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

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Practice 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

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Presentation Objectives

• To define key issues in the management of
  Parkinsons disease (PD) relating to
  neuroprotective strategies and alternative
  treatments
• To make evidence-based recommendations

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Overview

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

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Background

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

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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

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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)

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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

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American Academy of Neurology Guideline Process

• Clinical Question
• Evidence
• Conclusions
• Recommendations

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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

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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

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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

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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

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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?

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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

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Methods

• 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

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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
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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
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Neuroprotective Strategies
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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

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Clinical Question 1

• Are there any therapies that can slow
  progression of PD?

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PD Neuroprotection

• Neuroprotective therapies considered
• Vitamin E
• Riluzole
• Coenzyme Q10
• Levodopa
• Pramipexole
• Ropinirole
• Other

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Neuroprotective Strategies

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

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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)

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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)

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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)

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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

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PD Neuroprotection Levodopa
Parkinson Study Group 2004, NEJM.
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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)

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PD Neuroprotection Rasagiline
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Recommendations for Neuroprotection

• Insufficient evidence for neuroprotection (Level
  U)
• Coenzyme Q10
• Rasagile
• Riluzole
• Selegiline

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Recommendations for Neuroprotection

• Insufficient evidence for neuroprotection (Level
  U)
• Amantadine
• Ropinirole
• Pramipexole
• Thalamotomy

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Alternative Therapies
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Clinical Question 2

• Are there any non-standard pharmacological or
  nonpharmacological therapies that have been shown
  to improve motor function in PD?

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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)

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Alternative Therapies

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

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Alternative Therapies

• Manual Therapy
• Chiropractic manipulation
• Osteopathic manipulation
• Trager therapy
• Exercise therapy
• Speech therapy

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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

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Recommendations for Alternative Therapies in PD

• Insufficient evidence (Level U)
• M pruriens
• Acupuncture
• Biofeedback
• Manual therapy
• Alexander technique

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Exercise Therapy in PD

• Multidisciplinary rehabilitation
• Music therapy
• Treadmill training
• Balance training
• Cued exercise training

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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. 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
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Exercise 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
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Recommendation for Exercise Therapy in PD

• Exercise therapy may be considered to improve
  function (Level C)
• Results in improvement in UPDRS
• Decrease in falls

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Exercise Therapy in PD

• No specific exercise program shown to be superior
  to another
• Benefit not sustained after exercise is
  discontinued

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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

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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

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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

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Recommendations for Future Research

• Reliable and validated surrogated endpoints that
  mirror nigrostriatal dopaminergic neuron loss
• Accurate early diagnosis and improved knowledge
  of disease progression

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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

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Questions, Comments?
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Thanks for your participation!