Practice Parameter: Neuroprotective Strategies and Alternative Therapies for Parkinson’s Disease (An Evidence-Based Re

1. Practice Parameter: Neuroprotective Strategies and Alternative Therapies for Parkinson’s Disease (An Evidence-Based Review) American Academy of Neurology Quality Standard Subcommittee O. Suchowersky, MD; G. Gronseth, MD; J. Perlmutter, MD; S. Reich, MD; T. Zesiewicz, MD; W.J. Weiner, MD

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3. Presentation Objectives • To define key issues in the management of Parkinson’s disease (PD) relating to neuroprotective strategies and alternative treatments • To make evidence-based recommendations

4. Overview • Background and epidemiology • Gaps in PD care • AAN guideline process • Neuroprotective strategies • Alternative treatments • Summary • Recommendations for future research

5. Background • PD a neurodegenerative disorder • Classic symptoms: • Bradykinesia • Rigidity • Rest tremor • Strategies to delay onset or slow progression – important considerations in overall treatment

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

7. Gaps in PD Care • Widespread fear that levodopa is neurotoxic and speeds up disease symptoms • Neuroprotection: Is there anything that will help slow the advancement of the disease?

8. Gaps in PD Care • Many patients and caregivers use alternative or complementary medications and vitamins • 63% of patients use nutritional supplements, but less than 50% report this to their physician (Rajendran et al., 2001) • Only 4% are aware of possible drug interactions (Carter et al., 2003)

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

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. Complete Search Review abstracts Review full text Select articles Relevant 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 • Are there any therapies that can slow progression of PD? • Are there any nonstandard, pharmacologic or nonpharmacologic therapies that have been shown to improve motor function in PD?

17. Methods • Literature Search: • MEDLINE, EMBASE, CINHAL, and Cochrane Database of Systematic Reviews (1997-2002) • Only articles written in English included • Second MEDLINE search (1966 through Aug. 2004) • Followed by a secondary search extending to January 2005 using the bibliographies of retrieved articles

18. Methods • At least two authors reviewed each full article • 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. 112 articles 11 articles Literature Search/Review: Neuroprotective Strategies Exclusion criteria: -Articles dealing only with symptomatic benefit -Articles with at least 6 months of follow up -Articles that were off topic -Review articles

20. 167 articles 22 articles Literature Search/Review: Alternative Therapies Exclusion criteria: -Studies including at least 10 subjects with treatment of at least 1 week duration -Articles that were off topic -Review articles

21. Neuroprotective Strategies

22. PD Neuroprotection • Challenge in defining and measuring neuroprotection • Potential clinical surrogate markers not validated • Neuroimaging weakened by confounding • Long-term follow-up required to test possible neuroprotective benefit

23. Are there any therapies that can slow progression of PD? Clinical Question 1

24. PD Neuroprotection • Neuroprotective therapies considered: • Vitamin E • Riluzole • Coenzyme Q10 • Levodopa • Pramipexole • Ropinirole • Other

25. Neuroprotective Strategies • 11 articles met inclusion criteria for clinical question • 7 Class 1 studies • 1 Class II study • 3 Class IV studies

26. PD Neuroprotection: Vitamin E • Two articles identified • Class IV study (Fahn, 1992) • Nonrandomized, unblinded study • No independent assessment • Suggested slower rate of progression in patients with early PD treated with vitamin E (3,200 IU/day) combined with vitamin C (3,000 mg/day)

27. PD Neuroprotection: Vitamin E • Class I trial: DATATOP (PSG, 1993) • Randomized, double-blind, prospective • 800 patients randomized to a dose of 2,000 IU of vitamin E/day or placebo • Followed for 14 ± 6 months • Primary endpoint: onset of disability requiring use of levadopa • No difference between tocopherol and placebo groups in the average time to required levodopa (hazard ratio 0.91, 95% CI .74 to 1.12)

28. PD Neuroprotection: Recommendation for Vitamin E • For patients with PD, treatment with 2,000 units of vitamin E should not be considered for neuroprotection (Level B)

29. PD Neuroprotection: Levodopa • One Class I study (PSG, 2004) • Double-blinded, controlled trial • Randomized 361 patients with PD to placebo or levodopa (150mg/day, 300 mg/day, or 600 mg/day) • Primary outcome: masked assessment of change in UPDRS from baseline after 40 weeks of treatment and 2-week washout • Patients randomized to all levodopa doses: significantly better UPDRS scores than patients on placebo

30. PD Neuroprotection: Levodopa Parkinson Study Group 2004, NEJM.

31. PD Neuroprotection: Recommendation for Levodopa • Levodopa may be considered for initial treatment of PD (Level B) • 9 months • Does not accelerate disease progression • Safe • No long term evidence to recommend levodopa for neuroprotection (Level U)

32. PD Neuroprotection: Rasagiline

33. Recommendations for Neuroprotection • Insufficient evidence for neuroprotection (Level U): • Coenzyme Q10 • Rasagile • Riluzole • Selegiline

34. Recommendations for Neuroprotection • Insufficient evidence for neuroprotection (Level U): • Amantadine • Ropinirole • Pramipexole • Thalamotomy

35. Alternative Therapies

36. Are there any non-standard pharmacological or nonpharmacological therapies that have been shown to improve motor function in PD? Clinical Question 2

37. Alternative Therapies • Use of complementary medication and treatment common in patients with PD • 40% of patients in the United States and 54% of patients in the United Kingdom use herbs, vitamins, massage and acupuncture (Rajendran et al., 2001; Ferry et al., 2002)

38. Alternative Therapies • Foods: • Mucuna pruriens (cowhage or velvet bean) • Vicia faba (broad or fava bean) • Vitamins: • Vitamin C • Folic acid, pyridoxine • Vitamin E • Acupuncture

39. Alternative Therapies • Manual Therapy • Chiropractic manipulation • Osteopathic manipulation • Trager therapy • Exercise therapy • Speech therapy

40. Alternative Therapies • 22 articles met inclusion criteria for clinical question • 2 Class 1 studies • 15 Class II study • 2 Class III studies • 3 Class IV studies

41. Recommendations for Alternative Therapies in PD • Insufficient evidence (Level U): • M pruriens • Acupuncture • Biofeedback • Manual therapy • Alexander technique

42. Exercise Therapy in PD • Multidisciplinary rehabilitation • Music therapy • Treadmill training • Balance training • “Cued” exercise training

43. Exercise Therapy in PD

44. Exercise Therapy in PD

45. Recommendation for Exercise Therapy in PD • Exercise therapy may be considered to improve function (Level C) • Results in improvement in UPDRS • Decrease in falls

46. Exercise Therapy in PD • No specific exercise program shown to be superior to another • Benefit not sustained after exercise is discontinued

47. Speech Therapies in PD • For patients with PD complicated by dysarthria, speech therapy may be considered to improve speech volume (Level C) • 5 trials identified • No specific therapy shown to be superior to another

48. Summary • Levodopa does not appear to accelerate disease progression • No treatment has been shown to be neuroprotective • No evidence that vitamin or food additives can improve motor function in PD

49. Summary • Exercise may be helpful in improving motor function • Speech therapy may be helpful in improving speech volume • No manual therapy has been shown to be helpful in the treatment of motor symptoms

50. Recommendations for Future Research • Reliable and validated surrogated endpoints that mirror nigrostriatal dopaminergic neuron loss • Accurate early diagnosis and improved knowledge of disease progression