1. © 2006 American Academy of Neurology Practice Parameter: Treatment of Parkinson Disease with Motor Fluctuations and Dyskinesia (An Evidence-Based Review) American Academy of Neurology Quality Standards Subcommittee R. Pahwa, MD; S.A. Factor, DO; K.E.Lyons, PhD; W.G.Ondo, MD; G. Gronseth, MD; H. Bronte-Stewart, MD; M. Hallett, MD; J. Miyasaki, MD; J. Stevens, MD; and W.J. Weiner, MD

2. © 2006 American Academy of Neurology The AAN develops these presentation slides as educational tools for neurologists and other health care practitioners. You may download and retain a single copy for your personal use. Please contact guidelines@aan.com to learn about options for sharing this content beyond your personal use.guidelines@aan.com

3. © 2006 American Academy of Neurology Presentation Objectives To make evidence-based treatment recommendations for the medical and surgical treatment of patients with Parkinson disease (PD) with levodopa- induced motor fluctuations and dyskinesia

4. © 2006 American Academy of Neurology Overview Background and descriptive epidemiology Treatment of PD Gaps in PD Care AAN guideline process Medical treatments Surgical treatments Summary Recommendations for future research

5. © 2006 American Academy of Neurology Background PD a neurodegenerative disorder Cardinal motor features of tremor, bradykinesia, and rigidity Dopaminergic therapies complicated by motor fluctuations –Can be resistant to medical therapy

6. © 2006 American Academy of Neurology Treatment of PD Risk factors for motor complications: –Younger age –Higher levodopa dosage –Severe disease –Longer disease duration Treatment options: levodopa manipulation, adjunctive therapy, and surgical therapy

7. © 2006 American Academy of Neurology Descriptive Epidemiology of Parkinson Syndrome Incidence –5–24/10 5 worldwide (ref) –20.5/10 5 USA (ref) Prevalence –57–371/10 5 worldwide (ref) –300/10 5 USA/Canada (Strickland & Bertoni, 2004) –Prevalence of PS/PD rising slowly with aging population

8. © 2006 American Academy of Neurology Treatment of PD Resurgence in surgical approaches Deep brain stimulation (DBS) –Most commonly performed surgery for PD in North America –Uses an implanted electrode connected to an implantable pulse generator (IPG) that delivers electrical current to a targeted brain nucleus

9. © 2006 American Academy of Neurology Gaps in PD Care Levodopa is a commonly used and effective therapy Long term complications: motor fluctuations and dyskinesia Motor complications can cause significant disability and impair quality of life

10. © 2006 American Academy of Neurology Seeking Answers How do we find the answers to the questions that arise in daily practice? In order to keep up to date, need to read 29 articles a day, 365 days a year (Didsbury, 2003) Or find someone who has found and summarized the relevant data for you

11. © 2006 American Academy of Neurology American Academy of Neurology Guideline Process Clinical Question Evidence Conclusions Recommendations

12. © 2006 American Academy of Neurology Clinical Question Question should address an area of quality concern, controversy, confusion, or variation in practice Question must be answerable with sufficient scientific data –Potential to improve clinical care and patient outcomes

13. © 2006 American Academy of Neurology Literature Search/Review: Rigorous, Comprehensive, Transparent Search Review abstracts Review full text Select articles Relevant Complete

14. © 2006 American Academy of Neurology AAN Classification for Evidence All studies rated Class I, II, III, or IV Therapeutic Studies –Randomization, control, blinding Diagnostic Studies –Comparison to gold standard; spectrum Prognostic Studies

15. © 2006 American Academy of Neurology AAN Level of Recommendations A = Established as effective, ineffective, or harmful for the given condition in the specified population B = Probably effective, ineffective, or harmful for the given condition in the specified population C = Possibly effective, ineffective, or harmful for the given condition in the specified population U = Data is inadequate or conflicting; given current knowledge, treatment is unproven

16. © 2006 American Academy of Neurology AAN Level of Recommendations A = Requires two consistent Class I studies B = Requires one Class I study or two consistent Class II studies C = Requires one Class II study or two consistent Class III studies U = Studies not meeting criteria for Class I through Class III

17. © 2006 American Academy of Neurology Clinical Questions 1.Which medications reduce off time? 2.What is the relative efficacy of medications in reducing off time? 3.Which medications reduce dyskinesia? 4.Does DBS of the STN, GPi, or VIM reduce off time, dyskinesia, medication usage and improve motor function? 5.What factors predict improvement after DBS?

18. © 2006 American Academy of Neurology Methods Literature Search: –MEDLINE, EMBASE and Ovid databases Secondary search using bibliography of retrieved articles and knowledge of expert panel At least two authors reviewed each abstract for topic relevance At least two authors reviewed each full article

19. © 2006 American Academy of Neurology Methods Risk of bias determined using the classification of evidence for each study (Class I–IV) Strength of practice recommendations linked directly to level of evidence (Level A–U) Conflicts of interests disclosed

20. © 2006 American Academy of Neurology Methods: Medical Treatment (Q1-3) Search restricted to English language and medications available in the United States, or those having an approvable letter from the Food and Drug Administration Initial search from 1965 to June 2004 Supplemental search in 2005 to include the latest clinical trials

21. © 2006 American Academy of Neurology Methods: Surgical Treatment (Q4-5) Search restricted to English language Included articles from 1965 to June 2004

22. © 2006 American Academy of Neurology Literature Search/Review: Medical Treatment 29 articles 730 articles Exclusion criteria: -Not related to drugs examined -Review articles -Studies of early PD or non- fluctuators -Open label studies -Mechanisms of action, pharmacokinetics or animal studies -Other uses of drugs examined -< 20 subjects -Studies primarily about side effects -Study duration < 3 months -Not peer reviewed

23. © 2006 American Academy of Neurology Literature Search/Review: Surgical Treatment 20 articles 478 articles Exclusion reasons: --< 20 subjects -Not motor function outcome studies of DBS in PD -Review articles -Comment articles -< 6 month follow up -Not peer reviewed articles -Animal studies -Redundant reports of included data -No differentiation of results between PD and essential tremor -No standard outcome measures for PD

24. © 2006 American Academy of Neurology Medical Treatment

25. © 2006 American Academy of Neurology Clinical Question 1 Which medications reduce off time? 31 studies –7 Class I –16 Class II –8 Class III

26. © 2006 American Academy of Neurology Evidence: Dopamine Agonists AuthorDrugClassN Study Duration Decrease Off time Active Decrease Off time Placebo OlanowPergolideI189/18724 week32% (1.8 h)*4% (0.2 h) LiebermanPramipexoleI181/17932 week31%*7% GuttmanPramipexoleII79/8340 week15% (2.5 h)*3% RascolRopiniroleII23/2312 week23%*4% LiebermanRopiniroleII95/5426 week11.7%*5% DeweyApomorphineII20/94 week34% (2 h)*0% GuttmanBromocriptineII84/8340 week8%3% SteigerCabergolineIII19/1024 week40% (2 h)*18% (0.7 h) AhlskogCabergolineIII17/1024 week59% (3.3 h)*NS

27. © 2006 American Academy of Neurology Evidence: MAO B Inhibitors AuthorDrugClassN Study Duration Decrease Off time Active Decrease Off time Placebo PSG Rasagiline (0.5 mg)I164/15926 week23% (1.4 h)*15% (0.9 h) PSG Rasagiline (1.0 mg)I149/15926 week29% (1.8 h)*15% (0.9) Rascol Rasagiline (1.0 mg)I231/22918 week21% (1.2 h)*7% (0.4 h) Waters Orally Disintegrating SelegilineII94/4612 week32% (2.2 h)*9% (0.6 h) GolbeSelegilineIII50/466 weekNR

28. © 2006 American Academy of Neurology Evidence: COMT Inhibitors AuthorDrugClassN Study Duration Decrease Off time Active Decrease Off time Placebo PSGEntacaponeI103/10224 weekNR RascolEntacaponeI227/22918 week21% (1.2 h)*7% (0.4 h) PoeweEntacaponeII197/10424 week25.8% (1.6 h)*13.4% (0.9 h) RinneEntacaponeII85/8624 week23.6% (1.3 h)*1.9% (0.1 h) FenelonEntacaponeII99/6312 week0.9 h0.4 h Rajput Tolcapone (100 mg tid)II69/6612 week32% (2.3 h)20% (1.4 h) Rajput Tolcapone (200 mg tid)II67/6612 week48% (3.2 h)*20% (1.4 h) Baas Tolcapone (100 mg tid)II60/5812 week31.5%*11% Baas Tolcapone (200 mg tid)II59/5812 week26.20%11%

29. © 2006 American Academy of Neurology Evidence: Sustained Release Carbidopa/Levodopa AuthorDrugClassN Study Duration Decrease Off time Jankovic Carbidopa/levodopa CR/IRIII2016 weekNS Hutton Carbidopa/levodopa CR/IRIII2124 weekNS Ahlskog Carbidopa/levodopa CR/IRIII2816 weekNS Lieberm an Carbidopa/levodopa CR/IRIII2416 weekNS

30. © 2006 American Academy of Neurology Recommendations for Patients with PD and Motor Fluctuations Entacapone and rasagiline should be offered to reduce off time in PD patients (Level A)* *Strength indicates level of supporting evidence, not hierarchy of efficacy

31. © 2006 American Academy of Neurology Recommendations for Patients with PD and Motor Fluctuations Pergolide, pramipexole, ropinirole, and tolcapone should be considered to reduce off time (Level B)* –Tolcapone (hepatotoxicity) and pergolide (valvular fibrosis) should be used with caution and require monitoring *Strength indicates level of supporting evidence, not hierarchy of efficacy

32. © 2006 American Academy of Neurology Recommendations for Patients with PD and Motor Fluctuations Apomorphine, cabergoline, and selegiline may be considered to reduce off time (Level C)* Sustained release carbidopa/levodopa and bromocriptine may be disregarded to reduce off time (Level C)* *Strength indicates level of supporting evidence, not hierarchy of efficacy

33. © 2006 American Academy of Neurology Clinical Question 2: What is the relative efficacy of medications in reducing off time? 6 studies –1 Class I –4 Class II –1 Class III

34. © 2006 American Academy of Neurology Comparator Placebo Studies AuthorDrugClassN Study Duration Decrease Off time Active Decrease Off time Placebo RascolEntacaponeI227/22918 week21% (1.2 h)*7% (0.4 h) Rascol Rasagiline (1.0 mg)I231/22918 week21% (1.2 h)*7% (0.4 h) GuttmanPramipexoleII79/8340 week15% (2.5 h)*3% GuttmanBromocriptineII84/8340 week8%3%

35. © 2006 American Academy of Neurology Direct Comparator Studies DrugClassN Study Duration Decrease Off time Decrease Off time Cabergoline [c]/ Bromocriptine [b]II22/2236 week50% [c]31.3% [b] Ropinirole [r]/ Bromocriptine [b]II88/5124 week17.7% [r]4.8% [b] Tolcapone [t]/ Entacapone [e]II75/753 weekNR* Tolcapone [t]/ Pergolide [p]III101/10212 week17.9% [t]18.2% [p] *NR = Not reported

36. © 2006 American Academy of Neurology Relative Efficacy of Medications in Reducing Off Time Rasagiline similar to entacapone Bromocriptine similar to pramipexole Tolcapone similar to pergolide Cabergoline similar to bromocriptine Tolcapone similar to entacapone Ropinirole possibly superior to bromocriptine

37. © 2006 American Academy of Neurology Relative Efficacy of Medications in Reducing Off Time Many of these studies not powered to demonstrate superiority of one drug over another Other than comparisons of ropinirole and bromocriptine, there is insufficient evidence to conclude which one agent is superior to another in reducing off time

38. © 2006 American Academy of Neurology Recommendations: Relative Efficacy of Medications in Reducing Off Time Ropinirole may be chosen over bromocriptine for reducing off time (Level C). Otherwise, there is insufficient evidence to recommend one agent over another (Level U).

39. © 2006 American Academy of Neurology Clinical Question 3: Which medications reduce dyskinesia? 2 studies –1 Class II –1 Class III

40. © 2006 American Academy of Neurology Evidence Class II single center, double masked, placebo controlled, randomized, crossover trial with amantadine (100 mg BID) –24 subjects for 3 weeks –92% completed the trial –Total dyskinesia score (Goetz scale) decreased 24% (p< 0.004) –17% decrease in maximal dyskinesia score (p < 0.02) –Significant decrease in dyskinesia (UPDRS part IVa) (p< 0.02)

41. © 2006 American Academy of Neurology Recommendations for Medications that Reduce Dyskinesia Amantadine may be considered for PD patients with motor fluctuations to reduce dyskinesia (Level C) Insufficient evidence to support or refute the efficacy of clozapine in reducing dyskinesia (Level U)

42. © 2006 American Academy of Neurology Medications that Reduce Dyskinesia Clozapine’s potential toxicity: –Agranulocytosis –Seizures –Myocarditis –Orthostatic hypotension Required white blood cell count monitoring

43. © 2006 American Academy of Neurology Deep Brain Stimulation

44. © 2006 American Academy of Neurology Clinical Question 4 Does DBS of the STN, GPi, or VIM reduce off time, dyskinesia, medication usage, and improve motor function? 21 studies –5 Class III –16 Class IV

45. © 2006 American Academy of Neurology Evidence: Bilateral STN DBS AuthorTher Class Prog Class Baseline UPDRS Motor (% change meds on vs. off) Follow-up UPDRS Motor (% change: stim on meds off vs. baseline meds off) Dyskinesia/Off time improvement Meds Reduced DBSPDIIIIV56%52%Rush Dyskinesia: 58% Diary: dysk 23 to 7% Off time :49 to 19% 37% OstergaardIIIIV54%64% [1 yr]UPDRS dysk 86% UPDRS off time 83% 20% PahwaIIIIV40% [1 yr] 37% [2 yr] 32% [1 yr] 28% [2 yr] Diary: 1 yr dysk 18 to 4%, off 44 to 20%; 54% [1 yr] 57% [2 yr]

46. © 2006 American Academy of Neurology Evidence: Bilateral STN DBS AuthorTher Class Prog Class Baseline UPDRS Motor (% change meds on vs. off) Follow-up UPDRS Motor (% change: stim on meds off vs. baseline meds off) Dyskinesia/Off time improvement Meds Reduced EsselinkIIIIV59%49%UPDRS dysk 50% 33% WelterIVII71%65%UPDRS dysk 69% UPDRS off 87% 68% Kleiner- Fisman IVII55%48% [1 yr] 41% [2.5 yr] Dysk Rating Scale 48% [1 yr] 50% [2.5 yr] 38% [1 yr] 36% [2.5 yr]

47. © 2006 American Academy of Neurology Evidence: GPi DBS One Class III study –6-month, prospective, multicenter trial of 41 PD patients –33.3% improvement in UPDRS motor scores –35.8% improvement ADL scores –Diaries: on time increased from 28% to 64%; on time with dyskinesia decreased from 35% to 12%; and off time from 37% to 24%

48. © 2006 American Academy of Neurology Evidence: GPi DBS One Class III study –Rush Dyskinesia scale improved by 67% –No change in daily levodopa equivalence dose –AE included intracranial hemorrhage in 9.8% of patients (7.3% leading to hemiparesis); increased dyskinesia in 7.3%; dystonia in 4.9%; lead migrations in 4.9%; and dysarthria, seizure, infection, broken lead, seroma, and abdominal pain each in 2.4%

49. © 2006 American Academy of Neurology Evidence: VIM DBS Four articles met inclusion criteria All four articles were Class IV Due to the low quality of evidence, thalamic stimulation is not discussed

50. © 2006 American Academy of Neurology Adverse Effects with DBS 4 articles examining DBS complications 360 patients, 288 were PD patients Surgical AEs –Death due to PE and aspiration pneumonia: 0.6% –Permanent neurological sequelae: 2.8% –Other neurological sequelae: 5.6% –Hemorrhage: 3.1% –Confusion/Disorientation: 2.8% –Seizures: 1.1% –PE: 0.6%

51. © 2006 American Academy of Neurology Adverse Effects with DBS Complications related to DBS hardware –Lead replacement due to fracture, migration or malfunction: 5% –Lead reposition due to misplacement: 2.8% –Extension wire replacement due to fracture or erosion: 4.4%

52. © 2006 American Academy of Neurology Adverse Effects with DBS Complications related to DBS hardware –IPG replacement due to malfunction: 4.2% –IPG reposition due to cosmetic reasons: 1.7% –Allergic reaction due to hardware 0.6%

53. © 2006 American Academy of Neurology Recommendations for DBS DBS of the STN may be considered as a treatment option in PD patients to improve motor function and reduce motor fluctuations, dyskinesia, and medication usage (Level C) –Need for patient counseling about risks and benefits of this procedure

54. © 2006 American Academy of Neurology Recommendations for DBS Insufficient evidence to make any recommendations about the effectiveness of DBS of the GPi or VIM nucleus of the thalamus in reducing motor complications or medication usage, or in improving motor function in PD patients (Level U)

55. © 2006 American Academy of Neurology Clinical Question 5 What factors predict improvement after DBS? 14 studies –2 Class II –12 Class IV

56. © 2006 American Academy of Neurology Evidence Class II study examining factors predictive of STN DBS outcome –41 PD patients (mean age of 56.4) –Patients 56 and younger: significantly greater improvements than older patients –Patients with disease duration less than 16 years: greater improvements than those with longer disease duration –Levodopa responsiveness the strongest predictor of outcome

57. © 2006 American Academy of Neurology Evidence Class II study examining factors predictive of STN DBS outcome –25 patients with a mean age of 57.2 –No effect of age, sex, disease duration, baseline drug usage, baseline dyskinesia, age of onset –Levodopa responsiveness the only factor related to outcome No studies of GPi or VIM DBS examining predictive factors

58. © 2006 American Academy of Neurology Recommendations for Factors Predicting Improvement after DBS Pre-operative response to levodopa should be considered as a factor predictive of outcome after DBS of the STN (Level B)

59. © 2006 American Academy of Neurology Recommendations for Factors Predicting Improvement after DBS Age and duration of PD may be considered as factors predictive of outcome after DBS of the STN. Younger patients with shorter disease durations may possibly have improvement greater than that of older patients with longer disease durations (Level C).

60. © 2006 American Academy of Neurology Recommendations for Factors Predicting Improvement after DBS Insufficient evidence to make any recommendations about factors predictive of improvement after DBS of the GPi or VIM nucleus of the thalamus in PD patients (Level U)

61. © 2006 American Academy of Neurology Summary Entacapone and rasagiline should be offered to reduce off time (Level A) Pergolide, pramipexole, ropinirole and tolcapone should be considered to reduce off time (Level B)

62. © 2006 American Academy of Neurology Summary Sustained release carbidopa/levodopa and bromocriptine may be disregarded to reduce off time (Level C) Amantadine may be considered to reduce dyskinesia (Level C)

63. © 2006 American Academy of Neurology Summary DBS of the STN may be considered to improve motor function and reduce off time, dyskinesia, and medication usage (Level C)

64. © 2006 American Academy of Neurology Summary Not enough evidence to support or refute the efficacy of DBS of the GPi or VIM nucleus of the thalamus in reducing off time, dyskinesia, or medication usage, or to improve motor function (Level U) Preoperative response to levodopa predicts better outcome after DBS of the STN (Level B)

65. © 2006 American Academy of Neurology Recommendations for Future Research: Medical Treatment Comparative, randomized, double masked, controlled trials to determine which drugs are the most effective Uniform and more specific inclusion criteria Outcome measures should be standardized

66. © 2006 American Academy of Neurology Recommendations for Future Research: Medical Treatment Non-motor fluctuations, PD specific quality of life measures, and neuropsychiatric features require greater assessment and reporting Additional novel drug classes need further investigation

67. © 2006 American Academy of Neurology Recommendations for Future Research: Surgical Treatment Further research should include objective clinical measures Raters should be masked Factors predictive of a positive outcome Evaluate the optimal timing for surgery

68. © 2006 American Academy of Neurology Recommendations for Future Research: Surgical Treatment Determine cost-benefit analysis over the longer term Document regional disparity

69. © 2006 American Academy of Neurology Access the full guideline at: AAN.com/Guidelines

70. © 2006 American Academy of Neurology Questions, Comments?

71. © 2006 American Academy of Neurology Thanks for your participation!