1. Treatment of Parkinson‘s Disease in the Advanced Stage
Berlin, May 3rd,2012
Heinz Reichmann, FRCP, FAAN
Neurologische Klinik, Technische Universität Dresden

2. Levodopa therapy: the mainstay for treatment of Parkinson’s disease
Most efficacious symptomatic drug for Parkinson’s disease (PD)1
Increases survival2
Increases quality of life1
Virtually all PD patients will eventually require the superior symptomatic control of levodopa
1Olanow et al. Mov Disord 2004; 19(9): 997–1005;
2Rajput et al. Adv Neurol 2001; 86: 327–36;
3Holloway et al. Arch Neurol 2004; 61(7): 1044–53;
4PSG. N Engl J Med 1993; 328: 176–183

3. The majority of patients in dopamine agonist trials eventually require supplemental levodopa
Pramipexole1,2
Ropinirole3,4 80 80
72%
66% 60
53% 60
supplemental levodopa (%)
Patients requiring
supplemental levodopa (%)
Patients requiring 40 40
Although dopamine agonists have been shown to have moderate–good efficacy as monotherapy in early PD, it is clear that they are less efficacious than levodopa. Therefore, in practice, the majority of patients initiated on dopamine agonist therapy require levodopa within the first 2 years of treatment for symptomatic efficacy
In the CALM-PD trial of pramipexole as initial therapy, the majority of pramipexole patients required supplemental, open-label levodopa therapy by study end
Interestingly, the UPDRS scores of the pramipexole group never caught up with the levodopa group despite the option of open-label levodopa and other antiparkinsonian therapies. This might be related to the lower dose of levodopa used in the supplemented pramipexole patients (434 ± 498 mg/day) compared with those on levodopa monotherapy (702 ± 461 mg/day)
A 5-year, randomized, controlled, doubleblind, multicenter study found that ropinirole monotherapy provided adequate motor control for 6 months, however after 5 years the symptomatic efficacy of levodopa was required
Holloway et al. Arch Neurol 2004; 61(7): 1044–53
Rascol et al. NEJM 2000; 342: 1484
Rascol et al. Mov Disord 1998; 13(1): 39 20 20 4% 2 4
0.5 5
Years after randomization
Years after randomization
1Holloway RG et al. Arch Neurol 2004; 61(7): 1044;
2Parkinson Study Group. JAMA 2000; 284(15): 1931;
3Rascol O et al. N EngJ Med 2000; 342: 1484;
4Rascol O et al. Mov Disord 1998; 13(1): 39

4. ELLDOPA-Study
Fahn et al. NEJM

5. Spätkomplikationen bei IPS
Complications
Motor
Dopa-resistent
Symptoms
Fluctuations
Spätkomplikationen bei Morbus Parkinson
Die Abb. zeigt im Überblick die wichtigsten motorischen, psychischen und autonomen Spätkomplikationen bei Morbus Parkinson.
Möglichkeit: Video 13.3
Dyskinesia

6. Symptoms in the Advanced Stage
Daytime motor complications
end of dose or ‘wearing-off’ phenomenon
delayed ‘on’ or no ‘on’ response
unpredictable ‘off’ episodes
dyskinesias
Night-time non-motor symptoms
sleep disturbances
difficulty falling asleep
difficulty staying asleep
nocturia
Both daytime and night-time symptoms can have a serious impact on quality of life
Reichmann, adapted from Obeso et al, Neurology 2000
Levodopa long-term syndrome
Dose
Therapeutic window
Peak-dose dyskenesis
End-dose dyskenesis Wearing-off phases Early morning akinesia
Time
Levadopa plasma concenration

7. With advancing disease, patients receiving conventional levodopa begin to experience wearing-off
PD medication
Time
Medication
starts to work
Wearing-off period
Symptoms are alleviated
Symptoms begin to return
Symptoms not adequately controlled (‘off’ time)
Symptoms adequately controlled (‘on’ time)
Wearing-off can develop within only 6 months of therapy with conventional levodopa

8. Motor Complications in Patients with Chronic Conventional Levo-dopa Therapy
Dyskinesia
Wearing-off
30%
DATATOP1
18 months
(n=352)
50%
ELLDOPA
(levodopa
600 mg/day)2
6 months
(n=91)
Motor Complications May Occur Early
The emergence of motor complications following chronic levodopa therapy is a progressive problem – with increasing durations of disease, more patients develop motor complications, including both wearing-off and dyskinesias, which can be extremely disabling and detrimental to quality of life
Data from the recent CALM-PD (Comparison of the Agonist Pramipexole versus Levodopa on Motor Complications of Parkinson's Disease) and DATATOP (Deprenyl And Tocopherol Antioxidant Therapy Of Parkinsonism) clinical studies indicate that the development of wearing-off can occur early in the course of the disease
In the CALM-PD trial, 301 patients with early PD (de novo) were treated with either pramipexole (n=151) or levodopa (n=150). From week 11 to month 23.5 (the final trial endpoint) investigators were permitted to add open-label levodopa treatment
The major outcome measure was the time to the first occurrence of a motor complication (either wearing-off, dyskinesias or on-off motor fluctuations). In the levodopa-only treated patients, 38% of patients had experienced wearing-off and 31% of patients had experienced dyskinesias within 2 years of initiating levodopa treatment
In the DATATOP study 352 patients received levodopa therapy. After 18 months of therapy, 50% and 30% of levodopa-treated patients were experiencing wearing-off and dyskinesias, respectively
PSG. Ann Neurol 1996; 39: 37–45.
PSG. J Am Med Assoc 2000; 284: 1931–8.
17%
30% 10 20 30 40 50 60
% patients
1PSG. Ann Neurol 1996; 39: 37–45;
2Fahn et al. J Neurol 2005; 252(Suppl 4): IV37–42 †

9. Improved PK profile translates into clinical benefits in patients with Parkinson’s disease experiencing wearing-off
ON time1
OFF time2 8
Improvement
p<0.001
p<0.001
*p<0.05
Improvement
2.0 7
1.5
OFF time (hours)
Change in daily
1.0 6
Change in daily
ON time (hours)
0.5 5 *
–0.5 4 B 2 4 8 16 24
Withdrawal 1 2 3 4 5 6
Time (weeks)
Time (months)
Motor scores1,3
ADL scores2
p<0.05
p<0.05
Improvement –4
Improvement
–1.4
The efficacy and safety of levodopa/DDCI and entacapone therapy has been demonstrated in four prospective, randomized, double-blind, placebo-controlled Phase III studies performed in over 1000 patients with PD worldwide
On this slide, the results of the NOMECOMT study are shown demonstrating a significant increase in ON-time and the results of the CELOMEN study are shown to demonstrate a significant decrease in OFF-time with levodopa/DDCI and entacapone therapy compared with conventional levodopa/DDCI therapy plus placebo
Mean daily ON-time was assessed by home diaries. At 6 months, the mean daily ON-time was increased by 1.2 hours compared with placebo
Mean daily OFF-time was assessed by home diaries. At 6 months mean daily OFF-time was decreased by 1.6 hours in the entacapone-treated group compared with 0.9 hours in the placebo-treated group
Significant improvements in patient function have also been observed with levodopa/DDCI and entacapone versus conventional levodopa/DDCI therapy
In the CELOMEN study, activities of daily living (ADL) scores improved in fluctuating patients treated with levodopa/DDCI and entacapone by –1.1 points and deteriorated with conventional levodopa plus placebo by 0.2 points. This difference between the groups was statistically significant (p<0.05)
In the NOMECOMT study, motor scores decreased (i.e. improved) in the patients treated with levodopa/DDCI and entacapone from 25.5 to 22.5 points and decreased (i.e., improved) with conventional levodopa plus placebo from 24.6 to 23.8 points. This difference between the groups was statistically significant (p<0.05)
Data on the efficacy of catechol-O-methyl transferase (COMT) inhibition in the treatment of wearing-off was given a Level A status by the joint European Federation of Neurological Societies (EFNS) and Movement Disorder Society–European Section (MDS-ES) 2006 guidelines
Stalevo US prescribing information
Rinne et al. Neurology 1998; 51(5): 1309–14
Poewe et al. Neurology 2004; 62(1 Suppl): S31–38
Brooks et al. J Neurol Nurosurg Psychiatry 2003; 74: 1071–77
PSG Ann Neurol 1997; 42: 747
Horstink et al. Eur J Neurol 2006; 13(11): 1186–1202
–1.2
–1.0 –3
–0.8
Change in UPDRS III (motor) score
Change in UPDRS II (ADL) score
–0.6 –2
–0.4
–0.2 –1
0.2
0.4
Figures adapted from:
1Rinne UK, et al. Neurology 1998; 51(5): 1309;
2Poewe WH, et al. Acta Neurol Scand 2002; 105: 245; 3Stalevo US prescribing information.
Levodopa/DDCI and placebo
Levodopa/DDCI and entacapone*
*Levodopa/carbidopa/entacapone is available as Stalevo®

11. FIGURE 1: Kaplan-Meier survival curves show that patients randomized to L-dopa/carbidopa/entacapone (LCE) had greater risk of developing dyskinesia than patients receiving L-dopa/carbidopa (LC) (Cox proportional hazard ratio, 1.29; 95% confidence interval [CI], 1.0 – 1.65; p = 0.038). Survival time estimates for the first quartile of patients were 90.7 weeks (95% CI, 65.3 –104.0) for the LCE group and weeks (95% CI, 92.1 – 132.6) for LC-treated patients.
Stocchi F et al. (2010)

12. PD H+Y 2 left-sided

14. Continuous dopaminergic stimulation: dopamine agonists
Oral dopamine agonists with long elimination half-life
Subcutaneous infusion of apomorphine
Transdermal application

16. Watts et al. Mov Disord 2010; 25:858-866
Add-on Therapy with Dopamine Agonists
Seem to be a New Option
Watts RL et al. (2010)
Watts et al. Mov Disord 2010; 25:

17. Mean (± SD) change from baseline in UPDRS III
RECOVER Study Mean change from baseline to end of maintenance in UPDRS III
placebo-rotigotine LS mean (95% CI) treatment differences* (-5.37, -1.73) p=0.0002
Improvement
Mean (± SD) change from baseline in UPDRS III
(± 7.3)
(± 7.6)
placebo
n=89
rotigotine
n=178
At the end of maintenance , 19.1% of placebo-treated and 38.2% of rotigotine-treated patients had a ≥30% reduction in UPDRS part III score.
*ANCOVA (treatment and region as factors and baseline value as covariate) of rotigotine vs placebo
Trenkwalder et al, Movement Disorders, Vol. 26, No. 1, 2011

18. Mean (± SD) change from baseline in PDNMS placebo rotigotine
RECOVER (Randomized Evaluation of the 24-hour-COVerage: Efficacy of Rotigotine) Mean change from baseline in PDNMS (total score)
placebo-rotigotine LS mean (95% CI) treatment differences*
-6.65 (-11.99, -1.31) p=0.015
-3.9
(±25.5)
Mean (± SD) change from baseline in PDNMS
-10.3
(±21.2)
placebo
n=86
rotigotine
n=172
Trenkwalder et al, Movement Disorders, Vol. 26, No. 1, 2011

20. NICE: late (complicated) PD
Review
Choice of adjuvant therapy should reflect:
clinical and lifestyle characteristics
patient preference
Apomorphine
intermittent injections reduce “off” time
Continuous s.c. infusion reduces “off” time and dyskinesia
Bilateral STN stimulation
Thalamic stimulation for patients with severe tremor (for whom STN is unsuitable)
Severe motor complications
(unresponsive to oral therapy)
Refractory to best medical therapy
NICE. National clinical guideline for diagnosis and management in primary and secondary care. Parkinson's Disease: Diagnosis and Management
In Primary and Secondary Care: 2006:1–227.
Initiating dopamine agonists 20

21. Apomorphine Pump
Advantages: – Less Fluctuations in Plasma concentration
Limitations: – invasive Therapy
Katzenschlager R et al. Mov Disord 2005; 20:151-7 21

22. DuoDopa Pump Advantages: – fewer fluctuations in plasma concentrations
– reduction in “off” time
- reduction in the incidence of dyskinesia
Limitations: – invasive therapy

23. Intrajejunale Levodopa Infusion
Intrajejunal Levodopa
Oral Levodopa
5000 10 12
4000 8 9
3000 6
Plasma Levodopa- Conzentration (ug/ml)
No. off in hrs.
Dyskinesia score 6
2000 4 3
1000 2
9:00
11.00
13.00
15.00
17.00
19.00
Off Time
Dyskinesia
Time
Stocchi et al, 2005;
Syed et al, 2000 23

24. Deep Brain Stimulation

25. Decision Pathway for Sequence and Combination of Drugs in Advanced PD
Additional symptomatic benefit required
Consider MAO-B inhibitor
if not already started
Begin dopamine agonist
Titrate to maximum response or tolerance
Disability requiring additional therapy
Start levodopa
Levodopa
Dopamine agonist
MAO-B inhibitor
Titrate to maximum response or as symptoms progress
Refer to neurologist
Reference
Schapira AH. Treatment options in the modern management of Parkinson disease. Arch Neurol 2007;64(8):
Schapira AH. Arch Neurol 2007;64(8):

26. Spätkomplikationen bei IPS
Complications
Motor
ENS
Orthostatic
Hypotension
Thermoregu-lation
Dopa-resistent
Symptoms
Fluctuations
Spätkomplikationen bei Morbus Parkinson
Die Abb. zeigt im Überblick die wichtigsten motorischen, psychischen und autonomen Spätkomplikationen bei Morbus Parkinson.
Möglichkeit: Video 13.3
Genito- urinary
Intestinal
Dyskinesia

27. Tilting-Table Test in PD

28. Sleep Problems Sleep attacks Nightmares Obstructive sleep apnoea
Periodic limb movements
Restless legs syndrome
REM Sleep behviour disorder
Insomnia

29. Spätkomplikationen bei IPS
Complications
Motor
Psyche
ENS
Orthostatic
Hypotension
Thermoregu-lation
Dopa-resistent
Symptoms
Fluctuations
Spätkomplikationen bei Morbus Parkinson
Die Abb. zeigt im Überblick die wichtigsten motorischen, psychischen und autonomen Spätkomplikationen bei Morbus Parkinson.
Möglichkeit: Video 13.3
Genito- urinary
Intestinal
Dyskinesia
Depression
Dementia
Psychosis

30. Thank you for your kind attention
Dresden Opera House