- Email: [email protected]
Quality of life in Parkinson's disease patients with motor fluctuations and dyskinesias in five European countries
Accepted Manuscript Quality of life in Parkinson’s disease patients with motor fluctuations and dyskinesias in five European countries Marlene C. Hechtner, Thomas H. Vogt, York Zöllner, Sabrina Schröder, Julia B. Sauer, Harald Binder, Susanne Singer, Rafael Mikolajczyk PII:
S1353-8020(14)00219-3
DOI:
10.1016/j.parkreldis.2014.06.001
Reference:
PRD 2355
To appear in:
Parkinsonism and Related Disorders
Received Date: 10 December 2013 Revised Date:
21 May 2014
Accepted Date: 1 June 2014
Please cite this article as: Hechtner MC, Vogt TH, Zöllner Y, Schröder S, Sauer JB, Binder H, Singer S, Mikolajczyk R, Quality of life in Parkinson’s disease patients with motor fluctuations and dyskinesias in five European countries, Parkinsonism and Related Disorders (2014), doi: 10.1016/ j.parkreldis.2014.06.001. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Quality of life in Parkinson’s disease patients with motor fluctuations and dyskinesias in five European countries Marlene C. Hechtner*a,b,c, Thomas H. Vogtd, York Zöllnere, Sabrina Schröderf, Julia B. Sauerg, Harald Bindera, Susanne Singera,h, Rafael Mikolajczyki,j (a) Institute of Medical Biostatistics, Epidemiology and Informatics (IMBEI), University Medical Centre, Johannes Gutenberg University Mainz, Germany
(c) German Cancer Research Center (DKFZ), Heidelberg, Germany
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(b) German Cancer Consortium (DKTK), Heidelberg, Germany
(d) Department of Neurology, University Medical Centre, Johannes Gutenberg University Mainz, Germany (e) Department of Health Sciences, Faculty of Life Sciences, Hamburg University of Applied Sciences (HAW), Germany (f)
Department of Neurology, Skåne University Hospital, Lund, Sweden
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(g) Department of Psychology, University of Georgia, Athens, Georgia, USA
(h) Department of Psychosomatic Medicine and Psychotherapy, University of Leipzig, Germany Department of Epidemiology, Helmholtz Centre for Infection Research, Braunschweig, Germany
(j)
Hannover Medical School, Hannover, Germany
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(i)
*corresponding author: Marlene Hechtner
University Medical Centre of Johannes Gutenberg University
Institute of Medical Biostatistics, Epidemiology, and Informatics (IMBEI)
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Obere Zahlbacher Straße 69, 55131 Mainz, Germany Phone: ++49 6131 172433, Fax: ++49 6131 172968
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Email: [email protected]
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ACCEPTED MANUSCRIPT Abstract Background: Little is known about the relationship between specific subtypes of treatmentassociated motor complications and different domains of health-related Quality of Life (QoL) in patients with Parkinson’s disease (PD). Larger studies that investigate these aspects within a cross-cultural setting are scarce. Objective: To assess QoL and its association with on-off fluctuations, peak-dose dyskinesias,
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biphasic dyskinesias, and off-dystonias in PD patients from five European countries.
Methods: Data from 817 PD patients were collected cross-sectionally in France, Germany, Italy, Spain, and the UK. QoL was measured with the generic EuroQoL 5-Dimension questionnaire (EQ-5D) and the disease-specific Parkinson’s Disease Questionnaire-39
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(PDQ-39). Multivariable linear regression analyses were performed to test the associations of motor complication subtypes with QoL.
Results: Thirty-three percent of the patients (varying from 23% in Italy to 58% in France)
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suffered from motor complications, either a single subtype or a combination of different subtypes. On-off fluctuations were associated with a 7.1 percentage point decrease in the EQ-5D (p<0.001) and a 3.6 percentage point deterioration in the PDQ-39 (p=0.01). Dyskinesias were not seen to affect global QoL scores, but had detrimental effects on the PDQ-39 dimensions activities of daily living, cognitions, stigma, and bodily discomfort. Patients from Spain, Italy, and France had lower global QoL scores in the multivariable
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analyses than patients from Germany and the UK.
Conclusion: Motor complications, primarily on-off fluctuations, may impact QoL in PD patients. This substantiates the importance of clinical strategies targeting the prevention,
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delay of onset, and management of motor complications in PD patients.
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ACCEPTED MANUSCRIPT Introduction Dopaminergic medication, especially levodopa, is the current gold standard symptomatic treatment of Parkinson’s disease (PD) [1-3]. However, as a side effect of its long-term use, motor complications arise and manifest themselves in the form of motor fluctuations or dyskinesias. Their etiology is attributed to a combination of the loss of striatal dopaminergic neurons during disease progression, the change in drug pharmacodynamics, and the
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pulsatile stimulation of dopamine receptors by short-acting dopaminergic agents such as levodopa [4,5,6]. Along with non-motor symptoms, motor complications have been one of the major challenges in the management of PD patients.
The incidence of motor complications increases with the duration of chronic dopaminergic
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stimulation. Due to the increase in life expectancy in PD patients, and the subsequent prolonged course of PD, there has been a rise in the frequency of motor complications [7]. After one to two years of treatment with levodopa, approximately 46% of PD patients
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experience motor fluctuations and 26% experience dyskinesias. After four to six years the percentages are 42% and 39%, respectively. From nine to 15 or more years 70% and 88% of the patients experience motor fluctuations and dyskinesias, respectively [8]. Motor fluctuations and dyskinesias can manifest in several ways. A common subtype of motor fluctuations are on-off fluctuations. On-off fluctuations are characterized by sudden and unpredictable shifts between hyperkinetic (on) and hypokinetic (off) states. These shifts
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tend to be unrelated to the timing of the administration of the dopaminergic agent [5,9,10]. Alternatively, the most common form of dyskinesias, peak-dose dyskinesias, arises at the peak of the dosing cycle corresponding to when the drug-derived dopamine levels are at their greatest [9]. Biphasic dyskinesias occur both at the beginning and at the end of the drug
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response cycle, the latter often being more prolonged and severe [4,10]. Dyskinesias that manifest during off periods are known as off-dystonias. This subtype is frequently accompanied by severe disability and pain [4,9].
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As subtypes of motor complications differ in their clinical presentation and frequency it may be assumed that different subtypes are perceived in different ways by the patients. Accordingly, they may have distinct effects on various aspects of the patients’ health-related quality of life (QoL). Understanding these associations in greater detail could help clinicians to optimize the differentiated assessment and medical management of motor complications and, thus, minimize respective impairments of the patients’ QoL. Although a number of studies have already examined the association of motor complications and QoL [11], the applied methods are very heterogeneous, sample sizes are often small, and the resulting evidence is inconclusive. There are a lack of large studies that discriminate between specific subtypes of motor fluctuations and dyskinesias and their impact on global 3
ACCEPTED MANUSCRIPT QoL and different QoL domains in PD patients. This might, in part, be attributed to the major focus of research in the last years on non-motor symptoms and complications. Furthermore, as cross-cultural studies on QoL in PD are scarce, little is known about the relationship between the country and the QoL of PD patients. The aim of the present work was to analyze the association of four subtypes of motor complications (on-off fluctuations, peak-dose dyskinesias, biphasic dyskinesias, and off-
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dystonias) with QoL in a large sample of PD patients from five European countries. The primary outcomes were general and disease-specific QoL. Secondary outcomes comprised of different QoL dimensions as well as the effect of the country of residence on the patients’ QoL.
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Material and methods Data source and design
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The Parkinson’s Disease Specific Programme (DSP), a large multi-sponsor market research program suite conducted by Adelphi Real World, provided the data for this secondary analysis of PD patients from France, Germany, Italy, Spain, and the UK. The full DSP methodology has been described previously [12].
Data were collected cross-sectionally in clinical practice settings via nationally representative samples of specialized physicians (neurologists, plus geriatricians in the UK) and their PD
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patients between March and July, 2008. Physicians were selected according to specialty, location, personal responsibility for treatment decisions, and number of patients. They completed patient record forms (PRF) for ten consecutive PD patients. All patients with PD, as diagnosed by their physician, were eligible for inclusion in the study and were asked to fill out a complementary patient self-completion questionnaire (PSC). No further selection
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criteria were applied.
In total, 817 patients were included in our analyses. Thirty patients were excluded: 14 for
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whom no PRF was filled out and 16 who did not complete any of the QoL questionnaires in the PSC. All responses were anonymous to preserve doctors` and patients` confidentiality. The study protocol followed ethical procedures, including written informed consent of all study participants allowing anonymous and aggregated reporting of research findings based on the questionnaires employed. For this type of research, ethical approval was waived. It was conducted in adherence with the European Pharmaceutical Market Research Association (EphMRA) code of conduct and the US Department of Health and Human Services (HIPAA) standards.
Instruments 4
ACCEPTED MANUSCRIPT The presence, severity, and frequency of the four subtypes of motor complications were assessed in the PRF. Age, gender, Hoehn and Yahr (HY) stage (measured during on-time), and disease duration since diagnosis were also recorded in the PRF. Two QoL questionnaires were part of the PSC, the generic EuroQoL 5-Dimension (EQ-5D) questionnaire [13] and the disease-specific Parkinson's Disease Questionnaire-39 (PDQ-39) [14]. Both instruments have shown good validity and reliability in previous research in PD
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patients [15,16]. The EQ-5D descriptive system is comprised of five items, representing the dimensions mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each item is rated on a three-point scale (no problems, some problems, and severe problems). QoL can then be expressed as a single index value. For the calculation of the index score
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(IS), we applied a European-based preference value set [17]. The range of possible values is 0 (poor QoL) to 1 (good QoL).
The PDQ-39 comprises 39 items, each rated on a five-point scale (never, occasionally,
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sometimes, often, always). The scoring algorithm results in one summary index (SI) score and eight subscores, comprising the dimensions mobility, activities of daily living (ADL), emotional wellbeing, stigma, social support, cognitions, communication, and bodily discomfort [18]. PDQ-39 scores range from 0 to 100. Contrary to the EQ-5D lower values indicate better QoL.
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Analysis
We performed multivariable linear regressions to evaluate the association of each subtype of motor complications with QoL. All multivariable models were adjusted for age, gender, HY stage, disease duration, and country.
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Primary QoL outcomes were the EQ-5D IS and the PDQ-39 SI. To facilitate the comparison of the regression coefficients (β) across the QoL instruments the EQ-5D IS was rescaled from 0 (poor QoL) to 100 (good QoL). For the primary hypotheses, the association of motor
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complication subtypes with QoL, the global significance level was set at 5% and was adjusted per outcome using a Bonferroni correction. A difference was considered statistically significant if p<0.025.
The impact on PDQ-39 dimension scores as well as the effect of specific countries on QoL were considered secondary outcomes. These analyses were regarded as explorative, and the p-values of the corresponding regression models are presented for descriptive reasons only. Normal distribution of the outcome scores and correlation of covariates were checked by visual inspection of Q-Q plots and correlation coefficient tables, respectively. No strong deviations or correlations were found. 5
ACCEPTED MANUSCRIPT We performed sensitivity analyses that utilized the same models but included the severity of the respective motor complications (not present/mild/moderate/severe) in order to explore if there is a change in effect with different severity stages. In addition, we performed tests for linear trend within multivariable general linear models. A potential impact of mood disturbances and cognitive condition was examined by using subgroup analyses in which patients with present symptoms of depression and/or cognitive impairment were excluded.
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All statistical analyses were performed using the software programs SPSS© for windows version 20.0 (SPSS Inc., Chicago, Illinois, USA) and SAS for windows 9.3 (SAS Institute Inc., Cary, NC, USA).
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Results Description of the sample
The sample comprised 817 individuals with PD. Characteristics of the patients are shown in
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Table 1. Italian patients were the youngest with a mean age of 63.7 years (standard deviation (SD) 8.3) and had the shortest disease duration with a median of 2.2 years (interquartile range (IQR) 0.9-4.3). Patients from the UK were the oldest with a mean age of 69.6 years (SD 9.7). French patients had the longest median disease duration (5.5 years, IQR 3.0-9.8). The distribution of gender was similar across all countries. Mean HY scores ranged from 1.8 (SD 0.8) in Spain to 2.3 (SD 1.0) in Germany.
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Twenty percent of all patients suffered from a single motor complication, 10.0% from two, 2.3% from three, and 0.5% from all four types of motor complications. When present, on-off fluctuations occurred with a median frequency of 14.0 (IQR 7.0-21.0), peak-dose dyskinesias 14.0 (IQR 7.0-22.8), biphasic dyskinesias 12.0 (IQR 10.5-24.5), and off-dystonias 7.0 (IQR
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7.0-14.0) times per week. Twenty-eight percent of all patients had off-times. In patients who suffered from at least one subtype of dyskinesia, the median percentage of on-time with dyskinesias was 10.0% (IQR 10.0-34.0). Comparing the countries, on-off fluctuations were
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most frequently observed in France (45.0%) and were least common in Italy (15.6%). French patients also reported the highest proportion of peak-dose dyskinesias (32.5%), contrasted with only 10.5% in Italy. The prevalence of biphasic dyskinesias and off-dystonias were comparable among all countries. The mean EQ-5D IS of the total sample was 0.7 (SD 0.2) based on the ratings in the dimensions mobility (33.9% of the patients reported no, 64.8% some, 1.2% extreme problems), self-care (55.3% no, 39.9% some, 4.8% extreme problems), usual activities (36.4%, 57.8% some, 5.8% extreme problems), pain/discomfort (45.4% no, 51.1% some, 3.4% extreme problems), and anxiety/depression (54.1% no, 41.6% some, 4.3% extreme
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ACCEPTED MANUSCRIPT problems). The mean PDQ-39 SI was 25.4 (SD 18.5). The scorings of the PDQ-39 dimensions are listed in Table 1.
Multivariable Analyses In the multivariable regression models, the presence of on-off fluctuations was significantly associated both with poorer EQ-5D IS (β=-7.1, p<0.001) and PDQ-39 SI (β=3.6, p=0.01).
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None of the dyskinesia subtypes had a significant effect on the EQ-5D IS or the PDQ-39 SI (Table 2).
With regard to the PDQ-39 dimension scores, on-off fluctuations affected mobility (β=8.1, p<0.001) and ADL (β=7.3, p<0.001). Peak-dose dyskinesias were negatively associated with
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the dimensions ADL (β=5.9, p=0.01) and cognitions (β=4.0, p=0.03). Biphasic dyskinesias had a comparably strong detrimental effect on stigma (β=12.6, p=0.01). An effect of offdystonias was observed only on bodily discomfort (β=7.4, p=0.02) (Table 3).
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Sensitivity analyses considering motor complication severity indicated that compared to patients without on-off fluctuations the detrimental effect of on-off fluctuations was greater in patients with more severe complications (mild: β=-6.0, p<0.01; moderate: β=-9.0, p<0.001; severe: β=-3.2, p=0.58). A linear trend was, however, not confirmed in the trend analysis (p=0.48). The same was true for the severity of on-off fluctuations and the PDQ-39 SI (mild: β=2.9, p=0.09; moderate: β=5.4, p=0.01; severe: β=7.7, p=0.1; test for linear trend p=0.07).
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In subgroup analyses that excluded patients with present symptoms of depression and/or cognitive impairment the results did not notably alter. On-off fluctuations were associated with poorer EQ-5D IS (β=-6.4, p=0.003) and PDQ-39 SI (β=4.5, p=0.01) whereas dyskinesias did not impact QoL.
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Based on the estimated effects of the different countries on QoL in the multivariable analyses, the ranking from best to worst EQ-5D IS was: Germany, UK, France, Italy, and Spain (all differences compared to Germany p≤0.01). The country ranking from best to worst
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PDQ-39 SI was: UK, Germany, Italy, Spain, and France (UK compared to Germany p=0.03). Regarding the PDQ-39 dimension scores. A similar pattern was observed with comparably better QoL ratings in Germany and the UK and lower scores in Spain, Italy, and France (Table 4).
Discussion This is, to our knowledge, currently the largest study investigating the influence of different subtypes of motor fluctuations and dyskinesias on general QoL, disease specific QoL, and specific QoL dimensions simultaneously across five countries in Europe. Understanding the contribution of specific motor complications to different aspects of QoL may help minimize 7
ACCEPTED MANUSCRIPT the impact of these complications on patients’ lives. Due to the inconclusive evidence on these associations, large studies are needed. Our representative sample of 817 PD patients provided real-world data on the clinical presentation and QoL of PD patients in Europe. The multinational design allowed comparisons of the QoL of PD patients across France, Germany, Italy, Spain, and the UK. The results of our analyses show that the presence of on-off fluctuations had a detrimental
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impact on the QoL of PD patients, whereas the presence of peak-dose dyskinesias, biphasic dyskinesias, or off-dystonias did not change the patients’ global QoL scores significantly. A detrimental effect of on-off fluctuations is explainable due to the unpredictable occurrence of off-times and the abruptness of the transitions between on- and off-times. The interruptive
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nature of on-off fluctuations can force patients to give up former activities. This effect was reflected in the negative impact on the dimensions ADL and mobility. Moreover, motor fluctuations are often associated with non-motor fluctuations in mood, sensory, and
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autonomic symptoms that might, in turn, impair QoL [19,20].
Some investigators perceive dyskinesias to be less disabling for the patients as most dyskinesias occur in the on medication state or at the threshold of the on state [21]. As expected no significant association of dyskinesias was observed with the global QoL scores. Nevertheless, our data suggests that dyskinesias may at least impact single QoL domains. The detrimental effect of peak-dose dyskinesias on ADL might arise from the clinical
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presentation in the form of choreic or choreoathetotic movements that affect the upper limbs, face, neck, and trunk [4] which in turn may cause physical disability. In which way this is also causative for the association with cognitions remains unclear. Biphasic dyskinesias presenting as a mixture of choreic, ballistic, or dystonic movements that are often more
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prominent in the lower limbs [4], seem to be especially troublesome to the patients’ perception of stigma. Off-dystonias that occur in the off state might not impact global QoL significantly due to their short duration [21]. Nevertheless, their painful character is reflected
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in their comparably high association with the bodily discomfort dimension. Unfortunately, comparison of our results with previous studies was difficult. Published studies on the association of different types of motor complications with QoL show a heterogeneous picture, and methods of assessment vary considerably between the studies. There is also large heterogeneity concerning clinical characteristics of the samples as well as the methods applied for the analyses (e.g. adjustment for confounders). For comparison of the results concerning our primary objective, we considered only studies that used the same QoL measures, distinguished subtypes of motor complications, and applied multivariable analyses.
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ACCEPTED MANUSCRIPT A cross-sectional study on 130 PD patients in the UK found poorer PDQ-39 SI in patients with on-off fluctuations that remained a significant predictor for QoL when applying a stepwise linear regression (β=0.5, p<0.001) [22]. Similar to our results, the association of dyskinesias with global QoL did not meet the significance threshold. Our findings were further supported by two cross-sectional studies that were conducted within the framework of the European Cooperative Network for Research, Diagnosis and Therapy of Parkinson’s
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Disease (EuroPa): in these studies comprising 100 Austrian [23] and 70 Italian [24] PD patients, motor fluctuations significantly worsened the EQ-5D IS in multivariable analyses (β=-9.9, p=0.04 and β=-10.3, p=0.02 respectively). Dyskinesias showed no effect. In contrast to our findings, some studies showed a detrimental effect only of dyskinesias but not of motor
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fluctuations on the PDQ-39 SI in multivariable analyses [21,25]. Other multivariable evaluations found neither an effect of motor fluctuations nor of dyskinesias on the EQ-5D IS [16-28].
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Regarding the association of motor complication subtypes with PDQ-39 dimension scores, only one study by Chapuis and colleagues including 143 PD patients in France was found [21]. Unfortunately, comparability is limited, as these analyses were not adjusted for potential confounders and these patients had longer disease duration, higher prevalence of motor complications, and worse QoL scores compared to our sample. Nevertheless, the negative associations of on-off fluctuations with mobility and ADL in our study were consistent with the
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French study, which not only found an impact on these dimensions but also on stigma and communication. We found a negative association of peak-dose dyskinesias with ADL and cognitions; Chapuis et al. reported no respective effect on ADL, but also on cognitions, mobility, and emotional wellbeing. In our study, biphasic dyskinesias had the comparably
study,
but
they
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strongest negative association with the dimension stigma. This was also true in the French additionally
substantiated
associations
with
mobility,
ADL,
and
communication. Our results suggested that off-dystonias affect bodily discomfort. In the
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French study, off-dystonias worsened the dimensions social support and communication. We found that the likelihood of having comparably good QoL scores was higher in Germany and the UK. Poorer QoL was more likely to be observed in France, Italy, and Spain. Comparing the cost per case of PD and high-level indicators of the respective health care systems, no evidence for an explanatory pattern could be identified [29,30]. To what extent those differences might also be due to non-considered clinical characteristics, or to different attitudes, behaviors, and cultural aspects cannot be ascertained with confidence. No study was available which allowed for comparisons of country differences in EQ-5D and PDQ-39 scores of European PD patients.
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ACCEPTED MANUSCRIPT Our study has several limitations. The DSP IV study was designed as a real world observational study. Therefore, no strict selection criteria regarding the standardization of PD diagnosis, the assessment of motor complications, and the severity staging of motor complications were applied. This may cause some variability and impact the internal validity of our data. A benefit of this design is, however, the good representativeness of patients and
managed for PD by specialized physicians.
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physicians reflecting the real world treatment practice of patients who are diagnosed and
Another limitation refers to the consideration of confounders. We pre-specified the set of covariables that we used for adjustment. The relatively small absolute frequencies of the more rare subtypes of motor complications restricted the possible amount of adjustment
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variables from a statistical point of view. All analyses were adjusted for age, gender, HY stage, disease duration, and country. Further potentially relevant factors such as age at disease onset, duration and dose of dopaminergic therapy, duration and severity of disease
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at time of initiating drug therapy, clinical phenotype, cognitive impairment and mood disturbances were not considered in our main analyses. This was (i) either because the study data did not contain the respective information, or (ii) the variable was considered rather to be a predictor for QoL or causal factor on the pathway than a confounder, or (iii) the interrelation among some of these variables was considered too strong. Cognitive impairment and mood disturbances were further examined in subgroup analyses. Excluding
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patients with symptoms of depression and/or cognitive impairment yielded consistent results. The motor complications observed in our sample were mainly mild or moderate limiting the generalizability of results for patients with more severe motor complications as well as the power of the linear trend tests. To what extent our results might be influenced by differences
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in the duration of the motor complication subtypes could not be estimated, since this was not assessed in the study data.
In conclusion, motor complications, primarily on-off fluctuations, may adversely affect global
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QoL in patients with PD. Moreover, on-off fluctuations and different subtypes of dyskinesias impact different domains of their QoL. This substantiates the importance of clinical strategies targeting the prevention, delay of onset, and management of motor complications in PD patients. Health care providers should be sensitized to the specific impairments of patients presenting with different types of motor complications.
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ACCEPTED MANUSCRIPT Acknowledgements The Adelphi PD Specific Programme is an independent study conducted by the Adelphi group on behalf of Solvay Pharmaceuticals. M. Hechtner was an intern, Y. Zoellner and S. Schroeder were employees of Solvay Pharmaceuticals (now Abbott) at the time the research hypotheses were developed and the first analyses were run, all of which were completed under the banner of the authors’ current affiliations. This research received no grant,
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sponsorship or other financial support. We thank Adelphi and Solvay Pharmaceuticals for
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providing the data. The authors declare no conflicts of interest in preparing this article.
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related quality of life and its determinants in Parkinson's disease: results of an Italian cohort study. Parkinsonism Relat Disord 2011;17:265-9. [25] Reuther M, Spottke EA, Klotsche J, Riedel O, Peter H, Berger K, et al. Assessing health-related quality of life in patients with Parkinson's disease in a prospective longitudinal study. Parkinsonism Relat Disord 2007;13:108-14. [26] Winter Y, von Campenhausen S, Popov G, Reese JP, Balzer-Geldsetzer M, Kukshina A, et al. Social and clinical determinants of quality of life in Parkinson's disease in a Russian cohort study. Parkinsonism Relat Disord 2010;16:243-8.
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ACCEPTED MANUSCRIPT [27] Bach JP, Riedel O, Klotsche J, Spottke A, Dodel R, Wittchen HU. Impact of complications and comorbidities on treatment costs and health-related quality of life of patients with Parkinson's disease. J Neurol Sci 2012;314:41-7. [28] Rodríguez-Violante M, Cervantes-Arriaga A, Corona T, Martínez-Ramírez D, MoralesBriceño H, Martínez-Martín P. Clinical Determinants of Health-related Quality of Life in Mexican Patients with Parkinson's Disease. Arch Med Res 2013;44:110-4.
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[29] Organisation for Economic Co-operation and Development (OECD). OECD.Stat Extracts. [accessed 2010 Jul 10]. Available from: URL: http://stats.oecd.org/Index.aspx. [30] Andlin-Sobocki P, Jönsson B, Wittchen HU, Olesen J. Cost of disorders of the brain in
Table captions
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Europe. Eur J Neurol 2005;12(Suppl 1):1-27.
Table 1.
Demographic and clinical characteristics of the study sample (N=817)
Table 2.
Multivariable linear regression analyses of the association of motor complications with global QoL scores.
Table 3.
Multivariable linear regression analyses of the association of motor complications
Table 4.
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with PDQ-39 dimension scores.
Multivariable linear regression analyses of the association of country with global
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QoL scores and PDQ-39 dimension scores.
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ACCEPTED MANUSCRIPT Table 1. Demographic and clinical characteristics of the study sample (N=817)
a
Mean (SD) 66.5 (9.7)
439
53.8
40 288 256 108 125
4.9 35.3 31.3 13.2 15.3
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25,2 b 54.1 b 39.5 b 6.3 14,9 b 55.7 b 41.0 b 3.3 2,8 b 36.4 b 54.5 b 9.1 6,0 b 73.5 b 20.4 b 6.1
0.65 (0.23) 25.4 (18.5) 36.7 (27.4) 30.0 (26.8) 31.1 (22.0) 24.5 (24.4) 11.8 (19.1) 24.8 (20.7) 17.8 (21.5) 24.7 (21.9)
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206 111 81 13 122 68 50 4 23 8 12 2 49 36 10 3
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2.1 (1.0) a 3.3 (1.1-7.2)
b
Median (interquartile range), refers to patients with the respective motor complication
ADL: activities of daily living, HY: Hoehn and Yahr, SD: standard deviation
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%
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n Age [years] Gender (male) Country France Germany Italy Spain UK HY score (on) Disease duration since diagnosis [years] On-off fluctuations mild Moderate severe Peak dose dyskinesias mild moderate severe Biphasic dyskinesias mild moderate severe Off-dystonias mild moderate severe EQ-5D index score PDQ-39 summary index Mobility ADL Emotional wellbeing Stigma Social support Cognitions Communication Bodily discomfort
ACCEPTED MANUSCRIPT Table 2. a Multivariable linear regression analyses of the association of motor complications with global QoL scores. b
EQ-5D IS
PDQ-39 SI
95% CI
p-value
β
95% CI
On-off fluctuations
-7.1
-10.6; -3.6
<0.001
3.6
0.7; 6.5
Peak dose dyskinesias
-2.9
-6.9; 1.2
0.17
2.4
-0.9; 5.7
Biphasic dyskinesias
-2.4
-10.6; 5.8
0.56
6.1
-0.9; 13.0
p-value 0.01
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β
c
0.16
0.09
Off-dystonias -0.02 -5.9; 5.8 1.00 1.6 -3.1; 6.4 0.51 a b c adjusted for age, gender, Hoehn & Yahr stage, disease duration, and country, scores were linearly transformed to yield scores from 0 to 100; high scores represent better QoL, scored from 0
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to 100; high scores represent worse QoL
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β: parameter estimate (regression coefficient), CI: confidence interval, EQ-5D IS: EuroQoL 5 dimension questionnaire index score, PDQ-39 SI: Parkinson's Disease Questionnaire-39 summary index
ACCEPTED MANUSCRIPT Table 3. a b Multivariable linear regression analyses of the association of motor complications with PDQ-39 dimension scores .
Mobility
Emotional Wellbeing
ADL
β
95% CI
pvalue
β
95% CI
pvalue
β
95% CI
pvalue
0.08
2.4 -1.0; 5.8
0.17
0.3; 7.7
0.03
3.6 -0.3; 7.6
0.5 -7.2; 8.2
0.90
-4.9; 0.59 1.4 -5.4; 0.68 3.5 -2.7; 0.27 4.6 -2.4; 0.20 0.5 -5.1; 0.85 - -8.3; 8.6 8.2 9.7 11.5 6.1 2.9 2.5 a b adjusted for age, gender, Hoehn & Yahr stage, disease duration, and country; scored from 0 to 100; high scores represent worse QoL
0.29
8.1
4.0; 12.2
<0.001
7.3
3.2; 11.5
<0.001
3.2
-0.5; 6.9
0.09
2.5
-1.7; 6.7
0.23
2.3
Peak dose dyskinesias
3.3
-1.3; 8.0
0.16
5.9
1.2; 10.7
0.01
2.7
-1.6; 7.0
0.22
-0.4
-5.3; 4.4
0.86
0.1
Biphasic dyskinesias
5.4
-4.3; 15.1
0.28
4.2
-5.4; 13.7
0.39
5.9
-3.0; 14.7
0.19
12.6
2.7; 22.6
0.01
2.6
Off-dystonias
1.9
95% CI
pvalue
-1.1; 5.7
0.19
2.9 -0.4; 6.1
-3.8; 4.0
0.96
4.0
-5.4; 10.6
0.53
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On-off fluctuations
pvalue
β
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ADL: activities of daily living, β: parameter estimate (regression coefficient), CI: confidence interval, PDQ-39: Parkinson's Disease Questionnaire-39
Bodily Discomfort
Communication pvalue
β
95% CI
Cognitions
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pvalue
Social support
95% CI
β
95% CI
Stigma
95% CI
pvalue
2.5
-1.3; 6.3
0.20
0.07
2.2
-6.6; 2.2
0.32
- -8.2; 0.3 7.7
0.95
2.3
-6.6; 11.2
0.61
- -6.2; 0.4 5.3
0.88
7.4
1.1; 13.8
0.02
β
β
ACCEPTED MANUSCRIPT Table 4. a Multivariable linear regression analyses of the association of country with global QoL scores and PDQ-39 dimension scores. PDQ-39 SI
β
95% CI
p-value
c
c
Mobility
β
95% CI
p-value
β
95% CI
-8.2
-14.6; -1.8
0.01
3.7
-1.5; 8.8
0.16
5.8
-1.4; 13.0
-12.1
-15.4; -8.9
<0.001
2.7
-0.003; 5.4
0.05
15.8
12.1; 19.6
Spain
-14.5
-18.7; -10.3
<0.001
3.0
-0.3; 6.4
0.08
5.7
0.9; 10.5
-6.0
-10.1; -1.9
<0.01
-3.7
-7.0; -0.3
0.03
3.2
-1.5; 7.9
0
0
d
0
Table 4. (continued) Stigma
c
Social support
95% CI
France
13.6
6.2; 21.0
<0.001
Italy
-0.4
-4.2; 3.5
0.85
Spain
1.4
-3.6; 6.4
0.57
-2.0
-6.0; 2.1
UK
0.5
-4.4; 5.3
0.85
-8.8
-12.7; -4.8
p-value
β -3.8
-9.7; 2.2
-5.6
-8.7; -2.5
Country
d
c
d
95% CI
-6.2; 8.6
0.75
4.8
p-value
4.4
0.6; 8.2
0.02
4.5
1.1; 8.0
0.01
8.8
3.8; 13.7
<0.001
4.2
-0.2; 8.7
0.06
0.18
1.2
-3.6; 5.9
0.63
-9.3
-13.6; -4.9
0
d
0
p-value
0.15
<0.001
d
continued
Communication
95% CI
-1.8; 11.5
c
Bodily discomfort
β
95% CI
p-value
β
95% CI
c
p-value
0.21
-1.3
-7.0; 4.4
0.65
2.0
-4.0; 8.0
0.52
11.7
5.0; 18.5
<0.001
<0.001
-2.3
-5.3; 0.7
0.13
-1.5
-4.6; 1.7
0.37
2.4
-1.1; 5.9
0.18
0.34
1.6
-2.3; 5.5
0.41
-0.6
-4.7; 3.5
0.77
4.9
0.4; 9.5
0.03
<0.001
-0.04
-3.8; 3.7
0.98
-5.3
-9.3; -1.3
0.01
-5.6
-10.0; -1.2
0.01
d
d
d
0 0 0 0 Germany 0 b adjusted for age, gender, Hoehn & Yahr stage, disease duration, and motor complications, scores were linearly transformed to yield scores from 0 to 100; high scores represent better QoL, d
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a
β
p-value
p-value
0.02
c
95% CI
β
95% CI
c
<0.001
Cognitions
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β
c
d
Emotional wellbeing
1.2
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Germany
d
c
0.11
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Italy UK
β
p-value
Country France
ADL
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b
EQ-5D IS
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scored from 0 to 100; high scores represent worse QoL, reference category
ADL: activities of daily living, β: parameter estimate (regression coefficient), CI: confidence interval, EQ-5D IS: EuroQoL 5 dimension questionnaire index score, PDQ-39: Parkinson's Disease Questionnaire-39 summary index
ACCEPTED MANUSCRIPT Highlights
Different subtypes of motor complications have distinct effects on QoL
•
Global QoL is affected by on-off fluctuations but not by subtypes of dyskinesia
•
On-off fluctuations are associated with mobility and activities of daily living
•
Dyskinesias impact activities of daily living, cognitions, stigma, bodily discomfort
•
QoL lower in Sothern European compared to German and British PD patients
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•
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S1353-8020(14)00219-3
DOI:
10.1016/j.parkreldis.2014.06.001
Reference:
PRD 2355
To appear in:
Parkinsonism and Related Disorders
Received Date: 10 December 2013 Revised Date:
21 May 2014
Accepted Date: 1 June 2014
Please cite this article as: Hechtner MC, Vogt TH, Zöllner Y, Schröder S, Sauer JB, Binder H, Singer S, Mikolajczyk R, Quality of life in Parkinson’s disease patients with motor fluctuations and dyskinesias in five European countries, Parkinsonism and Related Disorders (2014), doi: 10.1016/ j.parkreldis.2014.06.001. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Quality of life in Parkinson’s disease patients with motor fluctuations and dyskinesias in five European countries Marlene C. Hechtner*a,b,c, Thomas H. Vogtd, York Zöllnere, Sabrina Schröderf, Julia B. Sauerg, Harald Bindera, Susanne Singera,h, Rafael Mikolajczyki,j (a) Institute of Medical Biostatistics, Epidemiology and Informatics (IMBEI), University Medical Centre, Johannes Gutenberg University Mainz, Germany
(c) German Cancer Research Center (DKFZ), Heidelberg, Germany
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(b) German Cancer Consortium (DKTK), Heidelberg, Germany
(d) Department of Neurology, University Medical Centre, Johannes Gutenberg University Mainz, Germany (e) Department of Health Sciences, Faculty of Life Sciences, Hamburg University of Applied Sciences (HAW), Germany (f)
Department of Neurology, Skåne University Hospital, Lund, Sweden
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(g) Department of Psychology, University of Georgia, Athens, Georgia, USA
(h) Department of Psychosomatic Medicine and Psychotherapy, University of Leipzig, Germany Department of Epidemiology, Helmholtz Centre for Infection Research, Braunschweig, Germany
(j)
Hannover Medical School, Hannover, Germany
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(i)
*corresponding author: Marlene Hechtner
University Medical Centre of Johannes Gutenberg University
Institute of Medical Biostatistics, Epidemiology, and Informatics (IMBEI)
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Obere Zahlbacher Straße 69, 55131 Mainz, Germany Phone: ++49 6131 172433, Fax: ++49 6131 172968
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Email: [email protected]
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ACCEPTED MANUSCRIPT Abstract Background: Little is known about the relationship between specific subtypes of treatmentassociated motor complications and different domains of health-related Quality of Life (QoL) in patients with Parkinson’s disease (PD). Larger studies that investigate these aspects within a cross-cultural setting are scarce. Objective: To assess QoL and its association with on-off fluctuations, peak-dose dyskinesias,
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biphasic dyskinesias, and off-dystonias in PD patients from five European countries.
Methods: Data from 817 PD patients were collected cross-sectionally in France, Germany, Italy, Spain, and the UK. QoL was measured with the generic EuroQoL 5-Dimension questionnaire (EQ-5D) and the disease-specific Parkinson’s Disease Questionnaire-39
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(PDQ-39). Multivariable linear regression analyses were performed to test the associations of motor complication subtypes with QoL.
Results: Thirty-three percent of the patients (varying from 23% in Italy to 58% in France)
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suffered from motor complications, either a single subtype or a combination of different subtypes. On-off fluctuations were associated with a 7.1 percentage point decrease in the EQ-5D (p<0.001) and a 3.6 percentage point deterioration in the PDQ-39 (p=0.01). Dyskinesias were not seen to affect global QoL scores, but had detrimental effects on the PDQ-39 dimensions activities of daily living, cognitions, stigma, and bodily discomfort. Patients from Spain, Italy, and France had lower global QoL scores in the multivariable
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analyses than patients from Germany and the UK.
Conclusion: Motor complications, primarily on-off fluctuations, may impact QoL in PD patients. This substantiates the importance of clinical strategies targeting the prevention,
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delay of onset, and management of motor complications in PD patients.
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ACCEPTED MANUSCRIPT Introduction Dopaminergic medication, especially levodopa, is the current gold standard symptomatic treatment of Parkinson’s disease (PD) [1-3]. However, as a side effect of its long-term use, motor complications arise and manifest themselves in the form of motor fluctuations or dyskinesias. Their etiology is attributed to a combination of the loss of striatal dopaminergic neurons during disease progression, the change in drug pharmacodynamics, and the
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pulsatile stimulation of dopamine receptors by short-acting dopaminergic agents such as levodopa [4,5,6]. Along with non-motor symptoms, motor complications have been one of the major challenges in the management of PD patients.
The incidence of motor complications increases with the duration of chronic dopaminergic
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stimulation. Due to the increase in life expectancy in PD patients, and the subsequent prolonged course of PD, there has been a rise in the frequency of motor complications [7]. After one to two years of treatment with levodopa, approximately 46% of PD patients
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experience motor fluctuations and 26% experience dyskinesias. After four to six years the percentages are 42% and 39%, respectively. From nine to 15 or more years 70% and 88% of the patients experience motor fluctuations and dyskinesias, respectively [8]. Motor fluctuations and dyskinesias can manifest in several ways. A common subtype of motor fluctuations are on-off fluctuations. On-off fluctuations are characterized by sudden and unpredictable shifts between hyperkinetic (on) and hypokinetic (off) states. These shifts
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tend to be unrelated to the timing of the administration of the dopaminergic agent [5,9,10]. Alternatively, the most common form of dyskinesias, peak-dose dyskinesias, arises at the peak of the dosing cycle corresponding to when the drug-derived dopamine levels are at their greatest [9]. Biphasic dyskinesias occur both at the beginning and at the end of the drug
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response cycle, the latter often being more prolonged and severe [4,10]. Dyskinesias that manifest during off periods are known as off-dystonias. This subtype is frequently accompanied by severe disability and pain [4,9].
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As subtypes of motor complications differ in their clinical presentation and frequency it may be assumed that different subtypes are perceived in different ways by the patients. Accordingly, they may have distinct effects on various aspects of the patients’ health-related quality of life (QoL). Understanding these associations in greater detail could help clinicians to optimize the differentiated assessment and medical management of motor complications and, thus, minimize respective impairments of the patients’ QoL. Although a number of studies have already examined the association of motor complications and QoL [11], the applied methods are very heterogeneous, sample sizes are often small, and the resulting evidence is inconclusive. There are a lack of large studies that discriminate between specific subtypes of motor fluctuations and dyskinesias and their impact on global 3
ACCEPTED MANUSCRIPT QoL and different QoL domains in PD patients. This might, in part, be attributed to the major focus of research in the last years on non-motor symptoms and complications. Furthermore, as cross-cultural studies on QoL in PD are scarce, little is known about the relationship between the country and the QoL of PD patients. The aim of the present work was to analyze the association of four subtypes of motor complications (on-off fluctuations, peak-dose dyskinesias, biphasic dyskinesias, and off-
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dystonias) with QoL in a large sample of PD patients from five European countries. The primary outcomes were general and disease-specific QoL. Secondary outcomes comprised of different QoL dimensions as well as the effect of the country of residence on the patients’ QoL.
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Material and methods Data source and design
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The Parkinson’s Disease Specific Programme (DSP), a large multi-sponsor market research program suite conducted by Adelphi Real World, provided the data for this secondary analysis of PD patients from France, Germany, Italy, Spain, and the UK. The full DSP methodology has been described previously [12].
Data were collected cross-sectionally in clinical practice settings via nationally representative samples of specialized physicians (neurologists, plus geriatricians in the UK) and their PD
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patients between March and July, 2008. Physicians were selected according to specialty, location, personal responsibility for treatment decisions, and number of patients. They completed patient record forms (PRF) for ten consecutive PD patients. All patients with PD, as diagnosed by their physician, were eligible for inclusion in the study and were asked to fill out a complementary patient self-completion questionnaire (PSC). No further selection
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criteria were applied.
In total, 817 patients were included in our analyses. Thirty patients were excluded: 14 for
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whom no PRF was filled out and 16 who did not complete any of the QoL questionnaires in the PSC. All responses were anonymous to preserve doctors` and patients` confidentiality. The study protocol followed ethical procedures, including written informed consent of all study participants allowing anonymous and aggregated reporting of research findings based on the questionnaires employed. For this type of research, ethical approval was waived. It was conducted in adherence with the European Pharmaceutical Market Research Association (EphMRA) code of conduct and the US Department of Health and Human Services (HIPAA) standards.
Instruments 4
ACCEPTED MANUSCRIPT The presence, severity, and frequency of the four subtypes of motor complications were assessed in the PRF. Age, gender, Hoehn and Yahr (HY) stage (measured during on-time), and disease duration since diagnosis were also recorded in the PRF. Two QoL questionnaires were part of the PSC, the generic EuroQoL 5-Dimension (EQ-5D) questionnaire [13] and the disease-specific Parkinson's Disease Questionnaire-39 (PDQ-39) [14]. Both instruments have shown good validity and reliability in previous research in PD
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patients [15,16]. The EQ-5D descriptive system is comprised of five items, representing the dimensions mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each item is rated on a three-point scale (no problems, some problems, and severe problems). QoL can then be expressed as a single index value. For the calculation of the index score
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(IS), we applied a European-based preference value set [17]. The range of possible values is 0 (poor QoL) to 1 (good QoL).
The PDQ-39 comprises 39 items, each rated on a five-point scale (never, occasionally,
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sometimes, often, always). The scoring algorithm results in one summary index (SI) score and eight subscores, comprising the dimensions mobility, activities of daily living (ADL), emotional wellbeing, stigma, social support, cognitions, communication, and bodily discomfort [18]. PDQ-39 scores range from 0 to 100. Contrary to the EQ-5D lower values indicate better QoL.
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Analysis
We performed multivariable linear regressions to evaluate the association of each subtype of motor complications with QoL. All multivariable models were adjusted for age, gender, HY stage, disease duration, and country.
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Primary QoL outcomes were the EQ-5D IS and the PDQ-39 SI. To facilitate the comparison of the regression coefficients (β) across the QoL instruments the EQ-5D IS was rescaled from 0 (poor QoL) to 100 (good QoL). For the primary hypotheses, the association of motor
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complication subtypes with QoL, the global significance level was set at 5% and was adjusted per outcome using a Bonferroni correction. A difference was considered statistically significant if p<0.025.
The impact on PDQ-39 dimension scores as well as the effect of specific countries on QoL were considered secondary outcomes. These analyses were regarded as explorative, and the p-values of the corresponding regression models are presented for descriptive reasons only. Normal distribution of the outcome scores and correlation of covariates were checked by visual inspection of Q-Q plots and correlation coefficient tables, respectively. No strong deviations or correlations were found. 5
ACCEPTED MANUSCRIPT We performed sensitivity analyses that utilized the same models but included the severity of the respective motor complications (not present/mild/moderate/severe) in order to explore if there is a change in effect with different severity stages. In addition, we performed tests for linear trend within multivariable general linear models. A potential impact of mood disturbances and cognitive condition was examined by using subgroup analyses in which patients with present symptoms of depression and/or cognitive impairment were excluded.
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All statistical analyses were performed using the software programs SPSS© for windows version 20.0 (SPSS Inc., Chicago, Illinois, USA) and SAS for windows 9.3 (SAS Institute Inc., Cary, NC, USA).
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Results Description of the sample
The sample comprised 817 individuals with PD. Characteristics of the patients are shown in
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Table 1. Italian patients were the youngest with a mean age of 63.7 years (standard deviation (SD) 8.3) and had the shortest disease duration with a median of 2.2 years (interquartile range (IQR) 0.9-4.3). Patients from the UK were the oldest with a mean age of 69.6 years (SD 9.7). French patients had the longest median disease duration (5.5 years, IQR 3.0-9.8). The distribution of gender was similar across all countries. Mean HY scores ranged from 1.8 (SD 0.8) in Spain to 2.3 (SD 1.0) in Germany.
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Twenty percent of all patients suffered from a single motor complication, 10.0% from two, 2.3% from three, and 0.5% from all four types of motor complications. When present, on-off fluctuations occurred with a median frequency of 14.0 (IQR 7.0-21.0), peak-dose dyskinesias 14.0 (IQR 7.0-22.8), biphasic dyskinesias 12.0 (IQR 10.5-24.5), and off-dystonias 7.0 (IQR
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7.0-14.0) times per week. Twenty-eight percent of all patients had off-times. In patients who suffered from at least one subtype of dyskinesia, the median percentage of on-time with dyskinesias was 10.0% (IQR 10.0-34.0). Comparing the countries, on-off fluctuations were
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most frequently observed in France (45.0%) and were least common in Italy (15.6%). French patients also reported the highest proportion of peak-dose dyskinesias (32.5%), contrasted with only 10.5% in Italy. The prevalence of biphasic dyskinesias and off-dystonias were comparable among all countries. The mean EQ-5D IS of the total sample was 0.7 (SD 0.2) based on the ratings in the dimensions mobility (33.9% of the patients reported no, 64.8% some, 1.2% extreme problems), self-care (55.3% no, 39.9% some, 4.8% extreme problems), usual activities (36.4%, 57.8% some, 5.8% extreme problems), pain/discomfort (45.4% no, 51.1% some, 3.4% extreme problems), and anxiety/depression (54.1% no, 41.6% some, 4.3% extreme
6
ACCEPTED MANUSCRIPT problems). The mean PDQ-39 SI was 25.4 (SD 18.5). The scorings of the PDQ-39 dimensions are listed in Table 1.
Multivariable Analyses In the multivariable regression models, the presence of on-off fluctuations was significantly associated both with poorer EQ-5D IS (β=-7.1, p<0.001) and PDQ-39 SI (β=3.6, p=0.01).
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None of the dyskinesia subtypes had a significant effect on the EQ-5D IS or the PDQ-39 SI (Table 2).
With regard to the PDQ-39 dimension scores, on-off fluctuations affected mobility (β=8.1, p<0.001) and ADL (β=7.3, p<0.001). Peak-dose dyskinesias were negatively associated with
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the dimensions ADL (β=5.9, p=0.01) and cognitions (β=4.0, p=0.03). Biphasic dyskinesias had a comparably strong detrimental effect on stigma (β=12.6, p=0.01). An effect of offdystonias was observed only on bodily discomfort (β=7.4, p=0.02) (Table 3).
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Sensitivity analyses considering motor complication severity indicated that compared to patients without on-off fluctuations the detrimental effect of on-off fluctuations was greater in patients with more severe complications (mild: β=-6.0, p<0.01; moderate: β=-9.0, p<0.001; severe: β=-3.2, p=0.58). A linear trend was, however, not confirmed in the trend analysis (p=0.48). The same was true for the severity of on-off fluctuations and the PDQ-39 SI (mild: β=2.9, p=0.09; moderate: β=5.4, p=0.01; severe: β=7.7, p=0.1; test for linear trend p=0.07).
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In subgroup analyses that excluded patients with present symptoms of depression and/or cognitive impairment the results did not notably alter. On-off fluctuations were associated with poorer EQ-5D IS (β=-6.4, p=0.003) and PDQ-39 SI (β=4.5, p=0.01) whereas dyskinesias did not impact QoL.
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Based on the estimated effects of the different countries on QoL in the multivariable analyses, the ranking from best to worst EQ-5D IS was: Germany, UK, France, Italy, and Spain (all differences compared to Germany p≤0.01). The country ranking from best to worst
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PDQ-39 SI was: UK, Germany, Italy, Spain, and France (UK compared to Germany p=0.03). Regarding the PDQ-39 dimension scores. A similar pattern was observed with comparably better QoL ratings in Germany and the UK and lower scores in Spain, Italy, and France (Table 4).
Discussion This is, to our knowledge, currently the largest study investigating the influence of different subtypes of motor fluctuations and dyskinesias on general QoL, disease specific QoL, and specific QoL dimensions simultaneously across five countries in Europe. Understanding the contribution of specific motor complications to different aspects of QoL may help minimize 7
ACCEPTED MANUSCRIPT the impact of these complications on patients’ lives. Due to the inconclusive evidence on these associations, large studies are needed. Our representative sample of 817 PD patients provided real-world data on the clinical presentation and QoL of PD patients in Europe. The multinational design allowed comparisons of the QoL of PD patients across France, Germany, Italy, Spain, and the UK. The results of our analyses show that the presence of on-off fluctuations had a detrimental
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impact on the QoL of PD patients, whereas the presence of peak-dose dyskinesias, biphasic dyskinesias, or off-dystonias did not change the patients’ global QoL scores significantly. A detrimental effect of on-off fluctuations is explainable due to the unpredictable occurrence of off-times and the abruptness of the transitions between on- and off-times. The interruptive
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nature of on-off fluctuations can force patients to give up former activities. This effect was reflected in the negative impact on the dimensions ADL and mobility. Moreover, motor fluctuations are often associated with non-motor fluctuations in mood, sensory, and
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autonomic symptoms that might, in turn, impair QoL [19,20].
Some investigators perceive dyskinesias to be less disabling for the patients as most dyskinesias occur in the on medication state or at the threshold of the on state [21]. As expected no significant association of dyskinesias was observed with the global QoL scores. Nevertheless, our data suggests that dyskinesias may at least impact single QoL domains. The detrimental effect of peak-dose dyskinesias on ADL might arise from the clinical
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presentation in the form of choreic or choreoathetotic movements that affect the upper limbs, face, neck, and trunk [4] which in turn may cause physical disability. In which way this is also causative for the association with cognitions remains unclear. Biphasic dyskinesias presenting as a mixture of choreic, ballistic, or dystonic movements that are often more
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prominent in the lower limbs [4], seem to be especially troublesome to the patients’ perception of stigma. Off-dystonias that occur in the off state might not impact global QoL significantly due to their short duration [21]. Nevertheless, their painful character is reflected
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in their comparably high association with the bodily discomfort dimension. Unfortunately, comparison of our results with previous studies was difficult. Published studies on the association of different types of motor complications with QoL show a heterogeneous picture, and methods of assessment vary considerably between the studies. There is also large heterogeneity concerning clinical characteristics of the samples as well as the methods applied for the analyses (e.g. adjustment for confounders). For comparison of the results concerning our primary objective, we considered only studies that used the same QoL measures, distinguished subtypes of motor complications, and applied multivariable analyses.
8
ACCEPTED MANUSCRIPT A cross-sectional study on 130 PD patients in the UK found poorer PDQ-39 SI in patients with on-off fluctuations that remained a significant predictor for QoL when applying a stepwise linear regression (β=0.5, p<0.001) [22]. Similar to our results, the association of dyskinesias with global QoL did not meet the significance threshold. Our findings were further supported by two cross-sectional studies that were conducted within the framework of the European Cooperative Network for Research, Diagnosis and Therapy of Parkinson’s
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Disease (EuroPa): in these studies comprising 100 Austrian [23] and 70 Italian [24] PD patients, motor fluctuations significantly worsened the EQ-5D IS in multivariable analyses (β=-9.9, p=0.04 and β=-10.3, p=0.02 respectively). Dyskinesias showed no effect. In contrast to our findings, some studies showed a detrimental effect only of dyskinesias but not of motor
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fluctuations on the PDQ-39 SI in multivariable analyses [21,25]. Other multivariable evaluations found neither an effect of motor fluctuations nor of dyskinesias on the EQ-5D IS [16-28].
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Regarding the association of motor complication subtypes with PDQ-39 dimension scores, only one study by Chapuis and colleagues including 143 PD patients in France was found [21]. Unfortunately, comparability is limited, as these analyses were not adjusted for potential confounders and these patients had longer disease duration, higher prevalence of motor complications, and worse QoL scores compared to our sample. Nevertheless, the negative associations of on-off fluctuations with mobility and ADL in our study were consistent with the
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French study, which not only found an impact on these dimensions but also on stigma and communication. We found a negative association of peak-dose dyskinesias with ADL and cognitions; Chapuis et al. reported no respective effect on ADL, but also on cognitions, mobility, and emotional wellbeing. In our study, biphasic dyskinesias had the comparably
study,
but
they
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strongest negative association with the dimension stigma. This was also true in the French additionally
substantiated
associations
with
mobility,
ADL,
and
communication. Our results suggested that off-dystonias affect bodily discomfort. In the
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French study, off-dystonias worsened the dimensions social support and communication. We found that the likelihood of having comparably good QoL scores was higher in Germany and the UK. Poorer QoL was more likely to be observed in France, Italy, and Spain. Comparing the cost per case of PD and high-level indicators of the respective health care systems, no evidence for an explanatory pattern could be identified [29,30]. To what extent those differences might also be due to non-considered clinical characteristics, or to different attitudes, behaviors, and cultural aspects cannot be ascertained with confidence. No study was available which allowed for comparisons of country differences in EQ-5D and PDQ-39 scores of European PD patients.
9
ACCEPTED MANUSCRIPT Our study has several limitations. The DSP IV study was designed as a real world observational study. Therefore, no strict selection criteria regarding the standardization of PD diagnosis, the assessment of motor complications, and the severity staging of motor complications were applied. This may cause some variability and impact the internal validity of our data. A benefit of this design is, however, the good representativeness of patients and
managed for PD by specialized physicians.
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physicians reflecting the real world treatment practice of patients who are diagnosed and
Another limitation refers to the consideration of confounders. We pre-specified the set of covariables that we used for adjustment. The relatively small absolute frequencies of the more rare subtypes of motor complications restricted the possible amount of adjustment
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variables from a statistical point of view. All analyses were adjusted for age, gender, HY stage, disease duration, and country. Further potentially relevant factors such as age at disease onset, duration and dose of dopaminergic therapy, duration and severity of disease
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at time of initiating drug therapy, clinical phenotype, cognitive impairment and mood disturbances were not considered in our main analyses. This was (i) either because the study data did not contain the respective information, or (ii) the variable was considered rather to be a predictor for QoL or causal factor on the pathway than a confounder, or (iii) the interrelation among some of these variables was considered too strong. Cognitive impairment and mood disturbances were further examined in subgroup analyses. Excluding
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patients with symptoms of depression and/or cognitive impairment yielded consistent results. The motor complications observed in our sample were mainly mild or moderate limiting the generalizability of results for patients with more severe motor complications as well as the power of the linear trend tests. To what extent our results might be influenced by differences
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in the duration of the motor complication subtypes could not be estimated, since this was not assessed in the study data.
In conclusion, motor complications, primarily on-off fluctuations, may adversely affect global
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QoL in patients with PD. Moreover, on-off fluctuations and different subtypes of dyskinesias impact different domains of their QoL. This substantiates the importance of clinical strategies targeting the prevention, delay of onset, and management of motor complications in PD patients. Health care providers should be sensitized to the specific impairments of patients presenting with different types of motor complications.
10
ACCEPTED MANUSCRIPT Acknowledgements The Adelphi PD Specific Programme is an independent study conducted by the Adelphi group on behalf of Solvay Pharmaceuticals. M. Hechtner was an intern, Y. Zoellner and S. Schroeder were employees of Solvay Pharmaceuticals (now Abbott) at the time the research hypotheses were developed and the first analyses were run, all of which were completed under the banner of the authors’ current affiliations. This research received no grant,
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sponsorship or other financial support. We thank Adelphi and Solvay Pharmaceuticals for
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providing the data. The authors declare no conflicts of interest in preparing this article.
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ACCEPTED MANUSCRIPT References
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ACCEPTED MANUSCRIPT [15] Schrag A, Selai C, Jahanshahi M, Quinn NP. The EQ-5D - a generic quality of life measure-is a useful instrument to measure quality of life in patients with Parkinson's disease. J Neurol Neurosurg Psychiatry 2000;69:67-73. [16] Martinez-Martin P, Serrano-Dueñas M, Forjaz MJ, Serrano MS. Two questionnaires for Parkinson's disease: are the PDQ-39 and PDQL equivalent? Qual Life Res 2007;16:1221-30.
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Questionnaire. PDQ-39 user manual (including PDQ-8 and PDQ summary index). Oxford: Health Services Research Unit University of Oxford, 2008.
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ACCEPTED MANUSCRIPT [27] Bach JP, Riedel O, Klotsche J, Spottke A, Dodel R, Wittchen HU. Impact of complications and comorbidities on treatment costs and health-related quality of life of patients with Parkinson's disease. J Neurol Sci 2012;314:41-7. [28] Rodríguez-Violante M, Cervantes-Arriaga A, Corona T, Martínez-Ramírez D, MoralesBriceño H, Martínez-Martín P. Clinical Determinants of Health-related Quality of Life in Mexican Patients with Parkinson's Disease. Arch Med Res 2013;44:110-4.
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[29] Organisation for Economic Co-operation and Development (OECD). OECD.Stat Extracts. [accessed 2010 Jul 10]. Available from: URL: http://stats.oecd.org/Index.aspx. [30] Andlin-Sobocki P, Jönsson B, Wittchen HU, Olesen J. Cost of disorders of the brain in
Table captions
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Europe. Eur J Neurol 2005;12(Suppl 1):1-27.
Table 1.
Demographic and clinical characteristics of the study sample (N=817)
Table 2.
Multivariable linear regression analyses of the association of motor complications with global QoL scores.
Table 3.
Multivariable linear regression analyses of the association of motor complications
Table 4.
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with PDQ-39 dimension scores.
Multivariable linear regression analyses of the association of country with global
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QoL scores and PDQ-39 dimension scores.
14
ACCEPTED MANUSCRIPT Table 1. Demographic and clinical characteristics of the study sample (N=817)
a
Mean (SD) 66.5 (9.7)
439
53.8
40 288 256 108 125
4.9 35.3 31.3 13.2 15.3
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25,2 b 54.1 b 39.5 b 6.3 14,9 b 55.7 b 41.0 b 3.3 2,8 b 36.4 b 54.5 b 9.1 6,0 b 73.5 b 20.4 b 6.1
0.65 (0.23) 25.4 (18.5) 36.7 (27.4) 30.0 (26.8) 31.1 (22.0) 24.5 (24.4) 11.8 (19.1) 24.8 (20.7) 17.8 (21.5) 24.7 (21.9)
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206 111 81 13 122 68 50 4 23 8 12 2 49 36 10 3
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2.1 (1.0) a 3.3 (1.1-7.2)
b
Median (interquartile range), refers to patients with the respective motor complication
ADL: activities of daily living, HY: Hoehn and Yahr, SD: standard deviation
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%
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n Age [years] Gender (male) Country France Germany Italy Spain UK HY score (on) Disease duration since diagnosis [years] On-off fluctuations mild Moderate severe Peak dose dyskinesias mild moderate severe Biphasic dyskinesias mild moderate severe Off-dystonias mild moderate severe EQ-5D index score PDQ-39 summary index Mobility ADL Emotional wellbeing Stigma Social support Cognitions Communication Bodily discomfort
ACCEPTED MANUSCRIPT Table 2. a Multivariable linear regression analyses of the association of motor complications with global QoL scores. b
EQ-5D IS
PDQ-39 SI
95% CI
p-value
β
95% CI
On-off fluctuations
-7.1
-10.6; -3.6
<0.001
3.6
0.7; 6.5
Peak dose dyskinesias
-2.9
-6.9; 1.2
0.17
2.4
-0.9; 5.7
Biphasic dyskinesias
-2.4
-10.6; 5.8
0.56
6.1
-0.9; 13.0
p-value 0.01
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β
c
0.16
0.09
Off-dystonias -0.02 -5.9; 5.8 1.00 1.6 -3.1; 6.4 0.51 a b c adjusted for age, gender, Hoehn & Yahr stage, disease duration, and country, scores were linearly transformed to yield scores from 0 to 100; high scores represent better QoL, scored from 0
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to 100; high scores represent worse QoL
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β: parameter estimate (regression coefficient), CI: confidence interval, EQ-5D IS: EuroQoL 5 dimension questionnaire index score, PDQ-39 SI: Parkinson's Disease Questionnaire-39 summary index
ACCEPTED MANUSCRIPT Table 3. a b Multivariable linear regression analyses of the association of motor complications with PDQ-39 dimension scores .
Mobility
Emotional Wellbeing
ADL
β
95% CI
pvalue
β
95% CI
pvalue
β
95% CI
pvalue
0.08
2.4 -1.0; 5.8
0.17
0.3; 7.7
0.03
3.6 -0.3; 7.6
0.5 -7.2; 8.2
0.90
-4.9; 0.59 1.4 -5.4; 0.68 3.5 -2.7; 0.27 4.6 -2.4; 0.20 0.5 -5.1; 0.85 - -8.3; 8.6 8.2 9.7 11.5 6.1 2.9 2.5 a b adjusted for age, gender, Hoehn & Yahr stage, disease duration, and country; scored from 0 to 100; high scores represent worse QoL
0.29
8.1
4.0; 12.2
<0.001
7.3
3.2; 11.5
<0.001
3.2
-0.5; 6.9
0.09
2.5
-1.7; 6.7
0.23
2.3
Peak dose dyskinesias
3.3
-1.3; 8.0
0.16
5.9
1.2; 10.7
0.01
2.7
-1.6; 7.0
0.22
-0.4
-5.3; 4.4
0.86
0.1
Biphasic dyskinesias
5.4
-4.3; 15.1
0.28
4.2
-5.4; 13.7
0.39
5.9
-3.0; 14.7
0.19
12.6
2.7; 22.6
0.01
2.6
Off-dystonias
1.9
95% CI
pvalue
-1.1; 5.7
0.19
2.9 -0.4; 6.1
-3.8; 4.0
0.96
4.0
-5.4; 10.6
0.53
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On-off fluctuations
pvalue
β
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ADL: activities of daily living, β: parameter estimate (regression coefficient), CI: confidence interval, PDQ-39: Parkinson's Disease Questionnaire-39
Bodily Discomfort
Communication pvalue
β
95% CI
Cognitions
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pvalue
Social support
95% CI
β
95% CI
Stigma
95% CI
pvalue
2.5
-1.3; 6.3
0.20
0.07
2.2
-6.6; 2.2
0.32
- -8.2; 0.3 7.7
0.95
2.3
-6.6; 11.2
0.61
- -6.2; 0.4 5.3
0.88
7.4
1.1; 13.8
0.02
β
β
ACCEPTED MANUSCRIPT Table 4. a Multivariable linear regression analyses of the association of country with global QoL scores and PDQ-39 dimension scores. PDQ-39 SI
β
95% CI
p-value
c
c
Mobility
β
95% CI
p-value
β
95% CI
-8.2
-14.6; -1.8
0.01
3.7
-1.5; 8.8
0.16
5.8
-1.4; 13.0
-12.1
-15.4; -8.9
<0.001
2.7
-0.003; 5.4
0.05
15.8
12.1; 19.6
Spain
-14.5
-18.7; -10.3
<0.001
3.0
-0.3; 6.4
0.08
5.7
0.9; 10.5
-6.0
-10.1; -1.9
<0.01
-3.7
-7.0; -0.3
0.03
3.2
-1.5; 7.9
0
0
d
0
Table 4. (continued) Stigma
c
Social support
95% CI
France
13.6
6.2; 21.0
<0.001
Italy
-0.4
-4.2; 3.5
0.85
Spain
1.4
-3.6; 6.4
0.57
-2.0
-6.0; 2.1
UK
0.5
-4.4; 5.3
0.85
-8.8
-12.7; -4.8
p-value
β -3.8
-9.7; 2.2
-5.6
-8.7; -2.5
Country
d
c
d
95% CI
-6.2; 8.6
0.75
4.8
p-value
4.4
0.6; 8.2
0.02
4.5
1.1; 8.0
0.01
8.8
3.8; 13.7
<0.001
4.2
-0.2; 8.7
0.06
0.18
1.2
-3.6; 5.9
0.63
-9.3
-13.6; -4.9
0
d
0
p-value
0.15
<0.001
d
continued
Communication
95% CI
-1.8; 11.5
c
Bodily discomfort
β
95% CI
p-value
β
95% CI
c
p-value
0.21
-1.3
-7.0; 4.4
0.65
2.0
-4.0; 8.0
0.52
11.7
5.0; 18.5
<0.001
<0.001
-2.3
-5.3; 0.7
0.13
-1.5
-4.6; 1.7
0.37
2.4
-1.1; 5.9
0.18
0.34
1.6
-2.3; 5.5
0.41
-0.6
-4.7; 3.5
0.77
4.9
0.4; 9.5
0.03
<0.001
-0.04
-3.8; 3.7
0.98
-5.3
-9.3; -1.3
0.01
-5.6
-10.0; -1.2
0.01
d
d
d
0 0 0 0 Germany 0 b adjusted for age, gender, Hoehn & Yahr stage, disease duration, and motor complications, scores were linearly transformed to yield scores from 0 to 100; high scores represent better QoL, d
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a
β
p-value
p-value
0.02
c
95% CI
β
95% CI
c
<0.001
Cognitions
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β
c
d
Emotional wellbeing
1.2
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Germany
d
c
0.11
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Italy UK
β
p-value
Country France
ADL
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b
EQ-5D IS
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scored from 0 to 100; high scores represent worse QoL, reference category
ADL: activities of daily living, β: parameter estimate (regression coefficient), CI: confidence interval, EQ-5D IS: EuroQoL 5 dimension questionnaire index score, PDQ-39: Parkinson's Disease Questionnaire-39 summary index
ACCEPTED MANUSCRIPT Highlights
Different subtypes of motor complications have distinct effects on QoL
•
Global QoL is affected by on-off fluctuations but not by subtypes of dyskinesia
•
On-off fluctuations are associated with mobility and activities of daily living
•
Dyskinesias impact activities of daily living, cognitions, stigma, bodily discomfort
•
QoL lower in Sothern European compared to German and British PD patients
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•
1