Title: Practice Parameter: Neuroprotective Strategies and Alternative Therapies for Parkinson’s Disease (An Evidence-Based Review)
1Practice Parameter Neuroprotective Strategies
and Alternative Therapies for Parkinsons
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
2Presentation Objectives
- To define key issues in the management of
Parkinsons disease (PD) relating to
neuroprotective strategies and alternative
treatments - To make evidence-based recommendations
3Overview
- Background and epidemiology
- Gaps in PD care
- AAN guideline process
- Neuroprotective strategies
- Alternative treatments
- Summary
- Recommendations for future research
4Background
- PD a neurodegenerative disorder
- Classic symptoms
- Bradykinesia
- Rigidity
- Rest tremor
- Strategies to delay onset or slow progression
important considerations in overall treatment
5 Descriptive Epidemiology of Parkinson
Syndrome
- Incidence 13/100,000
- (Van Den Eeden et al. Am J Epidemiol
20031015-22) - Prevalence
- 300/100,000 (Strickland Bertoni, 2004)
- Prevalence of PS/PD rising slowly with aging
population
6Gaps 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?
7Gaps 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)
8Seeking 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
9American Academy of Neurology Guideline Process
- Clinical Question
- Evidence
- Conclusions
- Recommendations
10Clinical 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
11Literature Search/Review Rigorous,
Comprehensive, Transparent
12 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
13AAN 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
14AAN 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
15Clinical 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?
16Methods
- 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
17Methods
- At least two authors reviewed each full article
- Risk of bias determined using the classification
of evidence for each study (Class IIV) - Strength of practice recommendations linked
directly to level of evidence (Level AU) - Conflicts of interests disclosed
18Literature 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
19Literature 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
20Neuroprotective Strategies
21PD 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
22Clinical Question 1
-
- Are there any therapies that can slow
progression of PD?
23PD Neuroprotection
- Neuroprotective therapies considered
- Vitamin E
- Riluzole
- Coenzyme Q10
- Levodopa
- Pramipexole
- Ropinirole
- Other
24 Neuroprotective Strategies
- 11 articles met inclusion criteria for clinical
question - 7 Class 1 studies
- 1 Class II study
- 3 Class IV studies
25 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)
26PD 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)
27PD 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)
28PD 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
29PD Neuroprotection Levodopa
Parkinson Study Group 2004, NEJM.
30PD 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)
31 PD Neuroprotection Rasagiline
32Recommendations for Neuroprotection
- Insufficient evidence for neuroprotection (Level
U) - Coenzyme Q10
- Rasagile
- Riluzole
- Selegiline
33Recommendations for Neuroprotection
- Insufficient evidence for neuroprotection (Level
U) - Amantadine
- Ropinirole
- Pramipexole
- Thalamotomy
34Alternative Therapies
35Clinical Question 2
- Are there any non-standard pharmacological or
nonpharmacological therapies that have been shown
to improve motor function in PD?
36 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)
37Alternative Therapies
- Foods
- Mucuna pruriens (cowhage or velvet bean)
- Vicia faba (broad or fava bean)
- Vitamins
- Vitamin C
- Folic acid, pyridoxine
- Vitamin E
- Acupuncture
38Alternative Therapies
- Manual Therapy
- Chiropractic manipulation
- Osteopathic manipulation
- Trager therapy
- Exercise therapy
- Speech therapy
39 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
40Recommendations for Alternative Therapies in PD
- Insufficient evidence (Level U)
- M pruriens
- Acupuncture
- Biofeedback
- Manual therapy
- Alexander technique
41Exercise Therapy in PD
- Multidisciplinary rehabilitation
- Music therapy
- Treadmill training
- Balance training
- Cued exercise training
42Exercise Therapy in PD
Author Cohort size Outcome Variables Treatment Duration
Wade et al 2003 144 PDQ-39, SC-36, peg test, walking multidisciplinary rehab vs. placebo 1 x per week x 6 weeks, FU 48 weeks
Marchese et al 2000 20 UPDRS cued vs. non-cued exercises 3 x per week x 6 weeks, FU 12 weeks
Miyai et al 2000 10 UPDRS, ambulation BWSTT vs. physiotherapy 3 x per week x 4 weeks, FU 8 weeks
43Exercise Therapy in PD
Author Cohort size Outcome Variables Treatment Duration
Miyai et al 2002 24 UPDRS, ambulation BWSTT vs. physiotherapy 3 x per week x 4 weeks, FU 6 months
Hirsch et al 2003 18 balance, falls, strength Balance/resistance vs. balance 3 x per week x 10 weeks, FU 14 weeks
Pachetti et al 2000 32 UPDRS, PDQualif Music therapy vs. physical therapy 1 x per week x 3 months, FU 5 months
Comella et al 1994 18 UPDRS, depression General exercise vs. placebo 3 x per week x 1 month, FU 12 months
44Recommendation for Exercise Therapy in PD
- Exercise therapy may be considered to improve
function (Level C) - Results in improvement in UPDRS
- Decrease in falls
45Exercise Therapy in PD
- No specific exercise program shown to be superior
to another - Benefit not sustained after exercise is
discontinued
46Speech 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
47Summary
- 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
48Summary
- 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
49Recommendations for Future Research
- Reliable and validated surrogated endpoints that
mirror nigrostriatal dopaminergic neuron loss - Accurate early diagnosis and improved knowledge
of disease progression
50Recommendations 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
51Questions, Comments?
52Thanks for your participation!