ORIGINAL ARTICLE
Different effectiveness of subthalamic deep
brain stimulation in Parkinson’s disease: A
comparative cohort study at 1 year and 5
years
Jiin-Ling Jiang
a,b, Shin-Yuan Chen
b,c,d,f, Tsung-Cheng Hsieh
b,
Chi-Wei Lee
c,d, Sheng-Huang Lin
e, Sheng-Tzung Tsai
c,d,f,*
aDepartment of Nursing, Tzu Chi University, Hualien, Taiwan b
Institute of Medical Sciences, Tzu Chi University, Hualien, Taiwan
cDepartment of Neurosurgery, Tzu Chi General Hospital, Hualien, Taiwan d
Department of Surgery, Tzu Chi University, Hualien, Taiwan
e
Department of Neurology, Tzu Chi General Hospital, Hualien, Taiwan
f
Parkinson’s Clinical and Research Center, Tzu Chi General Hospital, Hualien, Taiwan
Received 18 January 2013; received in revised form 2 September 2013; accepted 3 September 2013
KEYWORDS
deep brain stimulation; long-term;
Parkinson’s disease
Background/Purpose: Subthalamic nucleus deep brain stimulation (STN-DBS) has been shown to produce long-term symptom improvement in Parkinson’s disease. The aim of this study was to identify the target symptoms that show the most improvement at 1 year and at 5 years after STN-DBS.
Methods: This was a 5-year cohort study of 41 consecutive patients treated with bilateral STN-DBS. Clinical evaluations were performed 1 month prior to surgery and 1 year and 5 years after surgery. The outcome measurements at 1 year and 5 years were the changes compared with the baseline in Unified Parkinson’s Disease Rating Scale (UPDRS) parts I, II, III, and IV scores, the Hoehn and Yahr stage, and Schwab and England Activities of Daily Living (SEADL) scores in the conditions of off-medication/on-stimulation and off-medication/off-stimulation. Further analysis included changes in the levodopa equivalent daily dose.
Results: When compared to the preoperative baseline off-medication condition, significant im-provements were observed in the UPDRS parts I, II, III, and IV and SEADL (p< 0.001) scores in the off-medication/on-stimulation condition 1 year after STN-DBS. Five years after STN-DBS, improvements in UPDRS scores were observed only for parts II, III, and IV (p< 0.001). In the
Conflicts of interest: The authors have no conflicts of interest relevant to this article.
* Corresponding author. Division of Functional Neuroscience, Neuro-medical Scientific Center, Tzu-Chi General Hospital, 707, Section 3, Chung-Yang Road, Hualien 970, Taiwan.
E-mail address:flydream.tsai@gmail.com(S.-T. Tsai).
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Journal of the Formosan Medical Association (2015) 114, 835e841
off-medication/off-stimulation condition, no significant improvement was observed. At 5 years, significant deteriorations were observed in scores for the UPDRS part III axial subitem (pZ 0.005), UPDRS part I (p Z 0.005), UPDRS part II (p < 0.001), and SEADL (p Z 0.001). Conclusion: The long-term effect of STN-DBS on motor function is promising, although the magnitude of its effectiveness varied over the 5-year period.
Copyrightª 2013, Elsevier Taiwan LLC & Formosan Medical Association. All rights reserved.
Introduction
Parkinson’s disease (PD) is the second most common neurodegenerative disorder. It is characterized by muscle rigidity, resting tremor, bradykinesia, and postural insta-bility. The pathologic hallmarks of the disease are the degeneration of dopaminergic neurons in the substantia nigra pars compacta of the midbrain and the presence of Lewy bodies, which are cytoplasmic aggregations of the protein a-synuclein in brain neurons. Exposure to various toxins or pesticides may be a secondary etiology. PD is likely to be a result of multiple factors, including normal aging, genetic predisposition, and environmental expo-sure.1,2Although an optimal pharmacological therapy with levodopa and other adjuvant regimes can be achieved, complications associated with the treatment of PD, such as dyskinesia and motor fluctuation, inevitably occur 5 years after the initiation of therapy.3,4The progressive decline in motor function and the comorbidity associated with PD negatively affect health-related quality of life.5Since the first application of deep brain stimulation of the sub-thalamic nucleus (STN-DBS) for PD6in 1993, high frequency stimulation of the STN has rapidly become the surgical treatment of choice. The long-term effects of STN-DBS on medically refractory PD have been well documented. Ac-cording to some reports, the motor improvement induced by STN-DBS is sustained for up to 5e8 years after sur-gery,3,6e13 but part of the initial improvement, mainly
regarding axial signs, become progressively deteriorated. However, the effects of STN-DBS on the motor and non-motor symptoms may vary. The aim of this study was to identify the target symptoms that show the most improvement at short-term (1 year) and long-term (5 year) follow-up in the same group of patients after STN-DBS.
Methods
Patient enrollment
From 2002 to 2007, 41 patients from a single DBS center in Taiwan who underwent bilateral STN-DBS were enrolled in this cohort study. The diagnosis of PD followed the diag-nostic criteria of the United Kingdom PD Society Brain Bank.14 The inclusion criteria were: (1) a good levodopa
response on the Unified PD Rating Scale (UPDRS) part III; (2) drug-related complications (e.g., dyskinesia, oneoff phe-nomenon, or psychiatric symptoms), even under optimal antiparkinsonian medication adjustments; (3) no structural lesions on the brain magnetic resonance imaging (MRI); and (4) an absence of dementia. The study was approved by the
Tzu Chi General Hospital Research Ethical Board in Hualien, Taiwan. All the patients provided written informed consent for STN-DBS surgery and for the study’s evaluation procedure.
Surgical procedure
All the patients were evaluated for the STN-DBS surgery by standard MRI scans (1.5-T; General Electric, Milwaukee, WI, USA), using T1-weighted axial images (0.75 mm thick) and T2-weighted axial images (2 mm thick). The quadripolar DBS electrodes (model 3389; Medtronic, Englewood, CO, USA) were implanted after the microelectrode recording and test stimulation procedures. After 1 week, the elec-trode cables were connected to an implantable pulse generator (Kinetra; Medtronic, Minneapolis, MN, USA). The surgical procedures have been described in detail in our previous study, and the same surgical team performed all the operations.15 We arranged a postoperative computed
tomography immediately after the operation to ensure that the correct target was used for the stimulating electrode for each patient and an MRI 3 months later (Fig. 1).16We
Figure 1 (A) Preoperative computed tomography and (B) magnetic resonance imaging were both performed for the stereotactic surgery and to localize the subthalamic nucleus. (C) Postoperative computed tomography and (D) magnetic resonance imaging were conducted to verify the electrode coordinates and to evaluate any neurological lesions, such as intracerebral hemorrhage.
also performed an acute stimulation test through each contact to identify the electrode contact with the maximal clinical benefit.
Study design
The study was an open, nonrandomized, prospective cohort designed to evaluate changes in symptom improvement from 1 year to 5 years after bilateral STN-DBS. The patients were evaluated in the defined off-medication/on-stimulation and in the defined off-medication/off-stimulation conditions. The off-medication condition was evaluated after the with-drawal of dopaminergic medication for at least 12 hours, as defined by the Core Assessment Program for Surgical Inter-ventional Therapy in PD.17 Off-stimulation was defined either by the DBS being turned off for at least 4 hours or by the maximal tolerable period, if the DBS was turned off for less than 4 hours. UPDRS parts I, II, III, and IV scores, the Hoehn and Yahr (H&Y) stage, and Schwab and England Activities of Daily Living (SEADL) scores were obtained at 1 year and 5 years after the surgery.
Outcome measure
The outcome measurements were changes compared to the baseline in UPDRS part III total motor scores (motor skills were assessed by the range of the scores from 0 to 108 and by a reduction in the scores that indicated an improvement in function) as well as subscores for tremor at rest (items 20 and 21), rigidity (item 22), bradykinesia (items 23e26 and 31), posture and gait (items 28 and 29), and axial signs (items 18 and 27e30) in the two different treatment con-ditions at 1 year and 5 years. UPDRS part I (assessment of mentation, behavior, and mood; scores 0e16), part II (assessment of activities of daily living; scores 0e52), and part IV (assessment of the severity of the disability related to dyskinesia; scores 0e23) scores, the H&Y stage and SEADL scores (measurement of activities of daily living; 0e100%, with 100% indicating normal function and 70% or lower indicating that patients need the help of a caregiver) were also assessed. Further analysis included changes in the levodopa equivalent daily dose (LEDD) at 1 year and 5 years after surgery compared to the preoperative status.
Statistical analysis
The descriptive analysis was used for both the demographic data and the improvement percentage of the UPDRS and SEADL scores. Because normality could not be assumed for the relatively small group of patients, nonparametric testing was used. The Wilcoxon signed-rank test was used to compare UPDRS scores, the H&Y stage and SEADL scores. Repeated measures analysis via the generalized estimating equation was used to calculate the LEDD. Missing data were not entered. The data are presented as the means standard deviation. A p value < 0.05 was consid-ered to indicate statistical significance. The Bonferroni adjustment was also used to control for overall type-I error from multiple comparisons. The statistical significance level of 0.016 (Z 0.05/3) was used for the statistical tests when there were three comparisons for each outcome
variable. All the p values were two tailed. The statistical analyses were performed using the SPSS statistical package, version 19 (SPSS Inc., Chicago, IL, USA).
Results
Between 2002 and 2007, 100 PD patients underwent bilat-eral STN-DBS at Tzu Chi Genbilat-eral Hospital in Hualien, Taiwan. Complete data were obtained from 41 patients at the 1-year and 5-year follow-ups. Among these patients, 29 were men, and 12 were women. Their mean age at onset was 46.5 11.9 years, their mean age at surgery was 56.3 11.7 years, and the mean of their disease duration was 10.2 5.1 years. The mean H&Y stage was 3.1 0.8.
Off-medication/on-stimulation evaluation
Significant improvements were observed in the UPDRS part I (3.34 1.9 vs. 2.17 1.4; p < 0.001), part II (19.59 8.3 vs. 9.61 5.1; p < 0.001), part III (47.3 14.0 vs. 23.02 9.0; p < 0.001), and part IV (5.07 3.8 vs. 1.07 1.5; p < 0.001) scores at 1 year after STN-DBS when compared to the preoperative baseline off-medication condition. Significant improvements were also observed in the SEADL scores (77.07 2.7 vs. 94.76 7.7; p < 0.001). Five years after STN-DBS, improvements in the UPDRS scores were observed only for part II (19.59 8.3 vs. 14.37 7.1; p < 0.001), part III (47.3 14.0 vs. 28.32 10; p < 0.001), and part IV (5.07 3.8 vs. 1.97 2.2; p< 0.001) when compared to the preoperative baseline off-medication condition. No significant improvement was observed in the SEADL scores (77.07 2.7 vs. 79.74 21.6; pZ 0.260). However, the effects of STN-DBS had declined significantly at the 5-year follow-up for all the parts of the UPDRS, the H&Y stage, and the SEADL (p < 0.001, pZ 0.001, and p < 0.001, respectively).
Nevertheless, significantly sustained DBS effects were observed in the UPDRS part III subitems of tremor and ri-gidity at the 5-year follow-up (Table 1,Fig. 2).
Off-medication/off-stimulation evaluation
At the 1-year follow-up after STN-DBS, no significant improvement was observed when compared to the preop-erative baseline off-medication condition.
At the 5-year follow-up, when compared to the preopera-tive baseline off-medication condition, significant de-teriorations were observed in the scores for the UPDRS part III axial subitem (pZ 0.005), UPDRS part I (p Z 0.005), UPDRS part II (p < 0.001), and SEADL (p Z 0.001). Sustained improvement was observed only in the UPDRS part III subitems of tremor (7.41 4.4 vs. 6.58 5.2, p Z 0.358) and rigidity (10.22 3.9 vs. 9.84 3.6, p Z 0.523), as well as part IV (5.07 3.8 vs. 4.58 2.4, p Z 0.132), although these im-provements were not statistically significant (Table 2,Fig. 2).
LEDD and stimulation parameters
When compared to the preoperative LEDD (766.15 51.0 mg), significant reductions were observed at both the 1-year
(398.59 51.6 mg; p < 0.001) and 5-year (533.26 51.0 mg; p Z 0.050) follow-ups. However, a 55.5% increment was observed between the 1-year and 5-year follow-ups. The stimulation parameters did not show a significant difference between the 1-year and the 5-year follow-ups (Table 3).
Discussion
Significant improvements were observed in the UPDRS parts I, II, III, and IV scores and SEADL scores in the off-medication/on-stimulation condition at the 1-year follow-up. Five years after STN-DBS, improvements in UPDRS scores were observed only for parts II, III, and IV when compared to the baseline off-medication condition. In the off-medication/off-stimulation condition, no significant improvement was observed. At the 5-year follow-up, sig-nificant deteriorations were observed in the scores for the UPDRS part III axial sub-item, UPDRS part I, UPDRS part II, and SEADL when compared to the baseline.
Apart from symptoms assessed by the UPDRS part I (mentation, behavior, and mood) and SEADL, short-term and long-term significant symptom improvement as a result of STN-DBS was observed in this 5-year cohort study.
These findings are in line with previous 5-year studies,4,7,10,11and a more recent study in patients with 8
years of follow-up12 reported prolonged improvement in rigidity and tremor but progressive deterioration of axial signs.
The nonmotor features of PD, including depression, anxiety, cognitive decline, pain, fatigue, insomnia, and autonomic dysfunction, have been identified as significant factors in the diminished quality of life of PD patients.18,19
UPDRS part I scores returned to the baseline level at the 5-year follow-up, as a result of a deterioration in ADL, despite persistent significant improvements in motor function. The data presented in this report could be evidence that
nonmotor symptoms are contributing factors to the quality of life in PD patients.4
In our study, the effects of STN-DBS declined signifi-cantly between the 1-year and 5-year follow-ups for all the parts of the UPDRS, the H&Y stage, and the SEADL (p < 0.001, p Z 0.001, and p < 0.001, respectively). An elevation of the LEDD was also observed. Our results echo previous studies reporting that the clinical benefits of STN-DBS, particularly regarding axial symptoms, may decline over the years.4,7,10,11,13 Moro et al20 proposed that
STN-DBS patients show a deterioration of the levodopa response after 5e6 years, suggesting a closer relationship to the progression of PD than to the target of stimulation, the stimulation parameters, or the medication dose reduction.
Tremor was presented as the best target symptom for DBS. In this report, tremor had the greatest magnitude of improvement at 1 year, and it remained steady after 5 years, even during the off-medication period. A post mor-tem study showed that tremor-dominant PD patients pro-gressed more slowly to H&Y stage 4 than patients with akinetic-rigid symptoms.21 There is converging evidence from post mortem and nuclear imaging studies suggesting that patients with tremor-dominant PD have relatively benign nigrostriatal degeneration.22 Another study also suggested that neural activity during STN-DBS is an impor-tant modulator of the neural networks that are responsible for both resting and postural tremor genesis in PD.23
Moreover, STN-DBS was more effective than medication in reducing the amplitude and increasing the frequency of resting and postural tremor.23 This evidence may also
explain why the tremor features of PD take a more benign course after STN-DBS.
Our study showed a substantial reduction in the daily need for antiparkinsonian medications. These results are comparable to those reported in another published study with a long-term follow-up.23Nevertheless, between 1 year
Table 1 UPDRS and SEADL in the off-medication/on-stimulation condition.
Target and condition Scores p
Baseline 1-year 5-year 1-year vs.
baseline
5-year vs. baseline
5-year vs.
Mean (SD) Mean (SD) Mean (SD) 1-year
UPDRS III total 47.34 (14.0) 23.02 (9.0) 28.32 (10.0) 0.001* 0.001* 0.001**
Tremor 7.41 (4.4) 1.12 (1.6) 1.05 (1.5) 0.001* 0.001* 0.935 Rigidity 10.22 (3.9) 4.15 (2.9) 4.71 (3.2) 0.001* 0.001* 0.357 Bradykinesia 19.32 (5.8) 11.51 (4.2) 14.32 (4.6) 0.001* 0.001* 0.001** Posture-Gait 3.98 (1.5) 2.34 (1.3) 3.16 (1.4) 0.001* 0.006* 0.001** Axial 8.73 (3.1) 5.61 (2.6) 7.13 (3.1) 0.001* 0.008* 0.001** UPDRS I 3.34 (1.9) 2.17 (1.4) 3.26 (1.9) 0.001* 0.276 0.001** UPDRS II 19.59 (8.3) 9.61 (5.1) 14.37 (7.1) 0.001* 0.001* 0.001** UPDRS IV 5.07 (3.8) 1.07 (1.5) 1.97 (2.2) 0.001* 0.001* 0.007**
UPDRS I, II, III, IV 72.98 (24.2) 35.88 (13.6) 47.92 (17.5) 0.001* 0.001* 0.001** Hoehn &Yahr Stage 3.09 (0.8) 2.39 (0.5) 2.83 (0.7) 0.001* 0.002* 0.001**
SEADL % 77.07 (2.7) 94.76 (7.7) 79.74 (21.6) 0.001* 0.260 0.001**
Data are presented as mean (SD). *Improvement, p< 0.016. **Worsening, p< 0.016.
and 5 years postoperation, the LEDD significantly increased by 55.5% but remained much lower than prior to the sur-gery. The postoperative degradation of the L-dopa response could be related to the progression of the disease,4,7 a reduction in the dopaminergic receptor sensitivity due to a reduction in anti-PD drug doses, or a more direct effect of STN-DBS.20Previous studies also confirmed that the L-dopa
response is reduced after STN-DBS and that the long-term symptom improvement from STN-DBS is not predicted by the preoperative dopaminergic response.10
This study has several limitations, including the lack of a control group and double-blinded assessments. Only 41% of the patients who received implants for bilateral stimulation of the subthalamic nucleus at our institute from 2002 to 2007 participated in this 5-year cohort study, confirming the difficulty of conducting long-term follow-up studies in PD patients.10,12 Blinded assessments were difficult to perform because most of the patients were able to guess
whether the DBS was turned on, which was especially true in the patients who might experience transient paresthesia during the manipulation. Additionally, placebo effects in Parkinson’s disease are rarely sustained in repeated testing.24Finally, the development of nonmotor and
atyp-ical parkinsonian features may be a major limiting factor in any therapy for PD if the focus is limited to the conse-quences on the nigrostriatal dopaminergic efficiency.25 Nevertheless, our study’s evaluation period was 5 years, and repeated assessments were performed by the same investigators. The reliability of using scales is good, espe-cially considering the magnitude of the changes that were observed in the motor scores over time.
In conclusion, the long-term effects of STN-DBS on motor function are promising, although the magnitude of their effectiveness declined in the temporal domain. In terms of the UPDRS, nonmotor symptoms had the least effectiveness during long-term follow-up and were closely related to a Figure 2 Time course evolution of the baseline scores for the Unified Parkinson’s Disease Rating Scale (parts I, II, III, and IV), the Hoehn and Yahr stage and the Schwab and England Activities of Daily Living in the medication/on-stimulation and off-medication/off-stimulation conditions from preoperation to 1 year and 5 years postoperation. The off-medication/on-stimulation had lower Unified Parkinson’s Disease Rating Scale parts I, II, III, and IV scores and lower Hoehn and Yahr stages than the off-medication/off-stimulation at the 5-year follow-up.
decline in the ADL of the PD patients. Disease progression seems to be inevitable despite STN-DBS.
Acknowledgments
We are grateful for the support from Master Cheng Yen, President of the Tzu-Chi Foundation. This study was sup-ported by grants from Tzu Chi General Hospital (TCSP-01-04). We would like to acknowledge Miss Tingwen Ho for data processing.
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Table 2 UPDRS and SEADL in the off-medication/off-stimulation condition.
Target and condition Scores p
Baseline 1-year 5-year 1-year vs.
baseline
5-year vs. baseline
5-year vs. 1-year Mean (SD) Mean (SD) Mean (SD)
UPDRS III total 47.34 (14.0) 44.98 (13.5) 50.39 (13.7) 0.343 0.137 0.003**
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UPDRS I, II, III, IV 72.98 (24.2) 72.98 (24.4) 86.71 (25.0) 0.418 0.008** 0.001** Hoehn & Yahr Stage 3.09 (0.8) 3.09 (0.8) 3.67 (0.9) 0.139 0.039 0.002**
SEADL % 77.07 (2.7) 77.07 (20.5) 52.37 (28.5) 0.739 0.001** 0.001**
Data are presented as mean (SD). *Improvement, p< 0.016. **Worsening, p< 0.016.
SDZ standard deviation; SEADL Z Schwab and England Activities of Daily Living; UPDRS Z Unified Parkinson’s Disease Rating Scale.
Table 3 Stimulation parameters between 1 year and 5 years after surgery.
1 year 5 years
Ch1 Ch2 Ch1 Ch2
Voltage 3.23 0.58 3.12 0.75 3.54 0.44 3.57 0.42
Pulse width 62.18 7.86 61.13 5.77 63.1 9.3 64 10.37
Frequency 139.36 16.64 138.96 16.36 130.69 23.13 131.17 22.88
Data are presented as mean SD. ChZ channel.
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