Practice Parameter: Treatment of Parkinson Disease with Motor Fluctuations and Dyskinesia An Evidenc

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Practice Parameter Treatment of Parkinson
Disease with Motor Fluctuations and Dyskinesia
(An Evidence-Based Review)

• American Academy of Neurology
• Quality Standards Subcommittee

• R. Pahwa, MD S.A. Factor, DO K.E.Lyons,
  PhD W.G.Ondo, MD G. Gronseth, MD H.
  Bronte-Stewart, MD M. Hallett, MD J. Miyasaki,
  MD J. Stevens, MD and W.J. Weiner, MD

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Presentation Objectives

• To make evidence-based treatment recommendations
  for the medical and surgical treatment of
  patients with Parkinson disease (PD) with
  levodopa-induced motor fluctuations and
  dyskinesia

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Overview

• Background and descriptive epidemiology
• Treatment of PD
• Gaps in PD Care
• AAN guideline process
• Medical treatments
• Surgical treatments
• Summary
• Recommendations for future research

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Background

• PD a neurodegenerative disorder
• Cardinal motor features of tremor, bradykinesia,
  and rigidity
• Dopaminergic therapies complicated by motor
  fluctuations
• Can be resistant to medical therapy

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Treatment of PD

• Risk factors for motor complications
• Younger age
• Higher levodopa dosage
• Severe disease
• Longer disease duration
• Treatment options levodopa manipulation,
  adjunctive therapy, and surgical therapy

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Descriptive Epidemiology of Parkinson
Syndrome

• Incidence
• 524/105 worldwide (ref)
• 20.5/105 USA (ref)
• Prevalence
• 57371/105 worldwide (ref)
• 300/105 USA/Canada (Strickland Bertoni, 2004)
• Prevalence of PS/PD rising slowly with aging
  population

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Treatment of PD

• Resurgence in surgical approaches
• Deep brain stimulation (DBS)
• Most commonly performed surgery for PD in North
  America
• Uses an implanted electrode connected to an
  implantable pulse generator (IPG) that delivers
  electrical current to a targeted brain nucleus

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Gaps in PD Care

• Levodopa is a commonly used and effective therapy
• Long term complications motor fluctuations and
  dyskinesia
• Motor complications can cause significant
  disability and impair quality of life

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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

• Which medications reduce off time?
• What is the relative efficacy of medications in
  reducing off time?
• Which medications reduce dyskinesia?
• Does DBS of the STN, GPi, or VIM reduce off time,
  dyskinesia, medication usage and improve motor
  function?
• What factors predict improvement after DBS?

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Methods

• Literature Search
• MEDLINE, EMBASE and Ovid databases
• Secondary search using bibliography of retrieved
  articles and knowledge of expert panel
• At least two authors reviewed each abstract for
  topic relevance
• At least two authors reviewed each full article

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Methods

• 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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Methods Medical Treatment (Q1-3)

• Search restricted to English language and
  medications available in the United States, or
  those having an approvable letter from the Food
  and Drug Administration
• Initial search from 1965 to June 2004
• Supplemental search in 2005 to include the latest
  clinical trials

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Methods Surgical Treatment (Q4-5)

• Search restricted to English language
• Included articles from 1965 to June 2004

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Literature Search/Review Medical
Treatment

Exclusion criteria -Not related to drugs
examined -Review articles -Studies of early PD or
non-fluctuators -Open label studies -Mechanisms
of action, pharmacokinetics or animal
studies -Other uses of drugs examined -lt 20
subjects -Studies primarily about side
effects -Study duration lt 3 months -Not peer
reviewed
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Literature Search/Review Surgical
Treatment

Exclusion reasons --lt 20 subjects -Not motor
function outcome studies of DBS in PD -Review
articles -Comment articles -lt 6 month follow
up -Not peer reviewed articles -Animal
studies -Redundant reports of included data -No
differentiation of results between PD and
essential tremor -No standard outcome measures
for PD
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Medical Treatment
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Clinical Question 1

• Which medications reduce off time?
• 31 studies
• 7 Class I
• 16 Class II
• 8 Class III

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Evidence Dopamine Agonists
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Evidence MAO B Inhibitors
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Evidence COMT Inhibitors

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Evidence Sustained Release
Carbidopa/Levodopa
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Recommendations for Patients with
PD and Motor Fluctuations

• Entacapone and rasagiline should be offered to
  reduce off time in PD patients (Level A)
• Strength indicates level of supporting evidence,
  not hierarchy of efficacy

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Recommendations for Patients with
PD and Motor Fluctuations

• Pergolide, pramipexole, ropinirole, and tolcapone
  should be considered to reduce off time (Level
  B)
• Tolcapone (hepatotoxicity) and pergolide
  (valvular fibrosis) should be used with caution
  and require monitoring
• Strength indicates level of supporting evidence,
  not hierarchy of efficacy

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Recommendations for Patients with PD
and Motor Fluctuations

• Apomorphine, cabergoline, and selegiline may be
  considered to reduce off time (Level C)
• Sustained release carbidopa/levodopa and
  bromocriptine may be disregarded to reduce off
  time (Level C)
• Strength indicates level of supporting evidence,
  not hierarchy of efficacy

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Clinical Question 2

• What is the relative efficacy of medications in
  reducing off time?
• 6 studies
• 1 Class I
• 4 Class II
• 1 Class III

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Comparator Placebo Studies
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Direct Comparator Studies
NR Not reported
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Relative Efficacy of Medications in
Reducing Off Time

• Rasagiline similar to entacapone
• Bromocriptine similar to pramipexole
• Tolcapone similar to pergolide
• Cabergoline similar to bromocriptine
• Tolcapone similar to entacapone
• Ropinirole possibly superior to bromocriptine

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Relative Efficacy of Medications in
Reducing Off Time

• Many of these studies not powered to demonstrate
  superiority of one drug over another
• Other than comparisons of ropinirole and
  bromocriptine, there is insufficient evidence to
  conclude which one agent is superior to another
  in reducing off time

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Recommendations Relative Efficacy of
Medications in Reducing Off Time

• Ropinirole may be chosen over bromocriptine for
  reducing off time (Level C). Otherwise, there
  is insufficient evidence to recommend one agent
  over another (Level U).

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Clinical Question 3

• Which medications reduce dyskinesia?
• 2 studies
• 1 Class II
• 1 Class III

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Evidence

• Class II single center, double masked, placebo
  controlled, randomized, crossover trial with
  amantadine (100 mg BID)
• 24 subjects for 3 weeks
• 92 completed the trial
• Total dyskinesia score (Goetz scale) decreased
  24 (plt 0.004)
• 17 decrease in maximal dyskinesia score (p lt
  0.02)
• Significant decrease in dyskinesia (UPDRS part
  IVa) (plt 0.02)

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Recommendations for Medications that
Reduce Dyskinesia

• Amantadine may be considered for PD patients with
  motor fluctuations to reduce dyskinesia (Level C)
• Insufficient evidence to support or refute the
  efficacy of clozapine in reducing dyskinesia
  (Level U)

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Medications that Reduce Dyskinesia

• Clozapines potential toxicity
• Agranulocytosis
• Seizures
• Myocarditis
• Orthostatic hypotension
• Required white blood cell count monitoring

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Deep Brain Stimulation
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Clinical Question 4

• Does DBS of the STN, GPi, or VIM reduce off
  time, dyskinesia, medication usage, and improve
  motor function?
• 21 studies
• 5 Class III
• 16 Class IV

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Evidence Bilateral STN DBS
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Evidence Bilateral STN DBS
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Evidence GPi DBS

• One Class III study
• 6-month, prospective, multicenter trial of 41 PD
  patients
• 33.3 improvement in UPDRS motor scores
• 35.8 improvement ADL scores
• Diaries on time increased from 28 to 64 on
  time with dyskinesia decreased from 35 to 12
  and off time from 37 to 24

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Evidence GPi DBS

• One Class III study
• Rush Dyskinesia scale improved by 67
• No change in daily levodopa equivalence dose
• AE included intracranial hemorrhage in 9.8 of
  patients (7.3 leading to hemiparesis) increased
  dyskinesia in 7.3 dystonia in 4.9 lead
  migrations in 4.9 and dysarthria, seizure,
  infection, broken lead, seroma, and abdominal
  pain each in 2.4

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Evidence VIM DBS

• Four articles met inclusion criteria
• All four articles were Class IV
• Due to the low quality of evidence, thalamic
  stimulation is not discussed

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Adverse Effects with DBS

• 4 articles examining DBS complications
• 360 patients, 288 were PD patients
• Surgical AEs
• Death due to PE and aspiration pneumonia 0.6
• Permanent neurological sequelae 2.8
• Other neurological sequelae 5.6
• Hemorrhage 3.1
• Confusion/Disorientation 2.8
• Seizures 1.1
• PE 0.6

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Adverse Effects with DBS

• Complications related to DBS hardware
• Lead replacement due to fracture, migration or
  malfunction 5
• Lead reposition due to misplacement 2.8
• Extension wire replacement due to fracture or
  erosion 4.4

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Adverse Effects with DBS

• Complications related to DBS hardware
• IPG replacement due to malfunction 4.2
• IPG reposition due to cosmetic reasons 1.7
• Allergic reaction due to hardware 0.6

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Recommendations for DBS

• DBS of the STN may be considered as a treatment
  option in PD patients to improve motor function
  and reduce motor fluctuations, dyskinesia, and
  medication usage (Level C)
• Need for patient counseling about risks and
  benefits of this procedure

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Recommendations for DBS

• Insufficient evidence to make any recommendations
  about the effectiveness of DBS of the GPi or VIM
  nucleus of the thalamus in reducing motor
  complications or medication usage, or in
  improving motor function in PD patients (Level U)

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Clinical Question 5

• What factors predict improvement after DBS?
• 14 studies
• 2 Class II
• 12 Class IV

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Evidence

• Class II study examining factors predictive of
  STN DBS outcome
• 41 PD patients (mean age of 56.4)
• Patients 56 and younger significantly greater
  improvements than older patients
• Patients with disease duration less than 16
  years greater improvements than those with
  longer disease duration
• Levodopa responsiveness the strongest predictor
  of outcome

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Evidence

• Class II study examining factors predictive of
  STN DBS outcome
• 25 patients with a mean age of 57.2
• No effect of age, sex, disease duration, baseline
  drug usage, baseline dyskinesia, age of onset
• Levodopa responsiveness the only factor related
  to outcome
• No studies of GPi or VIM DBS examining predictive
  factors

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Recommendations for Factors Predicting
Improvement after DBS

• Pre-operative response to levodopa should be
  considered as a factor predictive of outcome
  after DBS of the STN (Level B)

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Recommendations for Factors Predicting
Improvement after DBS

• Age and duration of PD may be considered as
  factors predictive of outcome after DBS of the
  STN. Younger patients with shorter disease
  durations may possibly have improvement greater
  than that of older patients with longer disease
  durations (Level C).

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Recommendations for Factors Predicting
Improvement after DBS

• Insufficient evidence to make any recommendations
  about factors predictive of improvement after DBS
  of the GPi or VIM nucleus of the thalamus in PD
  patients (Level U)

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Summary

• Entacapone and rasagiline should be offered to
  reduce off time (Level A)
• Pergolide, pramipexole, ropinirole and tolcapone
  should be considered to reduce off time (Level B)

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Summary

• Sustained release carbidopa/levodopa and
  bromocriptine may be disregarded to reduce off
  time (Level C)
• Amantadine may be considered to reduce dyskinesia
  (Level C)

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Summary

• DBS of the STN may be considered to improve motor
  function and reduce off time, dyskinesia, and
  medication usage (Level C)

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Summary

• Not enough evidence to support or refute the
  efficacy of DBS of the GPi or VIM nucleus of the
  thalamus in reducing off time, dyskinesia, or
  medication usage, or to improve motor function
  (Level U)
• Preoperative response to levodopa predicts better
  outcome after DBS of the STN (Level B)

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Recommendations for Future Research Medical
Treatment

• Comparative, randomized, double masked,
  controlled trials to determine which drugs are
  the most effective
• Uniform and more specific inclusion criteria
• Outcome measures should be standardized

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Recommendations for Future Research Medical
Treatment

• Non-motor fluctuations, PD specific quality of
  life measures, and neuropsychiatric features
  require greater assessment and reporting
• Additional novel drug classes need further
  investigation

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Recommendations for Future Research Surgical
Treatment

• Further research should include objective
  clinical measures
• Raters should be masked
• Factors predictive of a positive outcome
• Evaluate the optimal timing for surgery

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Recommendations for Future Research Surgical
Treatment

• Determine cost-benefit analysis over the longer
  term
• Document regional disparity

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Questions, Comments?
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Thanks for your participation!