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Quality of life in advanced Parkinson’s disease after bilateral subthalamic stimulation: 2 years follow-up study
Clinical Neurology and Neurosurgery 124 (2014) 161–165
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Clinical Neurology and Neurosurgery journal homepage: www.elsevier.com/locate/clineuro
Quality of life in advanced Parkinson’s disease after bilateral subthalamic stimulation: 2 years follow-up study Michał Sobstyl a, *, Mirosław Za˛bek a , Wojciech Górecki b , Zbigniew Mossakowski b a b
Neurosurgical Department of Postgraduate Medical Center, Marymoncka 99/103 Street, Warsaw 01-813, Poland Neurosurgical Department of Bródno Regional Hospital, Kondratowicza Street, Warsaw 023-23, Poland
A R T I C L E I N F O
A B S T R A C T
Article history: Received 24 February 2014 Received in revised form 9 May 2014 Accepted 14 June 2014 Available online 23 June 2014
Objective: The aims of this study were to assess the quality of life (QoL) using Parkinson’s Disease Questionnaire PDQ-39 after bilateral subthalamic deep brain stimulation (STN DBS), and to identify correlations between changes in UPDRS score and separate PDQ-39 QoL dimensions and PDQ summary index (SI) score at long-term follow-up. Methods: We evaluated 16 patients with advanced PD after bilateral STN DBS. All 16 patients were assessed 1 year after surgery and 14 were studied 2 years after surgery. The patients were assessed using Unified Parkinson’s Disease Rating Scale (UPDRS) in medication-on and medication-off conditions, both preoperatively and postoperatively. All UPDRS evaluations were performed postoperatively during stimulation-on condition. QoL levels were determined by applying PDQ-39 questionnaire. Results: The UPDRS scores after 1 and 2 years in medication-off and -on conditions when bilateral STN DBS was switched on showed a significant difference between baseline scores and follow-up scores (both in -off and -on conditions) in every UPDRS measurement except for mentation after 2 years. Most of Pvalues indicated that the differences were highly significant (P < 0.01) based on Wilcoxon signed-rank test. All dimensions of PDQ-39 as well PDQ-39 SI score were highly significantly improved after 1 year. The same improvements were visible in 2 years follow-up with the exception of social support and communication. We found a positive correlation between ADL UPDRS, motor off UPDRS scores and PDQ39 ADL and PDQ-39 SI scores. A further analysis of separate motor PD features revealed that tremor, bradykinesia and axial features were correlated with improvements mostly seen in PDQ-39 ADL and PDQ-39 SI scores. Moreover, in medication-on condition, we found a strong correlation between dyskinesia UPDRS score and PDQ-39 mobility, ADL, and PDQ-39 SI score. We observed a negative correlation between improved fluctuation UPDRS score and PDQ-39 mobility. We identified no correlation between the duration of the off period and levodopa dose and changes in PDQ-39. Conclusion: STN DBS significantly improved important aspects of QoL as measured by PDQ-39. The improvements were maintained at 2 years follow-up except for social support and communication. We demonstrated a positive correlation between changes in the off condition of motor UPDRS scores and dyskinesia UPDRS scores in several PDQ-39 dimensions, whereas fluctuation UPDRS scores were negatively correlated with PDQ-39 mobility scores. ã 2014 Elsevier B.V. All rights reserved.
1. Introduction Several studies have confirmed the long-term efficacy of bilateral STN DBS on activities of daily living (ADL), motor and complications of therapy scores in patients with advanced PD [1–4]. The improvement in motor function correlates with benefits in QoL validated by Parkinson’s Disease Questionnaire 39 [5–8]. As of now,
* Tel.: +48 22 5693 700; fax: +48 22 5693 712. E-mail address: [email protected] (M. Sobstyl). http://dx.doi.org/10.1016/j.clineuro.2014.06.019 0303-8467/ ã 2014 Elsevier B.V. All rights reserved.
there are only a few studies which address QoL improvements in separate dimensions of PDQ-39 in short- and long-term follow-up. Correlations between UPDRS scores and changes in PDQ-39 dimensions after bilateral STN DBS surgery remain a matter of controversy. Some authors claim that the strongest correlation for QoL improvement is the duration of off periods [9], while others argue that it is the severity of off periods rather than their duration [10]. Bilateral STN DBS has the greatest impact on reducing complications of therapy. Interestingly, some authors have found a negative correlation between dyskinesia and changes in PDQ-39 QoL after STN DBS [10]. In the opinion of other authors, the impact on
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QoL in PD patients is strongly related to a reduction of disabling dyskinesia and motor fluctuations, which results in a more stable motor condition of patients [5]. Considering only outcomes for separate PDQ-39 dimensions, results obtained in different studies are conflicting. Some indicate that it is not only dimensions entirely dominated by motor function but also dimensions related to physical and emotional aspects that improve after STN DBS [7]. A number of authors stress that only physical PDQ-39 dimensions are improved, while others are unchanged or even deteriorate over time [11]. These contradictory findings require further investigation. The aims of our study were to assess QoL by applying PDQ-39, and to identify correlations between changes in UPDRS scores in medication-off and -on condition on health-related QoL after STN DBS. 2. Material and methods The clinical material consisted of 16 patients (11 men and 5 women) suffering from advanced PD who underwent bilateral STN DBS. The average age of the patients at PD diagnosis was 54.2 6.9 years (range 44.7–65.8 years), whereas the average age at surgery was 63.5 5.2 years (range 54.3–72.7 years). All the patients met the clinical criteria of the United Kingdom Parkinson’s Disease Society brain-bank for idiopathic PD [12]. Inclusion and exclusion criteria followed CAPSIT-PD guidelines [13]. The patients were operated on at the neurosurgical department between January 2008 and December 2011. All of them were preoperatively evaluated by UPDRS parts I–IV [14]. Levodopa equivalents and all levodopa containing medications were withdrawn, 48 h and 12 h (respectively) before assessment in medication off condition. The medication on condition was assessed after administration of levodopa i.e., 50 mg higher than the usual effective first dose taken in the morning when a patient reported the best response to medication. The assessment routine was as follows: first the patients were assessed in medication off condition in the morning and then in medication on condition. In accordance with the UPDRS the same assessments took place postoperatively in medication off and on conditions, but only when bilateral STN DBS was switched on. The UPDRS part III motor scores were separately assessed for tremor items 20–21, rigidity item 22, bradykinesia items 23–26. Axial features constituted the sum of the following items: speech item 18, facial expression item 19, arising from chair item 27, posture item 28, gait item 29, postural instability item 30, bradykinesia item 31. Levodopa-induced dyskinesias (LID) were assessed according to the following items: duration of dyskinesia item 32, disability of dyskinesia item 33, painful dyskinesia item 34, and the presence of early morning dystonia item 35. Fluctuations were evaluated by the following items: predictable off period item 36, unpredictable off period item 37 and sudden off item 38 and duration of the off period item 39. Preoperative and postoperative UPDRS scores were evaluated by a movement disorders neurologist. The patients were also evaluated according to the Hoehn and Yahr (H/Y) staging system. The total levodopa-equivalent dose was calculated on the basis of the formula proposed by Lyons and Pahwa [8,15]. QoL was assessed preoperatively by applying PDQ39 questionnaire. Answers to the PDQ-39 give the summary index PDQ-39 SI score, and dimensions scores for mobility, activities of daily living, emotional well being, stigma, social support, cognition, communication, and bodily discomfort. Postoperative assessment incorporated all the UPDRS parts, and the PDQ-39 questionnaire. The postoperative assessments were performed when the stimulators were switched on in medication-off condition, and medication-on condition. The study protocol was approved by the Institutional Review Board of Postgraduate Medical Center. All the patients provided their written informed consent.
The patients were operated in medication-off condition. After stereotactic frame fixation in local anesthesia, contrast-enhanced CT scanning was performed. CT images were merged with preoperative MRI scans. The target point – subthalamic nucleus – was calculated using an indirect method in relation to the midpoint of the intercommisural line, and direct methods that modified the position of the target depending on MRI scans. After electrophysiological confirmation of the target the DBS electrode was inserted and its position was verified with fluoroscopy. Following stereotactic frame removal, the patients were brought to general anesthesia, and internal pulse generators were placed in the subclavicular region in the chest wall. All surgical procedures were performed using Medtronic DBS equipment. The programming took place 2 or 3 days after surgery. Stimulation settings were adjusted at follow-up visits in order to achieve the best therapeutic results. Statistical analyses were performed using the Statistical Package for Social Sciences (SPSS version 21). Descriptive statistics (mean, standard deviation, range, confidence interval) were obtained for each variable as required. Preoperative and postoperative UPDRS scores were compared using Wilcoxon signed-rank test. Preoperative and postoperative PDQ-39 scores were compared by applying paired t-tests. Spearman rank order correlations were used to assess relationships between UPDRS scores and changes in PDQ-39 QoL dimensions and PDQ-39 SI scores. A probability value of P < 0.05 was considered significant. 3. Results Sixteen patients with PD were enrolled in the study. All the patients completed the 1 year evaluation, however only 14 patients were able to complete the follow-up review after 2 years. First, the Wilcoxon test was performed to check whether there was a significant difference between baseline scores in medication-off and -on conditions and UPDRS scores after 1 and 2 years in medication-off and -on condition when bilateral STN DBS was switched on. The test showed that there was a significant difference between baseline scores and follow-up scores (both in off and on conditions) in every measurement of UPDRS except mentation after 24 months. Most of P-values indicated that the differences were highly significant (P < 0.01). Detailed results are shown in Table 1. There was a significant difference in the Hoehn and Yahr (H/Y) staging system after surgery in medication-off and -on when compared to baseline H/Y staging system. The preoperative H/Y stage in off-condition was 3.4 0.6 and improved to 1.8 0.5 (P < 0.01) and 1.8 0.4 (P < 0.01) at 12 and 24 months respectively. The preoperative H/ Y stage in on-condition was 2.3 0.5 and improved to 1.7 0.4 (P < 0.01) and 1.6 0.4 (P < 0.01) at 12 and 24 months respectively. The effect on the patients’ ADL (UPDRS part II) in long-term followup was significant in medication-off and -on conditions, resulting in a 43% (P < 0.01) and 24% (P < 0.01) reduction, respectively. Similarly, significant improvements were noted in motor scores (UPDRS part III) in medication-off and -on conditions postoperatively, resulting in a 44% (P < 0.01) and 26% (P < 0.01) reduction, respectively. Long-term stimulation resulted in improved scores for tremor, rigidity, bradykinesia, axial features in medication-off and medication-on conditions after stimulation. Stimulation significantly reduced complications associated with therapy (UPDRS part IV). The dyskinesia score (UPDRS IVA items 32–35) was reduced by 73% (P < 0.01) and by 74% (P < 0.01) at 1 and 2 years after stimulation. The fluctuation score (UPDRS IVB items 36–39) decreased by 43% (P < 0.01) and by 47% (P < 0. 01) at 1 and 2 years. The duration of the off period (UPDRS IV item 39) showed a significant improvement, resulting in a 62% (P < 0.01) and 50% (P < 0.01) reduction at subsequent follow-up visits. The daily
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Table 1 Patients Unified Parkinson’s Disease Rating scale (UPDRS) scores in medication-off and -on conditions before and after bilateral STN stimulation in stimulation on condition. The UPDRS part III motor scores were separately assessed for tremor items 20–21, rigidity item 22, bradykinesia items 23–26. Axial features constituted the sum of the following items: 18,19, 27–31. Levodopa-induced dyskinesias (LID) were assessed according to UPDRS part IVA items: 32–35. Fluctuations were evaluated by UPDRS part IVB items: 36–39. The duration of the off period was assessed according to item 39. Preoperative and postoperative UPDRS scores were compared using Wilcoxon signed-rank test. A probability value of P < 0.05 was considered significant. Follow-up period
12 Mos follow up
Parts of UPDRS
Baseline
24 Mos follow up 1 year
Baseline a
2 years
UPDRS part I on UPDRS part I off
1.2 0.6 2.0 0.7
0,8 0.6 1,7 0.6a
1,1 0,6 2 0,8
UPDRS part II on UPDRS part II of
14.6 4.4 23.8 4.3
10.4 3.9b 12.7 1.5b
15.0 4.5 24.1 4.2
11.5 3.9b 13.7 1.8b
UPDRS tremor score on UPDRS tremor score of
1.3 0.6 4.5 2.5
0.7 0.6b 1.1 0.7b
1.3 0.6 4.5 2.7
0.7 0.7a 1.0 0.8b
UPDRS rigidity score on UPDRS rigidity score of
5.6 1.0 10.1 2.8
4.1 0.9b 4.9 1.6b
5.5 1.0 10.2 2.9
3.9 1.2b 5.2 1.8b
UPDRS bradykinesia score on UPDRS bradykinesia score of
7.4 1.5 12.6 3.5
5.4 1.0b 6.1 2.4b
7.5 1.6 12.5 3.6
5.6 1.5b 6.7 2.7b
UPDRS axial features score on UPDRS axial features score of
9.9 1.5 13.6 4.1
6.8 1.0zb 10.3 3.1b
9.9 1.5 13.2 4.0
7.6 0.8b 10.7 3.3b
Total UPDRS part III on Total UPDRS part III of
24.0 3.5 40.9 10.7
17.1 2.6b 22.3 5.5b
24.0 3.6 40.5 11.2
17.8 2.8b 23.0 7.3b
UPDRS part IV dyskinesia score UPDRS part IV fluctuation score UPDRS part IV of period duration
5.5 1.5 3.7 0.9 1.6 0.6
1.5 0.6b 2.1 0.4b 1 0.5b
5.2 1.4 3.6 1.0 1.6 0.6
0,9 0,5 2 0,8
1.4 0.4b 1.9 0.5b 0.8 0.4b
Values are expressed as means standard deviations. a Significant change from baseline at P < 0.05. b Significant change from baseline at P < 0.01.
medication equivalency units decreased from the preoperative value of 13.2 4.0 to 10.0 3.3 at 1 year, and to 8.0 2.0 at 2 years after bilateral STN DBS. All dimensions of PDQ-39 as well PDQ-39 SI score were highly significant improved after 1 year of stimulation when compared to baseline PDQ-39 scores. On the other hand, almost the same improvements were visible in 2 years follow-up except for social support and communication. The two measures were insignificantly different when comparing baseline scores to 2 year scores. The results obtained for all dimensions of PDQ-39 as well PDQ-39 summary index (PDQ-39 SI) are shown in Table 2. In order to examine the relationship between improvements in motor function and improvements in quality of life, correlation coefficients were determined to compare changes in UPDRS scores from the baseline to follow-up, and changes in PDQ-39 scores from baseline to follow-up. Initially, the analysis was carried out for medication-off condition at baseline to the medication-off stimulation-on condition at follow-up. Improvements in UPDRS mentation were strongly correlated with improvements in PDQ-39 ADL (r = 0.57; P = 0.021 and PDQ-39 SI (r = 0.59; P = 0.017) score at 1 year follow-up. Improvements in UPDRS ADL scores were strongly correlated with PDQ-39 emotional well-being (r = 0.71; P = 0.002), social support (r = 0.58; P = 0.018), cognition (r = 0.50; P = 0.049), bodily discomfort (r = 0.57; P = 0.020) and PDQ SI (r = 0.59; P = 0.012) score at 1 year but only with bodily discomfort (r = 0.74; P = 0.002) at 2 years follow-up. Improvements in axial features were correlated with PDQ-39 mobility (r = 0.57; P = 0.021), ADL (r = 0.58; P = 0.018), bodily discomfort (r = 0.53; P = 0.037), and PDQ-39 SI (r = 0.67; P = 0.004) score at 1 year follow-up, but only with ADL (r = 0.54; P = 0.045), social support (r = 0.56; P = 0.039), and PDQ-39 SI (r = 0.61; P = 0.020) score at 2 years. UPDRS tremor improvement was correlated with PDQ-39 ADL (r = 0.67; P = 0.005) and PDQ-39 SI (r = 0.64; P = 0.007) score at 1 year and with PDQ-39
ADL (r = 0.63; P = 0.015), stigma (r = 0.64; P = 0.015), bodily discomfort (r = 0.62; P = 0.019), PDQ-39 SI (r = 0.59; P = 0.026) score at 24 months. UPDRS rigidity improvement was correlated with social support only, but both at 1 year (r = 0.68; P = 0.003) and at 2 years (r = 0.60; P = 0.022). There was one significant correlation between bradykinesia improvement and PDQ-39 ADL (r = 0.50; P = 0.048) but only at 1 year follow-up. Improvements in UPDRS total score were correlated with PDQ-39 ADL at 1 year (r = 0.69; P = 0.003) and 2 years (r = 0.54; P = 0.046) and at 1 year with social support (r = 0.58; P = 0.017) and PDQ SI (r = 0.68; P = 0.003) score. As shown above, all the correlation coefficients are positive, which means that an improvement in one scale coincides with an improvement in the other scale. The same analysis of the relationship between improvements in motor function (UPDRS) and improvements in quality of life (PDQ-39) was performed at 1 and 2 years in medication-on stimulation-on condition, and compared to baseline scores in medication-on condition. The improvement of ADL UPDRS was correlated at 1 year follow-up with PDQ-39 mobility (r = 0.63; P = 0.009), cognition (r = 0.68; P = 0.004), bodily discomfort (r = 0.50; P = 0.049) and PDQ-39 SI (r = 0.54; P = 0.03) scores. Interestingly, ADL UPDRS improvement at 2 years follow up was correlated only with social support (r = 0.56; P = 0.039). The rigidity improvement correlated only with stigma (r = 0.53; P = 0.035) at 1 year follow-up. This was a strong negative correlation, meaning that an improvement in rigidity coincided with a reduced improvement in stigma scores. The effect was no longer identifiable at the 24 months follow-up. Improvements in dyskinesia score were significantly correlated with improvements in PDQ-39 ADL both at 1 year (r = 0.75; P = 0.001) and 2 years (r = 0.66; P = 0.01) follow-up, and only at 1 year follow-up with improvements in mobility (r = 0.66; P = 0.005) and PDQ-39 SI (r = 0.64; P = 0.008) scores. Fluctuations were
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Table 2 Patients PDQ-39 scores before and after bilateral STN stimulation. Preoperative and postoperative PDQ-39 scores were compared by applying paired t-tests. PDQ-39 dimensions
Mobility ADL Emotional well-being Stigma Social support Cognition Communication Bodily discomfort PDQ-39 summaryindex score
12 Mos follow up
24 Mos follow up
baseline
1 year
baseline
2 years
50.3 10.2 41.3 10.3 31.6 8.5 34.3 8.3 19.8 5.4 24.6 6.0 32.6 6.5 48.4 9.6 35.4 6.6
27.0 5.0a 23.6 4.5a 23.5 7.3a 25.2 5.7a 17.0 3.9a 21.1 4.9a 29.6 6.2a 30.4 5.5a 24.7 4.2a
49.5 10.1 41.0 10.8 33.2 7.7 36.0 7.5 19.9 5.7 25.1 6.1 33.4 6.5 48,0 10.1 35.8 6.9
29.0 6.6a 24.0 4.5a 26.0 5.9a 25.9 3.9a 18.5 4.3 21.5 5.4a 32.0 6.4 31.0 4.4a 26.0 3.9a
A probability value of P < 0.05 was considered significant. Values are expressed as means standard deviations. Significant change from baseline at P < 0.05. a Significant change from baseline at P < 0.01.
negatively correlated with PDQ-39 mobility (r = 0.53; P = 0.05) and positively correlated with emotional well-being (r = 0.57; P = 0.033) but only at 2 years follow-up. The first coefficient was negative, so there was a negative relation between improvements in fluctuations and improvements in mobility. The final significant correlation can be seen between duration of off period and improvement in PDQ-39 communication (r = 0.78; P = 0.001). It was a very strong and positive correlation but it only emerged at the 2 years follow-up. 4. Discussion The present study has shown that bilateral STN DBS remains an effective and safe treatment modality for patients with severe PD symptoms disabled by levodopa-induced dyskinesia, and motor fluctuations in medication-on state. The improvements of motor function are similar to studies reporting results after bilateral STN DBS in PD patients [1–4]. Moreover, patients with advanced PD are not only disabled by motor impairment but also affected by low QoL due to limitations for ADL, social role, reduced control over their own life, mainly due to disabling adverse effects of pharmacotherapy [5]. The growing role of bilateral STN DBS as a treatment for advanced PD has been recognized for nearly 25 years [1–3]. QoL levels after bilateral STN DBS have only been investigated in a few studies, as opposed to numerous studies focusing on UPDRS, especially motor score assessment. QoL assessment is increasingly recognized as an instrument that makes it possible to determine more accurately the impact of therapy on patient’s condition, particularly in progressive degenerative disorders such as PD [16–18]. QoL assessment should be the goal of every therapeutic strategy, and should be incorporated in upcoming studies addressing surgical therapies for PD [16,17]. The first studies which reported effects of bilateral STN DBS on QoL levels assessed by PDQ-39 in PD patients were published by Just and Ostergaard [6], and Martinez-Martin et al. [5]. Just and Ostergaard reported improvements in QoL at 6 months follow-up in 11 patients [6]. Similarly, Martinez-Martin et al. evaluated 17 patients at 6 months follow-up after bilateral STN DBS [5], demonstrating that two dimensions of PDQ-39 (mobility and ADL) significantly improved at 6 months after surgery. The change for emotional well being, stigma, and bodily discomfort were still weakly significant at 6 months follow-up. The domains of social support, cognition and communication were unchanged. The studies with a 6 months follow-up period confirmed the positive impact of bilateral STN DBS on QoL assessed by PDQ-39 in a short-
term perspective [5,6]. Studies with longer follow-up periods later emerged. Lezcano at al. evaluated a total of 11 patients at 2 years follow-up after bilateral STN DBS [7]. The authors found that improvements in PDQ-39 QoL were significant for mobility, ADL, stigma, and emotional well being; however the significance level decreased for communication and bodily discomfort. The dimensions for social support and cognition remained unchanged. In the present study, we observed a similar pattern of improvement at 2 years. We demonstrated that the improvements seen at 2 years were still significant for mobility, ADL, emotional well being, stigma, cognition, bodily discomfort and PDQ-39 SI score. Improvement for social support and communication were maintained at 1 year but unchanged at 2 years. These findings are consistent with observations made by other investigators who reported significant improvements in physical-related PDQ-39 dimensions rather than emotional and social PDQ-39 dimensions [11]. For example, PDQ-39 communication scores in the majority of reported studies have remained unchanged, but some authors have even observed a deterioration of PDQ-39 communication score [7,11,19]. This observation can be attributed to a deterioration of verbal fluency after STN DBS [20,21]. In conformity with other studies, the cognition of our patients showed no significant changes at 2 years. The results achieved by other groups and in our study indicate that psychosocial functioning after DBS surgery remains disturbed [5,11]. The observation can be explained by that fact that patients suffering from advanced PD more frequently experience disruptions of family life, loss of employment, and social dysfunction caused by the long-standing neurodegenerative disease [11]. This may suggest that STN DBS performed earlier would have a greater beneficial impact not only on physical aspects but also on emotional and social PDQ-39 dimensions. This conclusion is corroborated by the recent study by Shuepbach at al. reporting the application of STN DBS for the treatment of PD with early motor complications. The primary outcome measure was PDQ-39 SI, which was found to have improved by 7.8 points for the neurostimulation group with a simultaneous deterioration by 0.2 points in the medical therapy group at 2 years follow-up [22]. Nevertheless, scores for all the dimensions of the PDQ-39 except for social support and communication were found to have improved. We observed a correlation between the overall clinical improvement in medication-off condition postoperatively and QoL improvement measured by PDQ-39. The correlation coefficient analysis revealed a positive correlation between improvements in objective ADL UPDRS scores and several domains of PDQ39 including emotional well-being, social support, cognition and bodily discomfort as well as PDQ-39 SI scores. Our results indicate that there is a significant correlation between total motor off UPDRS scores and PDQ-39 ADL scores and PDQ-39 SI scores. In our study, improvements in tremor UPDRS scores and axial features exhibited a positive correlation with improvements of PDQ-39 ADL and PDQ-39 SI scores. Improvements in rigidity correlated only with improvements in PDQ-39 social support. Also, improvements in bradykinesia correlated only with PDQ-39 ADL at 1 year with a non-significant trend toward correlation with change in PDQ39 ADL scores at 2 years. Conversely, in the study by Lyons and Pahwa, the strongest correlation between improvement in PDQ-39 QoL and motor UPDRS score was an improvement in bradykinesia, indicating that bradykinesia is the motor symptom that exerts the strongest impact on QoL [8]. We failed to identify an equally strong correlation, the possible reason being our small study group. Similarly to improvements in ADL UPDRS scores in off condition, we found significant correlations in ADL UPDRS score improvements postoperatively in on condition with PDQ-39 improvements in mobility, social support, cognition, bodily
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discomfort, and PDQ-39 SI score. We demonstrated no correlations between motor UPDRS improvements in medication-on condition and PDQ-39 QoL improvements. We identified a strong correlation between improvements in UPDRS dyskinesia score and improvements in mobility, PDQ-39 ADL, and total PDQ SI scores at 1 year with a non-significant trend toward correlation at 2 years. The observation suggests that patients with a good clinical response to pharmacological treatment and levodopa-induced dyskinesia, which is a strong predictor of response to STN DBS, are likely to expect a sustained benefit in terms of QoL level after bilateral STN DBS. Surprisingly, we found a negative correlation between improvements in UPDRS fluctuation score and PDQ-39 mobility scores. In our study, we noted no correlation between the duration of off period and daily medication equivalency units and PDQ-39 SI score changes in spite of significant improvements of these factors from baseline to longterm follow-up. The findings were unexpected in that a reduction of fluctuations and duration of off period had no impact on QoL in our patients. This may suggest that the severity of motor disability in off condition and disabling dyskinesia in on condition may in fact exert a greater impact on QoL assessed by PDQ-39 than motor fluctuations and duration of off period. Our study has several limitations. Firstly, a small group of patients was investigated, which may have limited the possibility of identifying true correlations between several UPDRS changes and improvements in health-related QoL assessed by PDQ-39. Moreover, our results are prone to a type 2 error, i.e., failure to find a significant difference even if one does exist. This may explainwhy some separate motor UPDRS changes have non-significant correlations with PDQ39 QoL improvements. Another limitation is the lack of a control group to compare the individuals who had STN DBS. To our knowledge, only one study by Just and Ostergaard compares a surgery group with a similar group of patients who did not undergo surgery and were recruited from a waiting list for bilateral STN DBS [6]. Further studies, preferentially with larger study populations followed up over longer periods after STN DBS are warranted to determine the impact of surgery on patients’ subjective QoL. 5. Conclusion Based on our experience, bilateral STN DBS improves patient’s motor disability in off condition and complications of therapy in on condition, reducing disabling dyskinesia, motor fluctuations and the duration of off periods. These global improvements reflected in mentation, ADL, motor, and complications of therapy UPDRS scores have a major impact on health-related QoL assessed by diseasespecific PDQ-39. Our results indicate that the improvements are sustained in 2 years follow-up. In addition, we observed a strong correlation between improvements in ADL UPDRS score in medication-off and -on condition with subjective improvements reflected in PDQ-39 QoL scores and other dimensions of PDQ-39 including PDQ-39 SI score. Moreover, improvements in motor off medication UPDRS scores were strongly correlated to improvements in PDQ-39 SI scores. We observed a positive correlation between dyskinesia UPDRS score and PDQ-39 mobility, ADL, and PDQ-39 SI score. Interestingly, we documented a negative correlation between fluctuation UPDRS scores and PDQ-39 mobility scores. Our findings highlight the need to investigate further subjective QoL in patients after STN DBS. The results of future studies performed in larger study groups with longer follow-up periods may elucidate the true impact of surgery on the global subjective functioning of patients.
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Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.clineuro.2014.06.019. References [1] Krack P, Batir A, Van Blercom N, Chabardes S, Fraix V, Ardouin C, et al. Five-year follow-up of bilateral stimulation of the subthalamic nucleus in advanced Parkinson’s disease. N Engl J Med 2003;349:1925–34. [2] Kleiner-Fisman G, Fisman D, Sime E, Saint-Cyr JA, Lozano AM, Lang AE. Longterm follow up of bilateral deep brain stimulation of the subthalamic nucleus in patients with advanced Parkinson disease. J Neurosurg 2003;99: 489–95. [3] Limousin P, Pollak P, Benazzouz A, Hoffmann D, Broussolle E, Perret JE, et al. Bilateral subthalamic nucleus stimulation for severe Parkinson’s disease. Mov Disord 1995;10:672–4. [4] Mandat T, Tykocki T, Koziara H, Koziorowski D, Brodacki B, Rola R, et al. Subthalamic deep brain stimulation for the treatment of Parkinson disease. Neurol Neurochir Pol 2011;45:32–6. [5] Martinez-Martin P, Valldeoriola F, Tolosa E, Pilleri M, Molinuevo JL, Rumià J, et al. Bilateral subthalamic nucleus stimulation and quality of life in advanced Parkinson’s disease. Mov Diord 2002;17:372–7. [6] Just H, Ostergaard K. Health-related quality of life in patients with advanced Parkinson’s disease treated by deep brain stimulation of the subthalamic nuclei. Mov Disord 2002;17:539–45. [7] Lezcano E, Gómez-Esteban C, Zarranz J, Lambarri I, Madoz P, Bilbao G, et al. Improvement in quality of life in patients with advanced Parkinson’s disease following bilateral deep-brain stimulation in subthalamic nucleus. Eur J Neurol 2004;11(July):451–4. [8] Lyons KE, Pahwa R. Long-term benefits in quality of life provided by bilateral subthalamic stimulation in patients with Parkinson disease. J Neurosurg 2005;103:252–5. [9] Daniels C, Krack P, Volkmann J, Raethjen J, Pinsker MO, Kloss M, et al. Is improvement in the quality of life after subthalamic nucleus stimulation in Parkinson’s disease predictable? Mov Disord 2011;26(December (14)): 2516–21. [10] Siderowf A, Jaggi JL, Xie SX, Loveland-Jones C, Leng L, Hurtig H, et al. Long-term effects of bilateral subthalamic nucleus stimulation on health-related quality of life in advanced Parkinson’s disease. Mov Disord 2006;22:746–53. [11] Drapier S, Raoul S, Drapier D, Leray E, Lallement F, Rivier I, et al. Only physical aspects of quality of life are significantly improved by bilateral subthalamic stimulation in Parkinson’s disease. J Neurol 2005;252(5)583–8 Epub 2005 March 23. [12] Hughes AJ, Daniel SE, Kilford L, Lees AJ. Accuracy of clinical diagnosis of idiopathic Parkinson's disease. A clinico-pathological study of 100 cases. J Neurol Neurosurg Psychiatry 1992;55:181–4. [13] Defer GL, Widner H, Marie RM, Remy P, Levivier M. Core assessment program for surgical interventional therapies in Parkinson’s disease (CAPSIT-PD). Mov Disord 1999;14:572–84. [14] Fahn S, Elton RL. Members of the UPDRS development committee Unified Parkinson’s Disease rating Scale. In: fahn S, Marsden CD, Calne DB, editors. Recent developments in Parkinson’s disease. Florham park, NJ: Macmilan Health Care Information; 1987. p. 153–64. [15] Jenkinson C, Fitzpatrick R, Peto V, Greenhall R, Hyman N. The Parkinson’s Disease Questionnaire (PDQ-39): development and validation of a Parkinson’s disease summary index score. Age Aging 1997;26:353–7. [16] Martínez-Martín P, Deuschl G. Effect of medical and surgical interventions on health-related quality of life in Parkinson’s. Mov Disord. 2007;6:757–65. [17] Diamond A, Jankovic J. The effect of deep brain stimulation on quality of life in movement disorders. Neurol Neurosurg Psychiatry 2005;76:1188–93. [18] Tykocki T, Szalecki K, Koziara H, Nauman P, Mandat T. Quality of life and depressive symptoms in Parkinson’s disease after subthalamic deep brain stimulation: a 2-year follow-up study. Turk Neurosurg 2013;23(3):379–84. [19] Erola T, Karinen P, Heikkinen E, Tuominen J, Haapaniemi T, Koivukangas J, et al. Bilateral subthalamic nucleus stimulation improves health-related quality of life in Parkinsonian patients. Parkinsonism Relat Disord 2005;11(2)89–94 Cognitive and behavioural effects of chronic stimulation of the subthalamic nucleus in patients with Parkinson’s disease. [20] Daniele A, Albanese A, Contarino M, Zinzi P, Barbier A, Gasparini F, J Neurol Neurosurg Psychiatry 2003;74(February (2)):175–82. [21] Alegret M, Valldeoriola F, Martí M, Pilleri M, Junqué C, Rumià J, et al. Comparative cognitive effects of bilateral subthalamic stimulation and subcutaneous continuous infusion of apomorphine in Parkinson's disease. Mov Disord 2004;19(December (12)):1463–9. [22] Shuepbach M, Rau J, Knudsen J, Volkman P, Timmermann L, Haelbig TD, et al. Neurostimulation for Parkinson's disease with early motor complications. N Engl J Med 2013;368:610–22.
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Quality of life in advanced Parkinson’s disease after bilateral subthalamic stimulation: 2 years follow-up study Michał Sobstyl a, *, Mirosław Za˛bek a , Wojciech Górecki b , Zbigniew Mossakowski b a b
Neurosurgical Department of Postgraduate Medical Center, Marymoncka 99/103 Street, Warsaw 01-813, Poland Neurosurgical Department of Bródno Regional Hospital, Kondratowicza Street, Warsaw 023-23, Poland
A R T I C L E I N F O
A B S T R A C T
Article history: Received 24 February 2014 Received in revised form 9 May 2014 Accepted 14 June 2014 Available online 23 June 2014
Objective: The aims of this study were to assess the quality of life (QoL) using Parkinson’s Disease Questionnaire PDQ-39 after bilateral subthalamic deep brain stimulation (STN DBS), and to identify correlations between changes in UPDRS score and separate PDQ-39 QoL dimensions and PDQ summary index (SI) score at long-term follow-up. Methods: We evaluated 16 patients with advanced PD after bilateral STN DBS. All 16 patients were assessed 1 year after surgery and 14 were studied 2 years after surgery. The patients were assessed using Unified Parkinson’s Disease Rating Scale (UPDRS) in medication-on and medication-off conditions, both preoperatively and postoperatively. All UPDRS evaluations were performed postoperatively during stimulation-on condition. QoL levels were determined by applying PDQ-39 questionnaire. Results: The UPDRS scores after 1 and 2 years in medication-off and -on conditions when bilateral STN DBS was switched on showed a significant difference between baseline scores and follow-up scores (both in -off and -on conditions) in every UPDRS measurement except for mentation after 2 years. Most of Pvalues indicated that the differences were highly significant (P < 0.01) based on Wilcoxon signed-rank test. All dimensions of PDQ-39 as well PDQ-39 SI score were highly significantly improved after 1 year. The same improvements were visible in 2 years follow-up with the exception of social support and communication. We found a positive correlation between ADL UPDRS, motor off UPDRS scores and PDQ39 ADL and PDQ-39 SI scores. A further analysis of separate motor PD features revealed that tremor, bradykinesia and axial features were correlated with improvements mostly seen in PDQ-39 ADL and PDQ-39 SI scores. Moreover, in medication-on condition, we found a strong correlation between dyskinesia UPDRS score and PDQ-39 mobility, ADL, and PDQ-39 SI score. We observed a negative correlation between improved fluctuation UPDRS score and PDQ-39 mobility. We identified no correlation between the duration of the off period and levodopa dose and changes in PDQ-39. Conclusion: STN DBS significantly improved important aspects of QoL as measured by PDQ-39. The improvements were maintained at 2 years follow-up except for social support and communication. We demonstrated a positive correlation between changes in the off condition of motor UPDRS scores and dyskinesia UPDRS scores in several PDQ-39 dimensions, whereas fluctuation UPDRS scores were negatively correlated with PDQ-39 mobility scores. ã 2014 Elsevier B.V. All rights reserved.
1. Introduction Several studies have confirmed the long-term efficacy of bilateral STN DBS on activities of daily living (ADL), motor and complications of therapy scores in patients with advanced PD [1–4]. The improvement in motor function correlates with benefits in QoL validated by Parkinson’s Disease Questionnaire 39 [5–8]. As of now,
* Tel.: +48 22 5693 700; fax: +48 22 5693 712. E-mail address: [email protected] (M. Sobstyl). http://dx.doi.org/10.1016/j.clineuro.2014.06.019 0303-8467/ ã 2014 Elsevier B.V. All rights reserved.
there are only a few studies which address QoL improvements in separate dimensions of PDQ-39 in short- and long-term follow-up. Correlations between UPDRS scores and changes in PDQ-39 dimensions after bilateral STN DBS surgery remain a matter of controversy. Some authors claim that the strongest correlation for QoL improvement is the duration of off periods [9], while others argue that it is the severity of off periods rather than their duration [10]. Bilateral STN DBS has the greatest impact on reducing complications of therapy. Interestingly, some authors have found a negative correlation between dyskinesia and changes in PDQ-39 QoL after STN DBS [10]. In the opinion of other authors, the impact on
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QoL in PD patients is strongly related to a reduction of disabling dyskinesia and motor fluctuations, which results in a more stable motor condition of patients [5]. Considering only outcomes for separate PDQ-39 dimensions, results obtained in different studies are conflicting. Some indicate that it is not only dimensions entirely dominated by motor function but also dimensions related to physical and emotional aspects that improve after STN DBS [7]. A number of authors stress that only physical PDQ-39 dimensions are improved, while others are unchanged or even deteriorate over time [11]. These contradictory findings require further investigation. The aims of our study were to assess QoL by applying PDQ-39, and to identify correlations between changes in UPDRS scores in medication-off and -on condition on health-related QoL after STN DBS. 2. Material and methods The clinical material consisted of 16 patients (11 men and 5 women) suffering from advanced PD who underwent bilateral STN DBS. The average age of the patients at PD diagnosis was 54.2 6.9 years (range 44.7–65.8 years), whereas the average age at surgery was 63.5 5.2 years (range 54.3–72.7 years). All the patients met the clinical criteria of the United Kingdom Parkinson’s Disease Society brain-bank for idiopathic PD [12]. Inclusion and exclusion criteria followed CAPSIT-PD guidelines [13]. The patients were operated on at the neurosurgical department between January 2008 and December 2011. All of them were preoperatively evaluated by UPDRS parts I–IV [14]. Levodopa equivalents and all levodopa containing medications were withdrawn, 48 h and 12 h (respectively) before assessment in medication off condition. The medication on condition was assessed after administration of levodopa i.e., 50 mg higher than the usual effective first dose taken in the morning when a patient reported the best response to medication. The assessment routine was as follows: first the patients were assessed in medication off condition in the morning and then in medication on condition. In accordance with the UPDRS the same assessments took place postoperatively in medication off and on conditions, but only when bilateral STN DBS was switched on. The UPDRS part III motor scores were separately assessed for tremor items 20–21, rigidity item 22, bradykinesia items 23–26. Axial features constituted the sum of the following items: speech item 18, facial expression item 19, arising from chair item 27, posture item 28, gait item 29, postural instability item 30, bradykinesia item 31. Levodopa-induced dyskinesias (LID) were assessed according to the following items: duration of dyskinesia item 32, disability of dyskinesia item 33, painful dyskinesia item 34, and the presence of early morning dystonia item 35. Fluctuations were evaluated by the following items: predictable off period item 36, unpredictable off period item 37 and sudden off item 38 and duration of the off period item 39. Preoperative and postoperative UPDRS scores were evaluated by a movement disorders neurologist. The patients were also evaluated according to the Hoehn and Yahr (H/Y) staging system. The total levodopa-equivalent dose was calculated on the basis of the formula proposed by Lyons and Pahwa [8,15]. QoL was assessed preoperatively by applying PDQ39 questionnaire. Answers to the PDQ-39 give the summary index PDQ-39 SI score, and dimensions scores for mobility, activities of daily living, emotional well being, stigma, social support, cognition, communication, and bodily discomfort. Postoperative assessment incorporated all the UPDRS parts, and the PDQ-39 questionnaire. The postoperative assessments were performed when the stimulators were switched on in medication-off condition, and medication-on condition. The study protocol was approved by the Institutional Review Board of Postgraduate Medical Center. All the patients provided their written informed consent.
The patients were operated in medication-off condition. After stereotactic frame fixation in local anesthesia, contrast-enhanced CT scanning was performed. CT images were merged with preoperative MRI scans. The target point – subthalamic nucleus – was calculated using an indirect method in relation to the midpoint of the intercommisural line, and direct methods that modified the position of the target depending on MRI scans. After electrophysiological confirmation of the target the DBS electrode was inserted and its position was verified with fluoroscopy. Following stereotactic frame removal, the patients were brought to general anesthesia, and internal pulse generators were placed in the subclavicular region in the chest wall. All surgical procedures were performed using Medtronic DBS equipment. The programming took place 2 or 3 days after surgery. Stimulation settings were adjusted at follow-up visits in order to achieve the best therapeutic results. Statistical analyses were performed using the Statistical Package for Social Sciences (SPSS version 21). Descriptive statistics (mean, standard deviation, range, confidence interval) were obtained for each variable as required. Preoperative and postoperative UPDRS scores were compared using Wilcoxon signed-rank test. Preoperative and postoperative PDQ-39 scores were compared by applying paired t-tests. Spearman rank order correlations were used to assess relationships between UPDRS scores and changes in PDQ-39 QoL dimensions and PDQ-39 SI scores. A probability value of P < 0.05 was considered significant. 3. Results Sixteen patients with PD were enrolled in the study. All the patients completed the 1 year evaluation, however only 14 patients were able to complete the follow-up review after 2 years. First, the Wilcoxon test was performed to check whether there was a significant difference between baseline scores in medication-off and -on conditions and UPDRS scores after 1 and 2 years in medication-off and -on condition when bilateral STN DBS was switched on. The test showed that there was a significant difference between baseline scores and follow-up scores (both in off and on conditions) in every measurement of UPDRS except mentation after 24 months. Most of P-values indicated that the differences were highly significant (P < 0.01). Detailed results are shown in Table 1. There was a significant difference in the Hoehn and Yahr (H/Y) staging system after surgery in medication-off and -on when compared to baseline H/Y staging system. The preoperative H/Y stage in off-condition was 3.4 0.6 and improved to 1.8 0.5 (P < 0.01) and 1.8 0.4 (P < 0.01) at 12 and 24 months respectively. The preoperative H/ Y stage in on-condition was 2.3 0.5 and improved to 1.7 0.4 (P < 0.01) and 1.6 0.4 (P < 0.01) at 12 and 24 months respectively. The effect on the patients’ ADL (UPDRS part II) in long-term followup was significant in medication-off and -on conditions, resulting in a 43% (P < 0.01) and 24% (P < 0.01) reduction, respectively. Similarly, significant improvements were noted in motor scores (UPDRS part III) in medication-off and -on conditions postoperatively, resulting in a 44% (P < 0.01) and 26% (P < 0.01) reduction, respectively. Long-term stimulation resulted in improved scores for tremor, rigidity, bradykinesia, axial features in medication-off and medication-on conditions after stimulation. Stimulation significantly reduced complications associated with therapy (UPDRS part IV). The dyskinesia score (UPDRS IVA items 32–35) was reduced by 73% (P < 0.01) and by 74% (P < 0.01) at 1 and 2 years after stimulation. The fluctuation score (UPDRS IVB items 36–39) decreased by 43% (P < 0.01) and by 47% (P < 0. 01) at 1 and 2 years. The duration of the off period (UPDRS IV item 39) showed a significant improvement, resulting in a 62% (P < 0.01) and 50% (P < 0.01) reduction at subsequent follow-up visits. The daily
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Table 1 Patients Unified Parkinson’s Disease Rating scale (UPDRS) scores in medication-off and -on conditions before and after bilateral STN stimulation in stimulation on condition. The UPDRS part III motor scores were separately assessed for tremor items 20–21, rigidity item 22, bradykinesia items 23–26. Axial features constituted the sum of the following items: 18,19, 27–31. Levodopa-induced dyskinesias (LID) were assessed according to UPDRS part IVA items: 32–35. Fluctuations were evaluated by UPDRS part IVB items: 36–39. The duration of the off period was assessed according to item 39. Preoperative and postoperative UPDRS scores were compared using Wilcoxon signed-rank test. A probability value of P < 0.05 was considered significant. Follow-up period
12 Mos follow up
Parts of UPDRS
Baseline
24 Mos follow up 1 year
Baseline a
2 years
UPDRS part I on UPDRS part I off
1.2 0.6 2.0 0.7
0,8 0.6 1,7 0.6a
1,1 0,6 2 0,8
UPDRS part II on UPDRS part II of
14.6 4.4 23.8 4.3
10.4 3.9b 12.7 1.5b
15.0 4.5 24.1 4.2
11.5 3.9b 13.7 1.8b
UPDRS tremor score on UPDRS tremor score of
1.3 0.6 4.5 2.5
0.7 0.6b 1.1 0.7b
1.3 0.6 4.5 2.7
0.7 0.7a 1.0 0.8b
UPDRS rigidity score on UPDRS rigidity score of
5.6 1.0 10.1 2.8
4.1 0.9b 4.9 1.6b
5.5 1.0 10.2 2.9
3.9 1.2b 5.2 1.8b
UPDRS bradykinesia score on UPDRS bradykinesia score of
7.4 1.5 12.6 3.5
5.4 1.0b 6.1 2.4b
7.5 1.6 12.5 3.6
5.6 1.5b 6.7 2.7b
UPDRS axial features score on UPDRS axial features score of
9.9 1.5 13.6 4.1
6.8 1.0zb 10.3 3.1b
9.9 1.5 13.2 4.0
7.6 0.8b 10.7 3.3b
Total UPDRS part III on Total UPDRS part III of
24.0 3.5 40.9 10.7
17.1 2.6b 22.3 5.5b
24.0 3.6 40.5 11.2
17.8 2.8b 23.0 7.3b
UPDRS part IV dyskinesia score UPDRS part IV fluctuation score UPDRS part IV of period duration
5.5 1.5 3.7 0.9 1.6 0.6
1.5 0.6b 2.1 0.4b 1 0.5b
5.2 1.4 3.6 1.0 1.6 0.6
0,9 0,5 2 0,8
1.4 0.4b 1.9 0.5b 0.8 0.4b
Values are expressed as means standard deviations. a Significant change from baseline at P < 0.05. b Significant change from baseline at P < 0.01.
medication equivalency units decreased from the preoperative value of 13.2 4.0 to 10.0 3.3 at 1 year, and to 8.0 2.0 at 2 years after bilateral STN DBS. All dimensions of PDQ-39 as well PDQ-39 SI score were highly significant improved after 1 year of stimulation when compared to baseline PDQ-39 scores. On the other hand, almost the same improvements were visible in 2 years follow-up except for social support and communication. The two measures were insignificantly different when comparing baseline scores to 2 year scores. The results obtained for all dimensions of PDQ-39 as well PDQ-39 summary index (PDQ-39 SI) are shown in Table 2. In order to examine the relationship between improvements in motor function and improvements in quality of life, correlation coefficients were determined to compare changes in UPDRS scores from the baseline to follow-up, and changes in PDQ-39 scores from baseline to follow-up. Initially, the analysis was carried out for medication-off condition at baseline to the medication-off stimulation-on condition at follow-up. Improvements in UPDRS mentation were strongly correlated with improvements in PDQ-39 ADL (r = 0.57; P = 0.021 and PDQ-39 SI (r = 0.59; P = 0.017) score at 1 year follow-up. Improvements in UPDRS ADL scores were strongly correlated with PDQ-39 emotional well-being (r = 0.71; P = 0.002), social support (r = 0.58; P = 0.018), cognition (r = 0.50; P = 0.049), bodily discomfort (r = 0.57; P = 0.020) and PDQ SI (r = 0.59; P = 0.012) score at 1 year but only with bodily discomfort (r = 0.74; P = 0.002) at 2 years follow-up. Improvements in axial features were correlated with PDQ-39 mobility (r = 0.57; P = 0.021), ADL (r = 0.58; P = 0.018), bodily discomfort (r = 0.53; P = 0.037), and PDQ-39 SI (r = 0.67; P = 0.004) score at 1 year follow-up, but only with ADL (r = 0.54; P = 0.045), social support (r = 0.56; P = 0.039), and PDQ-39 SI (r = 0.61; P = 0.020) score at 2 years. UPDRS tremor improvement was correlated with PDQ-39 ADL (r = 0.67; P = 0.005) and PDQ-39 SI (r = 0.64; P = 0.007) score at 1 year and with PDQ-39
ADL (r = 0.63; P = 0.015), stigma (r = 0.64; P = 0.015), bodily discomfort (r = 0.62; P = 0.019), PDQ-39 SI (r = 0.59; P = 0.026) score at 24 months. UPDRS rigidity improvement was correlated with social support only, but both at 1 year (r = 0.68; P = 0.003) and at 2 years (r = 0.60; P = 0.022). There was one significant correlation between bradykinesia improvement and PDQ-39 ADL (r = 0.50; P = 0.048) but only at 1 year follow-up. Improvements in UPDRS total score were correlated with PDQ-39 ADL at 1 year (r = 0.69; P = 0.003) and 2 years (r = 0.54; P = 0.046) and at 1 year with social support (r = 0.58; P = 0.017) and PDQ SI (r = 0.68; P = 0.003) score. As shown above, all the correlation coefficients are positive, which means that an improvement in one scale coincides with an improvement in the other scale. The same analysis of the relationship between improvements in motor function (UPDRS) and improvements in quality of life (PDQ-39) was performed at 1 and 2 years in medication-on stimulation-on condition, and compared to baseline scores in medication-on condition. The improvement of ADL UPDRS was correlated at 1 year follow-up with PDQ-39 mobility (r = 0.63; P = 0.009), cognition (r = 0.68; P = 0.004), bodily discomfort (r = 0.50; P = 0.049) and PDQ-39 SI (r = 0.54; P = 0.03) scores. Interestingly, ADL UPDRS improvement at 2 years follow up was correlated only with social support (r = 0.56; P = 0.039). The rigidity improvement correlated only with stigma (r = 0.53; P = 0.035) at 1 year follow-up. This was a strong negative correlation, meaning that an improvement in rigidity coincided with a reduced improvement in stigma scores. The effect was no longer identifiable at the 24 months follow-up. Improvements in dyskinesia score were significantly correlated with improvements in PDQ-39 ADL both at 1 year (r = 0.75; P = 0.001) and 2 years (r = 0.66; P = 0.01) follow-up, and only at 1 year follow-up with improvements in mobility (r = 0.66; P = 0.005) and PDQ-39 SI (r = 0.64; P = 0.008) scores. Fluctuations were
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Table 2 Patients PDQ-39 scores before and after bilateral STN stimulation. Preoperative and postoperative PDQ-39 scores were compared by applying paired t-tests. PDQ-39 dimensions
Mobility ADL Emotional well-being Stigma Social support Cognition Communication Bodily discomfort PDQ-39 summaryindex score
12 Mos follow up
24 Mos follow up
baseline
1 year
baseline
2 years
50.3 10.2 41.3 10.3 31.6 8.5 34.3 8.3 19.8 5.4 24.6 6.0 32.6 6.5 48.4 9.6 35.4 6.6
27.0 5.0a 23.6 4.5a 23.5 7.3a 25.2 5.7a 17.0 3.9a 21.1 4.9a 29.6 6.2a 30.4 5.5a 24.7 4.2a
49.5 10.1 41.0 10.8 33.2 7.7 36.0 7.5 19.9 5.7 25.1 6.1 33.4 6.5 48,0 10.1 35.8 6.9
29.0 6.6a 24.0 4.5a 26.0 5.9a 25.9 3.9a 18.5 4.3 21.5 5.4a 32.0 6.4 31.0 4.4a 26.0 3.9a
A probability value of P < 0.05 was considered significant. Values are expressed as means standard deviations. Significant change from baseline at P < 0.05. a Significant change from baseline at P < 0.01.
negatively correlated with PDQ-39 mobility (r = 0.53; P = 0.05) and positively correlated with emotional well-being (r = 0.57; P = 0.033) but only at 2 years follow-up. The first coefficient was negative, so there was a negative relation between improvements in fluctuations and improvements in mobility. The final significant correlation can be seen between duration of off period and improvement in PDQ-39 communication (r = 0.78; P = 0.001). It was a very strong and positive correlation but it only emerged at the 2 years follow-up. 4. Discussion The present study has shown that bilateral STN DBS remains an effective and safe treatment modality for patients with severe PD symptoms disabled by levodopa-induced dyskinesia, and motor fluctuations in medication-on state. The improvements of motor function are similar to studies reporting results after bilateral STN DBS in PD patients [1–4]. Moreover, patients with advanced PD are not only disabled by motor impairment but also affected by low QoL due to limitations for ADL, social role, reduced control over their own life, mainly due to disabling adverse effects of pharmacotherapy [5]. The growing role of bilateral STN DBS as a treatment for advanced PD has been recognized for nearly 25 years [1–3]. QoL levels after bilateral STN DBS have only been investigated in a few studies, as opposed to numerous studies focusing on UPDRS, especially motor score assessment. QoL assessment is increasingly recognized as an instrument that makes it possible to determine more accurately the impact of therapy on patient’s condition, particularly in progressive degenerative disorders such as PD [16–18]. QoL assessment should be the goal of every therapeutic strategy, and should be incorporated in upcoming studies addressing surgical therapies for PD [16,17]. The first studies which reported effects of bilateral STN DBS on QoL levels assessed by PDQ-39 in PD patients were published by Just and Ostergaard [6], and Martinez-Martin et al. [5]. Just and Ostergaard reported improvements in QoL at 6 months follow-up in 11 patients [6]. Similarly, Martinez-Martin et al. evaluated 17 patients at 6 months follow-up after bilateral STN DBS [5], demonstrating that two dimensions of PDQ-39 (mobility and ADL) significantly improved at 6 months after surgery. The change for emotional well being, stigma, and bodily discomfort were still weakly significant at 6 months follow-up. The domains of social support, cognition and communication were unchanged. The studies with a 6 months follow-up period confirmed the positive impact of bilateral STN DBS on QoL assessed by PDQ-39 in a short-
term perspective [5,6]. Studies with longer follow-up periods later emerged. Lezcano at al. evaluated a total of 11 patients at 2 years follow-up after bilateral STN DBS [7]. The authors found that improvements in PDQ-39 QoL were significant for mobility, ADL, stigma, and emotional well being; however the significance level decreased for communication and bodily discomfort. The dimensions for social support and cognition remained unchanged. In the present study, we observed a similar pattern of improvement at 2 years. We demonstrated that the improvements seen at 2 years were still significant for mobility, ADL, emotional well being, stigma, cognition, bodily discomfort and PDQ-39 SI score. Improvement for social support and communication were maintained at 1 year but unchanged at 2 years. These findings are consistent with observations made by other investigators who reported significant improvements in physical-related PDQ-39 dimensions rather than emotional and social PDQ-39 dimensions [11]. For example, PDQ-39 communication scores in the majority of reported studies have remained unchanged, but some authors have even observed a deterioration of PDQ-39 communication score [7,11,19]. This observation can be attributed to a deterioration of verbal fluency after STN DBS [20,21]. In conformity with other studies, the cognition of our patients showed no significant changes at 2 years. The results achieved by other groups and in our study indicate that psychosocial functioning after DBS surgery remains disturbed [5,11]. The observation can be explained by that fact that patients suffering from advanced PD more frequently experience disruptions of family life, loss of employment, and social dysfunction caused by the long-standing neurodegenerative disease [11]. This may suggest that STN DBS performed earlier would have a greater beneficial impact not only on physical aspects but also on emotional and social PDQ-39 dimensions. This conclusion is corroborated by the recent study by Shuepbach at al. reporting the application of STN DBS for the treatment of PD with early motor complications. The primary outcome measure was PDQ-39 SI, which was found to have improved by 7.8 points for the neurostimulation group with a simultaneous deterioration by 0.2 points in the medical therapy group at 2 years follow-up [22]. Nevertheless, scores for all the dimensions of the PDQ-39 except for social support and communication were found to have improved. We observed a correlation between the overall clinical improvement in medication-off condition postoperatively and QoL improvement measured by PDQ-39. The correlation coefficient analysis revealed a positive correlation between improvements in objective ADL UPDRS scores and several domains of PDQ39 including emotional well-being, social support, cognition and bodily discomfort as well as PDQ-39 SI scores. Our results indicate that there is a significant correlation between total motor off UPDRS scores and PDQ-39 ADL scores and PDQ-39 SI scores. In our study, improvements in tremor UPDRS scores and axial features exhibited a positive correlation with improvements of PDQ-39 ADL and PDQ-39 SI scores. Improvements in rigidity correlated only with improvements in PDQ-39 social support. Also, improvements in bradykinesia correlated only with PDQ-39 ADL at 1 year with a non-significant trend toward correlation with change in PDQ39 ADL scores at 2 years. Conversely, in the study by Lyons and Pahwa, the strongest correlation between improvement in PDQ-39 QoL and motor UPDRS score was an improvement in bradykinesia, indicating that bradykinesia is the motor symptom that exerts the strongest impact on QoL [8]. We failed to identify an equally strong correlation, the possible reason being our small study group. Similarly to improvements in ADL UPDRS scores in off condition, we found significant correlations in ADL UPDRS score improvements postoperatively in on condition with PDQ-39 improvements in mobility, social support, cognition, bodily
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discomfort, and PDQ-39 SI score. We demonstrated no correlations between motor UPDRS improvements in medication-on condition and PDQ-39 QoL improvements. We identified a strong correlation between improvements in UPDRS dyskinesia score and improvements in mobility, PDQ-39 ADL, and total PDQ SI scores at 1 year with a non-significant trend toward correlation at 2 years. The observation suggests that patients with a good clinical response to pharmacological treatment and levodopa-induced dyskinesia, which is a strong predictor of response to STN DBS, are likely to expect a sustained benefit in terms of QoL level after bilateral STN DBS. Surprisingly, we found a negative correlation between improvements in UPDRS fluctuation score and PDQ-39 mobility scores. In our study, we noted no correlation between the duration of off period and daily medication equivalency units and PDQ-39 SI score changes in spite of significant improvements of these factors from baseline to longterm follow-up. The findings were unexpected in that a reduction of fluctuations and duration of off period had no impact on QoL in our patients. This may suggest that the severity of motor disability in off condition and disabling dyskinesia in on condition may in fact exert a greater impact on QoL assessed by PDQ-39 than motor fluctuations and duration of off period. Our study has several limitations. Firstly, a small group of patients was investigated, which may have limited the possibility of identifying true correlations between several UPDRS changes and improvements in health-related QoL assessed by PDQ-39. Moreover, our results are prone to a type 2 error, i.e., failure to find a significant difference even if one does exist. This may explainwhy some separate motor UPDRS changes have non-significant correlations with PDQ39 QoL improvements. Another limitation is the lack of a control group to compare the individuals who had STN DBS. To our knowledge, only one study by Just and Ostergaard compares a surgery group with a similar group of patients who did not undergo surgery and were recruited from a waiting list for bilateral STN DBS [6]. Further studies, preferentially with larger study populations followed up over longer periods after STN DBS are warranted to determine the impact of surgery on patients’ subjective QoL. 5. Conclusion Based on our experience, bilateral STN DBS improves patient’s motor disability in off condition and complications of therapy in on condition, reducing disabling dyskinesia, motor fluctuations and the duration of off periods. These global improvements reflected in mentation, ADL, motor, and complications of therapy UPDRS scores have a major impact on health-related QoL assessed by diseasespecific PDQ-39. Our results indicate that the improvements are sustained in 2 years follow-up. In addition, we observed a strong correlation between improvements in ADL UPDRS score in medication-off and -on condition with subjective improvements reflected in PDQ-39 QoL scores and other dimensions of PDQ-39 including PDQ-39 SI score. Moreover, improvements in motor off medication UPDRS scores were strongly correlated to improvements in PDQ-39 SI scores. We observed a positive correlation between dyskinesia UPDRS score and PDQ-39 mobility, ADL, and PDQ-39 SI score. Interestingly, we documented a negative correlation between fluctuation UPDRS scores and PDQ-39 mobility scores. Our findings highlight the need to investigate further subjective QoL in patients after STN DBS. The results of future studies performed in larger study groups with longer follow-up periods may elucidate the true impact of surgery on the global subjective functioning of patients.
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Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.clineuro.2014.06.019. References [1] Krack P, Batir A, Van Blercom N, Chabardes S, Fraix V, Ardouin C, et al. Five-year follow-up of bilateral stimulation of the subthalamic nucleus in advanced Parkinson’s disease. N Engl J Med 2003;349:1925–34. [2] Kleiner-Fisman G, Fisman D, Sime E, Saint-Cyr JA, Lozano AM, Lang AE. Longterm follow up of bilateral deep brain stimulation of the subthalamic nucleus in patients with advanced Parkinson disease. J Neurosurg 2003;99: 489–95. [3] Limousin P, Pollak P, Benazzouz A, Hoffmann D, Broussolle E, Perret JE, et al. Bilateral subthalamic nucleus stimulation for severe Parkinson’s disease. Mov Disord 1995;10:672–4. [4] Mandat T, Tykocki T, Koziara H, Koziorowski D, Brodacki B, Rola R, et al. Subthalamic deep brain stimulation for the treatment of Parkinson disease. Neurol Neurochir Pol 2011;45:32–6. [5] Martinez-Martin P, Valldeoriola F, Tolosa E, Pilleri M, Molinuevo JL, Rumià J, et al. Bilateral subthalamic nucleus stimulation and quality of life in advanced Parkinson’s disease. Mov Diord 2002;17:372–7. [6] Just H, Ostergaard K. Health-related quality of life in patients with advanced Parkinson’s disease treated by deep brain stimulation of the subthalamic nuclei. Mov Disord 2002;17:539–45. [7] Lezcano E, Gómez-Esteban C, Zarranz J, Lambarri I, Madoz P, Bilbao G, et al. Improvement in quality of life in patients with advanced Parkinson’s disease following bilateral deep-brain stimulation in subthalamic nucleus. Eur J Neurol 2004;11(July):451–4. [8] Lyons KE, Pahwa R. Long-term benefits in quality of life provided by bilateral subthalamic stimulation in patients with Parkinson disease. J Neurosurg 2005;103:252–5. [9] Daniels C, Krack P, Volkmann J, Raethjen J, Pinsker MO, Kloss M, et al. Is improvement in the quality of life after subthalamic nucleus stimulation in Parkinson’s disease predictable? Mov Disord 2011;26(December (14)): 2516–21. [10] Siderowf A, Jaggi JL, Xie SX, Loveland-Jones C, Leng L, Hurtig H, et al. Long-term effects of bilateral subthalamic nucleus stimulation on health-related quality of life in advanced Parkinson’s disease. Mov Disord 2006;22:746–53. [11] Drapier S, Raoul S, Drapier D, Leray E, Lallement F, Rivier I, et al. Only physical aspects of quality of life are significantly improved by bilateral subthalamic stimulation in Parkinson’s disease. J Neurol 2005;252(5)583–8 Epub 2005 March 23. [12] Hughes AJ, Daniel SE, Kilford L, Lees AJ. Accuracy of clinical diagnosis of idiopathic Parkinson's disease. A clinico-pathological study of 100 cases. J Neurol Neurosurg Psychiatry 1992;55:181–4. [13] Defer GL, Widner H, Marie RM, Remy P, Levivier M. Core assessment program for surgical interventional therapies in Parkinson’s disease (CAPSIT-PD). Mov Disord 1999;14:572–84. [14] Fahn S, Elton RL. Members of the UPDRS development committee Unified Parkinson’s Disease rating Scale. In: fahn S, Marsden CD, Calne DB, editors. Recent developments in Parkinson’s disease. Florham park, NJ: Macmilan Health Care Information; 1987. p. 153–64. [15] Jenkinson C, Fitzpatrick R, Peto V, Greenhall R, Hyman N. The Parkinson’s Disease Questionnaire (PDQ-39): development and validation of a Parkinson’s disease summary index score. Age Aging 1997;26:353–7. [16] Martínez-Martín P, Deuschl G. Effect of medical and surgical interventions on health-related quality of life in Parkinson’s. Mov Disord. 2007;6:757–65. [17] Diamond A, Jankovic J. The effect of deep brain stimulation on quality of life in movement disorders. Neurol Neurosurg Psychiatry 2005;76:1188–93. [18] Tykocki T, Szalecki K, Koziara H, Nauman P, Mandat T. Quality of life and depressive symptoms in Parkinson’s disease after subthalamic deep brain stimulation: a 2-year follow-up study. Turk Neurosurg 2013;23(3):379–84. [19] Erola T, Karinen P, Heikkinen E, Tuominen J, Haapaniemi T, Koivukangas J, et al. Bilateral subthalamic nucleus stimulation improves health-related quality of life in Parkinsonian patients. Parkinsonism Relat Disord 2005;11(2)89–94 Cognitive and behavioural effects of chronic stimulation of the subthalamic nucleus in patients with Parkinson’s disease. [20] Daniele A, Albanese A, Contarino M, Zinzi P, Barbier A, Gasparini F, J Neurol Neurosurg Psychiatry 2003;74(February (2)):175–82. [21] Alegret M, Valldeoriola F, Martí M, Pilleri M, Junqué C, Rumià J, et al. Comparative cognitive effects of bilateral subthalamic stimulation and subcutaneous continuous infusion of apomorphine in Parkinson's disease. Mov Disord 2004;19(December (12)):1463–9. [22] Shuepbach M, Rau J, Knudsen J, Volkman P, Timmermann L, Haelbig TD, et al. Neurostimulation for Parkinson's disease with early motor complications. N Engl J Med 2013;368:610–22.