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Dopaminergic treatment of non-motor problems in Parkinson’s Diseaseproblems in Parkinson s Disease
K R Ch dh iK. Ray ChaudhuriLondon, UK
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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
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Braak et al. Cell Tissue Res 2004;318:121–34.
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Chaudhuri and Schapira. Lancet Neurol 2009;8:464–74.
Chaudhuri et al. Lancet Neurology 2006;5:235-45.
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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
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• Fluctuation Related NMSChaudhuri and Schapira. Lancet Neurol 2009;8:464–74.
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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
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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
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Corrigan et al. Depress Anxiety 2000;11:58–65.
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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
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Reichmann et al. CNS Drugs 2003;17:965–73.
*SPES: Short Parkinson‘s Evaluation Scale
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Both pramipexole and sertraline improveddepressive symptomsdepressive symptoms
HAM-17 = 17-item Hamilton Depression Rating Scale
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Barone et al. J Neurol. 2006;253:601–7.
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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
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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
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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
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Pahwa et al. Neurology 2007;68:1108–15. Poewe et al. Lancet Neurol 2007;6:513–20.
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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
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Chaudhuri et al. Eur J Neurol 1999;6(Suppl 5):S11–5.
Reuter et al. Acta Neurol Scand 1999;100:163–7.
To view abstract, click pause then click Abstracts link above 13
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Chaudhuri and Schapira. Lancet Neurol 2009;8: 464–74.
14
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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
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Honig et al. Mov Disord 2009;24:1468–74.
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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
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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)
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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
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Central fatigue = failure in the integration of the limbic input and the motor function within the basal ganglia circuitry
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SPM analysis
Th k h t d th t thi The speaker has requested that this slide is not shown for copyright reasons
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Fatigue
D i i b i• Dopaminergic basis• Improved by – LevodopaLevodopa• Oral• I J infusion
Apomorphine– Apomorphine
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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
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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
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Brefel-Courbon et al. Mov Disord 2005;20:1557−63.
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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
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Schestatsky P et al. Neurology 2007;69:2162–9.
To view abstract, click pause then click Abstracts link above 25
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
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Reuter et al. Acta Neurol Scand 1999;100:163–7.
To view abstract, click pause then click Abstracts link above 26
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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
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Honig et al. Mov Disord 2009;24:1468–74.
To view abstract, click pause then click Abstracts link above 28
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
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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
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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
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oct
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atio
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ia
70
NM
S
NMS Quest in a control population & PD population
26%40%
Dribblin
gst
ew
allo
w
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nt ow
el
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ains
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ions
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izzy
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it
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NMS QuestPD patients Control
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Chaudhuri et al. Mov Disord 2006:21:916–23.
To view abstract, click pause then click Abstracts link above 31
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
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Honig et al. Mov Disord 2009;24:1468–74.
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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
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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
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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
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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
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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.
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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
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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
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Non-motor scale colleagues
Th k h t d th t thi The speaker has requested that this slide is not shown for copyright reasons
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Copyright statements
Slide 2 ©2004, reproduced with permission from Elsevier
Slide 5 ©2005, reproduced with permission from Oxford University Press
Slide 6 ©2000, reproduced with permission from John Wiley & Sons, Inc
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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