Longitudinal Assessment of Health-Related Quality of Life (HRQL) of Patients With Multiple Sclerosis

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1 Longitudinal Assessment of Health-Related Quality of Life (HRQL) of Patients With Multiple Sclerosis Wilma M. Hopman, MA; Helen Coo, MSc; Donald G. Brunet, MD; Catherine M. Edgar, BNSc, RN; and Michael A. Singer, MD Ms. Hopman is the Director of the MacKenzie Health Services Research Group, Queen s University, Kingston, Ontario. Ms. Coo is a Research Associate with the MacKenzie Health Services Research Group. Dr. Brunet is a Professor with the Department of Medicine, Queen s University, and the Director of the Multiple Sclerosis Clinic, Kingston General Hospital, in Kingston. Ms. Edgar is the Clinic Coordinator of the Multiple Sclerosis Clinic, Kingston General Hospital. Dr. Singer is a Professor with the Department of Medicine, Queen s University. Abstract Over the past decade, health-related quality of life (HRQL) has become an important tool for assessing health status. To evaluate factors that could influence changes in HRQL over time, we surveyed multiple sclerosis (MS) patients who had completed the Medical Outcomes Trust 36- item Health Survey (SF-36) as part of a cross-sectional analysis of HRQL in Of the 100 subjects in the original study, 45 provided follow-up surveys in The 1998 Expanded Disability Status Scale (EDSS) score was obtained from patient records. Disease severity (mild, moderate, or severe) was derived from the EDSS score. Differences from baseline scores for the eight domains and the two summary scales of the SF-36 were calculated. Patients were stratified by sex, baseline disease severity, and change in disease severity, to determine if any of these factors were associated with changes in HRQL. A significant decline in health status was observed in the physical functioning, role physical, general health, and social functioning domains and on the physical component summary of the SF-36. In contrast, slightly over half the group showed an improvement in the mental health domain. Baseline disease severity was not significantly associated with changes in HRQL. However, change in disease severity was associated with change in the role emotional domain. Also, men showed significantly more deterioration than women in the role emotional domain. There were several meaningful changes in HRQL over time in this small sample. Additional studies are warranted to investigate associated factors. This may lead to a better understanding of HRQL for MS patients, and ultimately to improved patient care. Over the past decade, health-related quality of life (HRQL) has emerged as an important health status measure. This focus is particularly relevant in view of the increasing prevalence of chronic diseases, 1 in which quality in addition to length of life is a major concern. HRQL measures capture patients assessments of the impact of illness on their ability to carry out activities and roles that are important to them. 2

2 Traditional instruments used to assess disability and disease progression, such as the Expanded Disability Status Scale (EDSS), fail to capture the range of symptoms experienced by people with MS. 3 Therefore, it is important to measure HRQL in MS patients. Research has shown that not only do EDSS scores correlate poorly with HRQL, 4 but also that psychosocial health is often unrelated to disease severity. 5 Further, patients frequently have health concerns different from those of clinicians. For example, clinicians tend to focus on physical functioning when asked to rate which areas of health are most important for assessing the impact of MS on different areas of health. In contrast, people with MS are substantially more likely to rate mental health and emotional role limitations as most important. 6 Evaluating health status among people with MS by using HRQL measures is therefore well supported. Several cross-sectional studies have examined HRQL in MS. 4,7,8 However, apart from findings from clinical trials (which often have strict inclusion criteria), little information is available about changes in HRQL. The objective of this study was to perform a longitudinal assessment of HRQL in a broader sample of people with MS, to gain a better understanding of how this measure changes over time. Methods Patients In 1994, a cross-sectional study was performed to examine HRQL among a sample of 100 patients attending the Multiple Sclerosis Clinic at Kingston General Hospital, in Kingston, Ontario. 4 Complete data were obtained on 97 individuals. It was found that the sample of MS patients scored considerably lower than an age-matched sample of the US population 9 in the domains of physical functioning, role limitations due to physical problems, and vitality. Moreover, disability as quantified by the EDSS correlated only with the physical functioning domain, suggesting that assessment of HRQL provides a broader assessment of disease burden than does the EDSS alone. This sample was considered to be representative of the wider MS population, because patients were enrolled consecutively as they came to the clinic for their annual visit. In 1998, our group decided to approach the original participants for a follow-up assessment of HRQL. After approval was obtained from the Queen s University Health Sciences & Affiliated Teaching Hospitals Research Ethics Board, a package was mailed out to 58 individuals who had taken part in the 1994 study. The package contained a letter describing the study; a consent form; two questionnaires (one to assess HRQL, the other to collect demographic information); and an addressed, stamped envelope for returning the survey forms. The other 39 individuals were not contacted for the following reasons: no longer active patients of the clinic (n = 30), deceased (n = 5), disabled to the extent that SF-36 could not be self-administered (n = 3), and concurrent neurologic disorder (n = 1). Those who were no longer active patients were not contacted, because they had moved away and were being followed through other MS Clinics. This meant that even though we could have obtained HRQL data by mailed questionnaires, the clinical data would have been unavailable to us. Instruments The Medical Outcomes Trust 36-item Health Survey (SF-36) was used to assess HRQL. This instrument can be self-administered and measures HRQL in eight domains (Table 1). Each of the eight domains is scored and transformed into a scale ranging from 0 (worst possible health status) to 100 (best possible health status). 9 A Physical Component Summary (PCS) score and a Mental Component Summary (MCS) score can be calculated using the domain scores and a published scoring algorithm. 10 The SF-36 is widely used to assess HRQL because of its welldocumented reliability and validity across different populations. 9 No neuropsychologic assessment was performed.

3 Table 1. The Eight Domains of HRQL Measurement in the SF-36* Health Survey. Physical functioning Role limitations due to physical problems (role physical) Bodily pain General health Vitality Social functioning Role limitations due to emotional problems (role emotional) Mental health *SF-36, Medical Outcomes Trust 36-Item Health Survey A research assistant abstracted the clinical information and the 1998 EDSS score, as assigned by the clinic neurologist, from the patient charts. If no updated EDSS score was available, the clinic nurse contacted the individual to schedule an appointment with the clinic neurologist. Statistical Methods All data were entered into a computer spreadsheet. Changes in HRQL were calculated by subtracting SF-36 baseline (1994) scores from follow-up (1998) scores. A negative value indicates deterioration in health status and a positive value indicates improvement. Disease severity was classified by the EDSS score as mild (< 3.5), moderate (4.0 to 6.5), or severe (> 7.0). All data were transferred to the Statistical Package for Social Sciences for Windows, version (SPSS Inc). The mean change in scores and 95% confidence intervals were computed for each of the SF-36 domains, the PCS, and the MCS. The paired-samples t-test was used to compute P values and 95% confidence intervals for the mean change from baseline. The proportions of individuals who showed an improvement, deterioration, or no change in health status were evaluated. The data were stratified by baseline disease severity (mild/moderate/severe), change in disease severity (yes/no), and sex. The Wilcoxon rank-sum test was used to test for differences in changes in HRQL by change in disease severity and by sex, as these variables had two levels. The Kruskal-Wallis test was used to test for differences in changes in HRQL by baseline disease severity, as this had three levels. These nonparametric tests were used, as most of the distributions were not normal once the data were stratified. Results with a P value of less than.05 were considered significant. Results reported for 1994 include only data from individuals for whom complete follow-up data were obtained (n = 45). Results Forty-nine of the 58 mailed questionnaires were returned. Four were not included in the analysis because current chart information was unavailable and a neurologic assessment could not be arranged. Follow-up telephone calls were made to the nine people who did not return their questionnaires. Three preferred not to participate, and six could not be contacted. The final response rate was 78% (45/58). Baseline (1994) EDSS scores and baseline scores for the eight SF-36 domains were compared between the 1994 cohort for whom complete follow-up data were available in 1998 (respondents; n = 45) and the group of 1994 participants who were not followed-up, who refused to participate, or who were ineligible for the follow-up study

4 (nonrespondents; n = 52). Nonrespondents had significantly higher EDSS scores (P =.045) and lower scores on the physical functioning (P =.002) and vitality (P =.028) domains. Table 2. Characteristics of Respondents. Age (y) (n = 45) 48.9 ± 9.5* No. (%) Sex Male 15 (33) Female 30 (67) EDSS score/disease severity Baseline (1994) < 3.5 Mild 25 (56) Moderate 12 (27) > 7.0 Severe 8 (18) Follow-up (1998) < 3.5 Mild 15 (33) Moderate 18 (40) > 7.0 Severe 12 (27) *mean ± standard deviation. EDSS, Expanded Disability Status Scale. Characteristics of respondents are given in Table 2. The ratio of women to men was 2:1, which conforms to the observed sex distribution of MS. 11 Disease severity as classified by the EDSS score changed fairly substantially over the four-year period. Figure 1. Mean SF-36 domain scores at baseline (1994) and follow-up (1998). Significant difference between baseline (1994) and follow-up (1998) score is based on paired-samples t-test., 95% confidence interval around estimated change in scores.

5 You can click on this image to see a larger version in a new browser window. A decline in health status scores was observed in all eight SF-36 domains (Figure 1 and Table 3). The decline was more than 5 points (the amount that the developers of the SF-36 consider to be clinically and socially relevant) in six domains. 9 Moreover, the decline was statistically significant in four domains: physical functioning, role physical, general health, and social functioning. The greatest mean change in SF-36 scores was observed in the physical functioning domain, in which slightly more than two-thirds of participants (68.9%) showed a deterioration in health status. Table 3. Change in SF-36 Scores Between Baseline (1994) and Follow-up (1998) (n = 45). SF-36 domain Physical functioning Mean change* to 8.8 Role physical to 0.6 Bodily pain to 3.7 General health to 8.8 Vitality to 0.7 Social functioning to 4.8 Role emotional to % CI No change No. (%) Improvement No. (%) Deterioration No. (%) 6 (13.3) 8 (17.8) 31 (68.9) 21 (46.7) 8 (17.8) 16 (35.6) 6 (13.3) 17 (37.8) 22 (48.9) 1 (2.2) 8 (17.8) 36 (80.0) 2 (4.4) 18 (40.0) 25 (55.6) 14 (31.1) 9 (20.0) 22 (48.9) 17 (37.7) 12 (26.7) 16 (35.6) Mental health to (6.7) 23 (51.1) 19 (42.2) *Mean change between SF-36 score at baseline (1994) and follow-up (1998) (SF-36 score at follow-up minus SF-36 score at baseline). SF-36, Medical Outcomes Trust 36-item Health Survey; CI, confidence interval. In terms of proportions, however, the most striking change was observed in the general health domain, in which 80% of the participants showed a deterioration in health status. Almost half (48.9%) of participants deteriorated in the social functioning domain, and nearly a third (31.1%) showed no change. Although many respondents had deteriorated in the bodily pain (48.9%) and vitality (55.6%) domains, some had improved in these domains (37.8% and 40.0%, respectively). In the mental health domain, more individuals showed an improvement than showed deterioration (51.1% vs 42.2%). However, Figure 2 (which displays the change in the PCS and MCS) reveals that changes were concentrated in the domains measuring physical health.

6 Figure 2. Mean SF-36 Summary scores at baseline (1994) and follow-up (1998)., 95% confidence interval around estimated change in scores. Stratification by baseline disease severity showed no significant differences in changes in HRQL (data not shown). However, change in disease severity over the four-year follow-up period was significantly associated with a decline in the role emotional domain (P =.032). Men also showed significantly more deterioration in the role emotional domain than women did (median change in score, 33.3 vs 0.0; P =.049). This finding was not the result of disproportionate changes in disease severity between men and women (P =.245). Furthermore, whether or not men experienced a change in disease severity, their scores on the role emotional domain tended to decline over the four-year period (median change, 33.3 for no change in disease severity; median change, 16.6 for worsening of disease severity). In contrast, role emotional scores tended to improve for women who experienced no change in disease severity (median change, +33.3) or to remain stable if the woman experienced a worsening of disease severity (median change, 0.0). Discussion Methodology Limitations Some limitations of the present study need to be kept in mind during interpretation of the results. Nonrespondents (from the previous study by the same investigators) had greater disability than respondents in terms of baseline EDSS, physical functioning, and vitality scores. It is difficult to know how this may have biased the results of this study, since baseline disease severity was not related to changes in HRQL among respondents. Another limitation concerns the responsiveness of the SF-36, or its sensitivity to change. One group of investigators concluded that the SF-36 was not all that responsive in a group of MS patients undergoing rehabilitation therapy, particularly for those with a moderate to severe form of the disease. 12 One aspect that influences the responsiveness of an instrument is whether a ceiling or floor effect is present. A ceiling effect is defined as a situation in which all or the majority of subjects achieve the maximum score because their HRQL is good; a floor (or

7 basement) effect is defined as the situation in which all or the majority of subjects attain the minimum score because their HRQL is poor. In both cases, the test does not differentiate among subjects. A substantial floor effect was seen in this sample in the role physical domain, in which 51% of the sample scored 0 at baseline. Likewise, a substantial ceiling effect was evident in the role emotional domain, in which 47% of the sample scored 100 at baseline. This means that responsiveness on the role physical and role emotional domains may have been compromised. Test Results Changes in SF-36 scores were significant in four domains. Three of these domains physical functioning, role physical, and general health are considered to be representative of physical health, as they are heavily weighted in the formula used to calculate the PCS. The fourth domain is the social functioning domain, which represents one aspect of mental health, because it is moderately weighted in the formula for the calculation of the MCS. The significant changes detected in this study are therefore more concentrated in the domains measuring physical health status. Despite this, slightly over half of respondents showed an improvement in the mental health domain. A comparable pattern has been reported by Singer and colleagues for persons with chronic illness. They postulate that these findings support the idea of a psychological adjustment process. 13 Perhaps this is why the mean change in mental health scores in the present study was minimal compared with the mean change in physical functioning scores. Another study found that older individuals with MS, while generally more disabled than their younger counterparts, also tended to focus less on their disability and more on other factors when rating their health. 14 The MS patients in the present study may have undergone a similar change in focus during the four-year interval between the baseline and follow-up assessments. The proportion of individuals who experienced a deterioration varied greatly within each domain, compared with the proportion who experienced an improvement or no change in health status. Unfortunately, the sample size was too small in this study to permit a multivariable analysis of factors that may be associated with changes in HRQL. Since only six people started interferon-beta therapy during the study period, it was not possible to do a stratified analysis by this variable, which is known to affect HRQL. 15,16 Sex Men showed a statistically significant greater deterioration than women had in the role emotional domain. Perhaps the greatest emotional impact of MS occurs at diagnosis rather than during disease progression, 17 but the data from this study indicate that this may not necessarily be the case for men. Their scores on the role emotional domain tended to deteriorate over time, whereas those of the women tended to improve if they did not experience a change in disease severity. There are conflicting reports in the literature with regard to sex differences in adjustment to chronic illness. One study found that the psychosocial adjustment to dialysis treatment was better in men than in women patients. 18 Another study found no difference between men and women patients in their psychological adjustment to a diagnosis of MS but did report that a masculine gender role orientation was associated with positive emotional adjustment. 19 Social support is known to affect health and health outcomes, 20 and the women in the present study may have had a stronger social support network than the men had. Another possible explanation is that this was a chance finding, since multiple analyses were performed, which may increase the likelihood of attaining falsely significant differences.

8 Conclusions From the results of this preliminary study, it would appear that persons with MS seem to undergo meaningful changes in HRQL over a four-year period. Additional trials should be undertaken to determine what factors are associated with these changes, as not all contributing factors can be determined by the present study. Identification of factors that contribute to either a deterioration or an improvement in HRQL could benefit the lives of people with MS. Acknowledgments This research was partially supported by a grant from the US National Multiple Sclerosis Society s Health Services Research Program. The authors wish to thank everyone who participated in this study. References 1. Schlenk EA, Erlen JA, Dunbar-Jacob J, et al. Health-related quality of life in chronic disorders: a comparison across studies using the MOS SF-36. Qual Life Res. 1998;7: Schipper H, Clinch JJ, Olweny CLM. Quality of life studies: definitions and conceptual issues. In: Spilker B, ed. Quality of Life and Pharmacoeconomics in Clinical Trials. 2nd edition. Philadelphia, Pa: Lippincott-Williams & Wilkins, 1996: Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology. 1983;33: Brunet DG, Hopman WM, Singer MA, et al. Measurement of health-related quality of life in multiple sclerosis patients. Can J Neurol Sci. 1996;23: Harper AC, Harper DA, Chambers LW, et al. An epidemiological description of physical, social and psychological problems in multiple sclerosis. J Chronic Dis. 1986; 39: Rothwell PM, McDowell Z, Wong CK, Dorman PJ. Doctors and patients don t agree: cross sectional study of patients and doctors perceptions and assessments of disability in multiple sclerosis. BMJ. 1997;314: The Canadian Burden of Illness Study Group. Burden of illness in multiple sclerosis: part II: quality of life. Can J Neurol Sci. 1998;25: Aronson KJ. Quality of life among persons with multiple sclerosis and their caregivers. Neurology. 1997;48: Ware JE, Snow KK, Kosinski M, Gandek B. SF-36 health survey manual and interpretation guide. Boston, Mass: The Health Institute; Ware JE, Kosinski M, Keller SD. SF-36 Physical and Mental Health Summary Scales: A User s Manual. Boston, Mass: The Health Institute;1994.

9 11. Duquette P, Pleines J, Girard M, et al. The increased susceptibility of women to multiple sclerosis. Can J Neurol Sci. 1992;19: Freeman JA, Hobart JC, Langdon DW, Thompson AJ. Clinical appropriateness: a key factor in outcome measure selection: the 36 item short form health survey in multiple sclerosis. J Neurol Neurosurg Psychiatry. 2000;68: Singer MA, Hopman W, MacKenzie TA. Physical functioning and mental health in patients with chronic medical conditions. Qual Life Res.1999;8: Roberts G, Stuifbergen AK. Health appraisal models in multiple sclerosis. Soc Sci Med.1998;47: Rice GP, Oger J, Duquette P, et al. Treatment with interferon beta-1b improves quality of life in multiple sclerosis. Can J Neurol Sci. 1999;26: Schwartz CE, Coulthard-Morris L, Cole B, Vollmer T. The quality-of-life effects of interferon beta-1b in multiple sclerosis. An extended Q-TWiST analysis. Arch Neurol. 1997;54: Grima DT, Torrance GW, Francis G, et al. Cost and health related quality of life consequences of multiple sclerosis. Mult Scler. 2000;6: Soskolne V, Kaplan De-Nour A. The psychosocial adjustment of patients and spouses to dialysis treatment. Soc Sci Med. 1989;29: Nichols EC. Effect of gender, age, and disease progression on emotional adjustment in multiple sclerosis patients [dissertation]. Tempe: Arizona State University; Berkman LF, Leo-Summers L, Horwitz RI. Emotional support and survival after myocardial infarction. A prospective, population-based study of the elderly. Ann Intern Med. 1992;117: