© 2006 American Academy of Neurology 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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© 2006 American Academy of Neurology 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

© 2006 American Academy of Neurology Overview Background and epidemiology Gaps in PD care AAN guideline process Neuroprotective strategies Alternative treatments Summary Recommendations for future research

© 2006 American Academy of Neurology Background PD a neurodegenerative disorder Classic symptoms: –Bradykinesia –Rigidity –Rest tremor Strategies to delay onset or slow progression – important considerations in overall treatment

© 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

© 2006 American Academy of Neurology 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?

© 2006 American Academy of Neurology 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)

© 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

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

© 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

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

© 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

© 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

© 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

© 2006 American Academy of Neurology Clinical Questions 1.Are there any therapies that can slow progression of PD? 2.Are there any nonstandard, pharmacologic or nonpharmacologic therapies that have been shown to improve motor function in PD?

© 2006 American Academy of Neurology Methods Literature Search: –MEDLINE, EMBASE, CINHAL, and Cochrane Database of Systematic Reviews ( ) 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

© 2006 American Academy of Neurology 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

© 2006 American Academy of Neurology Literature Search/Review: Neuroprotective Strategies 11 articles 112 articles Exclusion criteria: -Articles dealing only with symptomatic benefit -Articles with at least 6 months of follow up -Articles that were off topic -Review articles

© 2006 American Academy of Neurology Literature Search/Review: Alternative Therapies 22 articles 167 articles Exclusion criteria: -Studies including at least 10 subjects with treatment of at least 1 week duration -Articles that were off topic -Review articles

© 2006 American Academy of Neurology Neuroprotective Strategies

© 2006 American Academy of Neurology 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

© 2006 American Academy of Neurology Clinical Question 1 Are there any therapies that can slow progression of PD?

© 2006 American Academy of Neurology PD Neuroprotection Neuroprotective therapies considered: –Vitamin E –Riluzole –Coenzyme Q10 –Levodopa –Pramipexole –Ropinirole –Other

© 2006 American Academy of Neurology Neuroprotective Strategies 11 articles met inclusion criteria for clinical question –7 Class 1 studies –1 Class II study –3 Class IV studies

© 2006 American Academy of Neurology 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)

© 2006 American Academy of Neurology 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)

© 2006 American Academy of Neurology 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)

© 2006 American Academy of Neurology 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

© 2006 American Academy of Neurology PD Neuroprotection: Levodopa Parkinson Study Group 2004, NEJM.

© 2006 American Academy of Neurology 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)

© 2006 American Academy of Neurology PD Neuroprotection: Rasagiline

© 2006 American Academy of Neurology Recommendations for Neuroprotection Insufficient evidence for neuroprotection (Level U): –Coenzyme Q10 –Rasagile –Riluzole –Selegiline

© 2006 American Academy of Neurology Recommendations for Neuroprotection Insufficient evidence for neuroprotection (Level U): –Amantadine –Ropinirole –Pramipexole –Thalamotomy

© 2006 American Academy of Neurology Alternative Therapies

© 2006 American Academy of Neurology Clinical Question 2 Are there any non-standard pharmacological or nonpharmacological therapies that have been shown to improve motor function in PD?

© 2006 American Academy of Neurology 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)

© 2006 American Academy of Neurology Alternative Therapies Foods: –Mucuna pruriens (cowhage or velvet bean) –Vicia faba (broad or fava bean) Vitamins: –Vitamin C –Folic acid, pyridoxine –Vitamin E Acupuncture

© 2006 American Academy of Neurology Alternative Therapies Manual Therapy –Chiropractic manipulation –Osteopathic manipulation –Trager therapy Exercise therapy Speech therapy

© 2006 American Academy of Neurology 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

© 2006 American Academy of Neurology Recommendations for Alternative Therapies in PD Insufficient evidence (Level U): –M pruriens –Acupuncture –Biofeedback –Manual therapy –Alexander technique

© 2006 American Academy of Neurology Exercise Therapy in PD Multidisciplinary rehabilitation Music therapy Treadmill training Balance training “Cued” exercise training

© 2006 American Academy of Neurology Exercise Therapy in PD Author Cohort size Outcome VariablesTreatmentDuration Wade et al PDQ-39, SC-36, peg test, walking multidisciplinary rehab vs. placebo 1 x per week x 6 weeks, FU 48 weeks Marchese et al UPDRScued vs. non- cued exercises 3 x per week x 6 weeks, FU 12 weeks Miyai et al UPDRS, ambulation BWSTT vs. physiotherapy 3 x per week x 4 weeks, FU 8 weeks

© 2006 American Academy of Neurology Exercise Therapy in PD Author Cohort size Outcome VariablesTreatmentDuration Miyai et al UPDRS, ambulation BWSTT vs. physiotherapy 3 x per week x 4 weeks, FU 6 months Hirsch et al balance, falls, strength Balance/resistanc e vs. balance 3 x per week x 10 weeks, FU 14 weeks Pachetti et al UPDRS, PDQualif Music therapy vs. physical therapy 1 x per week x 3 months, FU 5 months Comella et al UPDRS, depression General exercise vs. placebo 3 x per week x 1 month, FU 12 months

© 2006 American Academy of Neurology Recommendation for Exercise Therapy in PD Exercise therapy may be considered to improve function (Level C) –Results in improvement in UPDRS –Decrease in falls

© 2006 American Academy of Neurology Exercise Therapy in PD No specific exercise program shown to be superior to another Benefit not sustained after exercise is discontinued

© 2006 American Academy of Neurology 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

© 2006 American Academy of Neurology 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

© 2006 American Academy of Neurology 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

© 2006 American Academy of Neurology Recommendations for Future Research Reliable and validated surrogated endpoints that mirror nigrostriatal dopaminergic neuron loss Accurate early diagnosis and improved knowledge of disease progression

© 2006 American Academy of Neurology Recommendations for Future Research Development of methods to identify presymptomatic patients for clinical trials Innovative trials with long-term follow-up Studies to demonstrate safety or effectiveness of neuroprotective therapies

© 2006 American Academy of Neurology To access the full guideline please visit: AAN.com/Guidelines Neurology® April 11, :

© 2006 American Academy of Neurology Questions or comments?

© 2006 American Academy of Neurology Thanks for your participation!