Dopaminergic treatment of non-motor problems in Parkinsonproblems in Parkinsons ... ·...

Dopaminergic treatment of non-motor problems in Parkinson’s Diseaseproblems in Parkinson s Disease

K R Ch dh iK. Ray ChaudhuriLondon, UK

GPSRC CNS 174 0709 RTG 1

Not all PD symptoms are due to dopamine degenerationdegeneration

STN:subthalamic nucleus; l b ll dGPi:globus pallidus

interna; GPe:externalsegment; SNc:substantianigra pars compacta; nigra pars compacta; VTA:ventral tegamental area

GPSRC CNS 174 0709 RTG

Braak et al. Cell Tissue Res 2004;318:121–34.

To view further details, click pause and then click notes tab 2

Chaudhuri and Schapira. Lancet Neurol 2009;8:464–74.

Chaudhuri et al. Lancet Neurology 2006;5:235-45.


NMS of PD that are in part driven by dopaminergic mechanismsdopaminergic mechanisms

• Sleep relatedSleep related– RLS, PLM, Akathisia, Akinesia, Nocturia, RBD

• Cognitive– Depression, Anxiety, Apathy, Anhedonia, ?MCI

• Pain– Central, Wearing off

• Bowel Dysfunction– Constipation unsatisfactory voiding– Constipation, unsatisfactory voiding

• Bladder– DO, Nocturia

• Sexual & General– ED, Fatigue

• Vision– Contrast sensitivity

• Fluctuation Related NMS


• Fluctuation Related NMSChaudhuri and Schapira. Lancet Neurol 2009;8:464–74.

4

Dopamine and depression

• 11C RTI 32 PET in vivo marker of dopamine and NA transporter binding• 11C-RTI-32 PET – in vivo marker of dopamine and NA transporter binding• Depressed PD ↓ 11C-RTI-32 PET binding vs non depressed (AC,

amygdala, Vent Str)• Anxiety severity ↓ 11C-RTI-32 PET bindingAnxiety severity ↓ C RTI 32 PET binding• Apathy severity ↓ 11C-RTI-32 PET binding in Vent Str• ↓ 11C-RTI-32 PET binding LC and thalamus (NA)1

• DA and NA pathways targeting limbic system2DA and NA pathways targeting limbic system

Reference 1


1Remy et al. Brain 2005;128:1314–22; 2Brooks DJ. J Neurol 2006;253(Suppl 4):IV8–IV15.

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Effect of pramipexole in major depressive disorder (MDD)

WeeksHAM-D17

disorder (MDD)

0 1 2 3 4 5 6 7 8 9

0

ase

lin

e

* p < 0 05 vs placebo

score

-3

-6

se f

rom

ba p < 0.05 vs placebo

-9

-12

an

decr

eas

**

Placebo

Pramipexole 0.26 mg

Pramipexole 0.70 mg

-15Mea

Washout

Pramipexole 3.50 mg

Fluoxetine 20 mg


Corrigan et al. Depress Anxiety 2000;11:58–65.

To view abstract, click pause then click Abstracts link above 6

Effect of pramipexole on depression in patients with Parkinson’s disease (PD) /1

Prospective observational cohort study (n=657)400

patients with Parkinson s disease (PD) /1

p y ( )

300

350Baseline

After 9 weeks on pramipexolemean dose 1 05 mg/day

200

250 mean dose 1.05 mg/dayn

150

50

100

150

Depression (SPES*)

0mild moderate severe none


Reichmann et al. CNS Drugs 2003;17:965–73.

*SPES: Short Parkinson‘s Evaluation Scale


Both pramipexole and sertraline improveddepressive symptomsdepressive symptoms

HAM-17 = 17-item Hamilton Depression Rating Scale


Barone et al. J Neurol. 2006;253:601–7.


Early morning and night-time symptoms

Th k h t d th t thi The speaker has requested that this slide is not shown for copyright reasons


0.34

0.44

*e B

P

Hypothalmus in PD

Fig. 3. Coronal section of statistical parametric map0 06

0.16

0.25

1C

-Rac

lopr

ide

Fig. 3. Coronal section of statistical parametric map (SPM). Yellow-red areas represent voxel clusters with significant decreases in 11C-raclopride (RAC) binding within the hypothalmic region mask in PD patients (n=14) compared with the group of normal volunteers (n=9). The color stripe indicates z values.

Normals PD*p=0.0005

0.061

GPSRC CNS 174 0709 RTGTo view abstract, click pause then click Abstracts link above 10

GPSRC CNS 174 0709 RTGTo view abstract, click pause then click Abstracts link above 11

Effect of rotigotine, pramipexole, ropinirole on PDSS in PDPDSS in PD

n=201

P = 0.0196

n= 190 n=201n=204

n=101P=0.2

P=0.0129

P=0.0006


Pahwa et al. Neurology 2007;68:1108–15. Poewe et al. Lancet Neurol 2007;6:513–20.


Insomnia in PD

• Onset/Initiation • MaintenanceOnset/Initiation– Adjustment of anti PD Rx– Sleep hygiene– Hypnotics

Maintenance• Cabergoline (CBG)(po)

(Ergot)• Apomorphine (Apo)(sc)Hypnotics • Apomorphine (Apo)(sc)

– Apo infusion over 24 hours

• Rotigotine patch10152025

Pre-CBGPost-CBGPre CR

* = p<0.05

*

ints

• Rotigotine patch• Ropinirole XP• STN/Pallidal stimulation

* = p < 0 .0 5-505

10 Pre-CRPost-CR

810 Pre Apo

AtsP

o

• Duodopa02468

Pain (0-10) Spasm

ApoPre PlaceboPlaceboP

oin

t

CR, controlled release levodopa


Chaudhuri et al. Eur J Neurol 1999;6(Suppl 5):S11–5.

Reuter et al. Acta Neurol Scand 1999;100:163–7.



Chaudhuri and Schapira. Lancet Neurol 2009;8: 464–74.

14


Honig et al. Mov Disord 2009;24:1468–74.

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Changes in sleep assessment following duodopaduodopa

100

120

140

Baseline Post Duo %

P=0.002

60

80

100 Baseline Post Duo %

0

20

40 P=0.0001

0PDSS % change Sleep NMS % change




REM off in redREM on in greenREM on in green

RBD in neurodegenerative disease Brain (2007)Proposed nuclei involved in REM sleep control

as shown on human brainstem templates

se

Proposed pathophysiology of REM sleep behaviour disorder in humans

LDT PPN

vIPAG

A

B D

C

RN

SLDRN

LCPCLDT PPN

ABCD

LDT PPN

RNSLD

vIPAGLPT

LCPC

Lesions in sublaterodorsal nucleus+

Sufficient locomotor drive=

REM sleep behaviour disorder

Lateral hypothalamus

Telencephalon diencephalon

Tegmentum mesencephali

ptum

eVLPO

PPNLDTNRN

vIPAGLPT ++

-+-+

LDT

LPTvIPAG

SLD

EMG tone in REMTegmentum pontis

Medulla oblongata

Spinal cord

-

--

-

RN

LC

MCRF

PCSLD

Locomotor generators

++

+

++

Spinal cord + +-

Muscle


Boeve et al. Brain 2007

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RBD treatment: no controlled trials

• Clonazepam Schenck et al JAMA 1987;257:1786–9Clonazepam Schenck et al. JAMA 1987;257:1786 9.Olson et al. Brain 2000;123:331–9. (3 patients)

• Pramipexole Fantini et al. Neurology 2003;61:1418–20. (5/8 patients)Schmidt et al. Sleep Med 2006;7:418–23. (10

ti t )patients)• Levodopa Tan et al. Mov Disord 1996;11:214–6.• Melatonin Kunz et al. Mov Disord 1999;14:507–11.

Boeve et al. Sleep Med 2003;4:281–4 (14 patients) D il Ri t l N l 2000 55 870 1 • Donepezil Ringman et al. Neurology 2000;55:870–1

• ?Clozapine• ?Quetiapine• ?Carbamazepine• Worsening Arnulf et al. Neurology 2000;55:281–8.

(subthalamic nucleus stimulation)


Fatigue in PD

• Feeling of constant tiredness (either mental or physical Feeling of constant tiredness (either mental or physical or both)

• No fatigability during sustained muscular contraction

• Not related to: disease severity disease duration treatment


Central fatigue = failure in the integration of the limbic input and the motor function within the basal ganglia circuitry


SPM analysis



Fatigue

D i i b i• Dopaminergic basis• Improved by – LevodopaLevodopa• Oral• I J infusion

Apomorphine– Apomorphine


PD and pain (Chaudhuri Schapira classification) (Chaudhuri, Schapira classification)

• Musculoskeletal painMusculoskeletal pain• PD related chronic pain

– Central pain– Indirectly aggravated pain– Visceral pain

• Fluctuation related pain (WO)• Fluctuation related pain (WO)– Dystonic– Central

• Dyskinesia related pain (Beginning dose, peak dose, end of dose. Diphasic)• Nocturnal painp

– RLS/PLM related– Noct akinesia

• Coat Hanger pain• Oro-facial pain

– TMJ painTMJ pain– Bruxism related pain– Burning mouth syndrome

• Peripheral limb pain– Drug induced


Chaudhuri and Schapria. Lancet Neurol 2008;8:464-74.

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Dopamine and pain

P i th h ld t ld i ifi tl l i PD ithd f • Pain threshold to cold significantly lower in PD withdrawn from Rx vs Control

• Normalisation after levodopa in PD but not Controlp

• Off Rx activation of AC, Insula and Rt PFC

• On Insular activation

• Pain threshold to cold are DA dependent


Brefel-Courbon et al. Mov Disord 2005;20:1557−63.


Dopamine and pain

• Primary central pain (no obvious cause):• Primary central pain (no obvious cause):

• 9 PD + PCP, 9 PD – pain, 9 central pain

– Hyperalgesia

– Lack of habituation of sympathetic sudomotor response to repetitive pain

– More marked on affected side– More marked on affected side

– Abnormalities improved by levodopa 100 mg

• Dysfunction of DA dependent autonomic centres regulating AF and inhibitory modulation of pain input


Schestatsky P et al. Neurology 2007;69:2162–9.


In PD pain responded to dopaminergic treatment changes in night-time pain and spasm scores before and after

hi (A )/ l b i f i i P ki i RLSapomorphine(Apo)/placebo infusion in Parkinsonian RLS


Reuter et al. Acta Neurol Scand 1999;100:163–7.


Effect size of duodenal levodopa on non-motor symptoms

00

-0.2

-0.4 Cognition

tatu

s

-0.6

-0.8

Attention

Sex

Gastro-i i l

Mood

in h

ealth s

t

-1

-1.2

CVSSleep Urinary

intestinal

Miscellaneous

Chan

ge

CVS: cardiovascular symptoms

< 0.2 = negligible; 0.2–0.49 = small; 0.5–0.79 = moderate; > 0.8 = large (Kazis et al. Med Care 1989;27:S178–89)

-1.4Miscellaneous




Swallowing problems

C l d t t lit d • Can lead to mortality and may cause – Asphyxiation / choking– Pulmonary aspiration/ Chest infections – Malnutrition – Dehydration– DroolingDrooling

• Can have a tremendous impact on quality of life• Problems swallowing

PD medications


Silent aspiration

40% f ti t ith PD h t b i ti d i id • 40% of patients with PD shown to be aspirating during video fluoroscopic examination were unaware and showed no external signs

• May be helped by DA therapy


Logemann 1995.

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Potential indications of a ‘non-oral’ or once-a-day therapy in PD

NMS Quest in a control population & PD population

or once-a-day therapy in PDg ti

pat

ion

gen

cyN

oct

uria

ry ntr

atio

ns y ty n

ia

70

NM

S

NMS Quest in a control population & PD population

26%40%

Dribblin

gst

ew

allo

w

Cons

nt ow

el

Ur g N

ains

tM

emor

Inte

rest

cinat

ions

Conce

nBlu

esAnxi

ety

Sex

_drive

Sex

_difficu

ltD

izzy

ls eepy In

som

nD

ream

sAct

ing_out

RLS

wel

ling

ing

pia

40

50

60

eri

en

cin

g

Ta Sw

Vom

it

Inco

ntinen B

o

Pa

Wei

ght

Hal

lu

S S

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eati

Dip

lop

Del

usi

on

10

20

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e

0% o

NMS QuestPD patients Control


Chaudhuri et al. Mov Disord 2006:21:916–23.


Duodopa study

NMS Gastrointestinal (GIT) domain Changes in GIT domain

• Does the patient dribble saliva during the day?

• Does the patient have difficulty

( ) g

62%

Does the patient have difficulty swallowing?

• Does the patient suffer from constipation? (Bowel action less than three times weekly) co

re

less than three times weekly)

Sc



32

Visual symptoms in PD

• DiplopiaDiplopia– Fleeting– Fluctuation related– Selective diplopia

• Ocular motility related– Low or reduced blink rate– Cogwheel pursuit movement– Impaired remembered saccades (hypometria of saccades)– Impaired upgaze– Convergence insufficiency– Convergence insufficiency– Square wave jerks

• Pupillary– Impaired response to light and pain

• Visual hallucinationsVisual hallucinations– Charles Bonnet

• Bye, Vamadevan, Chaudhuri. Non Motor Symptoms of PD. Oxford Univ Press. In Press

• Korczyn 2007


Dopaminergic basis

Dopaminergic cell bodies are located within the layer of amacrine cells, Dopaminergic cell bodies are located within the layer of amacrine cells, at the border of inner nuclear and inner plexiform layers


Dopamine and vision: Non-motor fluctuationsNon-motor fluctuations

PD ti t d ib bl d i i i ll t l • PD-patients describe blurred vision especially at lower luminosity during ‘OFF’ phases

• The pathophysiological correlate is likely a degeneration of p p y g y gfoveal retinal dopaminergic neurons (referenced group A17) which physiologically enhance visual contrast


Peppe et al. Electroencephalogr Clin Neurophysiol 1998; 106:374–82Wink B and Harris J. Vision Res 2000;40:1937–46..

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DA drugs may also have unwanted effectsDA drugs may have unwanted effects

DA drugs may also have

Parkinson's drugs

DA drugs may also have unwanted effects

Parkinson s drugs 'made me gambler, thief and gay sex

fiend‘Sunday Observer, Dec 2007


Brief Communications

• Falling asleep at the wheel: Motor vehicle mishaps in persons taking pramipexole and ropinirole

S. Frucht, MD, J. D. Rogers, MD, P. E. Greene, MD, M. F. Gordon, MD and S. Fahn, MD

From the Columbia-Presbyterian Medical Center (Drs. Frucht, Greene, and Fahn) and Beth From the Columbia Presbyterian Medical Center (Drs. Frucht, Greene, and Fahn) and Beth Israel Medical Center (Dr. Rogers), New York, NY; and the Long Island Jewish Medical Center (Dr. Gordon), New Hyde Park, NY.

The authors report a new side effect of the dopamine agonists pramipexole and ropinirole: dd i i tibl tt k f l Ei ht PD ti t t ki i l d t ki sudden irresistible attacks of sleep. Eight PD patients taking pramipexole and one taking

ropinirole fell asleep while driving, causing accidents. Five experienced no warning before falling asleep. The attacks ceased when the drugs were stopped. Neurologists who prescribe these drugs and patients who take them should be aware of this possible side effect.


Frucht et al. Neurology 1999;52:1908.

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Impact of dopaminergic drugs

Sleep disability

Motor symptoms Non-motor symptoms

Activities of daily living Disruption to daily life

Handwriting

Preparing food

Walking

Pain

Depression

Non motor offWalking

Speech

Non motor off

GIT, Bladder

GPSRC CNS 174 0709 RTGTo view further details, click pause and then click notes tab 39

Non-motor symptoms of PD

Non-motor Symptoms of Parkinson’s DiseaseNon motor Symptoms of Parkinson s DiseaseEdited by:

K. Ray ChaudhuriEd d T lEduardo Tolosa

Anthony SchapiraWerner PoewePublished by:

Oxford University Press


Non-motor scale colleagues



Copyright statements

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Slide 10 ©2008 reproduced with permission from Slide 10 ©2008, reproduced with permission from Elsevier

Slide 11 ©2007, reproduced with permission from ElsevierElsevier

Slide 13 ©1999, reproduced with permission from Wiley-Blackwell

Sl d ©2006 d d h fSlide 14 ©2006, reproduced with permission from Elsevier

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Copyright statements

Slide 17 ©2007, reproduced with permission from Oxford University Press

Slide 26 ©1999, reproduced with permission from Wiley-Blackwell

Slide 28 ©2009, reproduced with permission from John Wiley & Sons, Inc

Slide 30 ©1995 reproduced with permission from S Slide 30 ©1995, reproduced with permission from S. Karger AG

Slide 34 From: Kolb H, Fernandez E, Nelson R. Simple anatomy of the retina 2003; Available at: anatomy of the retina, 2003; Available at: http://webvision.med.utah.edu/sretina.html

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