Articles. Funding UK Medical Research Council, Parkinson s UK, and UK Department of Health.

Transcription

1 Deep brai stimulatio plus best medical versus best medical aloe for advaced Parkiso s disease (PD SURG trial): a radomised, ope-label trial Adria Williams*, Steve Gill, Thelekat Varma, Crispi Jekiso, Niall Qui, Rosalid Mitchell, Richard Scott, Natalie Ives, Carolie Rick, Jae Daiels, Smitaa Patel, Keith Wheatley*, o behalf of the PD SURG Collaborative Group Summary Backgroud Surgical itervetio for advaced Parkiso s disease is a optio if medical fails to cotrol symptoms adequately. We aimed to assess whether surgery ad best medical improved self-reported quality of life more tha best medical aloe i patiets with advaced Parkiso s disease. Methods The PD SURG trial is a ogoig radomised, ope-label trial. At 13 eurosurgical cetres i the UK, betwee November, 2000, ad December, 2006, patiets with Parkiso s disease that was ot adequately cotrolled by medical were radomly assiged by use of a computerised miimisatio procedure to immediate surgery (lesioig or deep brai stimulatio at the discretio of the local cliicia) ad best medical or to best medical aloe. Patiets were aalysed i the treatmet group to which they were radomised, irrespective of whether they received their allocated treatmet. The primary edpoit was patiet self-reported quality of life o the 39-item Parkiso s disease questioaire (PDQ-39). Chages betwee baselie ad 1 year were compared by use of t tests. This trial is registered with Curret Cotrolled Trials, umber ISRCTN Fidigs 366 patiets were radomly assiged to receive immediate surgery ad best medical (183) or best medical aloe (183). All patiets who had surgery had deep brai stimulatio. At 1 year, the mea improvemet i PDQ-39 summary idex score compared with baselie was 5 0 poits i the surgery group ad 0 3 poits i the medical group (differece 4 7, 95% CI 7 6 to 1 8; p=0 001); the differece i mea chage i PDQ-39 score i the mobility domai betwee the surgery group ad the best medical group was 8 9 (95% CI 13 8 to 4 0; p=0 0004), i the activities of daily livig domai was 12 4 ( 17 3 to 7 5; p<0 0001), ad i the bodily discomfort domai was 7 5 ( 12 6 to 2 4; p=0 004). Differeces betwee groups i all other domais of the PDQ-39 were ot sigificat. 36 (19%) patiets had serious surgery-related adverse evets; there were o suicides but there was oe procedure-related death. 20 patiets i the surgery group ad 13 i the best medical group had serious adverse evets related to Parkiso s disease ad drug treatmet. Iterpretatio At 1 year, surgery ad best medical improved patiet self-reported quality of life more tha best medical aloe i patiets with advaced Parkiso s disease. These differeces are cliically meaigful, but surgery is ot without risk ad targetig of patiets most likely to beefit might be warrated. Fudig UK Medical Research Coucil, Parkiso s UK, ad UK Departmet of Health. Itroductio Parkiso s disease is caused i part by loss of dopamiergic euros i the substatia igra pars compacta; the resultat abormal euroal oscillatory ad sychroous activity betwee the subthalamic ucleus, globus pallidus pars itera, ad cerebral cortex leads to icreasig problems with tremor, rigidity, bradykiesia, ad postural disturbaces. 1 Levodopa ad other dopamiergic drugs relieve these movemet disorders, 2 but dyskiesia ad motor fluctuatios develop after a few years. Most eurosurgery for Parkiso s disease has bee doe o the thalamus, globus pallidus pars itera, or subthalamic ucleus, usig either lesioig or high frequecy deep brai stimulatio. I recet years, advaces i imagig have icreased the precisio of surgical itervetios; this ad advaces i the uderstadig of basal gaglia physiology 3 5 have meat that deep brai stimulatio of the subthalamic ucleus has bee preferred. 6 I the late 1990s, there was little reliable evidece from radomised trials o the efficacy ad safety of surgery. 7 Thus, we started the PD SURG trial with the aim of comparig the effect of surgery with best medical i patiets with advaced Parkiso s disease. This report presets the results at 1 year s follow-up. Methods Patiets PD SURG is a radomised, ope-label trial. Patiets with Parkiso s disease for whom curret medical was ot providig adequate symptomatic cotrol were eligible. Iclusio criteria were diagosis of Parkiso s disease accordig to the UK Brai Bak Lacet Neurol 2010; 9: Published Olie April 29, 2010 DOI: /S (10) See Reflectio ad Reactio page 558 *Cotributed equally Members listed at ed of paper Quee Elizabeth Hospital, Birmigham, Birmigham, UK (Prof A Williams MD, R Mitchell FRCS); Frechay Hospital, Bristol, UK (Prof S Gill FRCS); Walto Cetre for Neurology ad Neurosurgery, Liverpool, UK (T Varma FRCS[Ed]); Uiversity of Oxford, Oxford, UK (Prof C Jekiso DPhil); UCL Istitute of Neurology, Lodo, UK (Prof N Qui MD); Russell Cairs Uit, Joh Radcliffe Hospital, Oxford, UK (R Scott PhD); ad Uiversity of Birmigham, Birmigham, UK (N Ives MSc, C Rick PhD, J Daiels MSc, S Patel MSc, Prof K Wheatley DPhil) Correspodece to: Natalie Ives, PD SURG Trial Office, Uiversity of Birmigham Cliical Trials Uit, College of Medical ad Detal Scieces, Robert Aitke Istitute, Uiversity of Birmigham, Birmigham B15 2TT, UK.j.ives@bham.ac.uk For the trial protocol see ivestigators/documetatio Vol 9 Jue

2 183 allocated to surgery 178 had surgery 174 had STN DBS 4 had GPi DBS 5 did ot have surgery 3 refused* 1 died 1 ufit for aaesthesia 162 had PDQ-39 data available for aalysis at 1 year criteria, 8 age-adjusted score of greater tha 5 o the demetia ratig scale-ii (DRS-II), 9 ad fitess for surgery. All patiets gave writte iformed coset before radomisatio. The trial was approved by the West Midlads multicetre research ethics committee ad local ethics committees at each cetre. Radomisatio ad maskig Patiets were radomly assiged by a telephoe call made to the cetral trial office. Allocatio (1:1) to surgery ad best medical (surgery group) or best medical aloe (medical group) was doe by use of a computerised miimisatio procedure with the followig categories: age at etry (<60, 60 69, ad 70 years); years sice diagosis of Parkiso s disease (<5, 5 9, 10 14, ad 15 years); Hoeh ad Yahr stage 10 i the o state ( 2 0, 2 5, 3 0, ad 4 0); reaso for cosiderig surgery (tremor, dyskiesia, severe off periods, or other reasos); type of surgery (stimulatio or lesio) ad regio to be targeted if allocated to surgery (subthalamic ucleus or globus pallidus pars itera); ad drug to be give if allocated to medical (apomorphie or other stadard drug treatmets for Parkiso s disease). A pair-wise radomisatio optio was available so that cetres could eter two patiets together, 11 with oe allocated to surgery ad oe to medical. Patiets ad cliicias were umasked to treatmet allocatio. 366 radomly assiged 21 had o PDQ-39 data available for aalysis at 1 year 1 refused surgery 2 died 18 forms ot retured 183 allocated to medical 171 had medical 12 had surgery withi 1 year 3 wated to have surgery, so paid for surgery themselves 6 uable to cope o medicatio 1 deteriorated 1 eeded Parkiso s disease cotrolled before kee operatio 1 slot became available for surgery 153 had PDQ-39 data available for aalysis at 1 year 30 had o PDQ-39 data available for aalysis at 1 year 4 withdrew 1 fell ad broke eck 1 had demetia 2 withdrew coset 1 died 25 forms ot retured Figure 1: Trial profile PDQ-39=39-item Parkiso s disease questioaire. STN=subthalamic ucleus. DBS=deep brai stimulatio. GPi=globus pallidus pars itera. *1 patiet who refused surgery the withdrew from the trial. As slots for surgery became available aroud the 1 year timepoit they were used for patiets i the medical group. I oe case, a slot became available earlier ad the treatig cliicia decided to cross this patiet over early (at 10 moths). Procedures Patiets allocated to surgery could receive ay stadard procedure i use at the time: either stimulatio or lesioig of either the subthalamic ucleus or globus pallidus pars itera. was to be doe withi 4 weeks of radom allocatio. The local cliicia selected the surgical techiques ad postoperative maagemet of stimulator settigs for each patiet. Patiets i both groups received medical, which could iclude apomorphie accordig to local practice, other dopamie agoists, mooamie oxidase type B ihibitors, catechol-o-methyltrasferase ihibitors, amatadie, or other drugs for treatmet of Parkiso s disease symptoms. Levodopa equivalets were calculated o the basis of 100 mg/day of stadard levodopa beig equivalet to the followig doses of other drugs: 133 mg cotrolled-release levodopa; 1 mg pergolide, pramipexole, cabergolie, or rasagilie; 1 25 mg subligual selegilie; 2 mg bezhexol; 3 3 mg rotigotie; 5 mg ropiirole; 10 mg bromocriptie, oral selegilie, or apomorphie; ad 100 mg amatadie. The total levodopa dose was multiplied by 1 33 for etacapoe ad by 1 5 for tolcapoe. Apart from the radom treatmet allocatio, all other aspects of the maagemet of patiets were at the discretio of the local cliicias. Patiets i the medical group could cross over to receive surgery after about 1 year. The primary edpoit was the patiet s self-evaluatio of their fuctioal status by use of the 39-item Parkiso s disease questioaire (PDQ-39). 12 Secodary edpoits icluded cliical assessmet of fuctioig (uified Parkiso s disease ratig scale [UPDRS] 13 i both o ad off states) ad cogitive status (DRS-II). 9 The UPDRS was assessed i the o state (o medicatio) ad off state (after overight withdrawal of medicatio) at study etry, ad i the o state (o medicatio ad o stimulatio if surgery was doe) ad off state (after overight withdrawal of medicatio but o stimulatio if surgery was doe) at follow-up. Neuropsychological assessmets were also doe i a subset of patiets ad ivolved a cliical iterview ad a battery of 16 psychometric tests ad questioaires. Neuropsychological assessmet could ot be doe o all patiets because traied examiers were ot available i some cetres. For cetres that did ot have traied examiers, a similar method to that used i a previous multicetre radomised cotrolled trial was adopted: 14 where possible, psychologists (who were based, traied, ad supervised cetrally i Oxford) visited the cetres to complete assessmets as required. We collected data o the type ad dose of drug treatmets for Parkiso s disease ad o the icidece of serious adverse evets (defied as ay evet that resulted i a prologed stay i hospital or admissio to hospital, was thought to be lifethreateig, or resulted i death). Data o serious adverse evets was collected o serious adverse evets forms, aual follow-up forms (completed by the local cliicia), resource usage forms (completed by the patiets), ad Vol 9 Jue 2010

3 partial review of medical otes ad iformatio from family doctors. Data for o-serious adverse evets was also collected for patiets i the surgery group by use of post-operatio forms (oe immediately after surgery ad oe 6 moths later) ad subsequet aual follow-up forms. Patiets i both groups were to be assessed at 1, 2, 3, 5, 7, ad 9 years after radomisatio. Here, we preset data from the 1-year follow-up. Statistical aalysis PD SURG was desiged to detect a te-poit differece (regarded as cliically importat) betwee groups i the PDQ-39 summary idex. Assumig a stadard deviatio of 30 (two-sided p of 0 05 ad 90% power), this required radom allocatio of about 400 patiets i total. A idepedet data moitorig committee reviewed efficacy ad safety data aually. If large differeces betwee the groups were observed, the data moitorig committee could recommed to the idepedet trial steerig committee that erolmet to the trial be stopped early or modified as appropriate. Patiets were aalysed i the treatmet group to which they were radomised, irrespective of whether they received their allocated treatmet, although patiets without follow-up at 1 year could ot be icluded i the aalysis. For cotiuous variables, chages from baselie to 1 year were compared betwee the groups usig t tests. Missig values i PDQ-39 domai scores were imputed by use of the expectatio maximisatio algorithm. 15 Categorical data were aalysed usig χ² tests or Fisher s exact tests. Subgroup aalyses by protocol-specified stratificatio parameters were doe to explore differeces i treatmet effect across subgroups, usig tests of heterogeeity or tests for tred. Aalyses were doe usig SAS versio 9.1 (Cary, NC, USA). This trial is registered with Curret Cotrolled Trials, umber ISRCTN Role of the fudig source The study fudig sources were ot ivolved i the study desig, data collectio, data aalysis, data iterpretatio, or the writig of the report, or were they ivolved i the decisio to submit the paper for publicatio. The maufacturers of the stimulators used i the trial had o role i the desig, data collectio, data aalysis, data iterpretatio, writig of the report, or the decisio to submit the paper for publicatio. The views expressed i this Article do ot ecessarily reflect those of the fudig bodies. All authors had full access to the study data, read ad approved the fial versio of the paper, ad were resposible for the decisio to submit the paper for publicatio. Results Betwee November, 2000, ad December, 2006, 366 patiets from 13 eurosurgical cetres i the UK were radomly assiged to the surgery group or to the best medical group (183 per group, figure 1). Baselie characteristics were similar betwee groups (tables 1, 2, ad 3). 348 of 366 patiets were aged less tha 70 years (mea age 59 years) ad 341 patiets had had Parkiso s disease for at least 5 years (mea duratio 11 4 years). Dyskiesia (=267) ad severe off periods (=280) were the most commo reasos for cosiderig surgery (table 1). I additio to levodopa, 357 of 366 patiets had received previous with a dopamie agoist, 197 with a mooamie oxidase type B ihibitor, 214 with a catechol-omethyltrasferase ihibitor, ad 145 with apomorphie (90 were still o apomorphie at radom allocatio). Five patiets i the surgery group did ot have surgery: three refused surgery, oe was ufit for aaesthesia, ad oe died before surgery (figure 1). 81 of 178 patiets had (=183) Medical (=183) Demographics Age (years) 59 (37 79) 59 (36 75) Me 125 (68%) 135 (74%) Baselie characteristics Duratio of Parkiso s disease (years) 11 5 ( ) 11 2 ( ) Hoeh ad Yahr stage (o state) 2 66 (36%) 68 (37%) (32%) 55 (30%) 3 54 (30%) 54 (30%) 4 5 (3%) 6 (3%) 5 0 (0%) 0 (0%) Hoeh ad Yahr stage (off state)* 2 12 (7%) 11 (6%) (11%) 29 (16%) 3 65 (38%) 59 (34%) 4 54 (32%) 55 (31%) 5 19 (11%) 22 (13%) Previous treatmet Dopamie agoist 179 (98%) 178 (97%) Mooamie oxidase type B ihibitor 99 (54%) 98 (54%) Catechol-O-methyltrasferase ihibitor 103 (56%) 111 (61%) Apomorphie 72 (39%) 73 (40%) O apomorphie at study etry 45 (25%) 45 (25%) Reaso for cosiderig surgery Tremor 73 (40%) 73 (40%) Dyskiesia 134 (73%) 133 (73%) Severe off periods 141 (77%) 139 (76%) Other 16 (9%) 17 (9%) PDQ-39 summary idex 37 5 (14 6) 38 7 (13 7) UPDRS part III: motor (o) 18 9 (11 4) 20 1 (11 4) UPDRS part III: motor (off) 47 6 (14 0) 48 6 (14 3) Data are mea (rage), umber (%), or mea. UPDRS=uified Parkiso s disease ratig scale. PDQ=Parkiso s disease questioaire. *Based o baselie UPDRS part IV: complicatios of, where patiets are asked what their worst Hoeh ad Yahr stage had bee i the past week. Data were available for 169 of 183 patiets i the surgery group ad 176 of 183 patiets i the medical group. Not mutually exclusive: more tha oe previous treatmet ad reaso for cosiderig surgery could apply. Icludig motor complicatios (fluctuatios or dystoia, =12), rigidity (=7), bradykiesia (=5), gait problems (=4), itolerace to drugs (=3), goose steppig (=1), ad pai (=1). Percetage values do ot add up to 100 i some cases because of roudig. Table 1: Demographics ad baselie characteristics Vol 9 Jue

4 Baselie 1 year Chage betwee baselie ad 1 year (=178) Medical (=178) (=162) Medical (=153) Differece i meas at 1 year (95% CI) p (=160) Medical (=150) Differece i the mea chage (95% CI) Summary idex 37 5 (14 6) 38 7 (13 7) 32 5 (15 8) 38 1 (13 5) 5 6 ( 8 9 to 2 4) (14 1) 0 3 (11 1) 4 7 ( 7 6 to 1 8) Mobility 56 3 (22 5) 60 1 (22 4) 48 1 (25 2) 60 2 (23 6) 12 0 ( 17 5 to 6 6) < (24 8) 0 7 (18 9) 8 9 ( 13 8 to 4 0) Activities of daily livig 49 6 (21 4) 51 4 (20 4) 37 0 (21 6) 51 0 (21 1) 14 0 ( 18 7 to 9 3) < (23 6) 0 1 (20 3) 12 4 ( 17 3 to 7 5) < Emotioal wellbeig 31 3 (19 7) 31 0 (19 5) 27 9 (21 1) 28 6 (18 8) 0 7 ( 5 1 to 3 8) (20 9) 1 2 (16 2) 2 1 ( 6 3 to 2 1) 0 33 Stigma 33 2 (25 2) 37 2 (26 0) 25 5 (24 2) 35 0 (24 6) 9 5 ( 14 9 to 4 1) (24 4) 3 0 (21 9) 5 2 ( 10 4 to 0 03) 0 05 Social support 18 8 (19 0) 16 6 (20 9) 19 2 (20 5) 16 8 (19 3) 2 4 ( 2 1 to 6 8) (18 4) 0 5 (19 3) 0 1 ( 4 1 to 4 4) 0 95 Cogitio 30 4 (19 7) 29 6 (20 5) 28 6 (21 3) 30 0 (19 4) 1 4 ( 5 9 to 3 1) (19 7) 1 4 (19 2) 3 0 ( 7 4 to 1 3) 0 17 Commuicatio 31 9 (23 1) 31 7 (23 1) 34 3 (23 0) 33 0 (21 0) 1 3 ( 3 6 to 6 2) (22 3) 1 6 (18 0) 1 4 ( 3 2 to 5 9) 0 55 Bodily discomfort 48 9 (23 1) 52 1 (23 8) 39 2 (23 7) 50 0 (23 0) 10 9 ( 16 1 to 5 7 ) < (23 1) 2 4 (22 6) 7 5 ( 12 6 to 2 4) Data are mea. The PDQ-39 rage is 0 100; the higher the score, the worse the self-reported quality of life; egative chage=improvemet. Te baselie forms ad 51 1-year forms were ot retured. Five patiets retured 1-year PDQ-39 forms, but did ot retur baselie PDQ-39 forms, so we were uable to calculate a chage from baselie for these patiets. Missig values i PDQ-39 domai scores were imputed usig the expectatio maximisatio algorithm. PDQ-39=39-item Parkiso s disease questioaire. Table 2: Primary outcome (PDQ-39) p Baselie 1 year Chage betwee baselie ad 1 year Medical Medical Differece i meas at 1 year (95% CI) p Medical Differece i the mea chage (95% CI) p Mea Mea Mea Mea Mea Mea UPDRS* Part I: metal (1 7) Part II: activities of daily livig (o) Part II: activities of daily livig (off) (6 5) (7 2) Part III: motor (o) (11 4) Part III: motor (off) (14 0) Part IV: complicatios of (3 4) Total (I III) score (o) (16 6) Total (I III) score (off) (19 7) Total (I IV) score (o) (17 8) Total (I IV) score (off) (21 4) Cogitio DRS-II (2 8) (1 6) (6 0) (7 3) (11 4) (14 3) (3 4) (16 3) (20 0) (15 4) (21 0) (2 9) (1 8) (5 9) (8 1) (8 8) (15 2) (3 1) (13 8) (21 3) (14 6) (22 4) (3 2) (1 7) (6 5) (7 6) (10 8) (15 4) (3 7) (15 6) (21 7) (16 3) (24 3) (3 0) 0 2 ( 0 6 to 0 2) (1 8) 1 0 ( 2 4 to 0 4) (6 4) 6 3 ( 8 2 to 4 4) < (7 2) 4 5 ( 6 8 to 2 2) (9 4) 16 6 ( 20 4 to 12 9) < (13 1) 4 6 ( 5 4 to 3 7) < (3 8) 5 9 ( 9 5 to 2 4) (14 2) 22 4 ( 27 8 to 17 1) < (17 5) 8 9 ( 13 0 to 4 7) < (15 3) 26 3 ( 32 8 to 19 9) < (18 9) 0 5 ( 0 3 to 1 2) (3 5) (1 6) (5 1) (5 9) (9 1) (13 3) (2 8) (11 5) (18 0) (12 2) (20 1) (2 9) 0 3 ( 0 7 to 0 1) ( 2 0 to 0 7) ( 8 0 to 4 7) < ( 6 3 to 1 8) ( 20 1 to 13 4) < ( 5 1 to 3 3) < ( 8 6 to 2 1) ( 27 9 to 18 6) < ( 12 3 to 4 3) < ( 32 3 to 20 9) < ( 0 7 to 0 8) 0 90 UPDRS=uified Parkiso s disease ratig scale. DRS-II=demetia ratig scale II. *177 patiets i the surgery group ad 181 i the medical group were assessed at baselie, ad 155 i the surgery group ad 152 i the medical group were assessed at 1 year. Data o 150 patiets i each group were icluded i assessmets of mea chages betwee baselie ad 1 year. The umbers aalysed for each part of the UPDRS are differet because of missig data. There are o imputatio methods for the UPDRS. UPDRS score rages: metal 0 16; activities of daily livig 0 52; motor 0 108; complicatios 0 23; total (parts I III) 0 176; total (parts I IV) (high scores=worse cliical assessmet of the patiet s Parkiso s disease). UPDRS egative chage=improvemet. Whe the trial started patiets were allowed to complete either the mii-metal state examiatio or DRS-II; therefore data o the DRS-II were ot available for all patiets. DRS-II rage: 0 18 (high score=better cogitive fuctio). DRS-II egative chage=deterioratio. Table 3: UPDRS ad DRS-II scores surgery withi 4 weeks of radom allocatio, 66 withi 4 8 weeks, 22 withi 8 16 weeks, ad ie more tha 16 weeks after radom allocatio. All 178 patiets i the surgery group who received surgery had deep brai stimulatio ad i 174 the subthalamic ucleus was the surgical target. 176 of 178 procedures were bilateral; there Vol 9 Jue 2010

5 was oe staged procedure with electrodes implated 10 moths apart. I the medical group, 12 patiets had surgery betwee baselie ad 1 year (figure 1), of whom three received surgery betwee 10 moths ad 12 moths after radom allocatio but completed 1-year assessmets before surgery. 118 patiets radomly allocated to medical had surgery at or after 1 year. The mea chage betwee baselie ad 1 year o the PDQ-39 summary idex was 5 0 poits i the surgery group ad 0 3 poits i the medical group (differece 4 7 poits, 95% CI 7 6 to 1 8, p=0 001; table 2). The mea chage i PDQ-39 summary idex betwee baselie ad 1 year raged from less tha 30 to more tha 30 (figure 2). The differece i mea chage i score betwee baselie ad 1 year was 8 9 for the PDQ-39 domai of mobility (95% CI 13 8 to 4 0; p=0 0004), 12 4 for activities of daily livig ( 17 3 to 7 5; p<0 0001), 7 5 for bodily discomfort ( 12 6 to 2 4; p=0 004), ad 5 2 for stigma ( 10 4 to 0 03; p=0 05). For the PDQ-39 summary idex score, there was o evidece that the size of the treatmet effect i favour of surgery varied with age, duratio of Parkiso s disease, Hoeh ad Yahr stage, reasos for cosiderig surgery, or whether apomorphie treatmet was plaed (figure 3). Full details of the subgroup aalyses will be reported elsewhere. The mea UPDRS (o) total (parts I IV) score decreased betwee baselie ad 1 year by 6 6 poits i the surgery group (ie, improvemet) ad icreased by 1 6 poits i the medical group (differece 8 3 poits, 95% CI 12 3 to 4 3; p<0 0001; table 3). The differece i the mea chage betwee baselie ad 1 year betwee the groups was 4 0 (95% CI 6 3 to 1 8; p=0 0006) for the motor (o) subsectio of the UPDRS ad 4 2 ( 5 1 to 3 3; p<0 0001) for the complicatios of subsectio. The mea UPDRS (off) total (parts I IV) score decreased betwee baselie ad 1 year by 27 4 poits i the surgery group ad by 0 9 poits i the medical group (differece 26 6 poits, 95% CI 32 3 to 20 9; p<0 0001). We ivestigated the aswers to UPDRS questios relatig specifically to dyskiesia ad off periods because these were the two mai reasos that patiets were cosidered for surgery. At 1 year, 75 patiets i the surgery group ad 21 i the medical group reported o wakig day dyskiesia (p<0 0001) ad 45 i the surgery group ad five i the medical group reported o off time (p<0 0001; table 4). The DRS-II score decreased by 0 4 poits (ie, deterioratio) betwee baselie ad 1 year i both groups (differece 0 05, 95% CI 0 7 to 0 8, p=0 90; table 3). 39 measures were compared i the europsychological assessmets o up to 163 patiets. The Delis-Kapla executive fuctio system phoemic mea score decreased by 6 5 poits (SD 9 4) betwee baselie ad 1 year i the surgery group ad decreased by Number of patiets to to to 0 0 to to 20 Mea chage Figure 2: Mea chage i 39-item Parkiso s disease questioaire summary idex score betwee baselie ad 1 year Negative scores=improvemet. Baselie 1 year 0 6 poits (8 7) i the medical group (differece 5 9, 95% CI 8 9 to 2 9; p=0 0002). The mea chage i score o the D-KEFS categorical verbal fluecy betwee baselie ad 1 year was 4 5 poits (SD 7 8) i the surgery group ad 0 2 (7 7) i the medical group (differece 4 4, 6 9 to 1 8; p=0 001). O the Wechsler abbreviated scale of itelligece vocabulary, the mea chage from baselie to 1 year was 1 5 (4 8) i the surgery group ad 0 6 (4 9) i the medical group (differece 2 1, 3 7 to 0 5; p=0 01). At 1 year, patiets i the surgery group were o a mea levodopa equivalet dose of 894 mg/day (SD 568) ad those i the medical group were o 1347 mg/day (585, p<0 0001). This differece of 453 mg/day (95% CI Medical 20 to 30 >30 Medical p* Medical p* Dyskiesia < Noe 19 (11%) 27 (15%) 75 (48%) 21 (14%) 1 25% 71 (40%) 63 (35%) 65 (42%) 56 (37%) 26 50% 55 (31%) 55 (31%) 10 (6%) 44 (29%) 51 75% 26 (15%) 27 (15%) 4 (3%) 27 (18%) % 6 (3%) 8 (4%) 1 (1%) 3 (2%) Off time < Noe 6 (3%) 2 (1%) 45 (29%) 5 (3%) 1 25% 66 (38%) 68 (38%) 83 (54%) 64 (42%) 26 50% 85 (49%) 88 (49%) 23 (15%) 63 (41%) 51 75% 16 (9%) 20 (11%) 3 (2%) 17 (11%) % 2 (1%) 2 (1%) 0 (0%) 3 (2%) Based o UPDRS part IV: complicatios of (Q32: what proportio of the wakig day is dyskiesia preset? Q39: what proportio of the wakig day is the patiet off o average?). *χ2 test for the differece betwee the surgery group ad the medical group across all categories. Table 4: Dyskiesia ad off periods Vol 9 Jue

6 Chage from baselie Differece Variace Differece (95% CI) Medical Number Mea Number Mea Age <60 years (1 6) (1 4) to years (1 7) (1 2) to years (3 3) (3 5) to 0 4 Subtotal to 2 0 Test for tred: χ 2 ₁=0 0; p=0 83 Duratio of Parkiso s disease <10 years (2 0) (1 6) to years (1 7) (1 2) to years (2 2) (2 1) to 3 4 Subtotal to 2 1 Test for tred: χ 2 ₁=0 2; p=0 67 Hoeh ad Yahr stage Stage (2 1) (1 2) to 2 7 Stage (1 7) (1 4) to 0 4 Stage (1 9) (2 0) to 1 9 Subtotal to 1 8 Test for tred: χ 2 ₁=2 0; p=0 16 Reaso for surgery: tremor No (1 5) (1 3) to 1 2 Yes (1 6) (1 3) to 0 0 Subtotal to 1 8 Test for heterogeeity: χ 2 ₁=0 1; 2p=0 73 Reaso for surgery: dyskiesia No (2 2) (1 7) to 4 4 Yes (1 3) (1 1) to 2 7 Subtotal to 1 9 Test for heterogeeity: χ 2 ₁=2 2; 2p=0 13 Reaso for surgery: severe off-periods No (2 3) (1 4) to 1 3 Yes (1 3) (1 1) to 1 6 Subtotal to 1 8 Test for heterogeeity: χ 2 ₁=0 1; 2p=0 78 Pla to prescribe apomorphie No (3 0) (1 5) to 2 1 Yes (1 2) (1 1) to 1 5 Subtotal to 1 8 Test for heterogeeity: χ 2 ₁=0 96; 2p=0 78 Total to Favours surgery Favours medical Figure 3: Subgroup aalyses of 39-item Parkiso s disease questioaire summary idex score 328 to 580) at 1 year represets a 34% reductio i mea drug dose i the surgery group compared with the medical group. At baselie, 45 patiets i each group were o apomorphie. By 1 year, this had decreased to 13 i the surgery group (te were o apomorphie at baselie ad three started o apomorphie after radom allocatio) ad had icreased to 63 i the medical group (34 were o apomorphie at baselie ad 29 started o apomorphie after radomisatio). Of the patiets o apomorphie at 1 year, 54 patiets were o cotiuous drug ifusios (six i the surgery group ad 48 i the medical group) ad 22 were o itermittet dosig (seve i the surgery group ad 15 i the medical group). 36 of 178 patiets i the surgery group had 43 surgeryrelated serious adverse evets. There were o serious Vol 9 Jue 2010

7 adverse evets i the 12 patiets i the medical group who received surgery i the first year. The most commo surgery-related serious adverse evets were ifectios (=16; table 5). There were 39 Parkiso s disease-related ad drugrelated serious adverse evets reported i 33 patiets (25 evets i 20 patiets i the surgery group ad 14 i 13 patiets i the medical group), the most commo of which were worseig of Parkiso s disease symptoms or ucotrolled Parkiso s disease symptoms (12 evets i 11 patiets i the surgery group ad two i the medical group; table 5). There was oe usuccessful postoperative suicide attempt i a patiet i the surgery group; however, this patiet had previously attempted suicide before trial etry. Three patiets died durig the first year: oe from haemorrhage durig surgery, oe i the surgery group from peumoia 3 weeks after study etry before surgery was doe, ad oe from stroke i the medical group 10 moths after etry. Discussio PD SURG was desiged with quality of life as the primary edpoit to examie the efficacy of deep brai stimulatio versus medical o the daily lives of people with Parkiso s disease ad thus provide practical iformatio to iform future use. PD SURG icluded a represetative sample of patiets likely to be offered surgery at eurosciece cetres i the UK, where apomorphie is readily available, thus eablig compariso of surgery with best medical ad providig evidece o the beefits of surgery i a real-world settig. The follow-up reported here was loger tha i two other large trials of deep brai stimulatio versus medical, 16,17 ad thus gives statistically more reliable results ad provides evidece o the loger term beefits of surgery (with less likelihood of a so-called hoeymoo effect 18 i the period just after surgery). Although oe trial has ivestigated the effects of surgery for Parkiso s disease to 18 moths, oly 20 patiets were icluded ad thus the trial was uderpowered; also, patiets with earlier stage disease were recruited. 19 From a purely scietific perspective, a log-term trial of surgery versus medical would have bee ideal; however, a realistic desig acceptable to both patiets ad cliicias was ecessary, ad so surgery was permitted after 1 year i the medical group. There were clear advatages for surgery compared with medical aloe at 1 year, both i patiet-assessed quality of life ad o cliical assessmet. These beefits are likely to be meaigful to patiets, as measured by use of the PDQ-39, 20 ad were foud i domais of the PDQ-39 that surgery would be expected to affect (eg, mobility ad activities of daily livig), but ot i others (eg, social support, cogitio, ad commuicatio). These fidigs were mirrored by cliically meaigful differeces o the UPDRS, 21 icludig the patiet-rated UPDRS part IV, which showed substatial beefits of (=183) surgery i the time ad severity of dyskiesia ad off periods the most commo reasos for patiets to be cosidered for surgery. Greater beefits for the surgery group tha the medical group were see for off-medicatio UPDRS assessmets. However, this represets a artificial situatio, created by a temporary withdrawal of medicatio ad does ot idicate a absece of drug because the washout period was ot log eough. Whe cosiderig the real-life o-medicatio assessmet, the magitude of the beefit Medical (=183) -related 43 evets i 36 patiets 0 evets i 12 patiets* Haemorrhage 4 (icludig 1 death) 0 Ifectio 16 0 DBS-specific adverse evets 13 evets i 12 patiets 0 Postoperative cofusio 5 0 Neck pai 2 0 Seizures 2 0 Deterioratig cotrol of Parkiso s disease 1 0 because battery was switched off Psychosis 1 0 Uresposive o operatig table (possibly 1 0 because of levodopa withdrawal) Visual eglect from oedema 1 0 Geeral surgery problems 10 evets i 9 patiets 0 evets Uriary retetio 4 0 Pulmoary embolism 2 0 Axiety attack 1 0 Difficulty removig catheter 1 0 Postoperative hypotesio 1 0 Pyrexia 1 0 Parkiso s-disease related ad drug-related 25 evets i 20 patiets 14 evets i 13 patiets Falls 3 7 Costipatio 4 i 3 patiets 2 Worseig of Parkiso s disease symptoms or 12 i 11 patiets 2 ucotrolled Parkiso s disease symptoms Psychiatric problems 4 1 Neuropsychiatric disturbaces (icludig 3 0 halluciatios or paraoia) Breakdow 0 1 Suicide attempt 1 0 Parkiso s disease drug-related 2 2 Other 26 evets i 19 patiets 14 evets i 13 patiets Deaths 2 (haemorrhage ad 1 (stroke) peumoia) Total 96 evets i 65 patiets 29 evets i 26 patiets Serious adverse evets were ay evet that prologed a patiet s stay i hospital, resulted i the patiet beig admitted to hospital, was cosidered to be life-threateig, or resulted i death. DBS=deep brai stimulatio. *12 patiets radomly assiged to medical received surgery betwee baselie ad 1 year. Oe patiet had a haemorrhage 5 moths after surgery ad this was probably ot treatmet related. Five uriary problems; five leg swellig or kee swellig, or both; three pai; two chest pai or agia; two chest ifectio; oe collapse; oe deep vei thrombosis (more tha 8 moths after surgery); oe pulmoary embolism (more tha 8 moths after surgery); oe polymyalgia rheumatica; oe vertigo; oe real colic; oe faitig episode; oe lacerated woud to forearm; ad oe head ijury. Four chest pai or agia; two uriary problems; two pai; oe abscess o chest wall leadig to ifectio; oe deep vei thrombosis; oe cauda equia sydrome; oe faitig episode; oe cofusio; ad oe chest problems. Table 5: Serious adverse evets i the first year Vol 9 Jue

8 Chage from baselie Differece Variace Differece (95% CI) Medical Number Mea Number Mea 6 moths Deuschl ad colleagues (1 8) (1 3) to 5 3 Weaver ad colleagues (1 3) (1 1) to 4 6 Subtotal to 6 0 Test for heterogeeity: χ 2 ₁=0 3; 2p= moths PD SURG (1 1) (0 9) to moths Schüpbach ad colleagues (3 3) (3 1) to 1 7 Total to 5 0 Test for heterogeeity (4 trials): χ 2 ₃=5 0; 2p=0 17 Test for tred betwee subtotals: χ 2 ₁=1 5; 2p= Favours surgery Favours medical Figure 4: Meta-aalysis of 39-item Parkiso s disease questioaire summary idex score i trials of deep brai stimulatio versus medical see i our trial is smaller tha perhaps aticipated from the umerous small ucotrolled series that have suggested large effects of surgery. 22,23 PD SURG, alog with other reported radomised trials, 16,17,19 shows beefits for surgery over best medical treatmet i patiets with advaced Parkiso s disease, eve whe apomorphie is available, while also cofirmig that there are risks associated with surgery. A meta-aalysis of PDQ-39 summary idex scores showed that the results of the trials are geerally cosistet with each other (test for heterogeeity, p=0 2; figure 4), although there is evidece of heterogeeity of treatmet effect betwee the trials with 6 moths of follow-up ad PD SURG with 12 moths of follow-up (test for iteractio, p=0 04). The PD SURG results at 1 year show smaller differeces betwee the groups i the PDQ-39 summary idex (4 7 poits) tha was see i the two trials that reported results after 6 moths (8 7 poits). 16,17 Although from a statistical perspective this differece is ot substatial ad might be a chace effect, it is worth cosiderig potetial alterative explaatios based o differeces i the trial desigs. First, it is possible that there is a large immediate effect of surgery, whether real or i part related to a early so-called hoeymoo effect, 18 which gradually decreases over time. If the beefits of surgery are relatively trasiet, this would call ito questio the log-term value of surgery. Secod, there might have bee better drug treatmet of Parkiso s disease i the medical group of PD SURG tha i the other two trials, because of the use of apomorphie i over oe-third of patiets i this group. Apomorphie is a effective drug i advaced Parkiso s disease 2 ad ca be give by cotiuous ifusio to eable a more costat dose to be delivered to the patiet, thereby smoothig out o off periods ad fluctuatios. However, apomorphie is expesive, ad thus i the UK teds to be used oly whe other drugs have failed to cotrol the symptoms of Parkiso s disease adequately; that is, it might be used i the same situatios as surgery for patiets with advaced Parkiso s disease. Hece, a compariso of the effects of surgery plus medical versus medical, i a populatio of patiets whose treatmet could have icluded apomorphie (as i PD SURG), provides better evidece o the relative beefits of surgery tha a compariso with medical ot icludig apomorphie. However, apomorphie is less widely used outside the UK, ad was ot reported as beig widely used i the other trials. 16,17 Admiistratio of apomorphie is more complicated tha for other Parkiso s disease drugs, requirig ifusio ad moitorig. Nevertheless, because of its efficacy, apomorphie use might become more commo, ad thus the results of PD SURG could have wider relevace i future. Optimisatio of medical might lead to a smaller comparative advatage for surgery. Nevertheless, surgery is still a valid treatmet because patiets would eed to have oly a oe-off procedure (albeit with eed for stimulator adjustmet ad replacemet) rather tha regular admiistratio of a expesive drug. Whether techical aspects of the procedure, such as electrode locatio withi the target site, are factors that could be improved are also importat to cosider. 24,25 Substatially more patiets i the surgery group had serious adverse evets tha did patiets i the medical group, cofirmig that deep brai stimulatio surgery for Parkiso s disease is ot without risks. 26,27 Reportig of all serious adverse evets, whether surgery related, disease related, or drug related, was madatory i both the surgical ad medical groups. Because a 6-moth postoperatio form that icluded serious adverse evets was completed oly i the surgical group, there could have bee differetial reportig of serious adverse evets Vol 9 Jue 2010

9 urelated to surgery, despite efforts through a case-ote review to collect these data i both groups. However, similar surgery-related serious adverse evets were see i the two other trials. 16,17 Furthermore, recetly raised cocers about the suicide rate after surgery were ot cofirmed i our study (oly oe patiet attempted suicide after surgery), ad oly oe patiet died as a result of the procedure. A limitatio of the study is that adverse evets that were ot serious eough to cause or prolog a patiet s stay i hospital were ot routiely recorded. However, adverse evets are difficult to record accurately (eg, there were three times more adverse evets i oe of two comparable trials tha i the other) 16,17 ad their combied effects should be reflected i the participats perceptio of their quality of life. Prelimiary aalysis of the europsychological outcomes, to be reported i detail elsewhere, did ot suggest ay major adverse effect of surgery other tha o verbal fluecy ad vocabulary. The chages i group meas for europsychological outcomes represet small decreases i idividual scores that are ot usually associated with cliically meaigful effects o ay activities of daily livig. 30 Subcliical decreases i verbal fluecy after deep brai stimulatio or lesioal surgery for Parkiso s disease have bee reported, ad are uderstood to be caused by disruptio to projectios from the basal gaglia to the prefrotal cortex, which are ivolved i laguage ad executive skills. For example, after deep brai stimulatio of the subthalamic ucleus, substatial associatios have bee reported betwee activatio of areas icludig the dorsolateral prefrotal cortex ad Broca s area, as measured with fluorie-18-labelled-fluorodeoxyglucose-pet, ad performace o verbal fluecy tasks. 33 These chages are ot associated with patiet age, disease duratio, or dose of dopamiomimetic drugs after surgery; 34 however, a frequecy-depedet reciprocal modulatio of verbal fluecy ad motor fuctios i deep brai stimulatio of the subthalamic ucleus has bee reported. 34 Discussios with potetial cadidates for surgery should iclude the potetial risks ad beefits of surgery. Deep brai stimulatio is a costly procedure ad therefore health ecoomic issues eed to be take ito accout. However, the amout of drug required i the surgery group was about oe third lower tha the amout required by those i the medical group. Thus, the cost of surgery will be partly offset by the reductio i the amout of drug required by patiets who have had surgery. I particular, if apomorphie or cotiuous itestial ifusios of levodopa, with high recurret costs, are the alterative drug treatmet optios, the costeffectiveess equatio might favour surgery (a full ecoomic aalysis of PD SURG will be reported elsewhere). Thus, it is importat to idetify patiets who are or are ot likely to beefit from surgery whe the risks ad costs are take ito accout. Subgroup aalyses are ureliable, with a high likelihood of chace effects beig observed. 35 The protocol-specified subgroup aalyses did ot provide clear evidece that the beefit of surgery differed i differet types of patiet, although, give the isesitivity of tests for iteractio, 36 the possible greater beefit i patiets with more advaced disease, as measured by Hoeh ad Yahr stage (p=0 2), is worthy of further ivestigatio. Some limitatios i the desig of PD SURG should be ackowledged, especially i relatio to a potetial placebo effect. Ideally, patiets ad assessors would have bee masked to treatmet allocatio. However, sham surgery o patiets i the medical group (ie, to isert electrodes ad stimulators but ot switch them o) would ot have bee practical (eg, icreased theatre time ad cost). Furthermore, attempts at maskig are likely to be ieffective because, i may cases, patiets will be able to tell if their stimulator is switched o. Thus, patiets perceptio of their quality of life could have bee iflueced by their kowledge of the treatmet they received. Use of idepedet masked assessors was beyod the resources available for this trial ad, because the UPDRS was a secodary edpoit, was ot cosidered essetial. The use of the isesitive DRS-II as a measure of cogitio was also a potetial drawback, but this was deemed to be adequate to provide a overall assessmet of the whole trial populatio, with a more detailed europsychological evaluatio beig doe i a subset of patiets. The absece of a stadard defiitio of the o state i the protocol might also have bee a limitatio of the study, although all cetres had experieced eurological teams familiar with doig the UPDRS ad the comparative ature of the trial meat that ay crosscetre differeces would apply to both groups ad would ot itroduce bias. Follow-up of PD SURG will cotiue for several years ad future papers will report o the loger term outcome of immediate surgery versus deferred surgery; subgroup ad progostic factor aalyses; europsychological effects of surgery; the effect of surgery o carers; further details o the procedure ad loger term outcomes; ad health ecoomic evaluatio. is likely to remai a importat treatmet optio for patiets with Parkiso s disease, especially if the way i which deep brai stimulatio exerts its therapeutic effects is better uderstood, if its use ca be optimised by better electrode placemet ad settigs, ad if patiets who would have the greatest beefit ca be better idetified. Cotributors AW (chief ivestigator), SG, TV, CJ, NQ, RM, JD, ad KW (co-chief ivestigator) desiged the trial. AW, NI, CR, JD, SP, ad KW ra the trial ad AW, SG, TV, NQ, ad RM recruited patiets. AW, SG, TV, CJ, NQ, RM, NI, CR, JD, SP, ad KW iterpreted the data ad wrote the paper. NI ad SP aalysed the data. RBS desiged ad ra the europsychological substudy. The authors assume resposibility for the accuracy ad completeess of the data ad for the overall cotet ad itegrity of the paper. Data moitorig committee: P Sadercock (chair), C Baiget, C Cousell, A Medelow, O Rascol. Steerig committee: D Chadwick (chair), M Baker, K McPherso, J Pickard, C Polkey, M Sculpher, C Warlow. Vol 9 Jue

10 Trial maagemet cetres Uiversity of Birmigham (icludig the trial maagemet cetre at the Birmigham Cliical Trials Uit), Birmigham T Boodell, C E Clarke, J Daiels, R Gray, N Hilke, M Hyde, N Ives, G Madde, M Nixo, S Parsos, S Patel, C Rick, C Tomliso, K Wheatley, A Williams; Uiversity of Oxford, Oxford R Fitzpatrick, A Gray, C Jekiso (quality of life), E McItosh (health ecoomics), R Scott (europsychology). Participatig cetres ad PD SURG collaborative group members Addebrookes Hospital, Cambridge P Buttery, C Watts (pricipal ivestigator), H Watso (umber of patiets 12); Frechay Hospital, Bristol S Gill (pricipal ivestigator), S Kha, N Heywood, L Mooey, N Patel, P Plaha (64); Hope Hospital, Salford P Cotto, J Dick (pricipal ivestigator), M Kellett, P Richardso, M Silverdale (7); Joh Radcliff e Ifirmary, Oxford T Aziz (pricipal ivestigator), C Fletcher, R Gregory (38); Kig s College Hospital, Lodo K Ashka, C Clough, N Hulse, M Samuel, R Selway (pricipal ivestigator) (26); Natioal Hospital for Neurology ad Neurosurgery, Lodo E Borrell, J Cadalario, T Foltyie, M Hariz, A Lees, P Limousi (pricipal ivestigator), N Qui, L Zrizo (38); Newcastle Geeral Hospital, Newcastle U Brechay, D Bur (pricipal ivestigator), A Jekis (42); Niewells Hospital, Dudee S Eljamel (pricipal ivestigator), R Swigler, C Youg (4); Quee Elizabeth Hospital, Birmigham S Holloway, J Kausar, J Martey, R Mitchell (pricipal ivestigator), H Pall, A Williams (65); Quee s Medical Cetre, Nottigham K Aderto, S Basu (pricipal ivestigator), G Sawle, J Wright (2); Royal Hallamshire Hospital, Sheffield A Fraks, R Gruewald, C Keeley, L Nelso, M Radatz (pricipal ivestigator), J Rowe (19); Souther Geeral Hospital, Glasgow L Du (pricipal ivestigator), D Grossett, T Murphy (9); Walto Cetre for Neurology ad Neurosurgery, Liverpool A Duffy, P Eldridge, N Fletcher, T R K Varma (pricipal ivestigator) (40). Coflicts of iterest TV received travel grats from Medtroic. NQ received reimbursemet fees from Medtroic for time spet collectig ad aalysig data as a member of the ad hoc adverse-evet committee for aother multicetre study o deep brai stimulatio i Parkiso s disease. The other authors have o coflicts of iterest. Ackowledgmets PD SURG was supported by fudig from the UK Medical Research Coucil ad Parkiso s UK. The Uiversity of Birmigham Cliical Trials Uit receives support from the UK Departmet of Health. The trial also received fudig from the UK Departmet of Health to cover some of the costs of surgery. We thak all the ivestigators who cotributed to the trial ad the patiets who agreed to eter the study. The PDQ-39 questioaire was developed by Crispi Jekiso, Ray Fitzpatrick, ad Viv Peto i 1993, who have asserted their moral rights i it, ad the copyright, which is owed by Isis Iovatio Limited. The questioaire was first published i 1995 i the joural Quality of Life Research. No part of this questioaire may be reproduced without the prior writte coset of Isis Iovatio Limited. Refereces 1 Williams D, Tijsse M, va Brugge G, et al. Dopamiedepedet chages i the fuctioal coectivity betwee basal gaglia ad cerebral cortex i humas. Brai 2002; 125: Poewe W. Treatmets for Parkiso disease past achievemets ad curret cliical eeds. Neurology 2009; 72 (7 Suppl): S Mitchell IJ, Clarke CE, Boyce S, et al. Neural mechaisms uderlyig parkisoia symptoms based upo regioal uptake of 2-deoxyglucose i mokeys exposed to 1-methyl-4-pheyl-1,2,3,6- tetrahydropyridie. Neurosciece 1989; 32: Bergma H, Wichma T, DeLog MR. Reversal of experimetal parkisoism by lesios of the subthalamic ucleus. Sciece 1990; 249: Aziz TZ, Peggs D, Sambrook MA, Crossma AR. Lesio of the subthalamic ucleus for the alleviatio of 1-methyl-4-pheyl-1,2,3,6- tetrahydropyridie (MPTP)-iduced parkisoism i the primate. Mov Disord 1991; 6: Limousi P, Krack P, Pollak P, et al. Electrical stimulatio of the subthalamic ucleus i advaced Parkiso s disease. N Egl J Med 1998; 339: Stowe RL, Wheatley K, Clarke CE, et al. for Parkiso s disease: lack of reliable cliical trial evidece. J Neurol Neurosurg Psychiatry 2003; 74: Gibb WRG, Lees AJ. The relevace of the Lewy body to the pathogeesis of idiopathic Parkiso s disease. J Neurol Neurosurg Psychiatry 1988; 51: Mattis S. Demetia ratig scale: professioal maual. Odessa, FL, USA: Psychological Assessmet Resources, Hoeh MM, Yahr MD. Parkisoism: oset, progressio ad mortality. Neurology 1967; 17: Daiels J, Wheatley K, Gray R. Pairwise radomisatio to balace withi cetres without possible forekowledge of allocatio. Cotrol Cli Trials 2003; 24 (suppl 3S): S (abstract P23). 12 Jekiso C, Fitzpatrick R, Peto V, Greehall R, Hyma N. The Parkiso s disease questioaire (PDQ-39): developmet ad validatio of a Parkiso s disease summary idex score. Age Ageig 1997; 26: Movemet Disorder Society Task Force o Ratig Scales for Parkiso s Disease. The uified Parkiso s disease ratig scale (UPDRS): status ad recommedatios. Mov Disord 2003; 18: Scott RB, Farmer E, Smito A, Tovey C, Clarke M, Carpeter K. Methodology of europsychological research i multicetre radomized cliical trials: a model derived from the Iteratioal Subarachoid Aeurysm Trial. Cli Trials 2004; 1: Jekiso C, Hefferma C, Doll H, Fitzpatrick R. The Parkiso s disease questioaire (PDQ-39): evidece for a method of imputig missig data. Age Ageig 2006; 35: Deuschl G, Schade-Brittiger C, Krack P, et al. A radomized trial of deep-brai stimulatio for Parkiso s disease. N Egl J Med 2006; 355: Weaver FM, Follett K, Ster M, et al. Bilateral deep brai stimulatio vs best medical for patiets with advaced Parkiso s disease: a radomized cotrolled trial. JAMA 2009; 301: Goetz CG, Wuu J, McDermott MP, et al. Placebo respose i Parkiso s disease: comparisos amog 11 trials coverig medical ad surgical itervetios. Mov Disord 2008; 23: Schüpbach WM, Maltête D, Houeto JL, et al. Neurosurgery at a earlier stage of Parkiso disease: a radomized, cotrolled trial. Neurology 2007; 68: Peto V, Jekiso C, Fitzpatrick R. Determiig miimally importat differeces for the PDQ-39 Parkiso s disease questioaire. Age Ageig 2001; 30: Schrag A, Sampaio C, Cousell N, Poewe W. Miimal cliically importat chage o the uified Parkiso s disease ratig scale. Mov Disord 2006; 21: Kleier-Fisma G, Herzog J, Fisma DN, et al. Subthalamic ucleus deep brai stimulatio: summary ad meta-aalysis of outcomes. Mov Disord 2006; 21: S Weaver F, Follett K, Hur K, Ippolito D, Ster M. Deep brai stimulatio i Parkiso disease: a metaaalysis of patiet outcomes. J Neurosurg 2005; 103: Laotte MM, Rizzoe M, Bergamasco B, Faccai G, Melcare A, Lopiao L. Deep brai stimulatio of the subthalamic ucleus: aatomical, europhysiological, ad outcome correlatios with the effects of stimulatio. J Neurol Neurosurg Psychiatry 2002; 72: Starr PA, Christie CW, Theodosopoulos PV, et al. Implatatio of deep brai stimulators ito the subthalamic ucleus: techical approach ad magetic resoace imagig-verified lead locatios. J Neurosurg 2002; 97: Hariz MI, Rehcroa S, Qui NP, Speelma JD, Wesig C, Multicetre Advaced Parkiso s Disease Deep Brai Stimulatio Group. Multiceter study o deep brai stimulatio i Parkiso s disease: a idepedet assessmet of reported adverse evets at 4 years. Mov Disord 2008; 23: Appleby BS, Dugga PS, Regeberg A, Rabis PV. Psychiatric ad europsychiatric adverse evets associated with deep brai stimulatio: a meta-aalysis of te years experiece. Mov Disord 2007; 22: Burkhard PR, Vigerhoets FJ, Berey A, Bogousslavsky J, Villemure JG, Ghika J. Suicide after successful deep brai stimulatio for movemet disorders. Neurology 2004; 63: Vol 9 Jue 2010