Practice Parameter: Treatment of Parkinson Disease with Motor Fluctuations and Dyskinesia An Evidence-Based Review

1. 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. 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

3. Overview Background and descriptive epidemiology Treatment of PD Gaps in PD Care AAN guideline process Medical treatments Surgical treatments Summary Recommendations for future research

4. 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

5. 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

6. Descriptive Epidemiology of Parkinson Syndrome Incidence 5�24/105 worldwide (ref) 20.5/105 USA (ref) Prevalence 57�371/105 worldwide (ref) 300/105 USA/Canada (Strickland & Bertoni, 2004) Prevalence of PS/PD rising slowly with aging population Add referenceAdd reference

7. 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

8. 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

9. 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

10. American Academy of Neurology Guideline Process Clinical Question Evidence Conclusions Recommendations Ask a question; seek all data that could answer the question�not just the articles supporting one bias; evaluate the evidence based on quality; summarize the data in answer to the clinical question; and provide practical recommendations for practiceAsk a question; seek all data that could answer the question�not just the articles supporting one bias; evaluate the evidence based on quality; summarize the data in answer to the clinical question; and provide practical recommendations for practice

11. 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

12. Literature Search/Review: Rigorous, Comprehensive, Transparent

13. 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

14. 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

15. 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

16. Clinical Questions Which medications reduce off time? What is the relative efficacy of medications in reducing off time? Which medications reduce dyskinesia? Does DBS of the STN, GPi, or VIM reduce off time, dyskinesia, medication usage and improve motor function? What factors predict improvement after DBS?

17. 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

18. 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

19. 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

20. Methods: Surgical Treatment (Q4-5) Search restricted to English language Included articles from 1965 to June 2004

21. Literature Search/Review: Medical Treatment

22. Literature Search/Review: Surgical Treatment

23. Medical Treatment

24. Clinical Question 1 Which medications reduce off time? 31 studies 7 Class I 16 Class II 8 Class III

25. Evidence: Dopamine Agonists

26. Evidence: MAO B Inhibitors

27. Evidence: COMT Inhibitors

28. Evidence: Sustained Release Carbidopa/Levodopa

29. 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

30. 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

31. 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

32. 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

33. Comparator Placebo Studies

34. Direct Comparator Studies

35. 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

36. 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

37. 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).

38. Clinical Question 3: Which medications reduce dyskinesia? 2 studies 1 Class II 1 Class III

39. 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)

40. 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)

41. Medications that Reduce Dyskinesia  Clozapine�s potential toxicity: Agranulocytosis Seizures Myocarditis Orthostatic hypotension Required white blood cell count monitoring

42. Deep Brain Stimulation

43. 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

44. Evidence: Bilateral STN DBS

45. Evidence: Bilateral STN DBS

46. 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%

47. 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%

48. 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

49. 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%

50. 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%

51. 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%

52. 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

53. 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)

54. Clinical Question 5 What factors predict improvement after DBS? 14 studies 2 Class II 12 Class IV

55. 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

56. 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

57. 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)

58. 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).

59. 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)

60. 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)

61. 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)

62. Summary DBS of the STN may be considered to improve motor function and reduce off time, dyskinesia, and medication usage (Level C)

63. 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)

64. 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

65. 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

66. 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

67. Recommendations for Future Research: Surgical Treatment Determine cost-benefit analysis over the longer term Document regional disparity

68. Questions, Comments?

69. Thanks for your participation!