practice parameter: treatment of parkinson disease with ... · cluded sufficient details or used a...

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Special Article

Practice Parameter Treatment ofParkinson disease with motor

fluctuations and dyskinesia(an evidence-based review)

Report of the Quality Standards Subcommittee of theAmerican Academy of Neurology

R Pahwa MD SA Factor DO KE Lyons PhD WG Ondo MD G Gronseth MDH Bronte-Stewart MD M Hallett MD J Miyasaki MD J Stevens MD and WJ Weiner MD

AbstractmdashObjective To make evidence-based treatment recommendations for the medical and surgical treatment ofpatients with Parkinson disease (PD) with levodopa-induced motor fluctuations and dyskinesia To that end five ques-tions were addressed 1 Which medications reduce off time 2 What is the relative efficacy of medications in reducing offtime 3 Which medications reduce dyskinesia 4 Does deep brain stimulation (DBS) of the subthalamic nucleus (STN)globus pallidus interna (GPi) or ventral intermediate (VIM) nucleus of the thalamus reduce off time dyskinesia andantiparkinsonian medication usage and improve motor function 5 Which factors predict improvement after DBSMethods A 10-member committee including movement disorder specialists and general neurologists evaluated the avail-able evidence based on a structured literature review including MEDLINE EMBASE and Ovid databases from 1965through June 2004 Results Conclusions and Recommendations 1 Entacapone and rasagiline should be offered to reduceoff time (Level A) Pergolide pramipexole ropinirole and tolcapone should be considered to reduce off time (Level B)Apomorphine cabergoline and selegiline may be considered to reduce off time (Level C) 2 The available evidence doesnot establish superiority of one medicine over another in reducing off time (Level B) Sustained release carbidopalevodopaand bromocriptine may be disregarded to reduce off time (Level C) 3 Amantadine may be considered to reduce dyskinesia(Level C) 4 Deep brain stimulation of the STN may be considered to improve motor function and reduce off timedyskinesia and medication usage (Level C) There is insufficient evidence to support or refute the efficacy of DBS of theGPi or VIM nucleus of the thalamus in reducing off time dyskinesia or medication usage or to improve motor function 5Preoperative response to levodopa predicts better outcome after DBS of the STN (Level B)

NEUROLOGY 200666983ndash995

Statement of purpose The Quality StandardsSubcommittee (QSS) develops scientifically soundclinically relevant practice parameters to aid in the

practice of neurology This article addresses medicaland surgical treatments for the management of pa-tients with Parkinson disease (PD) with levodopa-

Editorial see page 966See also pages 968 976 and 996

This article was previously published in electronic format as an Expedited E-Pub at wwwneurologyorgFrom the University of Kansas Medical Center (RP KEL GG) Kansas City Emory University School of Medicine (SAF) Atlanta GA Baylor Collegeof Medicine (WGO) Houston TX Stanford University Hospital (HB-S) San Francisco CA National Institutes of Health (MH) Bethesda MD TorontoWestern Hospital (JM) Canada Fort Wayne Neurological Center (JS) Fort Wayne IN and University of Maryland School of Medicine (WJW)BaltimoreQuality Standards Subcommittee Members are listed in appendix E-4 on the Neurology Web site at wwwneurologyorgApproved by QSS July 30 2005 Practice Committee December 15 2005 Board of Directors February 23 2006Endorsed by the National Parkinson Foundation and the Parkinsonrsquos Disease FoundationDisclosures are provided after the textReceived August 16 2005 Accepted in final form February 16 2006Address correspondence and reprint requests to the American Academy of Neurology 1080 Montreal Avenue St Paul MN 55116

Copyright copy 2006 by AAN Enterprises Inc 983

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induced motor fluctuations and dyskinesia Theserecommendations address the needs of specialistsand nonspecialists caring for patients with PD

Background PD is a progressive neurodegenera-tive disorder with cardinal motor features of tremorbradykinesia and rigidity Although initially effec-tive dopaminergic therapies are eventually compli-cated by motor fluctuations including off time(periods of return of PD symptoms when medicationeffect wears off) and dyskinesia (drug-induced invol-untary movements including chorea and dystonia) inmost patients These motor complications can impairquality of life and cause significant disability1 Riskfactors for motor complications include younger ageat onset of PD disease severity higher levodopa dos-age and longer disease duration2-4 These problemsare often addressed with levodopa adjustments andthe addition of adjunctive medications The first partof this article addresses the effectiveness of adjunc-tive medications in this situation

Motor fluctuations and dyskinesia can be resis-tant to medical therapy This along with advancesin the understanding of basal ganglia circuitry sur-gical techniques neuroimaging and intraoperativemicroelectrode recording has led to a resurgence insurgical approaches for medically refractory disabili-ties Initially ablative procedures like thalamotomyand pallidotomy were used to treat PD symptomsHowever due to concerns about morbidity5 espe-cially with bilateral procedures deep brain stimula-tion (DBS) has become the most commonlyperformed surgery for PD in North America

DBS is a stereotactic surgical procedure that usesan implanted electrode connected to an implantablepulse generator (IPG) that delivers electrical currentto a targeted nucleus in the brain6 The three pri-mary targets for DBS for PD are the ventral inter-mediate (VIM) nucleus of the thalamus globuspallidus interna (GPi) and the subthalamic nucleus(STN) The IPG is programmed externally from sev-eral days to 4 to 6 weeks after implantation Adjust-able stimulation parameters include amplitudefrequency and pulse width The device is generallyleft on but patients can turn the device off whendesired

Although the criteria are evolving currently pa-tients with PD who are considered candidates forDBS include levodopa-responsive non-dementedand neuropsychiatrically intact patients who haveintractable motor fluctuations dyskinesia or tremor

This practice parameter addresses five questions

1 Which medications reduce off time2 What is the relative efficacy of medications in re-

ducing off time3 Which medications reduce dyskinesia

4 Does DBS of the STN GPi or VIM reduce offtime dyskinesia and antiparkinsonian medica-tion usage and improve motor function

5 Which factors predict improvement after DBS

The conclusions and recommendations addressingthese questions are based only on the evidence avail-able in the literature and are limited by the qualityof the studies reviewed An inherent problem withthis process is that treatments may receive a recom-mendation lower than what may be expected basedon clinical experience This can be due to many fac-tors including the possibility that older treatmentsmay not have been studied as rigorously as newertherapies published manuscripts may not have in-cluded sufficient details or used a study design thatwould eliminate potential bias or a particular issuerelated to a specific treatment may not have beenaddressed in the literature

Description of the analytical process The QSSof the AAN identified an expert panel of experiencedmovement disorder specialists and general neurolo-gists with methodologic expertise For the literaturereview a research librarian searched MEDLINEEMBASE and Ovid databases This was supple-mented by a secondary search using the bibliographyof retrieved articles and knowledge from the expertpanel Panel members reviewed abstracts and titlesfor relevance Then at least two panel members re-viewed articles meeting inclusion criteria If a panel-ist was an author of one of the articles at least twoother panelists reviewed that article Disagreementswere arbitrated by an additional panel member Therisk of bias was determined using the classificationof evidence for each study (appendix E-1 the Neurol-ogy Web site at wwwneurologyorg) The strength ofthe practice recommendations was linked directly tothe level of evidence (appendix E-2) Conflicts of in-terest were disclosed Support was provided by theAAN Writing meetings were funded by the MichaelJ Fox Foundation Panelists were not compensated

Medical treatment For questions 1 2 and 3 theauthors used the following search terms Parkinsondisease advanced Parkinson disease dyskinesiamotor fluctuations double masked trials random-ized trials placebo controlled trials clinical trialsmedical treatment human studies adenosine A2Aantagonists amantadine apomorphine bromocrip-tine cabergoline controlled release carbidopalevo-dopa entacapone pergolide pramipexole rasagilineropinirole selegiline tolcapone clozapine rotigotine(search restricted to English language and medica-tions available in the United States or those havingan approvable letter from the Food and Drug Admin-istration) The initial search included articles from1965 to June 2004 and a supplemental search wasperformed in 2005 to include the latest clinical trials

The authors considered randomized masked trialsthat included at least 20 patients with motor fluctu-ations or dyskinesia followed for greater than 3

Additional material related to this article can be found on the NeurologyWeb site Go to wwwneurologyorg and scroll down the Table of Con-tents for the April 11 issue to find the title link for this article

984 NEUROLOGY 66 April (1 of 2) 2006

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months If no articles met the 3-month criterion for aspecific drug the authors included articles withshorter durations of therapy and this led to a drop inclass level

The initial search identified 730 articles of which670 were excluded during the abstract review Anadditional 34 articles were excluded during the arti-cle review leaving 26 articles for consideration Ofthe 704 articles eliminated 172 were not related tothe drugs examined but instead looked at alterna-tive agents alternative modes of administrationsuch as infusions and a variety of surgical proce-dures A total of 151 of the articles were reviews 99were studies of early PD or non-fluctuators 75 wereopen label studies 72 were about mechanisms ofaction pharmacokinetics or animal studies 69 eval-uated other uses of the drugs 30 had fewer than 20subjects 17 were primarily about adverse effects 11had a study duration less than 3 months and 8 werenot peer reviewed The supplemental search identi-fied three additional articles From each article theauthors abstracted the following methodologic char-acteristics trial design method of allocation conceal-ment mechanism of masking number of enrolleescomparative baseline characteristics of subjectsnumber of completers trial duration measure ofldquooffrdquo time or ldquoonrdquo time and dyskinesia magnitude ofresponse adverse events and levodopa dose change

Surgical treatment For questions 4 and 5 theauthors used the following search terms deep brainstimulation AND Parkinson disease DBS AND Par-kinson disease subthalamic stimulation AND Par-kinson disease pallidal stimulation AND Parkinsondisease and thalamic stimulation AND Parkinsondisease for all articles from 1965 through June 2004All non-English language articles review articlesand animal studies were excluded A total of 478articles resulted The authors included studies ofDBS for PD reporting postsurgical outcome in termsof motor improvement or reduction of motor compli-cations that had a sample size of at least 20 subjectsand a follow-up duration of at least 6 months post-DBS Twenty articles met all inclusion criteria 13for subthalamic stimulation 1 for subthalamic andpallidal stimulation 2 for pallidal stimulation and 4for thalamic stimulation A total of 458 articles wereexcluded for the following reasons 200 had less than20 patients in the study 152 were not motor functionoutcome studies of DBS in PD 41 were review arti-cles 26 were comments 18 had less than 6 monthsfollow-up 9 were not from peer-reviewed sources 4were animal studies 6 were redundant reports ofincluded data 1 did not differentiate results of PD vsessential tremor and 1 did not use standard outcomemeasures for PD The authors abstracted the follow-ing characteristics from the 20 articles meeting in-clusion criteria study design patient selectioncriteria follow-up duration number age sex anddisease duration of subjects baseline Unified PDRating Scale (UPDRS) activities of daily living (ADL)and motor scores in the medication on and medica-

tion off conditions at baseline and during follow-upevaluations in the stimulation on condition specificmeasures of dyskinesia and motor fluctuations ad-verse events and medication reduction

Brief summaries of the medical studies examiningoff time and the surgical studies can be found intables 1 and 2 and complete evidence tables describ-ing the methodologic details of the medical (tableE-1) and surgical (table E-2) studies are available onthe Neurology Web site

Results Question 1 Which medications reduce offtime Dopamine agonists Pergolide One ClassI 24-week multicenter placebo controlled parallelgroup double masked study compared 189 in theactive group (mean dose 29 mgday) and 187 in thecontrol group7 More than 80 of the patients com-pleted the study (84 on pergolide and 82 on pla-cebo) The active group had a 32 decrease (18hours) in off time compared to a 4 decrease (02hours) in the control group (p 0001) There werealso differences in level of improvement in UPDRSADL and motor scores in the on state in favor ofpergolide (p 0001) However 62 of the activegroup had a new onset or worsening of dyskinesiacompared to only 25 of the placebo group Levodopadose decreased 247 in the pergolide group com-pared to 49 in the placebo group (p 0001)

Pramipexole One Class I study8 and one Class IIstudy9 compared pramipexole to placebo The Class Imulticenter double masked parallel group studyrandomized 360 patients (181 active 179 control) for32 weeks8 Eighty-three percent of the active groupand 78 of the control group completed the studyOff time decreased by 31 in the active group (meandose 34 mgday) compared to 7 in the placebogroup (p 00006) UPDRS ADL in the on and offstates and motor examination in the on state allimproved with pramipexole vs placebo (p 001)Levodopa dose was reduced in the active group (27)compared to the placebo group (5) (p 00001)There was a significant difference with regard todyskinesia in the active group (61) compared to theplacebo group (40)

In the Class II multicenter double masked ran-domized parallel group study 79 patients receivedpramipexole (mean dose 34 mgday) and 83 receivedplacebo for 40 weeks9 There were 80 completers inthe active group and 60 in the control group Theactive group had a 15 (25 hour) decrease in offtime vs a 3 reduction in the control group (p 0007) In the on state the active group also experi-enced improvements in the UPDRS ADL and motorscores (p 00006) Levodopa reduction was not re-ported Dyskinesia was reported in 40 ofpramipexole patients and 27 of controls

Ropinirole Two Class II studies compared theeffect of ropinirole vs placebo on off time1011 Thefirst was a multicenter randomized parallel groupdouble masked placebo controlled 12-week studywith 23 patients randomized to each group10 The

April (1 of 2) 2006 NEUROLOGY 66 985

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ropinirole group had 87 completers and the controlgroup had 65 There was a greater reduction in offtime per day (from 47 to 24) in the active group(mean dose 68 mgday) compared to controls (44 to40) (p 008) Clinical Global Impression (CGI)favored ropinirole (p 0004) Levodopa dose changeand dyskinesia were not reported

The second multicenter randomized doublemasked placebo controlled study randomized 95subjects to ropinirole (maximum allowed dose 24mgday) and 54 to placebo for 26 weeks11 In theropinirole group 78 were completers and in theplacebo group 65 were completers Ropiniroledecreased off time by 117 compared to 51 withplacebo (p 004) The ropinirole group had a 31

decrease in levodopa dose compared to 6 in theplacebo group (p 0001) Dyskinesia occurred in337 taking ropinirole and 13 taking placebo(p 0006)

Apomorphine A single Class II study evaluatedsubcutaneously injected apomorphine (mean dose 54mginjection) in a double masked parallel group ran-domized study of 29 patients for 4 weeks (20 active 9placebo)12 There were over 80 completers (85 ac-tive 88 placebo) The active group experienced a 34decrease (2 hours) in off time compared to 0 in theplacebo group (p 002) Dyskinesia occurred in 35of the active group compared to 11 of the controlsUPDRS motor score in the off state improved more inthe apomorphine group (p 0001)

Table 1 Summary of medication studies examining off time changes

Ref Drug Class N Agedagger yDisease

durationdagger y

Studyduration

wk

Decreaseoff timeactive

Decreaseoff timeplacebo

Placebo-controlled studies

7 Pergolide I 189187 625 114 24 32 (18 h)Dagger 4 (02 h)

8 Pramipexole I 181179 633 9 32 31Dagger 7

9 Pramipexole II 7983 629 6sect 40 15 (25 h)Dagger 3

10 Ropinirole II 2323 62 8 12 23Dagger 4

11 Ropinirole II 9554 NR 86 26 117Dagger 5

12 Apomorphine II 209 66 92 4 34 (20 h)Daggersect 0

9 Bromocriptine II 8483 615 72sect 40 8 3

13 Cabergoline III 1918 608 136 24 40 (20 h)Dagger 18 (07 h)

14 Cabergoline III 1710 675para 123 24 59 (33 h)Dagger NS

15 Selegiline III 5046 614 95 6 NR NR

16 Orally disintegrating selegiline II 9446 66 63 12 32 (22 h)Dagger 9 (06 h)

17 Rasagiline (05 mg) I 164159 626 93 26 23 (14 h)Dagger 15 (09 h)


18 Rasagiline I 231229 639 87 18 21 (12 h)Dagger 7 (04 h)

19 Tolcapone (100 mg tid) II 6966 63 11 12 32 (23 h) 20 (14 h)

19 Tolcapone (200 mg tid) II 6766 64 11 12 48 (32 h)Dagger 20 (14 h)

20 Tolcapone (100 mg tid) II 6058 62 9 12 315Dagger 11

20 Tolcapone (200 mg tid) II 5958 63 10 12 262 11

21 Entacapone I 103102 639 108 24 NR NR

18 Entacapone I 227229 63 92 18 21 (12 h)Dagger 7 (04 h)

22 Entacapone II 197104 607 83 24 258 (16 h)Dagger 134 (09 h)


24 Entacapone II 9963 635 NR 12 09 h 04 h

Crossover studies (carbidopalevodopa CR vs carbidopalevodopa IR)

26 Carbidopalevodopa CRIR III 20 611 83 16 NS


28 Carbidopalevodopa CRIR III 28 NR NR 16 NS


Comparator studies (not placebo-controlled)

30 Cabergoline [c]bromocriptine [b] II 2222 71 10 36 50 [c] 313 [b]

31 Ropinirole [r]bromocriptine [b] II 8851 64 9 24 177 [r] 48 [b]

32 Tolcapone [t]entacapone [e] II 7575 NR NR 3 NR NR

33 Tolcapone [t]pergolide [p] III 101102 65 8 12 19 [t] 20 [p]

Activeplacebodagger Data for active group placebo not significantly different from active groupDagger p005sect Median valuespara Significantly older than placebo

NR not reported NS not significant CR controlled release IR immediate release


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Table 2 Summary of deep brain stimulation studies

RefTherClass

ProgClass Follow-up Site N

Agey

PDduration

BaselineUPDRSmotor

Follow-upUPDRSmotordagger

Dyskinesiaoff time

improvementMeds

reduction

36 III IV 6 mo B-STN 96 59 NA 56 52 Rush dyskinesia 58 Diary dyskinesiareduced 23 to 7 off time decreased49 to 19

37

37 III IV 1 y B-STN 26 59 15 54 64 (1 y) UPDRS (item 32) dyskinesia 86 UPDRS(item 39) off time 83

20

38 III IV 1 y B-STN 33 58 12 40 (1 y) 32 (1 y) Diary dyskinesia 18 to 4 (1 y) 19to 11 (2 y)

54 (1 y)

2 y 19 37 (2 y) 28 (2 y) Off time 44 to 20 (1 y) 43 to 17 (2 y) 57 (2 y)

39 III IV 6 mo B-STN 20 61 12 59 49 Dyskinesia UPDRS (item 32) 50dyskinesia UPDRS (item 33) 100

33

42 IV II 6 mo B-STN 41 56 16 71 65 Duration fluctuations 87 durationdyskinesia 69 UPDRS IV 78

68

45 IV II 2 y B-STN 25 57 13 55 48 (1 y) Dyskinesia Rating Scale 48 (1 y)50 (25 y)

38 (1 y)

41 (25 y) UPDRS (33) 83 (1 y) 82 (25 y)UDPRS (32) 58 (1 y) 80 (25 y)

36 (25 y)

40 IV IV 1 y B-STN 22 57 15 51 (1 y) 63 (1 y) Dyskinesia significantly reduced 32 (1 2 y)

2 y 9 51 (2 y) 48 (2 y) Data not shown in manuscript

41 IV IV 6 mo B-STN 38 56 13 43 44 (6 mo) Off time reduced 35 (10ndash60) 53

1 y 48 (1 y) Dyskinesia 72 (6 mo 1 y)

43 IV IV 6 mo B-STN 23 58 NA NA 53 (6 mo) Dyskinesia 77 (6 mo) 60 (1 y) 56 (6 mo)

1 y 14 61 (1 y) Off time 71 53 (1 y)

44 IV IV 2 y B-STN 48 60 15 5770 51 (6 mo) UPDRS (32) 77 (6 mo) 83 (1 y)73 (2 y)

49 (6 mo)

57 (1 y) UPDRS (33) 92 (6 mo1 y 2 y) 42 (1 y)

57 (2 y) 68 (2 y)

46 IV IV 5 y B-STN 42 55 15 7430 66 (1 y) UPDRS (32) Dyskinesia 71 (1 3 5 y) 59 (1 y)

59 (3 y) UPDRS (33) 63 (1 y) 68 (3 y)50 (5 y)

63 (3 y)

54 (5 y) 63 (5 y)

47 IV IV 1 y B-STN 25 57 14 5940 50 UPDRS (32) dyskinesia 80 (1 y)UPDRS (33) dyskinesia 86 (1 y)UPDRS (39) off duration 95 (1 y)

66 (1 y)

48 IV IV 30 mo B-STN 24 58 14 65 38 UPDRS IV (item 39) 16 dyskinesia69 (1 y) 71 (30 mo) fluctuations 52(1 y) 50 (30 mo)

39 (1 y)30 (30 mo)

49 IV IV 4 y B-STN 20 61 NA 56 43 NA 47 (4 y)

36 III IV 6 mo B-GPi 36 56 NA 53 33 Rush dyskinesia 67 3 more

Diary dyskinesia reduced 35 to 12off time reduced 37 to 24

51 IV IV 33 mo U-GPi 26 56 13 60 -8 Dyskinesia 28 (UPDRS IVA) off time35 worsening (UPDRS IVB)

53 more

50 IV IV 6 mo GPi 30 58 8 32 49 (6 mo) UPDRS (32ndash35) dyskinesia NA

1 y U-10 (total UPDRS) 46 (1 y) 93 (6 mo)

B-20 (total UPDRS)

52 IV IV 6 mo TS 80 NA NA NA NA NA 49 (3 mo)

15 (6 mo)

53 IV IV 1 y U-TS 24 65 NA NA NA NA NA

54 IV IV 21 mo U-TS 18 66 10 NA 29 NA NA

55 IV IV 1 y TS 73 62 10 NA 31 NA None

U-56

B-16

Improvement baseline meds OFF vs meds ONdagger Improvement follow-up meds OFFStim ON vs baseline meds OFF

Ther therapeutic Prog prognostic PD Parkinson disease UPDRS Unified PD Rating Scale STN subthalamic nucleus B-STN bilateralSTN Gpi globus pallidus interna B-GPi bilateral GPi U-GPi unilateral GPI NA not available TS thalamus U-TS unilateral TS


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Bromocriptine In a single Class II multicenterrandomized double masked study bromocriptinewas compared to pramipexole and placebo for 40weeks9 Eighty-four patients received bromocriptine(mean dose 226 mgday) and 83 received placeboEighty percent of the bromocriptine patients com-pleted compared to 60 of the placebo group Therewas an 8 decrease in off time for bromocriptinecompared to 3 in placebo which was not different(p 02) Maximum improvement occurred at 8weeks Bromocriptine therapy led to an improvementin the primary end points UPDRS ADL and motorscores compared to placebo (p 002) Change inlevodopa dose was not reported Dyskinesia occurredin 45 of bromocriptine patients and 27 ofcontrols

Cabergoline Two Class III studies evaluatedwhether cabergoline can reduce off time without asignificant increase in dyskinesia1314 In a Class IIIsingle center 24-week placebo controlled study of 37patients (19 active 18 placebo) the active group(cabergoline mean dose 54 mgday) had a 40 de-crease in off time (2 hoursday) compared to 18 (07hoursday) for the placebo group (p 005)13 How-ever there were confounding differences at baselinethe active group had an off time duration of 5 hourscompared to only 4 hours for the placebo groupFewer than 80 of the patients completed the study(58 active 39 placebo) and there was no informa-tion provided on allocation concealment Levodopadose decreased 8 in the cabergoline group and 5in the placebo group Neither group had worsening ofdyskinesia CGI was improved in the cabergolinegroup (p 005)

A Class III single center 24-week doublemasked parallel group study compared 17 patients(mean age 675 years) on cabergoline (mean dose 49mgday) to 10 patients (mean age 579 years) on pla-cebo14 No information on allocation concealment wasprovided and there were less than 80 completers(76 active 70 placebo) Neither group had achange in dyskinesia The active group had a 30(27 hours) increase in on time and a 59 decrease(33 hours) in off time No information was providedfor the placebo group UPDRS motor scores improved(p 0006) Levodopa dose decreased by 28 withcabergoline and 10 with placebo (p 0004)

Dopamine agonists adverse effects The adverseeffects associated with dopamine agonists are similarfor all the agents In the clinical trials reviewed thefollowing side effects were reported in the accompa-nying ranges in the actively treated groups nausea18 to 36 symptomatic orthostatic hypotension 5 to48 (highest with cabergoline and pramipexole) diz-ziness 11 to 37 somnolence 10 to 35 (highestwith apomorphine) and hallucinations 10 to 19Two studies reported pedal edema cabergoline 8and apomorphine 10 Two studies reported confu-sion pramipexole 14 and cabergoline 16 Rarecases of cardiac valvular fibrosis have been reportedwith pergolide although this was not reported in the

clinical trials Screening for valvular disease is rec-ommended with pergolide use Similarly problemswith impulse control have also been recently re-ported but not in the clinical trials

MAO B inhibitors Selegiline One Class IIImulticenter double masked parallel group studyrandomized 50 patients to selegiline (mean dose 10mgday) and 46 to placebo for 6 weeks15 There weregreater than 80 completers (100 active 93 con-trols) Fifty-eight percent of the selegiline group hadimproved ldquomean hourly overall symptom controlrdquoscores compared to 26 of the placebo group (p 0002) CGI change also favored selegiline (p 0001) Dyskinesia initially worsened in 60 of theselegiline patients and 30 of the placebo patients

Orally disintegrating selegiline One Class II 12-week multicenter randomized parallel group dou-ble masked study randomized 94 patients to orallydisintegrating selegiline (mean dose 25 mgday) and46 to placebo16 Information on allocation conceal-ment was not provided Off time was reduced by 32(22 hours) in the active group vs 9 (06 hours) inthe placebo group (p 0001) Hours on were in-creased 20 (18 hours) for the active group and 5(04 hours) for the control group (p 0006) Dyski-nesia did not significantly worsen with active treat-ment and was not reported in the placebo groupThere was no report on change in levodopa dose

Rasagiline Two Class I double masked placebocontrolled parallel group studies compared rasagi-line with placebo In the Parkinsonrsquos Rasagiline Ef-ficacy amp Safety in the Treatment of OFF (PRESTO)study rasagiline 10 mgday or rasagiline 05 mgdaywas compared with placebo for 26 weeks17 Therewere 875 completers The total daily off time de-creased by 29 (18 hours) for rasagiline 1 mgdayand 23 (14 hours) for rasagiline 05 mgday whichwere both more than the decrease of 15 (09 hours)with placebo (p 00001 for 10 mgday p 002 for05 mgday) Compared to placebo global impressionUPDRS ADL off and UPDRS motor scores also im-proved significantly Significant increases in on timecorresponded to decreases in off time However forthe 10 mg group 32 of the increase in on timeincluded troublesome dyskinesia (p 0048)

In the Lasting effect in Adjunct therapy withRasagiline Given Once daily (LARGO) study18 rasa-giline 10 mgday was compared to entacapone 200mg with each dose of levodopa (up to eight per day)and placebo in a double dummy paradigm (each drugcompared to placebo not directly compared to eachother) A total of 687 patients were randomized 231to rasagiline 227 to entacapone and 229 to placeboThere were 87 completers (90 rasagiline 87 en-tacapone and 85 placebo) The total daily off timedecreased by 21 (118 hours) for rasagiline 10 mgday and 21 (12 hours) for entacapone both ofwhich were more than the decrease of 7 (04 hours)with placebo (p 00001 for both rasagiline andentacapone) Compared to placebo global impres-sion UPDRS ADL off and UPDRS motor score on


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also improved significantly Significant increases inon time corresponded to decreases in off time Therewas no change in on time with troublesome dyskine-sia and the percent of subjects with dyskinesia as anadverse effect was similar for all three groups

MAO-B inhibitor adverse effects Adverse effectswith selegiline in the reviewed study16 included nau-sea 20 symptomatic orthostatic hypotension 12hallucinations and confusion 6 each There was nomention of insomnia In the article on orally disinte-grating selegiline 6 reported dizziness and 4 re-ported hallucinations The incidence of other adverseevents was not disclosed In PRESTO17 rasagilinewas associated with weight loss in 24 to 94 vom-iting in 37 to 67 anorexia in 18 to 54 balancedifficulties in 34 to 55 and three cases of mela-noma (06) In LARGO18 the primary side effectswere postural hypotension (2) nausea (3) pe-ripheral edema (2) depression (3) dizziness (3)hallucinations (2) dyskinesia (5) and sleep disor-ders (3) but none were significantly more commonthan in controls

COMT inhibitors Tolcapone Two Class IIstudies evaluated tolcapone vs placebo1920 The firstwas a double masked randomized placebo con-trolled multicenter 12-week trial with three treat-ment groups tolcapone 100 mg TID tolcapone 200mg TID and placebo19 There were 136 active and 66placebo patients No concealment allocation informa-tion was provided Tolcapone 100 mg TID decreasedoff time 32 (23 hours) tolcapone 200 mg TID de-creased off time 48 (32 hours) and placebo de-creased off time 20 (14 hours) (p 001 for thetolcapone 200 mg TID group) At both tolcaponedoses a significant improvement in investigatorglobal score occurred as well as a significant de-crease in levodopa dose (200 mg) and number oflevodopa doses per day (decreased by approximatelyone) Dyskinesia increased in the first 30 days butwas treated effectively with reductions in levodopadose

The second Class II study was multicenter doublemasked and placebo controlled with follow-up rang-ing from 3 to 12 months20 Patients were randomizedto one of three groups tolcapone 100 mg TID (n 60) tolcapone 200 mg TID (n 59) and placebo (n 58) There were 81 completers in the active groupsand 93 in the control group Off time decreased by262 on tolcapone 200 mg TID 315 on tolcapone100 mg TID and 105 on placebo (p 001) Therewas a corresponding increase in on time by 206 inthe 200 mg TID group and 213 in the 100 mg TIDgroup Levodopa doses dropped 16 for the tolca-pone 100 mg TID group and 18 in the tolcapone200 TID group compared to 4 for the placebo groupDyskinesia developed or worsened in 37 at 100 mgTID of tolcapone 525 at 200 mg TID of tolcaponeand in 21 of the placebo group

Entacapone Two Class I1821 and three Class IIstudies22-24 evaluated entacapone vs placebo In oneClass I double masked parallel group multicenter

trial 103 patients received entacapone (200 mg witheach dose of levodopa) and 102 received placebo for24 weeks21 On time increased by 5 in the entaca-pone group Patients who had the smallest percent ofon time at baseline (55) had the largest increasein on time with entacapone Dyskinesia developed in53 of the entacapone patients vs 32 of the placebopatients (p 0002) Masking may have been com-promised due to urine discoloration by entacaponeThe other Class I study was the LARGO study18 Inthis study rasagiline 1 mgday was compared to pla-cebo and entacapone 200 mg with each dose of levo-dopa (up to eight per day) was also compared toplacebo in a double dummy paradigm The activegroups were compared to placebo not each other Atotal of 687 patients were randomized 231 to rasagi-line 227 to entacapone and 229 to placebo Therewere 87 completers (90 rasagiline 87 entaca-pone and 85 placebo) The total daily off time de-creased by 21 (12 hours) for entacapone whichwas more than the decrease of 7 (04 hours) withplacebo (p 00001) Compared to placebo globalimpression UPDRS ADL off and UPDRS motorscore on also improved significantly Significant in-creases in on time corresponded to decreases in offtime There was no change in on time with trouble-some dyskinesia and the percent of subjects withdyskinesia as an adverse effect was similar for allthree groups

In a Class II multicenter parallel group random-ized placebo controlled double masked study 197patients received entacapone (200 mgdose) and 104received placebo in addition to their daily dose oflevodopa22 Only 78 of patients randomized com-pleted the trial Off time decreased by 258 (16hours) with entacapone compared to 134 (09hours) with placebo Thirty-four percent of patientsreported dyskinesia as an adverse event on entaca-pone compared to 26 on placebo

A Class II multicenter parallel group random-ized double masked study evaluated 171 patients onentacapone 200 mgdose (n 85) or placebo (n 86)for 6 months23 Allocation concealment was not de-scribed There were 90 completers in both groupsPatients taking entacapone had a decrease in offtime that was 22 more than the decrease with pla-cebo (p 0001) and a concomitant increase in ontime of 13 (p 0001) Worsening of dyskinesiawas more common in the entacapone group (82)than the placebo group (12) (p 005)

A Class II multicenter double masked placebocontrolled study of 162 patients randomized 32 toentacapone 200 mgdose or placebo failed to show abenefit in favor of entacapone24 Allocation conceal-ment was not described Seventy-seven percent com-pleted the 3-month study Patients on entacaponehad more dyskinesia (31) than those on placebo(13)

COMT inhibitor adverse effects The adverse ef-fects associated with tolcapone and entacapone weresimilar but more frequent with tolcapone in the stud-


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ies reported however it is important to stress thatthese studies cannot be directly compared Diarrheaoccurred in 20 to 34 of tolcapone treated patients inthe reviewed trials and 8 to 20 with entacaponeOther side effects included nausea in 28 to 50 withtolcapone and 10 to 20 with entacapone somno-lence in 16 to 32 with tolcapone and 4 with enta-capone and hallucinations in 24 with tolcaponeand 4 to 9 with entacapone Symptomatic orthosta-sis was reported with tolcapone in 24 of patients inone study Finally an elevation of liver enzymesALT and AST occurred in 1 of patients taking tol-capone 100 mg TID and 3 of patients taking tolca-pone 200 mg TID Rare cases of fatal hepatotoxicityhave been reported with tolcapone leading to a rec-ommendation of more stringent liver function moni-toring25 Tolcapone should only be used in PDpatients taking levodopa who are experiencing symp-tom fluctuations and are not responding satisfacto-rily to or are not appropriate candidates for otheradjunctive therapy If the patient does not have asubstantial clinical benefit within 3 weeks of initia-tion of tolcapone they should be withdrawn from thedrug In appropriate candidates for tolcapone liverfunction monitoring should be done at baseline andthen periodically (ie every 2ndash4 weeks) for the first6 months and thereafter as clinically necessary

Sustained release carbidopalevodopa FourClass III single center double masked crossoverstudies examining 97 total patients failed to demon-strate any difference in off time with sustained re-lease carbidopalevodopa compared to the immediaterelease preparation26-29 Baseline characteristics andallocation concealment were not described for any ofthe studies The daily dose of levodopa was higherwith the sustained release preparation but therewas a significant decrease in the number of doses perday with sustained release Dyskinesia was only de-scribed in one study27 which was similar in the sus-tained release and immediate release groups Theadverse effects of both drugs were the same

Conclusions Entacapone (two Class I studies)and rasagiline (two Class I studies) are establishedas effective in reducing off time

Pergolide (one Class I study) pramipexole (oneClass I and one Class II study) ropinirole (two ClassII studies) and tolcapone (two Class II studies) areprobably effective in reducing off time

Apomorphine subcutaneously injected (one ClassII study) cabergoline (two Class III studies) andselegiline (one Class II study one Class III study)are possibly effective in reducing off time

Based on four Class III studies sustained releasecarbidopalevodopa does not decrease off time com-pared to immediate release The doses of sustainedrelease carbidopalevodopa were higher but givenless frequently Based on one Class II study bro-mocriptine does not decrease off time compared toplacebo

Recommendations For patients with PD with

motor fluctuations the available evidence suggeststhe following (see appendix E-3)

bull Entacapone and rasagiline should be offered toreduce off time (Level A)

bull Pergolide pramipexole ropinirole and tolca-pone should be considered to reduce off time(Level B) Tolcapone (hepatotoxicity) and per-golide (valvular fibrosis) should be used withcaution and require monitoring

bull Apomorphine cabergoline and selegiline maybe considered to reduce off time (Level c)

bull Sustained release carbidopalevodopa and bro-mocriptine may be disregarded to reduce offtime (Level C)

Question 2 What is the relative efficacy of medica-tions in reducing off time There was one Class Istudy18 four Class II studies930-32 and one Class IIIstudy33 that compared the efficacy of antiparkinso-nian medications in reducing off time In one Class Istudy there was no significant difference betweenrasagiline 1 mgday and entacapone 200 mg witheach levodopa dose in reducing off time (reduction of08 hours relative to placebo for both not powered tocompare rasagiline to entacapone directly) Therewas no difference in dyskinesia or other adverseevents

In one Class II study there was no significantdifference between pramipexole mean dose 34 mgday and bromocriptine mean dose 226 mgday in thereduction in off time (15 vs 8)9 The study was notpowered to show a difference between the two activegroups There were no differences in adverse eventsin the two groups

In another Class II study there was no statisticaldifference between reduction in off time with caber-goline mean dose 32 mgday compared to bromocrip-tine 221 mgday (50 vs 313)30

In a Class II study comparing ropinirole meandose 10 mgday with bromocriptine mean dose 18mgday ropinirole reduced off time by 177 com-pared to 48 with bromocriptine31 Adverse eventswere similar except ropinirole caused more nauseaand bromocriptine caused more hallucinations

A three-week Class II study compared tolcapone100 mg TID and entacapone 200 mgdose32 Increasein on time showed a trend but was not statisticallydifferent between the two groups (tolcapone 13hours vs entacapone 06 hours) Adverse events weresimilar

In a Class III study there was no significant dif-ference in change in off time between tolcapone 100to 200 mg TID and pergolide mean dose 22 mgday(179 vs 182)33 Adverse events leading to with-drawal from the study were more common with per-golide (15 vs 5)

Conclusions Six studies (one Class I four ClassII one Class III study) compared the efficacy of anti-parkinsonian medications in reducing off time rasa-giline was similar to entacapone bromocriptine wassimilar to pramipexole tolcapone was similar to per-


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golide cabergoline was similar to bromocriptine tol-capone was similar to entacapone and ropinirolewas possibly superior to bromocriptine Many ofthese studies were not powered to demonstrate supe-riority of one drug over another Other than compar-isons of ropinirole and bromocriptine there isinsufficient evidence to conclude which one agent issuperior to another in reducing off time

Recommendations Ropinirole may be chosenover bromocriptine for reducing off time (Level C)Otherwise there is insufficient evidence to recom-mend one agent over another (Level U)

Question 3 Which medications reduce dyskinesiaTwo studies one Class II and one Class III evalu-ated the efficacy of medications in reducingdyskinesia3435

A Class II single center double masked placebocontrolled randomized crossover trial enrolled 24subjects for 3 weeks of treatment with amantadine(100 mg BID) and placebo34 Ninety-two percent ofthe subjects completed the trial Total dyskinesiascore (Goetz scale) decreased 24 after amantadine(p 0004) In addition there was a 17 decrease inmaximal dyskinesia score (p 002) and a signifi-cant decrease in percentage of time with dyskinesia(UPDRS part IVa) (p 002) on amantadine com-pared to placebo UPDRS motor off state score im-proved (p 004) and the on state score wasunchanged No adverse effects were reported in thisstudy

A Class III double masked placebo controlledparallel group study evaluated the effect of clozapineon the treatment of levodopa-induced dyskinesia inpatients with severe PD for 10 weeks35 There were76 completers Clozapine treatment (mean dose394 mgday) resulted in a decrease in hours on withdyskinesia per day of 17 while hours on with dyski-nesia increased in the placebo group by 07 hours(overall 24 hours difference between groups) Onsetof change was noted at 4 weeks Duration of on andoff time and UPDRS motor scores were not differentbetween groups The most common adverse effectsreported in this study were somnolence (100) hy-persalivation (38) and asthenia (62)

Studies of other drugs including bupidine dextro-methorphan idazoxan istradefylline memantinenabilone quetiapine remacemide riluzole sarizo-tan and talampanel did not meet the inclusioncriteria

Conclusions Amantadine is possibly effective inreducing dyskinesia (one Class II study)

There is insufficient evidence to support or refutethe effectiveness of clozapine in reducing dyskinesia(single Class III study)

Recommendations Amantadine may be consid-ered for patients with PD with motor fluctuations inreducing dyskinesia (Level C)

There is insufficient evidence to support or refutethe efficacy of clozapine in reducing dyskinesia(Level U) Clozapinersquos potential toxicity includingagranulocytosis seizures myocarditis and ortho-

static hypotension with or without syncope and re-quired white blood cell count monitoring must beconsidered

Surgical therapy Question 4 For patients withPD does DBS of the STN GPi or VIM reduce offtime dyskinesia and antiparkinsonian medicationusage and improve motor function Patients un-dergoing DBS surgery are evaluated with the UP-DRS ADL and motor sections before surgery in themedication off and medication on states to determinemaximum improvement with medication The im-provement with DBS except for the possibility ofincreased tremor control is generally equivalent tothe best improvement seen with medications how-ever this benefit persists for a longer amount of timeresulting in a decrease in off time Follow-up evalua-tions are generally performed in the medication offand on states with the stimulators turned on Thebaseline medication off scores are then compared tothe follow-up medication offstimulation on scores todetermine the effect of stimulation In order to reachan evidence class of III an objective measure ofsymptoms must be used such as timed tapping orwalking tests patient symptom diaries or patientself report questionnaires The effect of stimulationon dopaminergic medication use is examined by con-verting daily dosages of these medications with aformula which varies slightly across sites to a singlevalue referred to as the levodopa equivalence dose

Subthalamic nucleus stimulation Fourteen arti-cles met inclusion criteria for STN stimulationThere were 4 Class III studies36-39 and 10 Class IVstudies40-49 All studies examined bilateral DBS of theSTN Only the Class III studies are discussed indetail Details of the Class IV studies can be found inthe evidence tables (see table 2 and table E-2)

A Class III 6-month prospective multicentertrial examined 102 PD patients with 96 patients re-ceiving bilateral implants (mean age 590 96years) and 91 patients completing a 6-month follow-up36 At 6 months off medication with stimulationon there was a mean improvement of 524 in UP-DRS motor scores (p 0001) and a 437 improve-ment in UPDRS ADL scores compared to thebaseline off medication state (p 0001) Patientdiaries indicated an increase in on time without dys-kinesia from 27 to 74 of the waking day (p 0001) a decrease in on time with dyskinesia from23 to 7 and a decrease in off time from 49 to19 (p 0001) The Rush Dyskinesia scale im-proved 58 (p 0001) and there was a decrease indaily levodopa equivalence dose of 373 (p 0001)Adverse events included infections in 39 of pa-tients intracranial hemorrhage leading to hemipare-sis in 29 seizures in 29 increased dyskinesia in20 diplopia in 20 lead migrations in 29 de-vice infections in 29 improper lead placement in20 and brachial plexus injury dysarthria head-ache paresthesia confusion paralysis pulmonaryembolus abnormal healing seroma device erosion


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broken lead and device with intermittent functioneach in 10 of the patients

A second Class III study of 26 PD patients (meanage 59 8 years) one year after DBS of the STNreported similar results37 There was a 663 im-provement in UPDRS ADL scores (p 00001) and a643 improvement in UPDRS motor scores withstimulation in the medication off condition comparedto baseline (p 00001) Timed walking improved376 (p 0001) and number of steps to walk 45meters improved 466 (p 0003) Similarly tap-ping scores increased by 451 (p 00001) Therewas also an 86 improvement in dyskinesia (UPDRSitem 32 p 00001) and an 83 improvement inmotor fluctuations (UPDRS item 39 p 00001)Levodopa equivalence dose was decreased by 195(p 0001) Adverse events included worsening ofdysarthria in 154 of patients depression in 77memory worsening in 77 misplaced leads in 77scalp infection requiring system removal leading tothe development of meningitis in 38 seizures hal-lucinations confusion dysphagia eyelid apraxiaand lead fracture each in 38

A Class III study of 33 PD patients with a meanage of 585 ranging from 35 to 75 years 1 year afterDBS of the STN also showed improvements in motorfunction38 UPDRS ADL (323 p 0001) and mo-tor (381 p 0003) scores in the medication-offstimulation on condition were significantly improvedcompared to baseline medication off scores Fingertapping scores increased by 453 (p 0001) in theright hand and by 362 (p 0002) in the left handPatient diaries showed an increase in daily on timewithout dyskinesia from 38 at baseline to 76 at 1year (p 0002) On time with dyskinesia was re-duced from 18 to 4 and off time was also reducedfrom 44 to 20 Levodopa equivalence dose wasdecreased by 442 (p 0004) Similar improve-ments were maintained in 19 patients 24 monthsafter surgery Surgical adverse events included tran-sient confusion in 143 of patients seizures in86 infection in 86 visual disturbances in 29and hemiballismus in 29 Stimulation relatedevents included dysarthria in 286 gait problemsin 86 paresthesia in 57 depression in 29 andmuscle spasms in 29 Adverse events related tothe devices included lead replacements due to lack ofbenefit or misplacement in 257 of patients IPGmalfunctions in 229 lead revisions in 20 exten-sion fractures in 57 lead fracture in 29 andextension erosion in 29

The final Class III study compared patients ran-domized to pallidotomy or DBS of the STN39 Forpurposes of this article only the results of the 20DBS patients (mean age 61 ranging from 55 to 66years) are discussed (p values not included) The me-dian change in UPDRS ADL scores in the medicationoff and stimulation on condition compared to base-line medication off was 463 and for UPDRS motorscores was 485 The duration of dyskinesia de-creased by 50 (UPDRS item 32) and the severity of

dyskinesia decreased 100 (UPDRS item 33) Pa-tients also completed the PD Quality of Life ques-tionnaire that showed a median improvement of232 Levodopa equivalence dose was reduced by33 Adverse events included emotional lability in300 of patients increased drooling in 100 pos-tural instability in 100 severe cognitive deteriora-tion in 50 CSF leakage requiring drainage in50 mild dysphasia dysarthria and dysphagia in50 transient confusion in 50 extension strainin the neck (discomfort due to extension wire pullingwith or without neck movement) in 50 and dis-placed electrodes in 10

All 10 Class IV studies reported results similar tothe Class III studies All studies showed significantimprovements in motor function and significant re-ductions in motor fluctuations dyskinesia and anti-parkinsonian medication

Globus pallidus stimulation Three articles metinclusion criteria for GPi stimulation There was oneClass III study36 and two Class IV studies5051 Onlythe Class III study is discussed in detail howeverthe details of the Class IV studies are availablein the evidence tables (see table 2 and table E-2)The Class III study36 was a 6-month prospectivemulticenter trial of 41 PD patients 38 of whom re-ceived DBS (mean age 557 98 years) with 36patients completing the 6-month follow-up At 6months there was a 333 improvement in UPDRSmotor scores (p 0001) and a 358 improvementin UPDRS ADL scores (p 0001) with stimulationon compared to the baseline medication off conditionPatient diaries indicated an increase in on timewithout dyskinesia from 28 to 64 of the wakingday (p 0001) a decrease in on time with dyskine-sia from 35 to 12 and a decrease in off time from37 to 24 (p 001) The Rush Dyskinesia scaleshowed an improvement of 67 (p 001) Therewas no change in daily levodopa equivalence doseAdverse events included intracranial hemorrhage in98 of patients (73 leading to hemiparesis) in-creased dyskinesia in 73 dystonia in 49 leadmigrations in 49 and dysarthria seizure infec-tion broken lead seroma and abdominal pain eachin 24

One Class IV study50 of 20 patients receiving bilat-eral and 10 patients receiving unilateral DBS of theGPi (mean age 577 range 42 to 77 years) had re-sults similar to the Class III study with a significantimprovement 40 in UPDRS off medication withstimulation on at 6 and 12 months post surgery (p 0005) and a 929 reduction in dyskinesia at 6months p 005) The second Class IV study49 in-cluded 26 PD patients (mean age 562 86 years)with unilateral DBS of the GPi after 327 months offollow-up In contrast to the other two studies atlong-term follow-up UPDRS medication off andstimulation on motor scores worsened by 83UPDRS motor fluctuations worsened by 35 andmedication usage increased by 538 On the other


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hand dyskinesia scores were improved by 28 atlong-term follow-up (no p values included)

Thalamic stimulation Four articles met inclu-sion criteria for thalamic stimulation52-55 All four ar-ticles were Class IV Due to the low quality ofevidence thalamic stimulation is not discussed

Adverse events Given the importance of under-standing the riskbenefit ratio for DBS surgery fouradditional articles focusing specifically on adverseevents from large series of patients with DBS arediscussed56-59 The results from these studies arecombined to include 360 total patients undergoingDBS of which 288 were PD patients Adverse eventsare categorized as surgical (during or within 1 monthof surgery) hardware related and stimulation re-lated Of the 360 patients undergoing DBS deathresulted in two patients due to pulmonary embolismand aspiration pneumonia (06) and 28 had per-manent neurologic sequelae Other surgical compli-cations not resulting in permanent neurologicsequelae included infection in 56 of patients hem-orrhage in 31 confusiondisorientation in 28seizures in 11 pulmonary embolism in 06 CSFleak in 06 peripheral nerve injury in 06 andvenous infarction in 03 Complications related tothe DBS hardware included lead replacement due tofracture migration or malfunction in 5 of patientslead reposition due to misplacement in 28 exten-sion wire replacement due to fracture or erosion in44 IPG replacement due to malfunction in 42IPG repositioning for cosmetic purposes or due toskin growth in 17 and allergic reaction to thehardware in 06 Stimulation-related adverse ef-fects are generally mild and can be resolved withreprogramming of the stimulation parameters Themost common stimulation adverse effects are pares-thesia dysarthria eyelid opening apraxia hemibal-lismus dizziness dyskinesia and facial contractions

Conclusions Based on four Class III studiesDBS of the STN is possibly effective in improvingmotor function and reducing motor fluctuations dys-kinesia and antiparkinsonian medication usage inPD patients Adverse events may limit application ofthis therapy

Based on one Class III study and two Class IVstudies data are insufficient to determine if DBS ofthe GPi is effective in reducing motor fluctuationsdyskinesia and antiparkinsonian medications or inimproving motor function

There is insufficient evidence to support or refutethe efficacy of DBS of the VIM nucleus of the thala-mus in reducing motor fluctuations dyskinesia andmedication usage or to determine if DBS of the VIMimproves motor function

Recommendations DBS of the STN may be con-sidered as a treatment option in PD patients to im-prove motor function and to reduce motorfluctuations dyskinesia and medication usage(Level C) Patients need to be counseled regardingthe risks and benefits of this procedure

There is insufficient evidence to make any recom-

mendations about the effectiveness of DBS of theGPi or VIM nucleus of the thalamus in reducingmotor complications or medication usage or in im-proving motor function in PD patients (Level U)

Question 5 Which factors predict improvement af-ter DBS Of the 14 articles that met inclusion criteriafor DBS of the STN there were two prognostic Class IIstudies4245 and 12 Class IV studies36-41434446-49 Onlythe Class II studies are discussed in detail Althoughthese studies were rated Class IV relative to Ques-tion 4 regarding efficacy they earned grades of ClassII relative to prognosis for Question 5 Efficacy inthese two studies was similar to the Class III studiesreported above

One Class II study was designed to examine fac-tors predictive of outcome after DBS of the STN in41 PD patients (mean age 564 86)42 Regressionanalyses indicated that age (p 0005) and diseaseduration (p 0007) had a relationship with out-come Therefore patients were stratified by meanage examining those 56 and older separately fromthose younger than 56 years It was reported thatthe younger group had greater improvements inmedication off UPDRS ADL (706 vs 533 p 005) and UPDRS motor (706 vs 600 p 005)scores with stimulation compared to baseline Simi-larly the group was stratified by mean disease dura-tion and those with disease duration less than 16years had greater improvements than those with dis-ease duration 16 years or greater in medication offUPDRS ADL (645 vs 570 p 005) and UPDRSmotor (676 vs 616 p 005) scores with stimu-lation compared to baseline Levodopa responsive-ness defined as low residual motor disability ondrug compared to the off state correlated stronglywith benefit from STN DBS (correlation coefficient074) In addition to age and disease duration it wasconcluded that levodopa responsiveness is the stron-gest predictor of outcome (p 0002)

The second Class II study45 included 25 patientswith a mean age of 572 years ranging from 34 to 76years at the time of DBS implantation The studyexamined age sex disease duration baseline drugusage baseline dyskinesia age at onset and base-line levodopa responsiveness by stratifying eachvariable at the median Levodopa responsivenesswas the only factor that was shown to be related topostsurgical outcome (p 0004) The smaller size ofthis study reduced the ability to detect the associa-tion between age and disease duration and outcome

There were no studies of GPi or VIM DBS examin-ing predictive factors

Conclusions Based upon two Class II studiespreoperative response to levodopa is probably predic-tive of postsurgical improvement Based on one ClassII study younger age and shorter disease duration(less than 16 years) are possibly predictive of greaterimprovement after DBS of the STN

Data are insufficient to reach a conclusion on pre-dictive factors influencing improvement after DBS ofthe GPi and VIM DBS


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Recommendations Preoperative response tolevodopa should be considered as a factor predictiveof outcome after DBS of the STN (Level B)

Age and duration of PD may be considered asfactors predictive of outcome after DBS of the STNYounger patients with shorter disease durationsmay possibly have improvement greater than thatof older patients with longer disease durations(Level C)

There is insufficient evidence to make any recom-mendations about factors predictive of improvementafter DBS of the GPi or VIM nucleus of the thalamusin PD patients (Level U)

Recommendations for future research Medi-cal treatment Comparative randomized doublemasked controlled trials are needed to determinewhich drugs are the most effective in reducing offtime and dyskinesia in patients with moderate toadvanced PD Uniform and more specific inclusioncriteria need to be reported in these series Outcomemeasures should also be standardized to include aspecific diary form for measuring onoffdyskinesiaNon-motor fluctuations PD-specific quality of lifemeasures and neuropsychiatric features requiregreater assessment and reporting Additional noveldrug classes need further investigation

Surgical treatment Further research in DBS ofthe STN GPi and VIM nucleus of the thalamusshould include objective clinical measures such asfinger tapping walking times patient diaries or pa-tient global assessments and include the effect ofDBS on disability status Raters should be masked towhether surgery was performed for evaluations ofmotor function Currently most DBS series include ahomogeneous young fluctuating population basedon the clinical impression that this group most ro-bustly responds to DBS Additional studies shouldsystematically examine which factors are predictiveof a positive outcome and evaluate the optimal tim-ing for surgery Long duration prospective trials ofDBS vs optimal medical management would providetremendous clinical guidance A large multicenterrandomized double masked trial examining thelong-term effects of DBS of the GPi and the STNcompared to optimal medical management is cur-rently underway and is anticipated to provide astronger level of evidence for the effects of DBS vsoptimal medical management Research to deter-mine cost-benefit analysis over the longer term isnecessary In addition research to document re-gional disparity in access is needed

Disclaimer This statement is provided as an edu-cational service of the American Academy of Neurol-ogy It is based on an assessment of current scientificand clinical information It is not intended to includeall possible proper methods of care for a particularneurologic problem or all legitimate criteria forchoosing to use a specific procedure Neither is itintended to exclude any reasonable alternative

methodologies The AAN recognizes that specific pa-tient care decisions are the prerogative of the patientand the physician caring for the patient based on allof the circumstances involved

Disclosure R Pahwa has received research grantsupport or participated in clinical trials for GSKNovartis BI Medtronic and Teva is a consultantfor GSK Teva Novartis BI Medtronic and Valeantand is a speaker for GSK Novartis and MedtronicSA Factor has received research grant support fromTeva is a consultant for Valeant and GSK and is aspeaker for Novartis and BI KE Lyons has receivedresearch grant support from GSK and has been aconsultant for Teva GSK Novartis and MedtronicWG Ondo has received research grant support orparticipated in clinical trials for GSK and Novartisand is a speaker for GSK BI and NovartisJ Miyasaki has received research grant supportfrom BI and Elan has received educational grantsupport from Teva and is a consultant for BI WJWeiner has received research grant support fromTeva and BI is a consultant for Teva and a speakerfor BI G Gronseth H Bronte-Stewart M Hallettand J Stevens have no conflicts to declare

AcknowledgmentThe authors thank Nancy King and Wendy Edlund for adminis-trative support and Andrew Wilner MD for help with manuscriptpreparation

References1 Chapuis S Ouchchane L Metz O Gerbaud L Durif F Impact of the

motor complications of Parkinsonrsquos disease on the quality of life MovDisord 200520224ndash230

2 Ahlskog JE Muenter MD Frequency of levodopa-related dyskinesiasand motor fluctuations as estimated from the cumulative literatureMov Disord 200116448ndash458

3 Quinn N Critchley P Marsden CD Young onset Parkinsonrsquos diseaseMov Disord 1987273ndash91

4 Fahn S Oakes D Shoulson I et al Levodopa and the progression ofParkinsonrsquos disease N Engl J Med 20043512498ndash2508

5 Schuurman PR Bosch DA Bossuyt PM et al A comparison of continu-ous thalamic stimulation and thalamotomy for suppression of severetremor N Engl J Med 2000342461ndash468

6 Lyons KE Pahwa R Deep brain stimulation in Parkinsonrsquos diseaseCurr Neurol Neurosci Rep 20044290ndash295

7 Olanow CW Fahn S Muenter M et al A multicenter double-blindplacebo-controlled trial of pergolide as an adjunct to Sinemet in Parkin-sonrsquos disease Mov Disord 1994940ndash47

8 Lieberman A Ranhosky A Korts D Clinical evaluation of pramipexolein advanced Parkinsonrsquos disease results of a double-blind placebo-controlled parallel-group study Neurology 199749162ndash168

9 Guttman M Double-blind comparison of pramipexole and bromocrip-tine treatment with placebo in advanced Parkinsonrsquos disease Interna-tional Pramipexole-Bromocriptine Study Group Neurology 1997491060ndash1065

10 Rascol O Lees AJ Senard JM Pirtosek Z Montastruc JL Fuell DRopinirole in the treatment of levodopa-induced motor fluctuations inpatients with Parkinsonrsquos disease Clin Neuropharmacol 199619234ndash245

11 Lieberman A Olanow CW Sethi K et al A multicenter trial of ropini-role as adjunct treatment for Parkinsonrsquos disease Ropinirole StudyGroup Neurology 1998511057ndash1062

12 Dewey RB Jr Hutton JT LeWitt PA Factor SA A randomizeddouble-blind placebo-controlled trial of subcutaneously injected apo-morphine for parkinsonian off-state events Arch Neurol 2001581385ndash1392

13 Steiger MJ El-Debas T Anderson T Findley LJ Marsden CD Double-blind study of the activity and tolerability of cabergoline versus placeboin parkinsonians with motor fluctuations J Neurol 199624368ndash72

14 Ahlskog JE Wright KF Muenter MD Adler CH Adjunctive cabergo-line therapy of Parkinsonrsquos disease comparison with placebo and as-


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sessment of dose responses and duration of effect Clin Neuropharmacol199619202ndash212

15 Golbe LI Lieberman AN Muenter MD et al Deprenyl in the treatmentof symptom fluctuations in advanced Parkinsonrsquos disease Clin Neurop-harmacol 19881145ndash55

16 Waters CH Sethi KD Hauser RA Molho E Bertoni JM Zydis selegi-line reduces off time in Parkinsonrsquos disease patients with motor fluctu-ations a 3-month randomized placebo-controlled study Mov Disord200419426ndash432

17 Parkinson Study Group A randomized placebo-controlled trial of rasa-giline in levodopa-treated patients with Parkinson disease and motorfluctuations the PRESTO study Arch Neurol 200562241ndash248

18 Rascol O Brooks DJ Melamed E et al Rasagiline as an adjunct tolevodopa in patients with Parkinsonrsquos disease and motor fluctuations(LARGO Lasting effect in Adjunct therapy with Rasagiline Given Oncedaily study) a randomised double-blind parallel-group trial Lancet2005365947ndash954

19 Rajput AH Martin W Saint-Hilaire MH Dorflinger E Pedder S Tol-capone improves motor function in parkinsonian patients with theldquowearing-offrdquo phenomenon a double-blind placebo-controlled multi-center trial Neurology 1997491066ndash1071

20 Baas H Beiske AG Ghika J et al Catechol-O-methyltransferase inhi-bition with tolcapone reduces the ldquowearing offrdquo phenomenon and levo-dopa requirements in fluctuating parkinsonian patients J NeurolNeurosurg Psychiatry 199763421ndash428

21 Parkinson Study Group Entacapone improves motor fluctuations inlevodopa-treated Parkinsonrsquos disease patients Ann Neurol 199742747ndash755

22 Poewe WH Deuschl G Gordin A Kultalahti ER Leinonen M Efficacyand safety of entacapone in Parkinsonrsquos disease patients with subopti-mal levodopa response a 6-month randomized placebo-controlleddouble-blind study in Germany and Austria (Celomen study) Acta Neu-rol Scand 2002105245ndash255

23 Rinne UK Larsen JP Siden A Worm-Petersen J Entacapone en-hances the response to levodopa in parkinsonian patients with motorfluctuations Nomecomt Study Group Neurology 1998511309ndash1314

24 Fenelon G Gimenez-Roldan S Montastruc JL et al Efficacy and toler-ability of entacapone in patients with Parkinsonrsquos disease treated withlevodopa plus a dopamine agonist and experiencing wearing-off motorfluctuations A randomized double-blind multicentre study J NeuralTransm 2003110239ndash251

25 Olanow CW Tolcapone and hepatotoxic effects Tasmar Advisory PanelArch Neurol 200057263ndash267

26 Jankovic J Schwartz K Vander Linden C Comparison of Sinemet CR4and standard Sinemet double blind and long-term open trial in parkin-sonian patients with fluctuations Mov Disord 19894303ndash309

27 Hutton JT Morris JL Roman GC Imke SC Elias JW Treatment ofchronic Parkinsonrsquos disease with controlled-release carbidopalevodopaArch Neurol 198845861ndash864

28 Ahlskog JE Muenter MD McManis PG Bell GN Bailey PAControlled-release Sinemet (CR-4) a double-blind crossover study inpatients with fluctuating Parkinsonrsquos disease Mayo Clin Proc 198863876ndash886

29 Lieberman A Gopinathan G Miller E Neophytides A Baumann GChin L Randomized double-blind cross-over study of Sinemet-controlled release (CR4 50200) versus Sinemet 25100 in Parkinsonrsquosdisease Eur Neurol 19903075ndash78

30 Inzelberg R Nisipeanu P Rabey JM et al Double-blind comparison ofcabergoline and bromocriptine in Parkinsonrsquos disease patients with mo-tor fluctuations Neurology 199647785ndash788

31 Brunt ER Brooks DJ Korczyn AD Montastruc JL Stocchi F A six-month multicentre double-blind bromocriptine-controlled study of thesafety and efficacy of ropinirole in the treatment of patients with Par-kinsonrsquos disease not optimally controlled by L-dopa J Neural Transm2002109489ndash502

32 Agid Y Oertel W Factor S Entacapone to tolcapone switch studymulticenter double-blind randomized active-controlled trial in ad-vanced Parkinsonrsquos disease Mov Disord 200520(suppl 10)S94

33 Koller W Lees A Doder M Hely M Randomized trial of tolcaponeversus pergolide as add-on to levodopa therapy in Parkinsonrsquos diseasepatients with motor fluctuations Mov Disord 200116858ndash866

34 Snow BJ Macdonald L McAuley D Wallis W The effect of amantadineon levodopa-induced dyskinesias in Parkinsonrsquos disease a double-blindplacebo-controlled study Clin Neuropharmacol 20002382ndash85

35 Durif F Debilly B Galitzky M et al Clozapine improves dyskinesias inParkinson disease a double-blind placebo-controlled study Neurology200462381ndash388

36 Deep Brain Stimulation for Parkinsonrsquos Disease Study Group Deep-brain stimulation of the subthalamic nucleus or the pars interna of theglobus pallidus in Parkinsonrsquos disease N Engl J Med 2001345956ndash963

37 Ostergaard K Sunde N Dupont E Effects of bilateral stimulation ofthe subthalamic nucleus in patients with severe Parkinsonrsquos diseaseand motor fluctuations Mov Disord 200217693ndash700

38 Pahwa R Wilkinson SB Overman J Lyons KE Bilateral subthalamicstimulation in patients with Parkinson disease long-term follow up JNeurosurg 20039971ndash77

39 Esselink RA de Bie RM de Haan RJ et al Unilateral pallidotomyversus bilateral subthalamic nucleus stimulation in PD a randomizedtrial Neurology 200462201ndash207

40 Figueiras-Mendez R Regidor I Riva-Meana C Magarinos-Ascone CMFurther supporting evidence of beneficial subthalamic stimulation inParkinsonrsquos patients Neurology 200258469ndash470

41 Vesper J Klostermann F Stockhammer F Funk T Brock M Results ofchronic subthalamic nucleus stimulation for Parkinsonrsquos disease a1-year follow-up study Surg Neurol 200257306ndash311 discussion 311ndash303

42 Welter ML Houeto JL Tezenas du Montcel S et al Clinical predictivefactors of subthalamic stimulation in Parkinsonrsquos disease Brain 2002125575ndash583

43 Doshi PK Chhaya NA Bhatt MA Bilateral subthalamic nucleus stim-ulation for Parkinsonrsquos disease Neurol India 20035143ndash48

44 Herzog J Volkmann J Krack P et al Two-year follow-up of subtha-lamic deep brain stimulation in Parkinsonrsquos disease Mov Disord 2003181332ndash1337

45 Kleiner-Fisman G Fisman DN Sime E Saint-Cyr JA Lozano AMLang AE Long-term follow up of bilateral deep brain stimulation of thesubthalamic nucleus in patients with advanced Parkinson diseaseJ Neurosurg 200399489ndash495

46 Krack P Batir A Van Blercom N et al Five-year follow-up of bilateralstimulation of the subthalamic nucleus in advanced Parkinsonrsquos dis-ease N Engl J Med 20033491925ndash1934

47 Romito LM Scerrati M Contarino MF Iacoangeli M Bentivoglio ARAlbanese A Bilateral high frequency subthalamic stimulation in Par-kinsonrsquos disease long-term neurological follow-up J Neurosurg Sci200347119ndash128

48 Krause M Fogel W Mayer P Kloss M Tronnier V Chronic inhibitionof the subthalamic nucleus in Parkinsonrsquos disease J Neurol Sci 2004219119ndash124

49 Visser-Vandewalle V Temel Y van der Linden C Ackermans L BeulsE Deep brain stimulation in movement disorders The applicationsreconsidered Acta Neurol Belg 200410433ndash36

50 Ogura M Nakao N Nakai E Uematsu Y Itakura T The mechanismand effect of chronic electrical stimulation of the globus pallidus fortreatment of Parkinson disease J Neurosurg 2004100997ndash1001

51 Visser-Vandewalle V van der Linden C Temel Y Nieman F Celik HBeuls E Long-term motor effect of unilateral pallidal stimulation in 26patients with advanced Parkinson disease J Neurosurg 200399701ndash707

52 Benabid AL Pollak P Gao D et al Chronic electrical stimulation of theventralis intermedius nucleus of the thalamus as a treatment of move-ment disorders J Neurosurg 199684203ndash214

53 Koller W Pahwa R Busenbark K et al High-frequency unilateralthalamic stimulation in the treatment of essential and parkinsoniantremor Ann Neurol 199742292ndash299

54 Hariz MI Shamsgovara P Johansson F Hariz G Fodstad H Toleranceand tremor rebound following long-term chronic thalamic stimulationfor Parkinsonian and essential tremor Stereotact Funct Neurosurg199972208ndash218

55 Limousin P Speelman JD Gielen F Janssens M Multicentre Euro-pean study of thalamic stimulation in parkinsonian and essentialtremor J Neurol Neurosurg Psychiatry 199966289ndash296

56 Beric A Kelly PJ Rezai A et al Complications of deep brain stimula-tion surgery Stereotact Funct Neurosurg 20017773ndash78

57 Oh MY Abosch A Kim SH Lang AE Lozano AM Long-termhardware-related complications of deep brain stimulation Neurosur-gery 2002501268ndash1274 discussion 1274ndash1266

58 Umemura A Jaggi JL Hurtig HI et al Deep brain stimulation formovement disorders morbidity and mortality in 109 patients J Neuro-surg 200398779ndash784

59 Lyons KE Wilkinson SB Overman J Pahwa R Surgical and hardwarecomplications of subthalamic stimulation a series of 160 proceduresNeurology 200463612ndash616


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DOI 10121201wnl00002152508257687200666983-995 Published Online before print April 2 2006Neurology

R Pahwa S A Factor K E Lyons et al Subcommittee of the American Academy of Neurology

dyskinesia (an evidence-based review) [RETIRED] Report of the Quality Standards Practice Parameter Treatment of Parkinson disease with motor fluctuations and

This information is current as of April 2 2006

ServicesUpdated Information amp

httpnneurologyorgcontent667983fullincluding high resolution figures can be found at

Supplementary Material

257687DC1httpnneurologyorgcontentsuppl2006040301wnl00002152508



httpnneurologyorgcontentsuppl20060406667983DC1Supplementary material can be found at

Citations httpnneurologyorgcontent667983fullotherarticles

This article has been cited by 21 HighWire-hosted articles

Subspecialty Collections

httpnneurologyorgcgicollectionparkinsons_disease_parkinsonismParkinsons diseaseParkinsonismfollowing collection(s) This article along with others on similar topics appears in the

Permissions amp Licensing

httpwwwneurologyorgaboutabout_the_journalpermissionsits entirety can be found online atInformation about reproducing this article in parts (figurestables) or in

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httpnneurologyorgsubscribersadvertiseInformation about ordering reprints can be found online

Online ISSN 1526-632X1951 it is now a weekly with 48 issues per year Copyright All rights reserved Print ISSN 0028-3878

reg is the official journal of the American Academy of Neurology Published continuously sinceNeurology

RETIRED

induced motor fluctuations and dyskinesia Theserecommendations address the needs of specialistsand nonspecialists caring for patients with PD

Background PD is a progressive neurodegenera-tive disorder with cardinal motor features of tremorbradykinesia and rigidity Although initially effec-tive dopaminergic therapies are eventually compli-cated by motor fluctuations including off time(periods of return of PD symptoms when medicationeffect wears off) and dyskinesia (drug-induced invol-untary movements including chorea and dystonia) inmost patients These motor complications can impairquality of life and cause significant disability1 Riskfactors for motor complications include younger ageat onset of PD disease severity higher levodopa dos-age and longer disease duration2-4 These problemsare often addressed with levodopa adjustments andthe addition of adjunctive medications The first partof this article addresses the effectiveness of adjunc-tive medications in this situation

Motor fluctuations and dyskinesia can be resis-tant to medical therapy This along with advancesin the understanding of basal ganglia circuitry sur-gical techniques neuroimaging and intraoperativemicroelectrode recording has led to a resurgence insurgical approaches for medically refractory disabili-ties Initially ablative procedures like thalamotomyand pallidotomy were used to treat PD symptomsHowever due to concerns about morbidity5 espe-cially with bilateral procedures deep brain stimula-tion (DBS) has become the most commonlyperformed surgery for PD in North America

DBS is a stereotactic surgical procedure that usesan implanted electrode connected to an implantablepulse generator (IPG) that delivers electrical currentto a targeted nucleus in the brain6 The three pri-mary targets for DBS for PD are the ventral inter-mediate (VIM) nucleus of the thalamus globuspallidus interna (GPi) and the subthalamic nucleus(STN) The IPG is programmed externally from sev-eral days to 4 to 6 weeks after implantation Adjust-able stimulation parameters include amplitudefrequency and pulse width The device is generallyleft on but patients can turn the device off whendesired

Although the criteria are evolving currently pa-tients with PD who are considered candidates forDBS include levodopa-responsive non-dementedand neuropsychiatrically intact patients who haveintractable motor fluctuations dyskinesia or tremor

This practice parameter addresses five questions

1 Which medications reduce off time2 What is the relative efficacy of medications in re-

ducing off time3 Which medications reduce dyskinesia

4 Does DBS of the STN GPi or VIM reduce offtime dyskinesia and antiparkinsonian medica-tion usage and improve motor function

5 Which factors predict improvement after DBS

The conclusions and recommendations addressingthese questions are based only on the evidence avail-able in the literature and are limited by the qualityof the studies reviewed An inherent problem withthis process is that treatments may receive a recom-mendation lower than what may be expected basedon clinical experience This can be due to many fac-tors including the possibility that older treatmentsmay not have been studied as rigorously as newertherapies published manuscripts may not have in-cluded sufficient details or used a study design thatwould eliminate potential bias or a particular issuerelated to a specific treatment may not have beenaddressed in the literature

Description of the analytical process The QSSof the AAN identified an expert panel of experiencedmovement disorder specialists and general neurolo-gists with methodologic expertise For the literaturereview a research librarian searched MEDLINEEMBASE and Ovid databases This was supple-mented by a secondary search using the bibliographyof retrieved articles and knowledge from the expertpanel Panel members reviewed abstracts and titlesfor relevance Then at least two panel members re-viewed articles meeting inclusion criteria If a panel-ist was an author of one of the articles at least twoother panelists reviewed that article Disagreementswere arbitrated by an additional panel member Therisk of bias was determined using the classificationof evidence for each study (appendix E-1 the Neurol-ogy Web site at wwwneurologyorg) The strength ofthe practice recommendations was linked directly tothe level of evidence (appendix E-2) Conflicts of in-terest were disclosed Support was provided by theAAN Writing meetings were funded by the MichaelJ Fox Foundation Panelists were not compensated

Medical treatment For questions 1 2 and 3 theauthors used the following search terms Parkinsondisease advanced Parkinson disease dyskinesiamotor fluctuations double masked trials random-ized trials placebo controlled trials clinical trialsmedical treatment human studies adenosine A2Aantagonists amantadine apomorphine bromocrip-tine cabergoline controlled release carbidopalevo-dopa entacapone pergolide pramipexole rasagilineropinirole selegiline tolcapone clozapine rotigotine(search restricted to English language and medica-tions available in the United States or those havingan approvable letter from the Food and Drug Admin-istration) The initial search included articles from1965 to June 2004 and a supplemental search wasperformed in 2005 to include the latest clinical trials

The authors considered randomized masked trialsthat included at least 20 patients with motor fluctu-ations or dyskinesia followed for greater than 3

Additional material related to this article can be found on the NeurologyWeb site Go to wwwneurologyorg and scroll down the Table of Con-tents for the April 11 issue to find the title link for this article


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Agey

PDduration

BaselineUPDRSmotor


Dyskinesiaoff time

improvementMeds

reduction


37


20


54 (1 y)



33


68


38 (1 y)


36 (25 y)






1 y 14 61 (1 y) Off time 71 53 (1 y)


49 (6 mo)

57 (1 y) UPDRS (33) 92 (6 mo1 y 2 y) 42 (1 y)

57 (2 y) 68 (2 y)


59 (3 y) UPDRS (33) 63 (1 y) 68 (3 y)50 (5 y)

63 (3 y)

54 (5 y) 63 (5 y)


66 (1 y)


39 (1 y)30 (30 mo)

49 IV IV 4 y B-STN 20 61 NA 56 43 NA 47 (4 y)




53 more



B-20 (total UPDRS)


15 (6 mo)




U-56

B-16




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reduction


37


20


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33


68


38 (1 y)


36 (25 y)






1 y 14 61 (1 y) Off time 71 53 (1 y)


49 (6 mo)

57 (1 y) UPDRS (33) 92 (6 mo1 y 2 y) 42 (1 y)

57 (2 y) 68 (2 y)


59 (3 y) UPDRS (33) 63 (1 y) 68 (3 y)50 (5 y)

63 (3 y)

54 (5 y) 63 (5 y)


66 (1 y)


39 (1 y)30 (30 mo)

49 IV IV 4 y B-STN 20 61 NA 56 43 NA 47 (4 y)




53 more



B-20 (total UPDRS)


15 (6 mo)




U-56

B-16




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reduction


37


20


54 (1 y)



33


68


38 (1 y)


36 (25 y)






1 y 14 61 (1 y) Off time 71 53 (1 y)


49 (6 mo)

57 (1 y) UPDRS (33) 92 (6 mo1 y 2 y) 42 (1 y)

57 (2 y) 68 (2 y)


59 (3 y) UPDRS (33) 63 (1 y) 68 (3 y)50 (5 y)

63 (3 y)

54 (5 y) 63 (5 y)


66 (1 y)


39 (1 y)30 (30 mo)

49 IV IV 4 y B-STN 20 61 NA 56 43 NA 47 (4 y)




53 more



B-20 (total UPDRS)


15 (6 mo)




U-56

B-16




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PDduration

BaselineUPDRSmotor


Dyskinesiaoff time

improvementMeds

reduction


37


20


54 (1 y)



33


68


38 (1 y)


36 (25 y)






1 y 14 61 (1 y) Off time 71 53 (1 y)


49 (6 mo)

57 (1 y) UPDRS (33) 92 (6 mo1 y 2 y) 42 (1 y)

57 (2 y) 68 (2 y)


59 (3 y) UPDRS (33) 63 (1 y) 68 (3 y)50 (5 y)

63 (3 y)

54 (5 y) 63 (5 y)


66 (1 y)


39 (1 y)30 (30 mo)

49 IV IV 4 y B-STN 20 61 NA 56 43 NA 47 (4 y)




53 more



B-20 (total UPDRS)


15 (6 mo)




U-56

B-16




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practice parameter: treatment of parkinson disease with ... · cluded sufficient details or used a...

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