Factors affecting the health-related quality of life of patients with cervical dystonia and the impact of botulinum toxin type A injections

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1 Factors affecting the health-related quality of life of patients with cervical dystonia and the impact of botulinum toxin type A injections Jaroslaw Slawek a Andrzej Friedman b Anna Potulska b Pierre Krystkowiak c Claire Gervais c Marta Banach d Stanislaw Ochudlo e Slawomir Budrewicz f Daniel Ręclawowicz g Michal Rynkowski g Grzegorz Opala e a Department of Neurological-Psychiatric Nursing, Medical University, Gdansk and Department of Neurology, St Adalbert Hospital, Gdansk, Poland b Department of Neurology, Medical University, Warsaw, Poland c Department of Neurology, Medical University, Lille, France d Department of Neurology, Jagiellonian University, Cracow, Poland e Department of Neurology, Aging, Degenerative and Cerebrovascular Diseases, Silesian Medical University, Katowice, Poland f Department of Neurology, Medical University, Wroclaw, Poland g Department of Neurosurgery, Medical University, Gdansk, Poland Corresponding author: Dr Jaroslaw Slawek, Dept of Neurology, St Adalbert Hospital Al. Jana Pawla II, Gdansk, Poland jaroslawek@amg.gda.pl Received: October 2006 Accepted for publication: March 2007 Summary The purpose of this study was to analyze the health-related quality of life (HRQL) of patients with cervical dystonia (CD) and the impact of botulinum toxin A (BTX-A) therapy in these patients. The authors recruited 101 patients with CD, all previously treated with BTX-A. Both before and 4 weeks after injection of BTX-A the patients were assessed using the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS), a Visual Analogue Scale for pain (VAS: 0-100%), the Short Form 36 health survey questionnaire (SF-36), and the Montgomery-Asberg Depression Rating Scale (MADRS). A control group of 84 healthy volunteers was also evaluated. The patients baseline SF-36 scores were worse in all the domains when compared with those of the controls. Depression was found in 47.5% of the patients. Improvements were noticed 4 weeks after the single BTX-A injections in all the SF-36 domains, and in the VAS, TWSTRS and MADRS scores. The TWSTRS results did not correlate with any of the SF-36 subscores. Stepwise backward regression analysis revealed depression as the main predictor of poor HRQL, as well as female sex, poor financial situation, and living alone. On contrary, longer treatment with BTX-A was associated with better scores. Cervical dystonia has a marked impact on HRQL and treatment with BTX-A injections has a beneficial effect, seen both in objective and in subjective measures. Depression in CD patients is a main predictor of worse HRQL. KEY WORDS: botulinum toxin type A, cervical dystonia, health-related quality of life. Introduction Cervical dystonia (CD) is an abnormal posture of the head produced by muscle overactivity, in turn caused by a dysfunction of the central nervous system, particularly the basal ganglia. Of the various forms of idiopathic dystonia (abnormal, twisting postures resulting from prolonged and uncontrolled muscle contractions), CD is the most common. Dystonia may be focal (cervical dystonia, blepharospasm), segmental (e.g. Meige syndrome), or generalized (e.g. DYT1), and occasionally focal dystonic activity may spread from one part of the body to another. In most cases, CD is a chronic disease with onset between the ages of 40 and 60 years. The abnormal head posture is often accompanied by pain. Sensory tricks (e.g. touching the face with a hand) may give temporary relief of the symptoms. The position of the head (torticollis, laterocollis, retrocollis, anterocollis or combined) depends on the patterns of activity of different muscle groups (1-3). Treatment of dystonic posturing, and of the pain that is associated with it, has improved markedly since the introduction of botulinum toxin type A (BTX-A), which blocks neuromuscular transmission presynaptically (4,5). Most of the studies that have analyzed the clinical effectiveness of BTX-A injections were based on objective assessments using disease-specific rating scales, e.g. the Tsui Scale and the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS). Several studies have investigated the impact of CD on health-related quality of life (HRQL) and factors modifying a patient s ability to cope with this disease (6-10). In addition to their clinical problems, patients with CD may exhib- Functional Neurology 2007; 22(2):

2 J. Slawek et al. it social disabilities and impaired HRQL. The results of these studies show that factors (variable in the different studies) other than the abnormal posture itself can also contribute to the subjective discomfort. The aims of the present study were to evaluate HRQL and clinical outcome in CD patients, to identify the clinical and demographic factors associated with HRQL in these patients, as well as the impact of BTX-A therapy, and to compare the results of objective and subjective measures of HRQL. Methods Patients and controls One hundred and one consecutive patients with idiopathic CD were included in the study, which was conducted in six movement disorders centers, five Polish (n=83 patients) and one French (n=18 patients). The baseline demographics are presented in Table I. All the recruited patients had undergone treatment with BTX-A injections in the past (although not in the previous 4 months) and subjectively returned to baseline. Treatment with BTX-A is a fully reimbursed procedure both in Poland and in France. A control group of 84 healthy volunteers was also recruited. It comprised 55 women and 29 men with a mean age of 46.9 years (SD 12.6; range: years) and was matched with the group of patients for sex, Table I - Demographic data of cervical dystonia patients and controls. Cervical Control dystonia group n=101 n=84 Sex male 38% 37% female 62% 63% Age mean (SD) 49.9 (12.5) 46.9 (12.6) range Marital status single 26% 36% married 74% 64% Financial situation bad 16% 12% average 40% 43% good 42% 30% very good 2% 15% Other disorders yes 34% 55% no 66% 45% Employment employed 54% 38% status unemployed 46% 62% Place country 17% 13% of residence town 68% 57% city 15% 30% All differences between patients and controls failed to reach statistical significance, p>0.05. mean age, and other demographic determinants of HRQL (Table I). Study design and injections The demographic data and other determinants of HRQL, such as concomitant disorders, place of residence (country, town, city), marital status (single, married), employment status (employed, unemployed), and financial situation (bad, average, good, very good, as rated by the patients themselves) were recorded in questionnaires at the baseline visit. Injections were given at the baseline visit by physicians experienced in BTX-A treatment. Decisions regarding the pattern of the injections and the choice of BTX-A preparation and dosage (personalized for each patient according to the distribution and degree of the dystonic muscle activity) were based on the physicians personal experience (Table II). Clinical ratings Both before and 4 weeks after injection of BTX-A (the expected time of the peak effect), the severity of the dystonia was assessed using the severity subscale of the TWSTRS (11) and a Visual Analogue Scale for pain (VAS: 0-100%) as one of the most important, but subjective, outcome measures (12); the purpose of this was to allow comparisons to be made between objective ( purely motor) and subjective (VAS for pain and SF-36) factors. After the clinical evaluation, the patients were required to fill in the SF-36 questionnaire and the Montgomery- Asberg Depression Rating Scale (MADRS). The SF-36 questionnaire has 35 items, grouped into eight multi-item variables, and also an additional health change item. The eight multi-item variables are: physical functioning (10 items), social functioning (2 items), role limitations due to physical problems (4 items), role limitations due to emotional problems (3 items), mental health (5 items), energy and vitality (4 items), pain (2 items) and general health perception (5 items). A score from 0 (worst possible state of health measured by the questionnaire) to 100 (best possible state of health) was generated for each variable (13-15). On the MADRS, in accordance with the validation conducted by the authors of this scale, 0-11 was taken to indicate no depression, mild depression, moderate depression, and severe depression (16). All the patients seen in each single center were assessed by the same physician. Statistical methods The χ 2 test was used to compare the patient and control groups with regard to demographic variables, and t tests for independent variables were used for continuous variables. The eight multi-item variables of the SF-36 were calculated in accordance with the original instructions of the authors of the questionnaire (12). Changes in HRQL variables (i.e. SF-36 and its all items, TWSTRS, MADRS, and VAS scores) during treatment were tested using paired t tests, and unpaired t tests were used to 96 Functional Neurology 2007; 22(2):

3 Quality of life in cervical dystonia look for differences in the SF-36 dimensions between the patient and control groups. Multivariate analysis of variance (MANOVA) was performed in order to evaluate the influence of demographic as well as clinical factors on baseline HRQL. Variables included as covariates were TWSTRS, MADRS and VAS scores, illness duration and duration of previous BTX-A treatment. Categorical variables used in the analysis were sex, marital status, financial situation, place of residence, employment status, and side effects due to BTX-A therapy. Table II - Clinical characteristics of the group of 101 patients with cervical dystonia. Age at onset in years, mean (SD) 41.4 (12.5) Illness duration in years, mean (SD) 9.0 (9.2) Duration of botulinum treatment in years, mean (SD) 3.1 (2.6) BTX-A preparation Dysport 51.5% Botox 48.5% Total mean dose (SD) Dysport 557 (115.7) Botox 116 (27.0) Improvement (subjective) Yes 95% No 5% Days to improvement: mean (SD) 7.4 (4.3) Side effects Yes 19% No 81% Other disorders Yes 42% No 58% Bivariate Spearman s rank correlations were performed to look for correlations between baseline SF-36 subscores and TWSTRS, VAS and MADRS scores. The impact of BTX-A treatment was measured by calculating the effect size, which is a standardized, scale-free measure of the relative size of the effect of a therapeutic intervention (calculated as the difference between baseline and follow-up scores divided by the standard deviation of baseline scores). Effect sizes smaller than 0.2, between 0.2 and 0.5, and greater than 0.5 were considered small, moderate and large, respectively. From a clinical point of view this value gives an impression of how a given therapeutic intervention may influence the different variables describing a patient s health. With the aim of assessing the interference of demographic data with effect sizes, a multivariate ANOVA was performed, with sex, marital status, financial situation, place of residence, and employment status as nominal factors. In order to identify the impact of continuous variables on SF-36 score, a stepwise backward linear regression analysis was performed. Bonferroni correction was applied to parameters assessed using t tests. Statistical tests were considered significant at the level of p<0.05. The protocol was approved by the local ethics committee. Results Baseline The clinical characteristics of the patients included in the study are presented in Table II. The baseline assessments showed lower values on all eight variables of the SF-36 questionnaire in the CD patients when compared with the control group (unpaired t tests, Table III), the Table III - Comparison of the SF-36 dimension, MADRS, TWSTRS severity subscale and VAS for Pain scale scores in the control group, and in the patients at baseline and follow up (SD in parentheses). Control Baseline Follow up Effect size Physical functioning 72.1 (29.1)** *57.2 (29.0) 67.9 (22.9)** 0.4 (0.8) Social functioning 67.5 (26.9)** 58.0 (31.5) 70.1 (25.9)** 0.4 (0.7) Role limitations due to physical problems 54.7 (45.7)** 28.2 (40.4) 35.6 (39.4)** 0.2 (0.8) Role limitations due to emotional problems 63.1 (43.3)** 35.3 (42.1) 46.6 (41.1)** 0.3 (0.8) Mental health 59.3 (16.0)** 49.9 (20.0) 59.4 (16.7)** 0.5 (0.8) Energy and vitality 53.2 (16.9)** 46.6 (18.6) 56.9 (16.8)** 0.6 (0.9) Pain 59.2 (32.0)** 39.7 (24.1) 54.8 (23.1)** 0.6 (0.9) General health 57.9 (16.9)** 32.4 (22.4) 38.5 (18.5)** 0.3 (0.7) SF-36 (total) 65.7 (21.6)** 43.3 (19.8) 53.8 (16.5)** 0.5 (0.7) MADRS (score >11 at baseline, n=42) 21.9 (8.7) 16.9 (9.3)** 0.5 (0.7) TWSTRS severity subscale 21.9 (7.4) 15.8 (23.3)** 1.1 (0.6) VAS for pain 42.1 (26.3) 26.3 (21.2)** 0.6 (0.8) The single and double asterisks marking the p values in the control group indicate the significance of the test between the control group and baseline evaluation of the patients. The influence of botulinum treatment on outcome measures between baseline and follow up is shown in the follow-up column; *p<0.05, **p< Functional Neurology 2007; 22(2):

4 J. Slawek et al. most marked decreases emerging in the domains: role limitations due to physical problems, role limitations due to emotional problems, pain and general health perception. The women showed greatly impaired social functioning (with a mean value of 39.9 versus 55.5 in the men, p<0.03). Marital status influenced the mental health variable (mean value of 52.0 in married patients versus 64.9 in the unmarried ones, p<0.02). Financial situation influenced general health, with the lowest mean general health perception score (32.7) emerging among patients rating their financial situation as bad; the patients reporting an average, good or very good financial situation recorded mean general health perception scores of 50.8, 43.0 and 50.7, respectively (p<0.02). Depression, corresponding to a MADRS score greater than 11, was observed in 47.5 % of the patients at baseline. It was mild (score: 12-19) in 18, moderate (score: 19-28) in 15, and severe (score: 29-43) in 7 patients. At baseline, all the SF-36 items except for pain and role limitations due to physical problems showed significant decreases versus controls with concomitant increases in MADRS scores (correlation coefficients, p<0.05). The VAS for pain score correlated positively only with the SF-36 pain subscore (r=0.44, p<0.01), whereas it correlated negatively with mental health and the SF-36 total score. No significant correlation was found between any SF-36 subscore and the TWSTRS severity subscale. When performing linear regression with SF-36 as a dependent value, the independent variables included were TWSTRS severity subscale, MADRS, VAS for pain, illness duration, duration of BTX-A treatment, and age. After stepwise backward variable selection, the MADRS score emerged as the only statistically significant predictive factor. The MADRS score alone explained 44% of the variance of the SF-36 (beta = -0.67, p<0.001). The Polish and French groups of patients differed significantly in terms of their HRQL: SF-36 total score: 38.6 (SD 18.6) in the Polish patients versus 64.3 (SD 6.2) in the French patients (p<0.0001), but in the whole group normal data distribution was found and the French group of patients with CD significantly (p<0.05) differed from French controls as well. A significant (p<0.0001) difference in CD severity was found between the Polish and French groups [TWSTRS severity score: 23.2 (SD 7.2) versus 15.7 (SD 4.2), respectively], and this may explain the differences between their SF-36 scores. Follow up Ninety-five percent of patients reported at least some improvement after BTX-A. The mean TWSTRS severity subscore, VAS score, and MADRS score were lower at the follow-up visit and were significantly different from the baseline assessments (paired t tests, Table III). Follow-up assessments after BTX-A injection showed statistically significant increases in the SF-36 scores in each of the eight domains, when compared with the baseline measurements (paired t test, Table III). The level of improvement, measured as an effect size, is shown in Table III. The largest effect sizes (>0.5) were observed in the TWSTRS severity subscore, the VAS score, and the energy and vitality and pain subscores of the SF-36. Analysis of socio-demographic factors potentially impacting on effect sizes revealed an influence of place of residence and financial situation on treatment effect. Mean effect size in the general health dimension was significantly lower among patients living in towns [means: town 0.1 (SD 0.2); country 0.5 (SD 0.2); city 0.4 (SD 0.2); p<0.05, multivariate ANOVA]. With regard to the pain subscore, patients with a high standard of living (very good financial situation) recorded a mean effect size of 2.3 (SD 0.7), while this was significantly smaller among lower-income patients [ bad situation 0.6 (SD 0.3); average situation 0.7 (SD 0.2); good situation 0.4 (SD 0.3), p<0.025, multivariate ANOVA]. The reported side effects included mild dysphagia in 14% of patients, dry mouth in 2%, and mild general muscle weakness in 2%. Discussion The multidimensional profile of CD may be better assessed using scales describing not only motor dysfunction, but also the impact of the disease on everyday life, and on emotional and social wellbeing. The use of general health status measures (e.g. the SF-36) seems to be feasible, because they allow the comparison of quality of life and treatment results between patients and controls (17). Changes in Tsui Scale or TWSTRS scores as a result of BTX-A therapy do not necessarily reflect patients satisfaction and real HRQL these assessments focus mainly on motor disability and pain and other determining factors should be considered. Our study demonstrates the negative impact of CD on patients HRQL in all SF-36 domains when compared with controls (Tables I and III). The incidence of depression in our study was relatively high (47.5%) and comparable with the 47% reported by Müller et al. in their study (8); in another study, however, depression was found in only 24% of patients (18). In our study, it correlated with most of the SF-36 domains and improved after BTX-A treatment. The backward stepwise linear regression analysis showed depression to be the most predictive factor of poor HRQL in CD. Nevertheless, the size effect of BTX-A on the MADRS score was only moderate (Table III). Similar results were reported by other authors, the majority of whom speculated that depression constitutes a reaction to the presence of postural abnormalities of the head (6,19-21), but in view of the only moderate size effect on the MADRS score, depression might be considered an independent factor responsible for a patient s overall disability. Unfortunately, a variety of outcome measures have been used for mood assessment, and the differences could stem from this. In most studies Beck s Inventory was used, but in some studies, like that of Hilker et al. (7), depression was not separately evaluated at all. Treatment with BTX-A was clinically effective in all measures (TWSTRS, VAS, SF-36). Different results were obtained by Müller et al. (8). In their study, patients scored significantly worse than controls in all eight SF-36 domains at baseline, but after BTX-A treatment they improved in only two domains (energy and vitality and social functioning), despite an objective motor improvement measured on the Tsui Scale (8). Hilker et al. (7), like us, found improvements in SF-36 after BTX-A 98 Functional Neurology 2007; 22(2):

5 Quality of life in cervical dystonia treatment (energy and vitality, social functioning, mental health, limitations due to physical problems and pain). As in our study, and that of Odergren et al. (22), there was no correlation between BTX-A-induced changes in the clinical outcome scores (Tsui Scale) and the HRQL measures. The shortcomings of their study were the lack of assessment of depression and the relatively small group of patients included. Ben-Shlomo et al., in their assessment, included 289 patients with CD and found a considerable negative impact of CD on HRQL (9). However, while this group was the largest of those reported in published studies, the assessment was performed mainly using the SF-36 questionnaire sent by post, without any objective physician s evaluation. Nevertheless, the results were similar the domains most associated with poor HRQL of life were social participation, stigma, acceptance of illness, depression, and anxiety. On multivariate regression analysis the best predictors of poor HRQL were anxiety and, as in our study, depression. Patients who reported no benefit from BTX-A had a worse global severity score and had lower physical functioning and mental health scores (9). Significant BTX-A-induced improvements of single aspects of HRQL measured using the SF-36 were also demonstrated by the study of Gudex et al. (10), which is in concordance with that of Hilker et al. (7) and our study, showing the beneficial effect of BTX-A therapy on HRQL. Some discrepancies in the assessments may be due to the use of different objective clinical outcome measures (Tsui Scale in the majority of studies), and in our study TWSTRS was the main objective clinical measure. However, we used only the subscale assessing the severity of motor disability, to avoid subjective contamination of the result. This approach makes it possible to compare the value of subjective and objective outcome measures and the point of view of the patient and the physician. Unlike other forms of focal dystonia, pain is a predominant feature in CD and is reported in up to 75% of affected patients (23-25). Therefore, in our study, pain was evaluated separately as an independent outcome measure; it was found to be an important factor influencing the HRQL and the pain score improved significantly after BTX-A (with a relatively high size effect). In most studies, other non-disease related factors have been found to be unrelated to HRQL: Ben-Shlomo et al. did not find sex, age, educational level, or social support to be factors predictive of worse HRQL (9). Hilker et al. found no differences for sex and marital status, but did find that the positive response to BTX-A treatment was higher in employed patients (7). Our study found worse HRQL in the domain of social functioning among females, in that of mental health among those living alone, and in that of general health perception among those with a poor financial situation. Both the mean total SF-36 score and the role limitations due to physical problems and mental health subscores were seen to worsen both with increasing age and age at onset (p<0.05), a pattern that may be related to the effect of ageing itself. There was no correlation between changes in mean SF-36 score and the disease duration (p>0.05). Multivariate analyses highlighted the negative impact of a poor financial situation on HRQL. This could give rise to a problem of differences in HRQL between the French and Polish populations considered in our study, given the economic differences that emerged between the two groups. In fact, the overall SF-36 scores in the French group were higher, but at the same time the mean TWSTRS motor score was lower, which may indirectly explain the better HRQL found in that group. Equally, this result might reflect the impact of economic status on the overall wellbeing of patients with chronic disorders, the differences possibly also being due to the significant disproportion in mean annual national per capita income between France (23,375 USD) and Poland (5,008 USD) (source of data: Polish Chief Central Statistical Office, 2005). This may be regarded as a shortcoming of our study, but on the other hand the wide diversity of the population studied may reveal better the influence of the medical condition on HRQL itself, regardless of the economic situation of the society in which the patients live. It should be noticed that the duration of the BTX-A treatment positively correlated with the improvement of the single SF-36 domains (and particularly with the mean changes in the mental health and vitality scores, p<0.05). Comparable results were obtained by Lindeboom et al. (26). Recently, the first disease-specific questionnaire to evaluate the HRQL of patients with craniocervical dystonia (CDQ-24) was published (8). Unfortunately, as we began our investigations before the publication of this scale, we were unable to use it in this study. HRQL measurements provide useful information on the poor quality of life of patients with CD. Pain and depression seem to play an important role in deterioration of HRQL in CD patients. BTX-A injections are effective not only in improving the head posture and pain, but also the HRQL in CD after a single injection, particularly in patients with a long-term history of treatment. References 11. Nutt JG, Muenter MD, Aronson A, Kurland LT, Melton LJ. 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