significant difference in the rate of CI; it was present in 63.7% of the men (65 patients), while 45.0% of women (99 patients; p < .002; Table 2).
We evaluated all of the examined attributes' impact on all of the 14 subscales separately, both for the whole cohort and for men and women independently. Regarding the whole population, depression   (Table 3). Chiaravalloti & DeLuca, 2008). With more than 300 patients assessed, the sample size made it possible to stratify between sexes, we confirmed our previous and other results regarding the difference of CI's prevalence between men and women (Patti et al., 2015;Sandi et al., 2017).

| D ISCUSS I ON
Regarding the combined results of men and women, our results are in agreement with recent studies to a great extent; however, some differences are present. Depression and fatigue are by far the leading predictors of perceived HRQoL in all domains (Benedict et al., 2005;Fuvesi et al., 2010). Other factors were restricted to one or two domains only; EDSS to the physical aspects, educational status to the social domain. Surprisingly, CI-in general-appears to be a minor predictor. Current results on this topic are controversial.
Many studies showed cognitive impairment to be a primary determinant of patients' HRQoL, on the other hand, some studies relying on self-reported HRQoL measures did not find CI to be a significant factor (Miller & Allen, 2010;Mitchell, Benito-Leon, Gonzalez, & Rivera-Navarro, 2005). The reason behind the inconsistency of these results is multifactorial. One possible reason is that CI affects the vocational status, thus these patients are unable to report their problems sufficiently (Benedict et al., 2005). Another reason might be that patients with serious CI many times are unaware of their deficit, sometimes even affected by euphoria and moria, which make

TA B L E 3 (Continued)
their self-reports unrealistic (Benedict, Priore, Miller, Munschauer, & Jacobs, 2001;Benedict et al., 2004) (Benedict et al., 2005). Yet another reason for cognitive impairment's minor relationship with our cohort's HRQoL might be the patients' cognitive reserve capacity. Higher levels of active and passive cognitive reserve capacity have been shown to be associated with lower levels of perceived disability, higher levels of functional health, and higher levels of well-being in patient-reported outcome surveys (Schwartz, Snook, Quaranto, Benedict, & Vollmer, 2013).
As for the gender-specific impact of MS on the patients' HRQoL, the literature is scarce. Men were found to perceive their HRQoL significantly worse than women especially in the physical and social functioning and vitality domains (Casetta et al., 2009). It was also shown that male patients face a worse prognosis in general compared with women (Greer & McCombe, 2011;Zaffaroni & Ghezzi, 2000). In addition, prospective studies have found that a worse HRQoL can be a significant predictor for the change in the patients' disability status (Nortvedt, Riise, Myhr, & Nyland, 2000).
None of these studies have investigated whether there is a difference between the factors influencing HRQoL in different sexes though. In the current literature, information about gender's effect on the HRQoL is scarce, ours is among the first studies to show a difference between the sexes regarding the factors that influence HRQoL in PwMS. As for men, their physical status and their agewhich are two naturally intertwining aspects of one's physical decline over the years, hastened by MS-had a more profound and powerful impact on more subscales than it did for women. An explanation for this could be how western societies still attribute great importance to the role of physical disability, and how a person's "value" with a visible physical disability is perceived. Despite the rapid advancement of IT technology, many jobs have emerged that require no classical physical endurance and vitality, our culture still places great value upon appearances, how a person's stature emanates efficiency and capability. Living with a visible physical disability could induce a sensation of failure to meet social standards and to cease to be the provider in a household, which could be a more serious problem for men than women (Barnwell & Kavanagh, 1997;Duval, 1984).
We hypothesize that the reason cognitive impairment solely influenced the HRQoL of men but not women is due to the fact that CI's prevalence is much higher in men, and thus its impact has reached a threshold where its burden becomes a significant factor . The presence of CI makes an MS patient more likely to get divorced, thus self-reportedly he feels a significant decline in his sexual life (Hakim et al., 2000). Also as discussed before, a person with CI is not able to pinpoint exactly the problem present (and thus generally has a better overall HRQoL questionnaire), but to an extent feels that something has changed and, as we demonstrated CI can have a negative impact on one's overall quality of life, without influencing the different, more exact subscales individually.
Having spent more time in the educational system predicted worse scores on the social HRQoL domain for men, which was expected, as it has been shown that people with higher education have better prospects at well-paying jobs, better work hours, and economic prosperity (Weintraub et al., 2011). From this higher social state, a sudden fall-may it be real or only perceived-due to a debilitating sickness can decrease the HRQoL of a PwMS to a great extent, especially for men who are still the wage-earners in many societies.

| CON CLUS ION
The concept of HRQoL is far more complex than simply the physical impact as most care models would traditionally relate. Our assessment further underlines this opinion, as we have shown that the less evaluated, yet frequently prevalent psychological burdens of the disease (particularly depression and fatigue) are the main determinants of the self-reported well-being of PwMS. We have confirmed other studies' findings (Yalachkov et al., 2019), that fatigue and depression are the main determinants of MS patients' HRQoL not only at disease onset, as previously shown (Nourbakhsh, Julian, & Waubant, 2016; when one would expect a patient to have a drop in their HRQoL, and become burdened with depression, after being diagnosed with a lifelong, degenerative disease), but years after the diagnosis as well. Therefore the evaluation and treatment of PwMS should be conducted on a much broader spectrum than regular physical and MRI examinations, even in the youngest population (Rainone et al., 2017), a pre-emptive approach is proposed. These findings invoke the need for the regular assessment of depression, fatigue, cognition, and other psychopathological aspects with a multidimensional, quantitative approach.
Also, ours is one of the first studies in the literature to show that different burdens influence the HRQoL of men and women, and with different strength. This further supports the need for the complex and personalized care for these patients, furthermore, regular psychopathological assessments and periodic feedback regarding a patient's HRQoL are urged especially since different determinants influence the HRQoL of men and women. It also proves the need for involvement of psychological and psychiatric specialists and teamwork for the proper management of patients burdened by MS, as many of these symptoms can be ameliorated and managed by not only a psychopharmacological, but by a psychotherapeutic approach as well.

| S TUDY LIMITATI ON S
One of the limitations of this study was the lack of assessment of patient's anxiety, which has been shown to be a major contributing factor to the HRQoL of PwMS (Janssens et al., 2003;Salehpoor, Rezaei, & Hosseininezhad, 2014). Another limitation is the absence of administration of detailed neuropsychological tests and evaluation of the active and passive cognitive reserve capacity of our patients, which was beyond the scope and primary focus of this article, but is nonetheless a crucial element in the long-term treatment of MS patients living with cognitive impairment. The strong points of our paper include the relatively big cohort, the wide range of variables assessed and the strong statistical model measuring every examined variable's impact on the HRQoL of our patients and novel data on the difference of predictors constituting the HRQoL of men and women.

CO N FLI C T O F I NTE R E S T
The authors report no conflict of interest.

DATA AVA I L A B I L I T Y S TAT E M E N T
The data that support the findings of this study are available from the corresponding author upon reasonable request.