Download Treatment of Parkinson Disease with Motor Fluctuations and

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
© 2007 American Academy of Neurology
Presentation Objectives
• To make evidence-based treatment
recommendations for the medical and
surgical treatment of patients with
Parkinson disease (PD) with levodopainduced motor fluctuations and dyskinesia
© 2007 American Academy of Neurology
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© 2007 American Academy of Neurology
Overview
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Background and descriptive epidemiology
Treatment of PD
Gaps in PD Care
AAN guideline process
Medical treatments
Surgical treatments
Summary
Recommendations for future research
© 2007 American Academy of Neurology
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
© 2007 American Academy of Neurology
Descriptive Epidemiology of
Parkinson Syndrome
• Incidence 13/100,000
Van Den Eeden et al. Am J Epidemiol 2003;1015-22.
• Prevalence
– 300/100,000 (Strickland & Bertoni, 2004)
– Prevalence of PS/PD rising slowly with aging
population
© 2007 American Academy of Neurology
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
© 2007 American Academy of Neurology
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
© 2007 American Academy of Neurology
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
© 2007 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
© 2007 American Academy of Neurology
American Academy of
Neurology Guideline Process
Clinical Question
Evidence
Conclusions
Recommendations
© 2007 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
© 2007 American Academy of Neurology
Literature Search/Review:
Rigorous, Comprehensive, Transparent
Complete
Search
Review abstracts
Review full text
Select articles
Relevant
© 2007 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
© 2007 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
© 2007 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
© 2007 American Academy of Neurology
Clinical Questions
1. Which medications reduce off time?
2. What is the relative efficacy of
medications in reducing off time?
3. Which medications reduce dyskinesia?
4. Does DBS of the STN, GPi, or VIM
reduce off time, dyskinesia, medication
usage and improve motor function?
5. What factors predict improvement after
DBS?
© 2007 American Academy of Neurology
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
© 2007 American Academy of Neurology
Methods
• 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
© 2007 American Academy of Neurology
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
© 2007 American Academy of Neurology
Methods:
Surgical Treatment (Q4-5)
• Search restricted to English language
• Included articles from 1965 to June 2004
© 2007 American Academy of Neurology
Literature Search/Review:
Medical Treatment
730 articles
Exclusion criteria:
-Not related to drugs examined
-Review articles
-Studies of early PD or nonfluctuators
-Open label studies
-Mechanisms of action,
pharmacokinetics or animal studies
-Other uses of drugs examined
-< 20 subjects
29 articles
-Studies primarily about side effects
-Study duration < 3 months
-Not peer reviewed
© 2007 American Academy of Neurology
Literature Search/Review:
Surgical Treatment
478 articles
Exclusion reasons:
--< 20 subjects
-Not motor function outcome
studies of DBS in PD
-Review articles
-Comment articles
-< 6 month follow up
-Not peer reviewed articles
-Animal studies
-Redundant reports of included data
20 articles
-No differentiation of results
between PD and essential tremor
-No standard outcome measures
for PD
© 2007 American Academy of Neurology
Medical Treatment
© 2007 American Academy of Neurology
Clinical Question 1
Which medications reduce off time?
• 31 studies
– 7 Class I
– 16 Class II
– 8 Class III
© 2007 American Academy of Neurology
Evidence: Dopamine Agonists
Decrease
Off time
Active
Decrease Off
time
Placebo
Drug
Class
N
Study
Duration
Pergolide
I
189/187
24 week
32% (1.8 h)*
4% (0.2 h)
Lieberman
Pramipexole
I
181/179
32 week
31%*
7%
Guttman
Pramipexole
II
79/83
40 week
15% (2.5 h)*
3%
Rascol
Ropinirole
II
23/23
12 week
23%*
4%
Lieberman
Ropinirole
II
95/54
26 week
11.7%*
5%
Dewey
Apomorphine
II
20/9
4 week
34% (2 h)*
0%
Guttman
Bromocriptine
II
84/83
40 week
8%
3%
Steiger
Cabergoline
III
19/10
24 week
40% (2 h)*
18% (0.7 h)
Ahlskog
Cabergoline
III
17/10
24 week
59% (3.3 h)*
NS
Author
Olanow
© 2007 American Academy of Neurology
Evidence: MAO B Inhibitors
Decrease
Off time
Active
Decrease
Off time
Placebo
Drug
Class
N
Study
Duration
PSG
Rasagiline
(0.5 mg)
I
164/159
26 week
23% (1.4 h)*
15% (0.9 h)
PSG
Rasagiline
(1.0 mg)
I
149/159
26 week
29% (1.8 h)*
15% (0.9)
Rascol
Rasagiline
(1.0 mg)
I
231/229
18 week
21% (1.2 h)*
7% (0.4 h)
Waters
Orally
Disintegrating
Selegiline
II
94/46
12 week
32% (2.2 h)*
9% (0.6 h)
Golbe
Selegiline
III
50/46
6 week
NR
NR
Author
© 2007 American Academy of Neurology
Evidence: COMT Inhibitors
Decrease Off
time
Active
Decrease Off
time
Placebo
Drug
Class
N
Study
Duration
PSG
Entacapone
I
103/102
24 week
NR
NR
Rascol
Entacapone
I
227/229
18 week
21% (1.2 h)*
7% (0.4 h)
Poewe
Entacapone
II
197/104
24 week
25.8% (1.6 h)*
13.4% (0.9 h)
Rinne
Entacapone
II
85/86
24 week
23.6% (1.3 h)*
1.9% (0.1 h)
Fenelon
Entacapone
II
99/63
12 week
0.9 h
0.4 h
Rajput
Tolcapone
(100 mg tid)
II
69/66
12 week
32% (2.3 h)
20% (1.4 h)
Rajput
Tolcapone
(200 mg tid)
II
67/66
12 week
48% (3.2 h)*
20% (1.4 h)
Baas
Tolcapone
(100 mg tid)
II
60/58
12 week
31.5%*
11%
Baas
Tolcapone
(200 mg tid)
II
59/58
12 week
26.20%
11%
Author
© 2007 American Academy of Neurology
Evidence: Sustained Release
Carbidopa/Levodopa
Drug
Class
N
Study
Duration
Jankovic
Carbidopa/levodopa
CR/IR
III
20
16 week
NS
Hutton
Carbidopa/levodopa
CR/IR
III
21
24 week
NS
Ahlskog
Carbidopa/levodopa
CR/IR
III
28
16 week
NS
Lieberm
an
Carbidopa/levodopa
CR/IR
III
24
16 week
NS
Author
© 2007 American Academy of Neurology
Decrease
Off time
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
© 2007 American Academy of Neurology
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
© 2007 American Academy of Neurology
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
© 2007 American Academy of Neurology
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
© 2007 American Academy of Neurology
Comparator Placebo Studies
Decrease
Off time
Active
Decrease
Off time
Placebo
Drug
Class
N
Study
Duration
Rascol
Entacapone
I
227/229
18 week
21% (1.2 h)*
7% (0.4 h)
Rascol
Rasagiline
(1.0 mg)
I
231/229
18 week
21% (1.2 h)*
7% (0.4 h)
Guttman
Pramipexole
II
79/83
40 week
15% (2.5 h)*
3%
Guttman
Bromocriptine
II
84/83
40 week
8%
3%
Author
© 2007 American Academy of Neurology
Direct Comparator Studies
Drug
Class
N
Study
Duration
Cabergoline [c]/
Bromocriptine
[b]
II
22/22
36 week
50% [c]
31.3% [b]
Ropinirole [r]/
Bromocriptine
[b]
II
88/51
24 week
17.7% [r]
4.8% [b]
Tolcapone [t]/
Entacapone [e]
II
75/75
3 week
NR*
NR*
Tolcapone [t]/
Pergolide [p]
III
101/102
12 week
17.9% [t]
18.2% [p]
*NR = Not reported
© 2007 American Academy of Neurology
Decrease
Off time
Decrease
Off time
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).
© 2007 American Academy of Neurology
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
© 2007 American Academy of Neurology
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
© 2007 American Academy of Neurology
Clinical Question 3:
Which medications reduce dyskinesia?
• 31 studies
– 7 Class I
– 16 Class II
– 8 Class III
© 2007 American Academy of Neurology
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% (p< 0.004)
– 17% decrease in maximal dyskinesia score
(p < 0.02)
– Significant decrease in dyskinesia (UPDRS
part IVa) (p< 0.02)
© 2007 American Academy of Neurology
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)
© 2007 American Academy of Neurology
Medications that Reduce
Dyskinesia
• Clozapine’s potential toxicity:
– Agranulocytosis
– Seizures
– Myocarditis
– Orthostatic hypotension
• Required white blood cell count monitoring
© 2007 American Academy of Neurology
Deep Brain Stimulation
© 2007 American Academy of Neurology
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
© 2007 American Academy of Neurology
Evidence: Bilateral STN DBS
Author
Ther
Class
Prog
Class
Baseline
UPDRS
Motor
Follow-up
UPDRS
Motor
(% change
meds on vs.
off)
(% change:
stim on meds
off vs.
baseline meds
off)
Dyskinesia/Off
time improvement
Meds
Reduced
DBSPD
III
IV
56%
52%
Rush Dyskinesia:
58%
Diary: dysk 23 to 7%
Off time :49 to 19%
37%
Ostergaard
III
IV
54%
64% [1 yr]
UPDRS dysk 86%
UPDRS off time
83%
20%
Pahwa
III
IV
40% [1 yr]
37% [2 yr]
32% [1 yr]
28% [2 yr]
Diary: 1 yr dysk 18
to 4%, off 44 to
20%;
54% [1 yr]
57% [2 yr]
© 2007 American Academy of Neurology
Evidence: Bilateral STN DBS
Author
Ther
Class
Prog
Class
Baseline
UPDRS
Motor
Follow-up
UPDRS Motor
(% change
meds on
vs. off)
(% change:
stim on meds
off vs. baseline
meds off)
Dyskinesia/Off
time
improvement
Meds
Reduced
Esselink
III
IV
59%
49%
UPDRS dysk
50%
33%
Welter
IV
II
71%
65%
UPDRS dysk
69%
UPDRS off 87%
68%
KleinerFisman
IV
II
55%
48% [1 yr]
41% [2.5 yr]
Dysk Rating
Scale 48% [1 yr]
50% [2.5 yr]
38% [1 yr]
36% [2.5 yr]
© 2007 American Academy of Neurology
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%
© 2007 American Academy of Neurology
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%
© 2007 American Academy of Neurology
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
© 2007 American Academy of Neurology
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%
© 2007 American Academy of Neurology
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%
© 2007 American Academy of Neurology
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%
© 2007 American Academy of Neurology
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
© 2007 American Academy of Neurology
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)
© 2007 American Academy of Neurology
Clinical Question 5
What factors predict improvement
after DBS?
• 14 studies
– 2 Class II
– 12 Class IV
© 2007 American Academy of Neurology
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
© 2007 American Academy of Neurology
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
© 2007 American Academy of Neurology
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)
© 2007 American Academy of Neurology
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).
© 2007 American Academy of Neurology
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)
© 2007 American Academy of Neurology
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)
© 2007 American Academy of Neurology
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)
© 2007 American Academy of Neurology
Summary
• DBS of the STN may be considered to
improve motor function and reduce off
time, dyskinesia, and medication usage
(Level C)
© 2007 American Academy of Neurology
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)
© 2007 American Academy of Neurology
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
© 2007 American Academy of Neurology
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
© 2007 American Academy of Neurology
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
© 2007 American Academy of Neurology
Recommendations for
Future Research: Surgical Treatment
• Determine cost-benefit analysis over
the longer term
• Document regional disparity
© 2007 American Academy of Neurology
To access the full guideline please visit:
AAN.com/Guidelines
Neurology® April 11, 2006 66:983-995
© 2007 American Academy of Neurology
Questions or comments?
© 2007 American Academy of Neurology
Thanks for your participation!
© 2007 American Academy of Neurology