Transcript Slide 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
© 2006 American Academy of Neurology
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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
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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
– 5–24/105 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
© 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?
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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
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Literature Search/Review:
Rigorous, Comprehensive, Transparent
Complete
Search
Review abstracts
Review full text
Select articles
Relevant
© 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 (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
© 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
112 articles
Exclusion criteria:
-Articles dealing only
with symptomatic
benefit
-Articles with at least
6 months of follow up
11 articles
-Articles that were off
topic
-Review articles
© 2006 American Academy of Neurology
Literature Search/Review:
Alternative Therapies
167 articles
Exclusion criteria:
-Studies including at
least 10 subjects with
treatment of at least 1
week duration
-Articles that were off
topic
22 articles
© 2006 American Academy of Neurology
-Review articles
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
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Multidisciplinary rehabilitation
Music therapy
Treadmill training
Balance training
“Cued” exercise training
© 2006 American Academy of Neurology
Exercise 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. noncued exercises
3 x per week x 6
weeks, FU 12
weeks
UPDRS,
ambulation
BWSTT vs.
physiotherapy
3 x per week x 4
weeks, FU 8
weeks
Miyai et al 10
2000
© 2006 American Academy of Neurology
Exercise Therapy in PD
Author
Cohort
size
Outcome
Variables
Treatment
Duration
Miyai et al
2002
24
UPDRS,
ambulation
BWSTT vs.
physiotherapy
Hirsch et al
2003
18
balance, falls,
strength
Balance/resistanc 3 x per week x 10
e vs. balance
weeks, FU 14
weeks
Pachetti et
al 2000
32
UPDRS,
PDQualif
Music therapy vs. 1 x per week x 3
physical therapy
months, FU 5
months
Comella et
al 1994
18
UPDRS,
depression
General exercise
vs. placebo
© 2006 American Academy of Neurology
3 x per week x 4
weeks, FU 6
months
3 x per week x 1
month, FU 12
months
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 66:976-982
© 2006 American Academy of Neurology
Questions or comments?
© 2006 American Academy of Neurology
Thanks for your participation!
© 2006 American Academy of Neurology