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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 © 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 Sharing this information • The AAN develops these presentation slides as educational tools for neurologists and other health care practitioners. You may download and retain a single copy for your personal use. Please contact [email protected] to learn about options for sharing this content beyond your personal use. © 2007 American Academy of Neurology Overview • • • • • • • • 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