Long-Term Follow-up of Unilateral Pallidotomy in Advanced Parkinson's Disease

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Long-Term Follow-up of Unilateral Pallidotomy in Advanced Parkinson's Disease
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   1708  ·  June 8, 2000  The New England Journal of Medicine  LONG-TERM FOLLOW-UP OF UNILATERAL PALLIDOTOMY IN ADVANCED PARKINSON’S DISEASE  J   ENNIFER  F   INE  , M.D., J   AN  D   UFF  , R.N., R   OBERT  C   HEN  , M.B., B.C   HIR  ., W   ILLIAM  H   UTCHISON  , P   H  .D., A   NDRES  M. L   OZANO  , M.D., AND  A   NTHONY  E. L   ANG  , M.D.  A   BSTRACT  Background   Although the short-term benefits of posteroventral pallidotomy for patients with advancedParkinson’s disease have been well documented, lit-tle is known about the long-term outcome of the pro-cedure.  Methods   We conducted a long-term follow-up studyof a cohort of 40 patients who had undergone unilat-eral posteroventral medial pallidotomy between 1993and 1996. Twenty patients were not evaluated be-cause they had undergone a second surgical proce-dure (11 patients) or had died (2) or because theyhad dementia or another debilitating illness (4), livedtoo far away (1), or had been lost to follow-up (2). Weconducted serial postoperative assessments of par-kinsonism in the remaining 20 patients while theywere taking medications (“on” period) and after over-night withdrawal of the drugs (“off” period). The meanfollow-up time was 52 months (range, 41 to 64).  Results   The combined off-period score for activi-ties of daily living and motor function on the UnifiedParkinson’s Disease Rating Scale was 18.0 percentbetter at the last evaluation than at base line (95 per-cent confidence interval, 4.9 to 31.0 percent; P=0.01).Significant improvements were also evident in theoff-period scores for contralateral tremor (65.4 per-cent improvement, P=0.007), rigidity (43.2 percent,P=0.03), and bradykinesia (18.2 percent, P=0.04) andin the on-period score for contralateral dyskinesia (70.6percent, P<0.001). Changes in medication did notcontribute to the sustained improvement. The 20 pa-tients who could not be included in the long-termanalysis had similar base-line characteristics but aworse response to surgery at six months.  Conclusions   In the group of patients with advancedParkinson’s disease who could be enrolled in ourlong-term follow-up study of unilateral posteroven-tral medial pallidotomy (20 patients from the srcinalcohort of 40), significant early improvements in off-period contralateral signs of parkinsonism were sus-tained for up to 5   1   ⁄    2  years. There was a sustainedsignificant improvement in on-period contralateraldyskinesia but not in other on-period signs of parkin-sonism. (N Engl J Med 2000;342:1708-14.)  ©2000, Massachusetts Medical Society.  From the Divisions of Neurology, Department of Medicine (J.F., J.D.,R.C., A.E.L.) and Neurosurgery, Department of Surgery (W.H., A.M.L.),Toronto Western Hospital, University of Toronto, Toronto. Address reprintrequests to Dr. Lang at Toronto Western Hospital, Morton and GloriaShulman Movement Disorders Centre, 399 Bathurst St., MP 11-306, To-ronto, ON M5T 2S8, Canada.  ECAUSE of the limited efficacy of medicaltreatment for Parkinson’s disease and be-cause of advances in technology and in ourunderstanding of the function of the basalganglia,  1  certain patients with advanced Parkinson’sdisease are being treated surgically. Since the re-introduction of posteroventral medial pallidotomy,  2  numerous centers have reported significant benefitsof this procedure.  3-9  Most studies have demonstratedpostoperative improvements in motor function andactivities of daily living, with consistent improvementsin contralateral bradykinesia, tremor, and rigidity af-ter an overnight withdrawal of medications (“off”period) and with particular improvements in contra-lateral dyskinesias while patients are taking medica-tions (“on” period). The degree and duration of ip-silateral improvements vary among studies, and theresults with respect to on-period signs of parkinson-ism other than dyskinesia are contradictory. Although data from a large number of studies sup-port the efficacy of pallidotomy in the treatment of advanced Parkinson’s disease, most of these data arebased on assessments performed within the first yearafter surgery. We know of only three studies withlonger follow-up periods; in two of these studies,patients were followed for up to two years,  4,9  and inone, 10 patients were evaluated more than two yearsafter surgery.  5  Thus, little is known about the long-term outcome of a procedure that is widely viewedas an important adjunctive therapy in the advancedstages of Parkinson’s disease and that is the mostcommon surgical treatment for the disorder. We re-port long-term follow-up data on 20 of 40 patients who underwent unilateral posteroventral medial pal-lidotomy for medically intractable Parkinson’s disease.  4  METHODS  Patients  The patients in our follow-up study were part of a cohort of 40 patients who underwent posteroventral medial pallidotomy between June 1993 and January 1996.   4  This study was approvedby the Toronto Hospital Committee for Research on HumanSubjects, and the patients gave written informed consent for sur-gery and for ongoing follow-up evaluations. B The New England Journal of Medicine Downloaded from nejm.org on September 13, 2015. For personal use only. No other uses without permission. Copyright © 2000 Massachusetts Medical Society. All rights reserved.   LONG-TERM FOLLOW-UP OF UNILATERAL PALLIDOTOMY IN ADVANCED PARKINSON’S DISEASE   Volume 342Number 23  ·  1709  *PDCI denotes peripheral decarboxylase inhibitor.†There was no significant difference between the mean total levodopa-equivalent dose at base line and at the last evaluation (P=0.17 by Student’st-test).  T  ABLE  2.   A   NTIPARKINSONIAN  M  EDICATIONS    AT  B   ASE  L   INE    AND    AT   THE  L    AST  E   VALUATION  .   M   EDICATION   B   ASE   L   INE   L   AST   E   VALUATION  Levodopa plus PDCI*No. of patients Dose (mg)MeanRange201110400–1900201148400–2050BromocriptineNo. of patientsDose (mg)MeanRange820.65.0–40.0528.017.5–50.0PergolideNo. of patientsDose (mg)MeanRange73.11.0–6.0114.40.5–14.0PramipexoleNo. of patientsDose (mg)0—12.25TolcaponeNo. of patientsDose (mg)MeanRange0——3333300–400Total levodopa-equivalent dose†No. of patientsDose (mg)MeanRange201300±564200–2350201554±580600–2250  Of the 40 patients, 20 were not included in the current study.Eleven of these 20 patients subsequently underwent a second sur-gical procedure. One patient underwent an ipsilateral pallidotomy six months after the first procedure because the benefit of thesrcinal procedure was not sustained; the second procedure re-sulted in long-lasting improvement. The other 10 patients under- went a contralateral procedure to treat disability stemming largely from the unoperated side. Three of the 10 patients underwentcontralateral pallidotomy 8, 16, and 18 months after the first pro-cedure, with improvement in all 3 patients, particularly with re-spect to disabling dyskinesias. However, debilitating cognitive andbehavioral complications developed in two of the three patients,   10  and this outcome prompted us to make a smaller lesion on thesecond side when subsequently using this approach. Two patients with pronounced tremor on the ipsilateral side underwent suc-cessful contralateral deep-brain stimulation of the thalamus 10and 32 months after the pallidotomy. Five patients with other dis-abling parkinsonian features on the unoperated side underwentdeep-brain stimulation of the contralateral globus pallidus 12 to40 months (mean, 21) after the pallidotomy, with further bene-fit.   11  Of the other nine patients who were not evaluated, two died,four had dementia or other debilitating conditions, one lived toofar away, and two were lost to follow-up. The remaining 20 pa-tients were all assessed and are the primary focus of this analysis.The base-line characteristics of the patients are shown in Table1. All patients underwent microelectrode-guided posteroventralmedial pallidotomy as described in detail elsewhere.   4,12,13  The an-tiparkinsonian medications that the patients received were changedduring the years after surgery, and some patients received neweragents such as pramipexole and tolcapone. The doses of antipar-kinsonian medications before surgery and at the last evaluation areshown in Table 2. The total levodopa-equivalent dose was calculat-ed as the sum of the dose of regular levodopa–carbidopa (or levo-dopa–benserazide), plus 0.75 times the dose of controlled-releaselevodopa–carbidopa, plus 10 times the dose of bromocriptine,plus 100 times the dose of pergolide, plus 100 times the dose of pramipexole.   14  For patients who were receiving tolcapone, thesum of the dose of regular levodopa and 0.75 times the dose of controlled-release levodopa was multiplied by a factor of 1.33.  Evaluations  Patients were evaluated as described previously,   12  according to amodified protocol of the Core Assessment Program for Intracere-bral Transplantations,   15   which incorporates components of the Uni-fied Parkinson’s Disease Rating Scale (UPDRS) that measure mo-tor function (part III) and activities of daily living (part II), as wellas the evaluation of dyskinesia.   16  Separate scores for axial and hemi-body dyskinesia were recorded. For patients who had been givennew antiparkinsonian drugs or substantially increased doses of drugs since the base-line assessment, the new agents or additionaldoses were withdrawn 36 to 48 hours before the off-period assess-ment, in order to approximate base-line conditions as closely aspossible. All the assessments were performed by a single investiga-tor, who had also evaluated each patient before surgery and at eachof the initial postoperative visits. All 20 patients were evaluated sixmonths after surgery, 19 were evaluated at one year, and 17 at two years. The mean follow-up period was 52 months (range, 41 to 64).  Outcome Measures   As in our earlier study,   4  the primary measure of efficacy was theoverall off-period score on the UPDRS, defined as the sum of the  *Plus–minus values are means ±SD.†The Hoehn and Yahr stage of parkinsonism isbased on a scale ranging from 0 to 5, with a lowerstage indicating better function.‡The Schwab and England score for activitiesof daily living (ADL) is based on a scale rangingfrom 0 to 100, with a higher score indicating betterfunction.  T  ABLE  1.  B   ASE  -L   INE  C  HARACTERISTICS   OF   THE  20 P   ATIENTS  .*   C   HARACTERISTIC   V   ALUE  Sex (no. of patients)MaleFemale155 Age (yr)MeanRange57.1±7.145–69Duration of disease (yr)MeanRange11.9±3.75–21Hoehn and Yahr stage†On periodMedianRangeOff periodMedianRange2.51.5–33.252.5–4.5Schwab and England ADL score (%)‡On periodMeanRangeOff periodMeanRange81.350–10044.510–70 The New England Journal of Medicine Downloaded from nejm.org on September 13, 2015. For personal use only. No other uses without permission. Copyright © 2000 Massachusetts Medical Society. All rights reserved.   1710  ·  June 8, 2000  The New England Journal of Medicine  scores for activities of daily living and motor function. This com-bined score was considered to reflect the overall severity of func-tional impairment due to Parkinson’s disease. The Schwab andEngland scale for evaluating activities of daily living (part VI of the UPDRS) was also used.Secondary measures of efficacy included aspects of motor func-tion that had shown sustained improvement in our earlier study:the off-period scores on the UPDRS for contralateral bradykine-sia, tremor, and rigidity    12  and the on-period score for contralat-eral dyskinesia.   16  Statistical Analysis   We performed pairwise comparisons of the base-line (preoper-ative) scores and the scores at the last evaluation with the use of the Wilcoxon signed-rank test for each variable. The mean totaldaily levodopa-equivalent doses were compared with the use of Student’s t-test. For significant differences between base-line andfollow-up values, the percent change in the mean value and the95 percent confidence interval were calculated. For variables thatstill showed a significant improvement at the last evaluation, analy-sis of variance with repeated measures was used to determine whether these variables changed with time. The follow-up inter- val (six months, one year, two years, or the interval between sur-gery and the most recent evaluation) was the repeated measure.In an attempt to identify clinical variables that were predictiveof a good long-term outcome, we calculated nonparametric Spear-man correlations. For the purpose of the correlational analyses,overall improvement after surgery was defined as the percentchange in the overall off-period UPDRS score (the primary out-come measure) between base line and the final assessment. Sim-ilarly, the response to surgery at six months was defined as thepercent change in the off-period UPDRS score between base lineand the assessment at six months. Additional components of theUPDRS that were analyzed included the preoperative responseto levodopa, calculated as the difference between the total off-period and on-period motor scores, and the hemibody scores formotor function (tremor, rigidity, and bradykinesia; i.e., UPDRSitems 20 through 26). To assess the generalizability of the long-term data, we used the Mann–Whitney U test to compare the 20patients in the current study with the 20 patients in the srcinalcohort who could not be included in this study. All reported P val-ues are two-sided.  RESULTS  There were no significant differences in the meantotal levodopa-equivalent doses of medications be-tween base line and the most recent follow-up visit(P=0.17) (Table 2). The means (±SD) for the over-all off-period UPDRS score, the component activi-ties of daily living and motor scores, and the scoreson the various subscores for motor function areshown in Table 3. The P values are for the pairwisecomparison of scores at base line and at the last eval-uation. *Plus–minus values are means ±SD. Lower scores indicate better function for all items except theSchwab and England activities of daily living (ADL) scores. Scores are described in detail elsewhere.   3  UPDRS denotes Unified Parkinson’s Disease Rating Scale.†P values (determined with the use of the Wilcoxon signed-rank test) are for pairwise comparisonsbetween the base-line scores and the scores of the last evaluation.‡The scores for postural instability and gait disorder represent a composite of five items, as de-scribed in a previous report.   4  T  ABLE  3.  M  EAN  O  FF  -P  ERIOD    AND  O  N  -P  ERIOD  S  CORES    AT  B   ASE  L   INE  , S  IX   M  ONTHS  ,  AND   THE  L    AST  E   VALUATION  .*   M   EASURE   S   CORE   R   ANGE   B   ASE   L   INE   S   IX   M   ONTHS   L   AST   E   VALUATION   PV   ALUE   †  Off period  Overall UPDRS scoreMotor ADL Schwab and England ADL score0–1600–1080–520–10066.2±14.541.7±12.324.5±5.244.5±16.441.1±16.525.7±11.115.5±7.068.2±16.556.1±18.333.8±12.222.1±7.753.5±19.50.020.010.230.07Contralateral motor scoresBradykinesiaTremorRigidity 0–160–120–89.0±2.62.6±2.33.4±2.34.8±2.40.7±1.11.3±1.17.4±3.00.9±1.21.9±1.50.040.0070.03Ipsilateral motor scoresBradykinesiaTremorRigidity 0–160–120–86.7±2.91.9±2.22.8±1.84.9±2.91.3±1.92.4±1.65.7±3.61.2±1.62.1±1.80.30.150.16 Axial motor scoresGait disorderPostural instability FreezingPostural instability and gait disorder‡0–40–40–40–202.2±0.82.0±1.02.3±1.110.0±3.81.6±0.91.3±1.11.3±0.96.4±3.42.2±1.12.3±1.22.4±1.111.0±4.90.980.20.980.43  On period  Overall UPDRS scoreMotor ADL Schwab and England ADL score0–1600–1080–520–10023.4±8.915.0±7.58.5±4.181.3±10.719.8±10.913.8±8.26.2±4.087.2±7.829.0±12.517.9±8.611.1±5.280.8±13.40.040.120.060.75Contralateral dyskinesia score0–42.2±0.80.4±0.70.7±1.0<0.001Ipsilateral dyskinesia score0–41.6±0.91.1±0.81.2±0.70.08 The New England Journal of Medicine Downloaded from nejm.org on September 13, 2015. For personal use only. No other uses without permission. Copyright © 2000 Massachusetts Medical Society. All rights reserved.   LONG-TERM FOLLOW-UP OF UNILATERAL PALLIDOTOMY IN ADVANCED PARKINSON’S DISEASE   Volume 342Number 23  ·  1711  Primary Outcome Measure  The mean overall off-period UPDRS score in the20 patients was significantly better during long-termfollow-up than at base line (P=0.02) (Fig. 1A). Al-though the change remained significant throughoutthe follow-up period, there was a trend toward lossof improvement, with an improvement of 37.4 per-cent at six months (95 percent confidence interval,27.7 to 47.1 percent) and 18.0 percent at the finalevaluation (95 percent confidence interval, 4.9 to31.0 percent). Analysis of variance with repeatedmeasures for scores at six months and at the finalevaluation showed a significant effect of time on thescores (P=0.001), confirming a deterioration in thescores during the follow-up period.There was an 18.2 percent improvement from baseline in the off-period motor score during long-termfollow-up (95 percent confidence interval, 4.9 to 31.4percent; P=0.01). However, the postoperative scoresdeteriorated significantly over time (P=0.003 by analysis of variance with repeated measures). In addi-tion, the improvement at six months in the off-periodscore for activities of daily living was not sustained, with the mean score approaching the base-line valueover the follow-up period and no longer significant-ly different at the last evaluation (Fig. 1A). Similarly,the off-period score on the Schwab and England scaleof activities of daily living was not significantly bet-ter at the final assessment than at base line (P=0.07).  Secondary Outcome Measures  The significant early improvements in the off-peri-od scores for contralateral bradykinesia, tremor, andrigidity, noted in our previous reports,  4,12   were main-tained during long-term follow-up (Fig. 1B). Thescore for tremor improved by 65.4 percent (95 percentconfidence interval, 22.4 to 108.4 percent; P=0.007),and the score for rigidity improved by 43.2 percent(95 percent confidence interval, 9.0 to 77.3 percent;P=0.03). The early amelioration of tremor and rigid-ity was sustained throughout the follow-up period;analysis of variance with repeated measures showed nosignificant effect of time on the postoperative scores. Although the improvement in the score for bradyki-nesia was sustained at the final assessment (P=0.04),analysis of variance showed that the score worsenedover time (P=0.006).There was sustained, significant improvement inthe score for contralateral on-period dyskinesia, with achange of 70.6 percent (95 percent confidence inter- val, 47.2 to 94.0 percent; P<0.001) between base lineand the last evaluation. Analysis of variance showedno significant trend toward a worsening of the scoreover time (P=0.22).  Predictors of the Long-Term Outcome  The patient’s age, the duration of the disease, andthe overall off-period UPDRS score at base line werenot significantly correlated with the long-term out-come of surgery. The percent improvement in theoverall off-period UPDRS score at six months wassignificantly correlated with the percent improve-ment at the final evaluation (P=0.01, r=0.55), in-dicating that the early response was predictive of thelong-term outcome. There was a slight but signifi-cant correlation between the degree of off-periodasymmetry before surgery (the score for contralater-al motor function expressed as a percentage of the to-tal motor score) and overall long-term improvement   Figure 1. Mean (±SD) Scores for Functional Impairment (PanelA) and for Contralateral Bradykinesia, Tremor, and Rigidity(Panel B) before Surgery and during Long-Term Follow-up.Panel A shows the off-period scores for part III (motor compo-nent) and part II (activities of daily living [ADL]) of the UnifiedParkinson’s Disease Rating Scale (UPDRS). Panel B shows theoff-period scores for contralateral bradykinesia, tremor, and ri-gidity and the on-period scores for contralateral dyskinesia. P val-ues are for comparisons of scores before surgery and at thelast evaluation. Lower scores indicate better function. ;  ; ;  0100A Base line Six months One year Two years Last evaluation ;; ;; ;;  ; ; ; ; ; ; ;  UPDRS II and III P=0.02 ; ;  ; ; ; ;  Motor P=0.01 ;; ;;  ; ; ;  P=0.23 ADL 752550    U   P   D   R   S   S  c  o  r  e ; ;  ; ; ; ;  ;  ;  ;  ; ; ;  ;  ; ; ; ;  0.010.0    B  r  a  d  y   k   i  n  e  s   i  a B    T  r  e  m  o  r   R   i  g    i  d   i  t  y P=0.04P=0.007P=0.03P<0.001    D  y  s   k   i  n  e  s   i  a 2.55.07.5    S  c  o  r  e The New England Journal of Medicine Downloaded from nejm.org on September 13, 2015. For personal use only. No other uses without permission. Copyright © 2000 Massachusetts Medical Society. All rights reserved.   1712  ·  June 8, 2000  The New England Journal of Medicine  (P=0.05, r=0.45). Patients with a higher degree of contralateral motor dysfunction had a greater long-term benefit from surgery. Preoperative responsive-ness to levodopa was not predictive of the percent-age improvement in the off-period UPDRS score.  Ipsilateral, Axial, and On-Period Scores  Pallidotomy had no long-term benefit with respectto ipsilateral off-period or on-period motor function,including dyskinesia (Table 3). The off-period com-posite score for postural instability and gait disorderand the subscores for gait disorder, postural instabil-ity, and freezing were all similar at base line and atthe final evaluation. The degree of axial involvement was similar at six months and at the final evaluation.The off-period score for axial motor function (the to-tal motor score on the UPDRS minus the sum of theipsilateral and contralateral hemibody motor scores) was 40±16 percent of the total motor score at sixmonths and 44±9 percent at the final evaluation.The overall on-period UPDRS score deterioratedover time (from 23.4±8.9 before surgery to 29.0±12.5 at the final evaluation, P=0.04). The individu-al ipsilateral and contralateral on-period motor sub-scores did not change significantly (data not shown),except for the contralateral bradykinesia score, which was worse at the final evaluation than at base line(P<0.001). The on-period axial scores also tendedto worsen with time (data not shown). Significantdeterioration was noted in the composite score forpostural instability and gait disorder (P=0.03), as wellas in the subscores for postural instability (P=0.04)and freezing (P=0.05).  Comparison with Patients Not Includedin the Long-Term Analysis   A comparison between the 20 patients enrolled inthe long-term analysis and the 20 who could not beincluded is shown in Table 4. There were no signif-icant differences between the two groups at base line with respect to age, the overall off-period UPDRSscore, and its two component scores for activities of daily living and motor function. At six months, theoverall off-period UPDRS score and the motor sub-score were higher in the group of patients who werenot enrolled in the long-term analysis, indicating thatthis group derived significantly less early benefit fromsurgery (overall UPDRS score, P=0.005; motor score,P=0.001). At base line, the degree of responsivenessto levodopa, off-period asymmetry (hemibody mo-tor scores), and axial involvement were similar in thetwo groups and therefore did not account for thedifference in the overall UPDRS and motor scoresat six months.  DISCUSSION   We found that pallidotomy resulted in a significantreduction in the overall off-period UPDRS score (theprimary outcome measure) and the component mo-tor score; this improvement was sustained for up to5  1   ⁄   2   years. These scores worsened with time, perhapsreflecting a loss of benefit from the surgery or pro-gression of the disease. However, patients’ clinicalstatus was still improved at the final assessment ascompared with the base-line scores. The absence of significant increases in the off-period scores for con-tralateral rigidity and tremor and in the on-periodscore for contralateral dyskinesia suggests that theinitial benefit was sustained. The score for contralat-eral bradykinesia, like the overall UPDRS score, dete-riorated with time.In spite of the persistent improvement in off-peri-od motor score, the initial improvement in the levelof daily functioning, as reflected by the UPDRS andSchwab and England scores for activities of daily liv-ing, was not sustained. A deterioration in the off-period ipsilateral motor scores did not account forthis decline. Off-period axial scores were also not sig-nificantly worse at the final evaluation than at baseline, although corresponding on-period scores did worsen significantly.  *Plus–minus values are means ±SD. UPDRS denotes Unified Parkin-son’s Disease Rating Scale, and ADL activities of daily living.†P values (determined with the use of the Mann–Whitney U test) arefor comparisons between the patients included in the long-term study andthe patients who could not be included.‡Responsiveness to levodopa was defined as the difference between theoverall off-period and on-period scores for motor function at base line.§The score for axial motor function was calculated as the total motorscore minus the sum of the scores for ipsilateral and contralateral motorfunction.¶Two excluded patients were not evaluated at six months. One had al-ready been scheduled to undergo a second surgical procedure, and the oth-er lived too far away.  T  ABLE  4.  C  HARACTERISTICS   OF   THE  20 P   ATIENTS   IN   THE  L  ONG -T ERM  S TUDY     AND   THE  20 P  ATIENTS  W  HO  C OULD  N OT  B E  I NCLUDED ,  AT  B  ASE  L  INE    AND    AT  S IX   M ONTHS .* C HARACTERISTIC P ATIENTS  I NCLUDED   AT  F OLLOW - UP (N=20)P ATIENTS N OT  I NCLUDED (N=20)PV ALUE † At base line  Age (yr)57.1±7.160.5±9.10.20Duration of disease (yr)11.9±3.714.2±5.20.76Responsiveness to levodopa‡26.7±10.428.1±10.50.76Off-period UPDRS scoreOverall ADL MotorContralateralIpsilateral Axial§66.2±14.524.5±5.241.7±12.315.2±5.211.4±4.815.2±6.472.8±11.224.9±5.247.8±9.417.0±4.913.3±4.217.5±4.40.110.830.070.230.230.13 At six months Off-period UPDRS scoreOverall ADL Motor41.2±16.515.6±725.7±11.156.8±13.0¶19.4±6.737.2±7.70.0050.200.001 The New England Journal of Medicine Downloaded from nejm.org on September 13, 2015. For personal use only. No other uses without permission. Copyright © 2000 Massachusetts Medical Society. All rights reserved.
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