神经再生-帕金森-单侧丘脑底核电刺激治疗偏侧型帕金森病患者：23例5年随访.pdf

NEURAL REGENERATION RESEARCH Volume 7,Issue 18,June 2012 Cite this article as:Neural Regen Res.2012;7(18):1428-1435.1428 Jinchuan Liang,Master,Physician,Department of Neurosurgery,Changhai Hospital of the Second Military Medical University of Chinese PLA,Shanghai 200433,China Corresponding author:Xiaowu Hu,Master,Professor,Department of Neurosurgery,Changhai Hospital of the Second Military Medical University of Chinese PLA,Shanghai 200433,China Received:2012-01-08 Accepted:2012-04-23 (N20110107002/WJ)Liang JC,Hu XW,Zhou XP,Jiang XF,Cao YQ,Wang LX,Jin AG,Liu JM.Five-year follow-up of 23 asymmetrical Parkinsons disease patients treated with unilateral subthalamic nucleus stimulation.Neural Regen Res.2012;7(18):1428- www.nrronline.org doi:10.3969/j.issn.1673-5374.2012.18.010 Five-year follow-up of 23 asymmetrical Parkinsons disease patients treated with unilateral subthalamic nucleus stimulation*Jinchuan Liang1,Xiaowu Hu1,Xiaoping Zhou1,Xiufeng Jiang1,Yiqun Cao1,Laixing Wang1,Aiguo Jin2,Jianmin Liu1 1Department of Neurosurgery,Changhai Hospital of the Second Military Medical University of Chinese PLA,Shanghai 200433,China 2Department of Radiology,Changhai Hospital of the Second Military Medical University of Chinese PLA,Shanghai 200433,China Abstract In this study,23 asymmetrical Parkinsons disease patients were treated with unilateral deep brain stimulation of the subthalamic nucleus and followed up for 5 years.At 5 years after stimulation treatment,Unified Parkinsons Disease Rating Scale II,III and axial symptom scores in the off-drug condition were significantly increased compared those at baseline.However,total Unified Parkinsons Disease Rating Scale II,III and axial symptom scores were significantly lower with stimulation-on compared with the synchronous stimulation-off state in off-drug condition,and the motor symptoms of contralateral side limbs were effectively controlled.Only low Hoehn-Yahr stage was correlated with good long-term postoperative improvement in motor symptoms.The mean levodopa-equivalent daily dose after stimulation treatment was significantly lower than that before treatment,but dyskinesias became worse.Our experimental findings indicate that unilateral deep brain stimulation of the subthalamic nucleus is an effective treatment for improving motor symptoms in well selected asymmetrical Parkinsons disease patients presenting no severe axial symptoms and dyskinesias.Key Words Parkinsons disease;deep brain stimulation;subthalamic nucleus;neural regeneration Abbreviations PD,Parkinsons disease;DBS,deep brain stimulation;STN,subthalamic nucleus;UPDRS,Unified Parkinsons Disease Rating Scale INTRODUCTION Subthalamic nucleus(STN)deep brain stimulation(DBS)has become the most important neurosurgical therapy for advanced Parkinsons disease(PD)1-4.However,bilateral procedures are more time-consuming and invasive than unilateral procedures,and may be associated with increased risks of surgical and neurological complications and neuropsychological sequelae5-9.Recently,several studies have shown that unilateral STN DBS produces a significant improvement in advanced PD patients without the adverseness reported in studies of bilateral STN DBS10-14.However,the follow-up durations of most studies were only 312 months or the sample sizes were not large enough for statistical analysis.There are still two important questions in this field:(1)is unilateral STN DBS a long-term effective candidate therapy for advanced asymmetrical PD patients?(2)How can appropriate patients be selected to ensure good results and avoid unnecessary secondary operations?This study followed a prospective cohort study of 23 patients www.nrronline.org Liang JC,et al./Neural Regeneration Research.2012;7(18):1428-1435.1429 with advanced asymmetrical PD who underwent chronic unilateral STN DBS for at least 5 years,aiming to explore the long-term efficacy and indications of unilateral STN DBS for advanced asymmetrical PD.RESULTS Quantitative analysis of patients A series of 31 consecutive asymmetrical PD patients were involved in this study.Four patients died of other systemic diseases before the final assessment.Another four patients,who received contralateral STN DBS within 2-4 years of the original operation,were excluded as having had bilateral procedures.No patient withdrew or was lost to follow up.In total,23 patients completed the follow-up period of at least 5 years with unilateral STN DBS treatment.Baseline information of involved patients The preoperative characteristics,Hoehn and Yahr(H&Y)staging scale scores and levodopa-equivalent daily doses(LEDDs)of these 23 patients are summarized in Table 1.Unified Parkinsons Disease Rating Scale(UPDRS)scores assessed at baseline are shown in Table 2.UPDRS improvement at 1-year follow-up At 1 year postoperatively,compared with baseline,the UPDRS III scores were significantly increased in the stimulation-off state.However,in the stimulation-on state,the UPDRS II and III scores were significantly decreased by 28.98%and 36.22%,respectively,as were the resting tremor,rigidity and bradykinesia scores.Almost all contralateral motor symptoms were well controlled but the scores of most ipsilateral motor symptoms improved only a little.The total score for the axial part of UPDRS III decreased by 14.82%,and this decrease was non-significant.Only neck rigidity manifested a significant improvement.Compared with the stimulation-off state at 1 year,the UPDRS II and III scores with stimulation-on were significantly lower,as were the scores for contralateral motor symptoms and neck rigidity,gait and rising from a chair,but the score for the axial part of UPDRS III was not significantly different.UPDRS improvement at 5-year follow-up At 5 years postoperatively,the total UPDRS II and III scores and the score for the axial part of UPDRS III,in the stimulation-off state,were significantly higher than those at baseline.In the stimulation-on state,the total UPDRS II score was 15.76%lower than that at baseline.The score for the axial part of UPDRS III was equal to that at baseline.The total UPDRS III score was significantly decreased by 27.46%compared with that at baseline.All contralateral motor symptoms,except action tremor,showed significant improvement,similar to the results at 1 year.Compared with the stimulation-off state,total UPDRS II and III scores and the score for the axial part of UPDRS III in the stimulation-on state were lower by 37.37%,41.14%and 26.91%,respectively,and all differences were significant.All contralateral motor symptoms were well controlled.Prediction factors for improvement of UPDRS and second operation The results of binary logistic regression analysis(backwards:conditional)are shown in Table 3.Only when both B 1 and P 0.05 were met,would the predictor be considered an effective prediction factor.Only surgical side and preoperation H&Y stage predicted improvement of UPDRS II score in the first year.No factors could reliably predict whether the patients would have to receive a second operation.Further analysis of the usefulness of surgical side and H&Y stage as prediction factors for improvement There were no significant differences in the degrees of improvements in UPDRS II and III scores at 1 and 5 years between procedure sides.At 1 year postoperation,although there was a trend toward lower H&Y stage being associated with better improvements,no significant difference was found between H&Y stages.At 5 years,lower H&Y stage was associated with significantly greater improvements in UPDRS II and III scores(P 5,mean 7.77 3.39).In six of the 27 patients,the motor scores for the less affected sides were 19.70(the mean preoperative motor score on the more affected side)at 5 years(Table 4).Table 2 Unified Parkinsons Disease Rating Scale(UPDRS)scores and P values with medication-off after unilateral deep brain stimulation of the subthalamic nucleus in 23 patients Off stimulation P value Item Score range Preop 1 yr 5 yr Off 1-yr vs.preop Off 5-yr vs.preop Total UPDRS-II score 0-52 17.396.32 19.046.73 23.396.52 0.350 0.005 Total UPDRS-III score 0-108 44.1712.89 48.3512.86 54.4312.82 0.001a 0.001 Resting tremor 0-20 9.304.81 9.614.93 11.044.64 0.814 0.241 Action tremora 0-8 0.651.85 0.701.26 1.041.26 0.888 0.208 Rigidity 0-20 8.354.72 9.095.01 10.914.59 0.552 0.041 Bradykinesia 0-36 16.917.03 18.616.81 19.615.82 0.388 0.171 Contralateral resting tremor 0-8 5.132.12 5.522.11 6.132.03 0.464 0.063 Contralateral action tremor 0-4 0.480.79 0.520.90 0.740.81 0.845 0.242 Contralateral rigidity 0-8 4.782.24 4.962.31 5.781.93 0.751 0.070 Contralateral bradykinesia 0-16 9.303.56 10.133.43 10.262.78 0.406 0.336 Ipsilateral resting tremora 0-8 3.132.05 2.962.25 3.132.18 0.783 1.000 Ipsilateral action tremora 0-4 0.170.49 0.170.49 0.300.63 1.000 0.363 Ipsilateral rigiditya 0-8 2.221.57 2.571.83 3.482.09 0.526 0.023 Ipsilateral bradykinesiaa 0-16 5.703.15 6.132.03 7.002.110.615 0.133 Total axial score 0-24 8.573.99 10.043.88 11.783.41 0.197 0.005 Speech 0-4 1.520.95 1.650.93 1.700.88 0.638 0.530 Neck rigiditya 0-4 1.351.11 1.571.08 1.780.90 0.428 0.114 Posture 0-4 1.480.79 1.610.66 1.870.69 0.540 0.068 Gait 0-4 1.390.78 1.830.89 2.170.78 0.058 0.001 Postural stability 0-4 1.480.85 1.650.83 2.170.72 0.450 0.003 Rising from chair 0-4 1.350.98 1.741.01 2.090.95 0.133 0.005 On stimulation P value Item Score range 1 yr 5 yr On vs.off 1-yrOn vs.off 5-yr On 1-yr vs.preopOn 5-yr vs.preop Total UPDRS-II score 0-52 12.354.88 14.655.12 0.001 0.001 0.005 0.122 Total UPDRS-III score 0-108 28.1712.46 32.0411.76 0.001 0.001 0.001 0.001 Resting tremor 0-20 3.573.64 4.353.51 0.001 0.001 0.001 0.001 Action tremora 0-8 0.260.62 0.390.780.163 0.037 0.208 0.401 Rigidity 0-20 4.303.25 5.173.01 0.001 0.001 0.001 0.012 Bradykinesia 0-36 11.837.1412.616.320.001 0.001 0.011 0.030 Contralateral resting tremor 0-8 0.741.25 1.001.31 0.001 0.001 0.001 0.001 Contralateral action tremor 0-4 0.260.62 0.220.600.242 0.020 0.329 0.242 Contralateral rigidity 0-8 1.171.40 1.091.08 0.001 0.001 0.001 0.001 Contralateral bradykinesia 0-16 4.963.65 4.303.31 0.001 0.001 0.001 0.001 Ipsilateral resting tremora 0-8 2.392.08 2.832.100.371 0.630 0243 0.630 Ipsilateral action tremora 0-4 0.040.21 0.170.490.363 0.363 0.363 1.000 Ipsilateral rigiditya 0-8 2.481.86 3.301.890.874 0.751 0.634 0.049 Ipsilateral bradykinesiaa 0-16 5.092.92 6.392.690.229 0.482 0.482 0.422 Total axial score 0-24 7.303.15 8.613.230.063 0.030 0.561 0.503 Speech 0-4 1.390.94 1.350.980.347 0.211 0.638 0.530 Neck rigiditya 0-4 0.650.78 0.740.690.001 0.001 0.012 0.028 Posture 0-4 1.480.73 1.610.720.540 0.222 1.000 0.540 Gait 0-4 1.260.69 1.740.690.014 0.058 0.566 0.128 Postural stability 0-4 1.350.78 1.650.710.188 0.025 0.571 0.450 Rising from chair 0-4 1.170.65 1.520.730.031 0.031 0.502 0.502 Superscript a:test of homogeneity of variances.preop:Preoperation;yr:year;on:stimulation-on;off:stimulation-off.Liang JC,et al./Neural Regeneration Research.2012;7(18):1428-1435.1431 LEDD and levodopa-related complications reduced postoperatively The average LEDD significantly decreased to 432.39 211.99 mg per day(decreased by 33.92%compared with baseline,P 0.01)at 1 year,but then increased to 491.30 169.93 mg per day(decreased by 24.92%compared with baseline,P 0.01)at 5 years postoperatively.With the decreasing dose of levodopa,the average off-duration period in the waking day significantly decreased by 23.53%(P 0.01)at 1 year,but the difference at 5 years was not significant.Oppositely,the duration of and disability induced by dyskinesias increased by 52.63%and 59.65%,respectively,at 5 years,and continuously got worse.Stimulation parameters were kept stable with no severe adverse events postoperatively Postoperative magnetic resonance imaging verified that Table 3 Prediction factors,and B and P values for Unified Parkinsons Disease Rating Scale(UPDRS)II&III scores at 1 and 5 years after surgery Predictors BP1 yearUPDRS II Side-3.58 0.035 Age of onset 031 0.063 Hoehn and Yahr stage-3.26 0.048 Parkinsons disease duration 0.56 0.027 UPDRS III Motor score on the less affected side-0.53 0.007 Age-3.89 1.000 Age of onset-3.94 1.000 Parkinsons disease duration-4.03 1.0005 years UPDRS II Motor score on the less affected side-0.22 0.094 Levodopa-equivalent daily dose-0.01 0.131 UPDRS III Age-0.16 0.112 Hoehn and Yahr stage-2.37 0.087Figure 1 Improvements in Unified Parkinsons Disease Rating Scale(UPDRS)II&III scores at 1 and 5 years postoperatively analyzed by left-and right-side procedures.Although right-side procedures always produced greater improvements in symptoms than left-side procedures,no significant difference was found between them with Students t-test(P=0.207,0.143,0.172,0.208 respectively).Data are expressed as mean SD.The improvement calculation was compared with baseline(1-)baselineUPDRS100%.At 1 year At 5 years At 1 yearAt 5 yearsRight side(n=10)Left side(n=13)0 10 20 30 40 50 60 70 80 Improvement(%)Figure 2 Improvements in Unified Parkinsons Disease Rating Scale(UPDRS)II&III scores at 1 and 5 years analyzed by Hoehn and Yahr(H&Y)stages.In summary,lower H&Y stage was associated with greater improvements in UPDRS II and III scores(aP 19.70(the preoperation mean score on the more affected side)at 5 years.Only one of them had a low baseline(motor score=8),but the disease in that patient worsened rapidly(motor scores of less affected side increased by 13).The baseline scores of the others ranged from 14 to 20 and their motor scores on the less affected side increased by 68 during the 5-year study period,which is higher than average increase(3.33).If disease advances quickly(in our study,the mean worsened motor score among nine greatly worsened cases was 7.77 per 5 years),then the motor score on the less affected side should be lower than 11.93.Thus,patients with baseline motor scores on the less affected side of 40%,or as 0 when they were 40%.The variables included side(left or right STN),gender,age,age of onset,PD duration,motor score on the more affected side,motor score on the less affected side,side difference,preoperational H&Y stage and LEDD.The Students t-test was performed to analyze differences in improvements with different procedure sides and the least significant difference t-test was also used to compare differences in improvements between different H&Y stages.The threshold for significance was a P value of 0.05.All P-values reported are two-sided.Acknowledgments:We are grateful to Xiaojun Hou,Professor of Neurology,Changhai Hospital,the Second Military Medical University of Chinese PLA,for his advice on diagnosis and medication for the patients.We also wish to thank the staff of the Radiology Department,Changhai Hospital,the Second Military Medical University of Chinese PLA,for their technical support in magnetic resonance imaging and CT scanning.Funding:The study was supported by the foundation of Science and Technology Commission of Shanghai Municipality,No.101195400.Author