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

Treatment of Parkinson‘s Disease in the Advanced StageBerlin, May 3rd,2012Heinz Reichmann, FRCP, FAANNeurologische Klinik, Technische Universität Dresden

www.uniklinikum-dresden.de

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


The majority of patients in dopamine agonist trials eventually require supplemental levodopa

Pramipexole1,2 Ropinirole3,4

Years after randomizationYears after randomization

Pat

ien

ts r

equ

irin

g

sup

ple

men

tal l

evo

do

pa

(%)

53%

72%

0

20

40

60

80

2 4

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

Pat

ien

ts r

equ

irin

g

sup

ple

men

tal l

evo

do

pa

(%)

4%

66%

0

20

40

60

80

50.5


ELLDOPA-Study

Fahn et al. NEJM


Spätkomplikationen bei IPS

Dyskinesia

Motor

Dopa-resistent

Symptoms

Fluctuations

Complications


Symptoms in the Advanced Stage

I Daytime motor complications

― end of dose or ‘wearing-off’ phenomenon

― delayed ‘on’ or no ‘on’ response

― unpredictable ‘off’ episodes

― dyskinesias

I Night-time non-motor symptoms

― sleep disturbances

• difficulty falling asleep

• difficulty staying asleep

• nocturia

I 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 Dose Dose

Therapeutic window

Peak-dose dyskenesis

End-dose dyskenesisWearing-off phasesEarly morning akinesia

Time

Le

va

do

pa

pla

sm

a c

on

ce

nra

tio

n


With advancing disease, patients receiving conventional levodopa begin to experience wearing-off

PD medication PD medication PD medication

TimeMedicationstarts to work

Wearing-off period

Symptoms a

re

allevia

ted

Symptoms begin

to return

Sym

ptom

s no

tad

equa

tely

co

ntro

lled

(‘off’

tim

e)

Sym

ptom

s ad

equa

tely

co

ntro

lled

(‘on’

tim

e)

• Wearing-off can develop within only 6 months of therapy withconventional levodopa


Motor Complications in Patients with Chronic Conventional Levo-dopa Therapy

Dyskinesia

Wearing-off

†

% patients

DATATOP1

18 months(n=352)

ELLDOPA (levodopa 600 mg/day)2

6 months(n=91) 0 10 20 30 40 50 60

50%

30%

30%

17%

1PSG. Ann Neurol 1996; 39: 37–45;2Fahn et al. J Neurol 2005; 252(Suppl 4): IV37–42


Improved PK profile translates into clinical benefits in patients

with Parkinson’s disease experiencing wearing-off

ADL scores2

Levodopa/DDCI and placeboLevodopa/DDCI and entacapone*

*Levodopa/carbidopa/entacapone is available as Stalevo®

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.

ON time1

Ch

an

ge

in

da

ily

ON

tim

e (

ho

urs

)

p<0.001p<0.001

B 2 4 8 16 24 WithdrawalTime (weeks)

–0.5

0

0.5

1.0

1.5

2.0

Ch

an

ge

in

UP

DR

S I

II

(mo

tor)

sc

ore

p<0.05

0

–1

–2

–3

–4

Motor scores1,3

0.2Ch

an

ge

in

UP

DR

S I

I (A

DL

) s

co

re

0

–1.2–1.4

–1.0–0.8–0.6–0.4

–0.2

0.4

Imp

rove

me

nt

Imp

rove

me

nt

Imp

rove

me

nt

OFF time2

Imp

rove

me

nt

Ch

an

ge

in

da

ily

OF

F t

ime

(h

ou

rs)

Time (months)

*

4

7

6

8

5

*p<0.05

p<0.05

0 1 2 3 4 5 6



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 117.1 weeks (95% CI, 92.1 – 132.6) for LC-treated patients.

Stocchi F et al. (2010)


PD H+Y 2 left-sided



Continuous dopaminergic stimulation: dopamine agonists

Oral dopamine agonists with long elimination half-life

Subcutaneous infusion of apomorphine

Transdermal application



Watts RL et al. (2010)

Watts et al. Mov Disord 2010; 25:858-866

Add-on Therapy with Dopamine Agonists Seem to be a New Option


RECOVER Study

Mean change from baseline to end of maintenance in UPDRS III

17

placebon=89

rotigotine n=178

Me

an

(±

SD

) c

ha

ng

e f

rom

b

as

eli

ne

in

UP

DR

S I

II

(± 7.3)

(± 7.6)

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

Improvement

placebo-rotigotine LS mean (95% CI) treatment differences*

-3.55 (-5.37, -1.73) p=0.0002

Trenkwalder et al, Movement Disorders, Vol. 26, No. 1, 2011


RECOVER (Randomized Evaluation of the 24-hour-COVerage: Efficacy of Rotigotine)

Mean change from baseline in PDNMS (total score)

18

Me

an

(±

SD

) c

ha

ng

e f

rom

b

as

eli

ne

in

PD

NM

S

placebon=86

rotigotine n=172

-3.9(±25.5)

-10.3 (±21.2)

placebo-rotigotine LS mean (95% CI) treatment differences*

-6.65 (-11.99, -1.31) p=0.015

Trenkwalder et al, Movement Disorders, Vol. 26, No. 1, 2011



NICE: late (complicated) PD

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

Review

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.


Advantages: – Less Fluctuations in Plasma concentrationLimitations: – invasive Therapy

Katzenschlager R et al. Mov Disord 2005; 20:151-7

Apomorphine Pump


DuoDopa Pump

Advantages: – fewer fluctuations in plasma concentrations – reduction in “off” time

- reduction in the incidence of dyskinesiaLimitations: – invasive therapy


Oral Levodopa

Intrajejunal Levodopa

0

1000

2000

3000

4000

5000

9:00 11.00 13.00 15.00 17.00 19.00

Pla

sma

Lev

od

op

a-

Co

nze

ntr

atio

n (

ug

/ml)

Time

Intrajejunale Levodopa Infusion

0

2

4

6

8

10

Off Time

No

. off

in h

rs.

0

3

6

9

12

Dyskinesia

Dys

kin

esia

sco

re

Stocchi et al, 2005;Syed et al, 2000


Deep Brain Stimulation


Additional symptomatic benefit requiredAdditional symptomatic benefit required

Consider MAO-B inhibitor if not already started

Consider MAO-B inhibitor if not already started

Begin dopamine agonistif not already started

Begin dopamine agonistif not already started

Titrate to maximum response or tolerance Titrate to maximum response or tolerance

Disability requiring additional therapyDisability requiring additional therapy

Start levodopaif not already startedStart levodopaif not already started

LevodopaLevodopa Dopamine agonistDopamine agonist MAO-B inhibitorMAO-B inhibitor

Titrate to maximum response or as symptoms progress

Titrate to maximum response or as symptoms progress

Refer to neurologistRefer to neurologist

Decision Pathway for Sequence and Combinationof Drugs in Advanced PD

Schapira AH. Arch Neurol 2007;64(8):1083-8.



Dyskinesia

Motor

Dopa-resistent

Symptoms

ENS

IntestinalGenito-urinary

OrthostaticHypotensionFluctuations

Thermoregu-lation

Complications


Tilting-Table Test in PD


Sleep Problems

Sleep attacks

Nightmares

Obstructive sleep apnoea

Periodic limb movements

Restless legs syndrome

REM Sleep behviour disorder

Insomnia



Depression

Dyskinesia

Motor

Dopa-resistent

Symptoms

Psyche ENS

Intestinal

Dementia

Genito-urinary

Psychosis

OrthostaticHypotensionFluctuations

Thermoregu-lation

Complications


Thank you for your kind attention

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Documents

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