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Factors affecting MS patients’ health-related quality of life and measurement challenges in Lebanon and the MENA region

Background In the Middle East and North Africa (MENA) region, few studies explored the quality of life of multiple sclerosis patients and the factors affecting it. Objective The objective of this study was to explore studies on multiple sclerosis quality of life in the MENA area through a comprehensive literature review. To validate the Multiple sclerosis international Quality of Life (MusiQoL) and Modified Fatigue Impact Scale (MFIS) in Arabic, and investigate the impact of sociodemographic and clinical variables of Lebanese multiple sclerosis patients on quality of life. Methods As part of an ongoing observational prospective research study, data from 663 stable multiple sclerosis patients were analysed. Results In Lebanese multiple sclerosis patients, the Arabic MusiQoL and MFIS seem to be accurate and valid tools with high reliability coefficients and confirmatory factor analytic indices. Variables such as age and disease type predicted multiple sclerosis quality of life, yet were significantly affected by psychosocial fatigue. The influence of sociodemographic and clinical variables on quality of life dimensions varied. Being a woman with multiple sclerosis, receiving medications and experiencing physical fatigue worsens the psychological wellbeing quality of life dimension. Conclusion Several sociodemographic and clinical variables predicted the health-related quality of life dimensions of multiple sclerosis patients in MENA. Further in-depth investigation to guide more targeted clinical management is recommended. We encourage using validated multidimensional tools to measure quality of life in MENA such as the Arabic MusiQoL.


Introduction
Multiple sclerosis (MS) affects the patients' healthrelated Quality of Life (QoL) at all disease stages. 1,2 Eckhart and colleagues theoretically defined healthrelated QoL as 'physical and mental health perceptions of positive and negative aspects of life'. 3 The construct 'health-related QoL' is subjective and multidimensional. It includes physical and occupational functions, as well as psychological and social interactions. 4 These discrete QoL components can be affected by several factors including sociodemographic and clinical ones. 5 The most significant predictors include age and sex, 5,6 disability (Expanded Disability Status Scale; EDSS) and depression. 5,[7][8][9][10][11] Often, a discrepancy between clinician and patient-perceived importance of different health-related QoL domains exists. 12 Some clinicians tend to place more importance on physical domains and less importance on mental and emotional domains when compared to patients. 12 Therefore, measuring the different patients' perceived health-related QoL components accurately is essential, especially during clinical assessment and therapy planning. It is as essential to use cross-culturally valid measures to capture variances between sociocultural groups to ensure adequate treatment plans. 13 Several QoL measures have been used with MS patients. Some are generic or MS specific, while others combine both. 2 Disease-specific MS QoL measures were developed such as the Multiple sclerosis international Quality of Life (MusiQoL) questionnaire, 14 and the Multiple Sclerosis Impact Scale-29 (MSIS-29). 15 Both have good internal consistency and test-retest reliability. While the MSIS-29 assesses the disease physical and psychological aspects, 15 the multidimensional MusiQOL assesses different MSrelated domains: activities of daily living, psychological wellbeing, symptoms, relationships, sentimental and sexual life, coping and rejection. 14 Fatigue is another incapacitating MS symptom; 16,17 it hinders the patients' physical functions and employment. 17,18 As fatigue is a multidimensional phenomenon affecting various dimensions, the two most commonly used multifactorial questionnaires are the fatigue severity scale (FSS) and the modified fatigue impact scale (MFIS). 19 While the FSS focuses primarily on the physical aspects, the MFIS reports the physical, psychosocial and cognitive aspects of fatigue symptoms. 18 MS prevalence in the Middle East and North Africa (MENA) regions is estimated to be 51.52/100,000 and is expected to increase over time. 20

Literature search
We searched Cochrane, Embase, Medline, Pubmed and Scopus databases for the MENA MS-related QoL literature. Figure 1 represents the search process and criteria followed at different stages.

Fatigue
The Arabic MFIS-21 version was used in this study. The MFIS is a modified form of the fatigue impact scale, 25 comprised of items derived from interviews with MS patients about how fatigue affects their lives. It includes physical, cognitive and psychosocial subscales ( 9, 10 and 2 items, respectively), and assesses the impact of fatigue impact on various daily activities. A total MFIS score is computed by adding the subscale scores, and can range from 0 to 84. The scale translation from English into Arabic followed the World Health Organization recommended process of instruments translation and adaptation. 26 The MFIS was translated and backtranslated by a professional translator and the corresponding author. To assess face and content validity, a panel of five bilingual experts evaluated the 21 items in Arabic, and the items were modified according to the experts' ratings and suggestions, then backtranslated. The experts included two neurologists, two nurses and one family medicine specialist. This MFIS Arabic version can be obtained from the corresponding author. The English version of the MFIS is also known to have good reliability, with Cronbach a values for the total, physical, cognitive and psychosocial scores equal to 0.92, 0.88, 0.92 and 0.65, respectively. 27

Statistical analysis
Statistical analysis was performed using SAS System's PROC CALIS (SAS Institute, 1990) and SPSS statistical software (version 24; SPSS Inc., Chicago, IL, USA). Descriptive statistical analysis was conducted on complete data (the mean and standard deviations for continuous variables, and frequency and percentages for the categorical variables). Group comparisons using independent t-tests and one-way analysis of variance (ANOVA) followed. Partial eta-squared (g 2 ) was used as an effect size estimate. Pearson's correlations were used to assess associations. Significant variables on these three sets of tests were then entered into multiple regression models as predictors. Unstandardised beta coefficients (b) are reported. P < 0.05 (two-tailed) was considered significant. Cronbach's a values were calculated. Confirmatory Factor Analyses (CFA) were performed to assess a nine-factor structure of the MusiQoL and the MFIS 3-factor structure. To examine fit, v 2 values and four measures of goodness of fit were used to assess the CFA models: (a) the Root Mean Square Error of Approximation (RMSEA); (b) the Standardised Root Mean Squared Residual (SRMR); (c) the Non-Normed Fit Index (NNFI); and (d) the Comparative Fit Index (CFI). For the measures of fit, RMSEA should not be higher than 0.10, the SRMR value should be less than 0.08, and the values of NNFI and the CFI should be above 0.90. 28,29 Results
Only three validation studies were published about MS-related QoL scales in MENA; they were all validation of the Persian QoL scales. [48][49][50] In addition, although the three previously mentioned Persian validation studies reported good psychometric properties, 48-50 these validated measures either cover one QoL dimension or are specific to particular MS-related events or symptoms. [48][49][50] Another identified gap is related to the psychometric properties of these measures. When examining the validated tools' internal structure, we found that two of the previous validation studies relied solely on calculating Cronbach's alpha only as an indicator of internal consistency; 48,49 while the third study did not address this matter. 50 In addition to reliability, measuring validity is fundamental; providing CFA evidence of validity was missing for most of the QoL tools previously used in the MENA. 51  Table 2).

Predictors of health-related QoL in MS
Multiple regression analysis was run for each dependent variable, the MusiQoL index and seven of its dimensions, yielding eight models in total. The analysis was not performed on the dimensions 'relationships with friends' and 'relationships with family' because these were not significantly associated with any variable. The models' summaries (including entered variables and results) are shown in Table  4. All tested regression models were found to be statistically significant.
When examining the MusiQoL index, the variables entered into the model predicted 41.9% of the variance. However, only psychosocial fatigue was a significant predictor (b ¼ -3.4, P ¼ 0.007). A decrease in psychosocial fatigue was associated with an improvement in the MusiQoL index.
The dimension 'activities of daily living' varied by 52.2% with the predictors entered in the model. For every one unit decrease in the EDSS score and physical fatigue, this QoL dimension improved by 4.6 (P ¼ 0.04) and 1.1 (P ¼ 0.02) units respectively. The 'psychological wellbeing' dimension had 45.3% of its' variance explained by the variables entered. This dimension seems to be negatively affected by physical fatigue, but positively affected by male sex, as opposed to women, and with the 'increase of previous DMT count'. The 'symptoms' dimension was largely associated with cognitive fatigue. For every one unit decrease in cognitive fatigue, there was a 1.4 improvement in MS symptom-related QoL (P < 0.001). Within the 'coping' dimension, higher EDSS and less psychosocial fatigue were found to be significant predictors of more coping. Finally, when exploring the 'relationship with the healthcare system' dimension, current DMT intake was associated with a 12.3 (P < 0.001) increase in this QoL dimension as opposed to no intake. Although the models about 'sentimental and sexual life' and 'rejection' were significant, none had significant predictor coefficients.

MusiQoL and MFIS psychometric properties
The reliability coefficients of the MusiQoL index score and MFIS were 0.9 and 0.96 and ranged between 0.71 and 0.94, and between 0.89 and 0.95 for its' dimensions respectively. The two instruments showed excellent internal consistency properties (Supplementary Table 5).
The CFA results and chi-square values were statistically significant for both questionnaires. RMSEA   SRMR values were 0.06 (MusiQoL) and 0.07 (MFIS). The CFI was above 0.9 in both models, and the NNFI was above 0.9 for the MusiQoL and borderline (0.8986) for the MFIS. The CFAs showed data fitting the hypothesised measurement models which suggest good psychometric validity (Supplementary Table 5).

Discussion
The findings of this study suggest one more time that health-related QoL in MS patients is multifactorial.
In addition, we showed for the first time in an Arab country that certain sociodemographic and clinical variables seem to affect particular QoL dimensions more than others. For instance, physical fatigue was associated with worse QoL, as well as several dimensions such as 'rejection'. Moreover, this fatigue form affected 'activities of daily living' and 'psychological wellbeing' dimensions only.
Our results from Lebanon are in line with the literature from developed countries and the MENA areas. 52,53 The MusiQoL index was associated with various sociodemographic, clinical and fatigue factors. Taken together, these findings are comparable to those of several previous studies. [5][6][7][8]10 However, psychosocial fatigue was the only significant predictor of how the overall health-related QoL varied in MS patients. The importance of psychosocial factors in MS was previously highlighted. 11 This is particularly relevant to Lebanon whereby its social structure is mainly collectivistic, 54 and social support is one of the primary ways by which individuals cope with stressful events. 55 One pilot study conducted on Lebanese MS patients showed that received social support had a positive association with the MusiQoL index, and with five of its' dimensions including 'psychological wellbeing' and 'coping'. 56 Other studies in MENA also highlight the importance of social support in MS. 10,57 The absence of associations between psychosocial fatigue and the MusiQoL dimensions 'relationships with friends' and 'relationships with family' could be due to the difference in the type of information captured by these two MusiQoL factors and the fatigue subscale. The MusiQoL asks about 'talking, feeling understood, and feeling encouraged', whereas the MFIS psychosocial fatigue dimension focuses on motivation to participate in social activities and limitation of ability to perform certain activities away from home.
Further research is needed to understand better the relationship between psychosocial fatigue and the QoL in MS. We recommend adding more items to the MusiQoL scale to encompass additional psychosocial aspects beyond the relationship with family and friends. These cumulative findings encourage examining these constructs in more detail to open new avenues within the therapeutic context of MS patients and ultimately improve their QoL.
Another finding worthy of further investigation is the significantly worse impact of MS on women's 'psychological wellbeing' and 'coping' QoL dimensions albeit with similar disease duration and EDSS levels as male participants, This is not the first study to report such differences in QoL perception between the sexes. 58 The three fatigue forms evaluated in this study were associated with most QoL aspects and predicted variance in several dimensions. This is similar to findings on fatigue in MS reported in developed countries by Pittion-Vouyovitch et al. (2006), also concurrent with findings within the MENA region. 10,32,34,35,59 Fatigue remains one of the most disabling MS symptom awaiting more effective therapeutic interventions.
Higher EDSS was associated with poorer MusiQoL index; it also predicted worse 'activities of daily living' and 'coping'; similar to previous findings. 8,31,32,35,36,[60][61][62] Developing interventions to improve the QoL coping dimension in MS patients with higher EDSS is necessary, with particular relevance to women in our sample.
This study has several strengths including the large sample size utilised and the validity analyses performed. It is the first study in the MENA region which validated the MusiQoL and encourages the instrument's adaptation into other countries. However, the literature search was limited to manuscripts in the English language, and some studies did not have full text available. Additional discriminant measures and test-retest reliability analysis should be performed to understand the questionnaires' properties further. Although predictors were examined, causal inferences cannot be made given the study cross-sectional nature. Finally, the impact of modifiable lifestyle factors and depression on QoL was not explored.
Both measures explored in this study could enhance clinical practice outcomes when integrated into healthcare. Characterising MS health-related QoL and a better understanding of its different dimensions will facilitate the devise of targeted care plans.

Conflict of Interests
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding
The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study received funding from the Nehme and Therese Tohme MS Center at the American University of Beirut Medical Center.

Supplemental Material
Supplemental material for this article is available online.