Management in Parkinson s Disease

(1)

Management

in

Parkinson

’

s

Disease

Apichart Pisarnpong

Apichart Pisarnpong,, MM..DD..

Director of Parkinson

Director of Parkinson’’s Disease Clinic, s Disease Clinic, Siriraj Hospital,

(2)

overview

History of ParkinsonHistory of Parkinson’’s Diseases Disease

Clinical manifestation of PDClinical manifestation of PD

Etiology and secondary cause of ParkinsonismEtiology and secondary cause of Parkinsonism

Classification Classification Treatment : Treatment : medical medical

surgical (new in Thailand)surgical (new in Thailand)

(3)

overview

History of Parkinson

’

s Disease

(4)

History

1817

:

James Parkinson

“

“An Essay on the Shaking PalsyAn Essay on the Shaking Palsy”” Almost 200 years ago

Almost 200 years ago

ในประเทศไทยเคยเรียกวา

(5)

(6)

(7)

(8)

(9)

1961 using IV levodopa to treat PD patients 1961 using IV levodopa to treat PD patients

1966 combine with Decaboxylase inhibitor 1966 combine with Decaboxylase inhibitor

(benzerazide) less side effect and more potent

(10)

Pathology of Parkinson

(11)

Normal Basal Ganglia Functional

Anatomy

Cortex Prefrontal Insular Cingulate Sensory Motor Suppl. Motor Premotor Premotor Prefrontal Striatum D2 D1 Thalamus_VA/VL + = excitatory - = inhibitory Brainstem SC SNc SNr GPi STN GPe -+ + + -+ + + + + + Normal

(12)

Function Anatomy of Parkinson

’

s

Disease

Cortex Prefrontal Insular Cingulate Sensory Motor Suppl. Motor Premotor Premotor Prefrontal Striatum D2 D1 Thalamus_VA/VL + = excitatory - = inhibitory Brainstem SC SNc SNr GPi STN GPe -+ + + + + + -+ + + + + + -Parkinson’s Disease

(13)

Cortex Prefrontal Insular Cingulate Sensory Motor Suppl. Motor Premotor Premotor Prefrontal Striatum D2 D1 ThalamusVA/VL + = excitatory - = inhibitory Brainstem SC SNc SNr GPi STN GPe -+ + + -+ + + + + + Normal Cortex Prefrontal Insular Cingulate Sensory Motor Suppl. Motor Premotor Premotor Prefrontal Striatum D2 D1 ThalamusVA/VL + = excitatory - = inhibitory Brainstem SC SNc SNr GPi STN GPe -+ + + + + + -+ + + + + + -Parkinson’s Disease

(14)

overview

Clinical manifestation of PD

(15)

Signs and Symptoms

Cardinal CharacteristicsCardinal Characteristics

Resting tremorResting tremor

BradykinesiaBradykinesia

RigidityRigidity

Later; Postural instability (3Later; Postural instability (3--5 years after 5 years after

Dx)

Gait disturbance esp. dystonic posture of Gait disturbance esp. dystonic posture of

feet, fluctuation of symptoms (YOPD)

(16)

Additional Signs and Symptoms

Difficulty arising from a chairDifficulty arising from a chair

Difficulty turning in bedDifficulty turning in bed

Hypophonic speechHypophonic speech

SialorrheaSialorrhea

Loss of the sense of smellLoss of the sense of smell

(17)

OtherOther

MicrographiaMicrographia

Masked faceMasked face

Slowing of ADLsSlowing of ADLs

Stooped, shuffling gaitStooped, shuffling gait

(18)

Clues Suggesting

Atypical Parkinsonism

Early onset Early onset ““offoff””, or rapidly progressing , or rapidly progressing

dementia

dementia

Rapidly progressive courseRapidly progressive course

Supranuclear gaze palsySupranuclear gaze palsy

Upper motor neuron signsUpper motor neuron signs

Cerebellar signsCerebellar signs——dysmetria, ataxiadysmetria, ataxia

Urinary incontinenceUrinary incontinence

(19)

(20)

Criteria for Diagnosis

At least two of three:

rest tremor, bradykinesia, rigidity

Absence of a secondary cause; drugs,

metabolic, etc.

Definitive diagnosis can only be made

by autopsy

(21)

overview

Etiology and secondary cause of

Parkinsonism

(22)

Cause of PD

Unknown in most cases

10% associated with genetic

(23)

Parkinson

’

s Disease

Risk Factors

DefiniteDefinite: Old age: Old age

Highly likelyHighly likely: MZ co: MZ co--twin with earlytwin with early--onset PDonset PD

ProbableProbable: Positive family history: Positive family history

PossiblePossible: Herbicides, pesticides, heavy metals, proximity : Herbicides, pesticides, heavy metals, proximity to industry, rural residence, well water, repeated head

to industry, rural residence, well water, repeated head

trauma, etc.

(24)

overview

Etiology and secondary cause of PDEtiology and secondary cause of PD

Classification

Treatment : Treatment : medical medical

(25)

Parkinsonian syndrome

Classification

1.

1. Idiopathic ParkinsonIdiopathic Parkinson’’s Diseases Disease 2.

2. Secondary ParkinsonismSecondary Parkinsonism 3.

3. Parkinson Plus syndromeParkinson Plus syndrome 4.

(26)

2.

Secondary

Parkinsonism

Drug

-

induced

Toxin

-

induced

Metabolic

Structural lesions

Hydrocephalus

(27)

Drug

-

Induced Parkinsonism

Antipsychotics

haloperidol, chlorpromazine,

thioridizine, perphenazine

risperidone, olanzapine

Antiemetics

metoclopramide, prochlorperazine

(28)

Drug

-

Induced Parkinsonism

Dopamine depletors

methyldopa, reserpine, tetrabenazine

Antivertigo medications

Ca Channel blockers: flunarizine, cinnerizine

Treatment: Stop offending medications

(29)

Metabolic Causes of Parkinsonism

Metabolic

Often reversible

Hypo- or hyper-thyroidism

Hypo- or hyper-parathyroidism Liver failure

(30)

Infectious Causes of Parkinsonism

InfectiousInfectious

PostPost--encephaliticencephalitic

CreutzfeldtCreutzfeldt--Jakob diseaseJakob disease

Infectious massesInfectious masses

(31)

Toxin

-

induced Parkinsonism

MPTPMPTP

Carbon monoxideCarbon monoxide

ManganeseManganese

(32)

Structural Lesions Causing Parkinsonism Structural Lesions Causing Parkinsonism

Acute or subacute onsetAcute or subacute onset

Other signsOther signs——hemiparesis, hyperreflexia, hemiparesis, hyperreflexia,

aphasia, sensory loss, seizures

Brain tumorBrain tumor

Infectious massInfectious mass

(33)

Vascular Parkinsonism

Abrupt onset, usually unilateralAbrupt onset, usually unilateral

StepStep--wise or no progressionwise or no progression

Other signsOther signs——hemiparesis, aphasia, hyperreflexiahemiparesis, aphasia, hyperreflexia

Infarcts on neuroimaging helpful in confirming Infarcts on neuroimaging helpful in confirming diagnosis

(34)

Hydrocephalus

-

induced Parkinsonism

Can be communicating or obstructive

Normal pressure hydrocephalus—

idiopathic

Clinical triad:

parkinsonism/gait disorder urinary/fecal incontinence dementia

(35)

3. Parkinson Plus Syndrome

Progressive supranuclear palsy

Multiple system atrophy

Corticobasal ganglia degeneration

Diffused Lewy body disease

Parkinson

-

dementia complex

syndrome

(36)

4 Associated disease

Essential tremor

(37)

Classification

by age of onset

Juvenile

-

onset

Age of onset less than Age of onset less than 21₂₁ years oldyears old

Young

-

onset

Age onset less than Age onset less than 40₄₀ years old years old

but

(38)

Mean age of onset 60 to 65 yr.Mean age of onset 60 to 65 yr.

55--10% start below age of 40 yr.10% start below age of 40 yr.

Incidence about 200Incidence about 200--250 : 100,000 in normal 250 : 100,000 in normal

population in developed country

(39)

Siriraj Parkinson's Disease Clinic Jan 2000- June 2002

242 medical records were enrolled

224 were reviewed 18 were excluded due

to incomplete data

174 medical records

of IPD 50 medical records

of other diagnosis Statistical analysis

(40)

Demographic data

Sex: Sex: 98 males 98 males (56.3%)(56.3%)

76 females

76 females (43.7%)(43.7%) M : F = 1.29 : 1

M : F = 1.29 : 1

Age of onset : 12Age of onset : 12--90 y (mean 55.6 y)90 y (mean 55.6 y)

age > 40 yr age > 40 yr = 82.3% = 82.3% age 20 age 20--40 yr 40 yr = 15.9%= 15.9% age < 20 yr age < 20 yr = 1.8% = 1.8% (age < 40 yr (age < 40 yr = 17.7%)= 17.7%)

(41)

Modified Hoehn and Yahr

Clinical staging of PD

Stage

0

0 no signs of diseaseno signs of disease

1

1 Unilateral diseaseUnilateral disease

1.5

1.5 Unilateral plus axial involvementUnilateral plus axial involvement 2

2 Bilateral disease, without impairment of balanceBilateral disease, without impairment of balance 2.5

2.5 Mild Bilateral disease, with recovery on pull testMild Bilateral disease, with recovery on pull test

3

3 Mild to moderate bilateral disease: some postural instability: Mild to moderate bilateral disease: some postural instability:

physical independent

4

4 Severe disability: still able to walk or stand unassistedSevere disability: still able to walk or stand unassisted 5

(42)

(43)

Current concept in treating PD

(continuous dopaminergic

stimulation)

Tonic and continuous dopaminergic

stimulation occurs in normal

(44)

Pulsatile dopaminergic stimulation

promote more dopaminergic cell lost

(post synaptic change) resulting in

development of motor fluctuation and

dyskinesia

(

(45)

Lost of striatal dopamine receptor that occurs

with disease progression results in a diminished

capacity of these terminal to buffer in

fluctuation in plasma levodopa

Continuous delivery of dopaminergic agents can

prevent or attenuate the development of

dyskinesia

(46)

Motor complications associated with levodopa

therapy include motor fluctuations and

dyskinesia are

particular problems in younger patients

Less likely to occur in those whose symptoms

begin after the age of 70 years

(Golbe LI, neurology 1991, Quinn N, Mov Disord 1987)

(47)

overview

Classification Classification

Treatment :

medical medical

surgical (new in Thailand)surgical (new in Thailand)

(48)

When to start treatment

Determine whether the patients have

functional impairment or not

functional impairment or not 1.

1. Whether the symptoms effect the dominant or nonWhether the symptoms effect the dominant or non-

-dominant hand

dominant hand

2.

2. Whether the patient is employed or employableWhether the patient is employed or employable

3.

3. The type of parkinsonian symptoms that are present The type of parkinsonian symptoms that are present

(e.g. bradykinesia tends to be more disabling than

tremor)

4.

4. Individual patient sentimentIndividual patient sentiment

5.

(49)

Symptomatic treatment

1.

Levodopa

2.

Dopamine agonist

3.

COMT inhibitor

4.

MAO

_B_B

inhibitor

5.

Anticholinergic

6.

(50)

Sites of action for two types of

medical therapies to treat PD

(51)

Decision tree for early management of PD

American Academy of Neurology, 2001 American Academy of Neurology, 2001

(52)

Levodopa

¾

Most

effective

symptomatically

antiparkinsonian drug

¾

All PD patients respond

¾

Improves disability and prolongs capacity

to maintain employment and independent

activities of daily living

¾

(53)

0 10 20 30 40 50 60 70 80 90 100 0 ₂ ₄ ₆ ₈ ₁₀ ₁₂ ₁₄ ₁₆ Control Group

Years after 1st _presentation

Percent Survival P < 0.0001 with control group P = 0.024 with treated group Levodopa treated Group N = 565 Levodopa non-treated Group N = 215 P < 0.0292 with control group

Adapt from A.H. Rajput/ Parkinson and related Disorders 8 (2001) 95-100

Levodopa prolongs life expectancy

and non

(54)

Is Levodopa Toxic?

¾

¾ Early patients develop motor fluctuations, but may be a Early patients develop motor fluctuations, but may be a function of neuronal cell loss

function of neuronal cell loss

¾

¾ Increased life expectancy with LD introduction Increased life expectancy with LD introduction

¾

¾ LDLD--naive advanced PD patients develop fluctuations naive advanced PD patients develop fluctuations almost immediately with LD induction

almost immediately with LD induction

¾

¾ No LD neuronal dropout in laboratory animalsNo LD neuronal dropout in laboratory animals

¾

¾ Recent data suggest possible neuroprotectionRecent data suggest possible neuroprotection

¾

¾ Some believe continuous infusion may be safer than Some believe continuous infusion may be safer than pulsatile therapy

(55)

ELLDOPA study

360 never360 never--treated PD patients randomized to treated PD patients randomized to

placebo or carbidopa/levodopa (37.5/150,

75/300, 150/600 mg/day)

No evidence that levodopa had any deleterious No evidence that levodopa had any deleterious

effect on disease progression and failed to

support the notion of levodopa toxicity

Levodopa is not harmful to

(56)

Levodopa

-

Induced Dyskinesias

9

9 Manifestation of excessive dopaminergic stimulationManifestation of excessive dopaminergic stimulation

9

9 Typically late effect, and with higher dosesTypically late effect, and with higher doses

9

9 Narrowing of therapeutic windowNarrowing of therapeutic window

9

9 Rare in LDRare in LD--naive patients on DA monotherapy naive patients on DA monotherapy

9

9 Most common is Most common is ““peak dosepeak dose”” dyskinesiadyskinesia

9

9 disappears with dose reductiondisappears with dose reduction

9

9 Choreiform, ballistic and dystonic movementsChoreiform, ballistic and dystonic movements

9

9 Most patients prefer some dyskinesias over the Most patients prefer some dyskinesias over the alternative of akinesia and rigidity

(57)

Levodopa/Carbidopa Formulations

Onset

Duration

Immediate Release 20-40 min 2-4 hr

10/100, 25/100, 25/250

Controlled Release 30-60 min 3-6 hr

25/100, 50/200

“Fast acting” 10-20 min 0.5-1 hr

(58)

Levodopa taking alone without DDC Levodopa taking alone without DDC inhinh. only 1 . only 1

% reach the brain

(59)

Prospective, double blind trial in 618

levodopa

-

na

ï

ve patients

sustained

sustained--release Sinemetrelease Sinemet intermidiate

intermidiate--release Sinemetrelease Sinemet

After 5 years there is no difference in the prevalence

of motor complications between two groups

Control

-

released levodopa

Indication

Early morning akinesia Night time wearing off

(61)

Fast acting levodopa

Madopar DT 125Madopar DT 125

Early morning dystonia or akinesiaEarly morning dystonia or akinesia

End of dose wearing offEnd of dose wearing off

DysphagiaDysphagia

(62)

(63)

DB RANDOMIZED

DA

DA--AGONIST MONOTHERAPYAGONIST MONOTHERAPY--TRIALSTRIALS

-- DropDrop--outs resulting from outs resulting from AEsAEs-

-*Calculated from published figure

*Calculated from published figure

13%

15%

Pramipexole vs. L

Pramipexole vs. L--DopaDopa

10%

18%

Pergolide vs. L

Pergolide vs. L--DopaDopa

-20% 20% Bromocriptine Bromocriptine -20% 20% Ropinirole Ropinirole vsvs 33% 33% 27% 27% Ropinirole vs. L

Ropinirole vs. L--DopaDopa

13%

16%

Cabergoline

Cabergoline vs.Lvs.L--DopaDopa**

L

L--DopaDopa--ArmArm Agonist

Agonist--ArmArm Study

(64)

DB RANDOMIZED

DA

DA--AGONIST MONOTHERAPYAGONIST MONOTHERAPY--TRIALSTRIALS

-- Incidence of Incidence of HallucinosisHallucinosis-

-*2

*2 –– monthsmonths--analysisanalysis

3.3%

9.3%

Pramipexole vs. L

Pramipexole vs. L--DopaDopa

0%

3.4%

Pergolide vs. L

Pergolide vs. L--DopaDopa

-7.7% 7.7% Bromocriptine Bromocriptine -9.0% 9.0% Ropinirole vs. Ropinirole vs. 5.6% 5.6% 17.3% 17.3% Ropinirole vs. L

Ropinirole vs. L--DopaDopa

1.5%

1.4%

Cabergoline

Cabergoline vs.Lvs.L--DopaDopa**

L

L--DopaDopa--ArmArm Agonist

Agonist--ArmArm Study

(65)

(66)

Motor Complication During

Long

Long--term Lterm L--DopaDopa TherapyTherapy

Dose

a: Lee et all 1971,

a: Lee et all 1971, BarbeauBarbeau and Roy 1976, and Roy 1976, BattistinBattistin et al 1978, et al 1978, RajputRajputet alet al 1984, power et al 1986

1984, power et al 1986

b: Shaw et al 1980, Sweet and McDowell 1975, Markham et al 197

b: Shaw et al 1980, Sweet and McDowell 1975, Markham et al 1974, 4, YahrYahr 1976,

1976, BarbeauBarbeau 1976, McDowell and Sweet 1979, 1976, McDowell and Sweet 1979, PoewePoewe et al 1986.et al 1986.

23

23--88%88% 41

41--64%64% Peak

Peak--dose dyskinesiasdose dyskinesias

65 65--80%80% 35 35--58%58% Motor fluctuations Motor fluctuations >950 mg/d >950 mg/dbb 400 400--800mg/d800mg/daa

(67)

Levodopa Overview

(cont(cont’’d)d)

z Levodopa induces motor complications1-4

Up to 80% of Parkinson’s disease patients suffer from motor fluctuations and dyskinesias after

approximately 5 to 10 years of treatment with levodopa4

50% to 75% of patients develop motor

fluctuations 3 to 6 years after initiating therapy1-3

1. Fahn S. Adv Neurol. 1996;69:477-486.

2. Poewe WH, Wenning GK. Neurology. 1996;47(suppl 3):S146-S152. 3. Parkinson Study Group. Ann Neurol. 1996;39:37-45.

(68)

Dykinesias

and motor fluctuations in

a community

-

based study of PD

Schrag

Schrag et al, 2000et al, 2000

DykinesiasDykinesias in 28% of the patients in 28% of the patients

Motor fluctuations in 40% of the patientsMotor fluctuations in 40% of the patients

Predictors for the evolution of motor fluctuation:Predictors for the evolution of motor fluctuation:

-- Disease durationDisease duration

-- LD doseLD dose

Predictors for the evolution of dyskinesias:Predictors for the evolution of dyskinesias:

(69)

Mortality of Parkinson

’

s Disease

-- Role of LRole of L--DopaDopa Therapy Therapy -

-* pre

* pre--LL--DopaDopa

1,58 1,58 48% 48% 13 years 13 years 130 130 Hely

Hely et al., 1999et al., 1999

0,8 0,8 17% 17% 8 years 8 years 800 800 DATATOP, 1988 DATATOP, 1988 1,43 1,43--2,662,66 34 34--63%63% 15 years 15 years 359 359 Diamond et al. 1987 Diamond et al. 1987 1,46 1,46 27% 27% 13 years 13 years 178 178 Shaw et al. 1980 Shaw et al. 1980 1, 46 1, 46 12% 12% 12 years 12 years 597 597 Yahr Yahr, 1976, 1976 2,90 2,90 38% 38% 9 years 9 years 241 241 * *Hoehn&YahrHoehn&Yahr, 1967, 1967 Mortality Mortality Ratio Ratio Death Death Rate Rate Follow Follow--upup n n

(70)

Mechanism of developing dyskinesia

Risk factors

1.

1. Chronic exogenous exposure to dopaminergic Chronic exogenous exposure to dopaminergic

drugs (mainly when given intermittently);

dopamine receptor

dopamine receptor supersensitivitysupersensitivity

2.

2. Severe dopamine depletion resulting from Severe dopamine depletion resulting from

nigrostriatal

nigrostriatal denervationdenervation

3.

3. The required presence of anatomically intact The required presence of anatomically intact

striatal neurons

(71)

Dopamine Receptor Subtypes

D1, D2 subcorticalD1, D2 subcortical

D3, D4, D5 corticalD3, D4, D5 cortical

Differentiated biochemically & Differentiated biochemically &

pharmacologically into two families:

D1 family: D1, D5D1 family: D1, D5

(72)

Dopamine agonist

(1)

Ergotamine

Bromocriptine

Pergolide

Lisuride

* Apomorpine

Carbergoline

(73)

Dopamine agonist

(2)

Non ergotamine

Ropinirole

Pramipexole

Piribedil

(74)

Dopamine agonist

(3)

Reduced motor complication compare

with levodopa

Antiparkinsonian effect superior to

placebo in early

-

stage PD

Antiparkinsonian effect comparable to

levodopa in early

-

stage PD

(75)

Dopamine agonist

(4)

Supplementation with levodopa

provides clinical benefits comparable

to levodopa alone but with reduced

motor complications

(76)

(77)

DAs: Common Adverse Effects

Nausea, vomiting

Dizziness, postural hypotension

Headache

(78)

Association of

effusions

and

fibrosis

with

ergot vs.

non

-

ergot

dopamine

agonists

Cabergoline 1997 12 1 0 13 DHEC 1989 1 0 1 2 Lisuride 1968 6 0 1 7 Pergolide 1988 104 8 19 131 Pramipexole 1997 0 0 0 0

Müller T, Fritze J. Clinical Neuropharmacol 2003; 26: 109-111

Year of launch in PD Pleural Pericardial Peritoneal Total Bromocriptine 1979 215 0 29 244

(79)

DAs: Common Adverse Effects

Drowsiness & somnolence

Dyskinesias (less than Levodopa)

Confusion, hallucinations, paranoid

(80)

DAs: Common Adverse Effects(2)

Pulmonary & retroperitoneal fibrosis, pleural

effusion & pleural thickening, Raynaud

’

s

phenomena.

(May be more common with ergotamine DAs)

(81)

Dopamine agonist dose ranges

Initiating

(mg)

Usual dose

range (mg)

Bromocripti

ne

1.25 bid-tid

7.5-40

Pergolide 0.05

qd 0.75-6

Pramipexole 0.125

tid 0.75-3

Ropinirole 0.25

tid 9-24

Cabergoline 0.25

qd 0.5-5

Peribedil 50

qd 50-250

(82)

Dopamine agonist

Drug T

½ (h)

Carbidopa/levodopa 1-1.5

Pergolide 12-27

Pramipexole 8-12

Cabergoline 65+

Ropinirole

Bromocriptine

4

6

(83)

Dopamine Agonists in

comparison

As As monotherapy monotherapy and adjunctive and adjunctive to levodopa to levodopa As adjunctive As adjunctive to levodopa to levodopa only only Not being Not being approved approved As As monotherapy monotherapy and and adjunctive to adjunctive to levodopa levodopa US FDA approval US FDA approval (http:// (http://www.accewww.acce ssdata.fda.gov/scri ssdata.fda.gov/scri pts/cder/drugsatf pts/cder/drugsatf da/index.cfm da/index.cfm)) 74.40 74.40 (10 mg/d) (10 mg/d) 137.60 137.60 (1 mg/d) (1 mg/d) 43.68 43.68 (150 mg/d) (150 mg/d) 135.00 135.00 (1.5 mg/d) (1.5 mg/d)

Daily cost (min.

maint.dose maint.dose)) 18.60 18.60 15.00 15.00--34.4034.40 14.56 14.56 26.00 26.00--90.0090.00 Price/tab Price/tab Tab 2.5 mg. Tab 2.5 mg. Tab 0.05, Tab 0.05, 0.25 mg. 0.25 mg. Tab SR 50 Tab SR 50 mg. mg. Tab 0.25, 1 Tab 0.25, 1 mg. mg. Presentation Presentation 10 10--40 divided 40 divided t.i.d t.i.d.. 1 1--4 4 divided

divided t.i.dt.i.d.. 150 150--250 250 divided 3 divided 3--55 1.5 1.5--4.5 4.5 divided

divided t.i.dt.i.d.. Usual daily dosage

Usual daily dosage

(mg) (mg) Bromocriptine Bromocriptine Pergolide Pergolide Piribedil Piribedil Pramipexole Pramipexole

(84)

Assessment of Dopamine Agonists for the

treatment of PD according to

Evidence Based

Medicine

*

3 Efficacious (maximum strength of evidence)

± Likely efficacious

? Insufficient evidence 0 No studies

(*adapted from Rascol O. et al. Lancet 2002; 359: 1589-1598)

Category Bromocriptine Cabergoline Lisuride Pergolide Piribedil Pramipexole Ropinirole Monotherapy

in early PD ± ? ± 3 ? 3 3

Combination therapy

with L-Dopa in late PD 3 3 ± 3 ? 3 ?

Treatment of motor fluctuations ± ± ? 3 ? 3 3 Prevention of motor complications ± 3 ? ? ? 3 3 Imaging indicates slowed loss of 0 0 0 0 0 3 3 dopaminergic neurons

(85)

Dopamine agonist

Start lowStart low,, go slow go slow

(

(gradually titrated over several weeks or monthsgradually titrated over several weeks or months))

Improved motor and ADL scoresImproved motor and ADL scores

Decreases Decreases ““offoff”” timetime

(86)

Apomorphine (1)

D1/D2 agonistD1/D2 agonist

Parenteral delivery (s.c., i.v., sublingual, Parenteral delivery (s.c., i.v., sublingual,

intranasal, rectal)

Rapid Rapid ““offoff”” period rescueperiod rescue

(87)

Apomorphine (2)

Treatment of unpredictable, frequent motor Treatment of unpredictable, frequent motor

fluctuations

continuous s.c. infusion via minicontinuous s.c. infusion via mini--pumppump

SE: nausea, vomiting, hypotensionSE: nausea, vomiting, hypotension

trimethobenzamide 250 mg t.i.d.trimethobenzamide 250 mg t.i.d.

(88)

COMT inhibitor

No titration easy to administerNo titration easy to administer

Decreased Decreased ““offoff”” timetime,, increased increased ““onon”” time and time and

enhanced motor responses in patients with

levodopa motor fluctuation

Improved motor and ADL scores in stable Improved motor and ADL scores in stable

levodopa responders

May reduce risk for motor complications if used May reduce risk for motor complications if used

from onset of levodopa therapy

(89)

COMT inhibitor

Entacapone

200

mg with each dose of

levodopa

Talcapone

100

-

200

mg tid

Side effect

;

discoloration of urine

,

increase

dyskinesia

(90)

COMT inhibitor

Increase plasma levodopa elimination half life by Increase plasma levodopa elimination half life by

50%

50% and area under the curve by and area under the curve by 75%75% without without

rising of either the maximal plasma

concentration

concentration((CmaxCmax)) or the time to reach or the time to reach

maximal plasma concentration

(91)

Anticholinergics

Dopaminergic Dopaminergic depletiondepletion→→cholinergiccholinergic

overactivity

Initially used in the 1950sInitially used in the 1950s

Effective mainly for tremor (rigidity)Effective mainly for tremor (rigidity)

Common agents (Start low, go slow):Common agents (Start low, go slow):

TrihexyphenidylTrihexyphenidyl: 2: 2--15 mg/day15 mg/day

(92)

Anticholinergics

Side effects:

Dry

mouth, sedation, delirium,

confusion, hallucinations,

constipation, urinary retention,

impaired cognition

(93)

Selegiline

Irreversible MAO

-

B inhibitor

Clinically active by inhibiting dopamine

metabolism in brain

May be neuroprotective (DATATOP,

SINDEPAR)

(94)

Selegiline

Side effects: insomnia, hallucinations,

nausea (rarely), dyskinesia

Potential interactions with tricyclics and

SSRI antidepressants

As adjunct to levodopa, provides reduced

motor fluctuations and increased

“

on

”

time

(95)

DATATOP Follow

-

Up

DATATOP: 3 year followDATATOP: 3 year follow--up studies (Ann Neurol up studies (Ann Neurol

1996)

subjects requiring levodopa (n=352)subjects requiring levodopa (n=352)

selegiline made no difference with regard to disease selegiline made no difference with regard to disease

severity, wearing

severity, wearing--off or dyskinesiasoff or dyskinesias

subjects not requiring levodopa (n=162)subjects not requiring levodopa (n=162)

No difference in parkinsonian disability between the two No difference in parkinsonian disability between the two

groups

8 year follow8 year follow--up (Ann Neurol 1998)up (Ann Neurol 1998)

(96)

overview

Late complications:

motor VS non

(97)

Stages in Decline of Response to LD

I: Patient not aware of effect of individual doseI: Patient not aware of effect of individual dose

II: MidII: Mid--afternoon loss of benefitafternoon loss of benefit

III: Loss of sleep benefit; earlyIII: Loss of sleep benefit; early--morning akinesia, morning akinesia, possible foot dystonia

possible foot dystonia

IV: Regular IV: Regular ““wearing offwearing off”” every 4 hours at first, every 4 hours at first, shortens with time

shortens with time

V: Frequent wearing off, abrupt onV: Frequent wearing off, abrupt on--off, unpredictable off, unpredictable dose response

(98)

Late Complications

MotorMotor

response fluctuations, dyskinesias, dystonia, freezing, response fluctuations, dyskinesias, dystonia, freezing,

falls

NonNon--motor (Behavioral/neuropsychological)motor (Behavioral/neuropsychological)

depression, sleep disorders, psychosisdepression, sleep disorders, psychosis

AutonomicAutonomic

orthostatic hypotension; hyperhidrosis, constipation, orthostatic hypotension; hyperhidrosis, constipation,

impotence, urinary incontinence or retention

(99)

(100)

LD Response Fluctuations

Peripheral causes:Peripheral causes:

delayed gastric emptyingdelayed gastric emptying

dietary proteindietary protein

short plasma halfshort plasma half--lifelife

Central causes:Central causes:

pulsatile delivery to striatal receptorspulsatile delivery to striatal receptors

impaired storage capacityimpaired storage capacity

(101)

Response Fluctuations: Treatment

Increase LD doseIncrease LD dose

Increase DCI doseIncrease DCI dose

Add dopamine agonistAdd dopamine agonist

Add COMT inhibitorAdd COMT inhibitor

reduce LDreduce LD

liver function monitoringliver function monitoring

(102)

Peak Dose Dyskinesia or Dystonia

Chorea more common than dystoniaChorea more common than dystonia

May be worse on more affected sideMay be worse on more affected side

May not be as disabling as akinesia/rigidityMay not be as disabling as akinesia/rigidity

Dose adjustments, addDose adjustments, add--ons:ons:

reduce LD dose, increase dose frequencyreduce LD dose, increase dose frequency

(103)

Off

-

period Dystonia

Appears when LD level is low, especially early Appears when LD level is low, especially early

AM

w/ or w/o parkinsonismw/ or w/o parkinsonism

more frequent LD dosing to avoid low plasma levelsmore frequent LD dosing to avoid low plasma levels

(104)

Wearing Off

Regular and predictable decline in response 2Regular and predictable decline in response 2--4 4

hours after LD dose

Most common motor fluctuationMost common motor fluctuation

change to LDchange to LD--CR, or increase LD frequencyCR, or increase LD frequency

(105)

On

-

off Response

Sudden and unpredictable off periods unrelated Sudden and unpredictable off periods unrelated

to dosing schedule

One of the hardest features to manageOne of the hardest features to manage

(106)

Other Motor Complications

Diphasic dyskinesiaDiphasic dyskinesia

dyskinesia at beginning and end of dosedyskinesia at beginning and end of dose

Dose adjustments, addDose adjustments, add--ons: add DAons: add DA

Drug failureDrug failure

late afternoon, probably related to poor gastric emptying or late afternoon, probably related to poor gastric emptying or

absorption

liquid preparations; increase gastric motility; decrease dietaryliquid preparations; increase gastric motility; decrease dietary

protein

(107)

Freezing and Falls

FreezingFreezing

motoric block; at initiation of gait, turning, narrow spacesmotoric block; at initiation of gait, turning, narrow spaces

use auditory, visual, proprioceptive cuesuse auditory, visual, proprioceptive cues

FallsFalls

physical therapy evaluationphysical therapy evaluation

(108)

Psychosis

FeaturesFeatures

Vivid dreams/nightmares, disorientation, hallucinations, delusioVivid dreams/nightmares, disorientation, hallucinations, delusional nal

thought

Simplify medical regimenSimplify medical regimen

Stop unnecessary nonStop unnecessary non--PD medsPD meds

Stop: anticholinergic drugs, amantadine, selegiline, dopamine agStop: anticholinergic drugs, amantadine, selegiline, dopamine agonists, onists,

COMT inhibitors

Change from CR to standard carbidopa/levodopaChange from CR to standard carbidopa/levodopa

Try atypical antipsychotic agentsTry atypical antipsychotic agents

(109)

Depression

Reported in 30Reported in 30--90% of PD patients90% of PD patients

Difficult to discern from vegetative symptomsDifficult to discern from vegetative symptoms

Requires inquiry into depression symptomsRequires inquiry into depression symptoms

Usually responds quickly to medicationsUsually responds quickly to medications

Tricyclic agentsTricyclic agents

Selective serotonin reSelective serotonin re--uptake inhibitorsuptake inhibitors

(110)

Anxiety/Restlessness

Primary anxiety disorder: treat with Primary anxiety disorder: treat with

benzodiazepines

Associated with Associated with ““offoff--periodsperiods”” or lowor low--levodopa levodopa

levels: adjust levodopa dosing

Restless Leg Syndrome: benzodiazepines, Restless Leg Syndrome: benzodiazepines,

narcotics, levodopa, dopamine agonists

(111)

Sleep Disorders (1)

InsomniaInsomnia

careful historycareful history

difficulty with sleep initiation: tricyclic agents, difficulty with sleep initiation: tricyclic agents,

benzodiazepines, diphenhydramine, chloral hydrate

treat depressiontreat depression

(112)

Sleep Disorders (2)

Excessive daytime sleepinessExcessive daytime sleepiness

Correct poor sleep at nightCorrect poor sleep at night

Discontinue anticholinergics, amantadineDiscontinue anticholinergics, amantadine

Reduce dopamine agonist, levodopa dosages if Reduce dopamine agonist, levodopa dosages if

possible

(113)

Orthostatic Hypotension

LightLight--headedness, dizziness, fatigue, shoulder or neck headedness, dizziness, fatigue, shoulder or neck pain, blood pressure drops when standing

pain, blood pressure drops when standing

Taper antiTaper anti--hypertensive agentshypertensive agents

Taper nonTaper non--PD drugsPD drugs

Increase salt intakeIncrease salt intake

Compression stockingsCompression stockings

Fludrocortisone (0.1Fludrocortisone (0.1--0.4 mg/d)0.4 mg/d)

(114)

Urinary Incontinence/Frequency

Rule out urinary tract infectionRule out urinary tract infection

Bladder evaluation forBladder evaluation for

detrusor hyperactivitydetrusor hyperactivity

oxybutinin 5 oxybutinin 5 --30 mg/d; propanthaline 7.5 30 mg/d; propanthaline 7.5 -- 15 mg/d15 mg/d

detrusor hypoactivitydetrusor hypoactivity

phenoxybenzamine; prazosinphenoxybenzamine; prazosin

Urinary frequencyUrinary frequency

avoid fluid pooling in feetavoid fluid pooling in feet

(115)

Sexual Dysfunction

Medical screeningMedical screening

depression, anxiety, iatrogenic causesdepression, anxiety, iatrogenic causes

Endocrinologic evaluationEndocrinologic evaluation

prolactin, testosterone, lutenizing hormone, thyroid prolactin, testosterone, lutenizing hormone, thyroid

screen

Urologic evaluationUrologic evaluation

(116)

Nausea

LevodopaLevodopa--related: take with meals, add related: take with meals, add

carbidopa, add domperidone

Other antiOther anti--PD medications: same. PD medications: same.

If no improvement: withdraw newest agent, reIf no improvement: withdraw newest agent, re-

-initiate at minimal doses, slowly increase

(117)

Excessive Sweating

Usually levodopa related, and may be seen at Usually levodopa related, and may be seen at

peak or trough dose drug levels

reduce levodopareduce levodopa

add dopamine agonist or COMT inhibitoradd dopamine agonist or COMT inhibitor

add carbidopaadd carbidopa

(118)

Surgical Treatment

in

Parkinson

’

s Disease

(119)

Surgical Treatments for Parkinson

Surgical Treatments for Parkinson’’s Diseases Disease

AblativeAblative thalamotomythalamotomy pallidotomypallidotomy

Electrical stimulationElectrical stimulation

VIM thalamus, globus pallidus internus, subVIM thalamus, globus pallidus internus, sub-

-thalamic nucleus

thalamic nucleus

TransplantTransplant

autologous adrenal, human fetal, xenotransplants, autologous adrenal, human fetal, xenotransplants,

genetically engineered transplants

(120)

Thalamotomy

Significant improvement in contralateral tremorSignificant improvement in contralateral tremor

depends on correct placementdepends on correct placement

Minimal improvement in other PD signsMinimal improvement in other PD signs

Bilateral procedures poorly toleratedBilateral procedures poorly tolerated

AEs: bulbar, sensory and motor deficits, gait, AEs: bulbar, sensory and motor deficits, gait,

surgical complications

(121)

Deep Brain Stimulation (DBS)

High frequency, pulsatile, bipolar electrical High frequency, pulsatile, bipolar electrical

stimulation

Stereotactically placed into target nucleusStereotactically placed into target nucleus

Can be activated and deactivated with an Can be activated and deactivated with an

external magnet

Exact physiology unknown, but higher Exact physiology unknown, but higher

frequencies mimic cellular ablation, not

stimulation

(122)

Movement Disorder Surgery

ศรัณย นันทอารี Siriraj Movement Disorder Group อภิชาติ พิศาลพงศ กนกวรรณ บุญญพิสิฎฐ อรสา ชวาลภาฤทธิ์ นิพนธ พวงวรินทร ไพรัช สายวิรุณพร วรพรรณ เสนาณรงค นันทศักดิ์ ทิศาวิภาค

(123)

VIM Thalamic DBS

80% reduction in contralateral arm and leg tremor80% reduction in contralateral arm and leg tremor

Possible mild improvement in bradykinesia and rigidityPossible mild improvement in bradykinesia and rigidity

No functional improvement (UPDRS part II), but No functional improvement (UPDRS part II), but significant improvement based upon global scores

significant improvement based upon global scores

No effect: gait and bulbar symptomsNo effect: gait and bulbar symptoms

(124)

Globus Pallidus internus DBS

Effects tend to mimic those of pallidotomyEffects tend to mimic those of pallidotomy

Significant improvement in dyskinesiaSignificant improvement in dyskinesia

Moderate improvement in cardinal Moderate improvement in cardinal ““offoff”” signssigns

No comparison between unilateral and bilateral No comparison between unilateral and bilateral

Bilateral DBS may be better tolerated than bilateral Bilateral DBS may be better tolerated than bilateral pallidotomy

pallidotomy

(125)

Bilateral Subthalamic DBS

Bilateral placement appears to be superior to Bilateral placement appears to be superior to

unilateral placement

Theorized neuroprotective mechanism, but no Theorized neuroprotective mechanism, but no

clinical evidence supporting this

AE: confusion and hallucinations, increased AE: confusion and hallucinations, increased

dyskinesia before medication adjustments, eyelid

opening apraxia, weight gain, surgical

complications

(126)

Patient Diary Data

Subthalamic Nucleus

Patient Diary Data

Subthalamic Nucleus

Clinical Results Asleep 27% “on” time 23% “off” time 35% “on” with Dyskinesia 14% Asleep 33% “on” time 53% “off” time 11% “on” with Dyskinesia 3% Asleep 33% “on” time 53% “off time” 12% “on” with Dyskinesia 2%

Pre-Implant 6 Months 12 Months

n = 39 L-dopa equiv. = 1325 mg n = 25 L-dopa equiv. = 1016 mg n = 12 L-dopa equiv. = 988 mg

(127)

Subthalamic DBS

All cardinal features of PD noted to improve All cardinal features of PD noted to improve

in open label trials

““OffOff”” UPDRS improved 60%UPDRS improved 60%

““OnOn”” UPDRS improved 10%UPDRS improved 10%

Dyskinesia tends to improve but this is Dyskinesia tends to improve but this is

probably due to decreased levodopa dose

(128)

Activa

®

Parkinson’s Control System

Activa

®®

Parkinson

’

s Control System

(129)

Implanted Components

(130)

DBS™ Leads

Model 3389 Model 3387 Cap, Ring, Stylet

(131)

(132)

(133)

T2W FSE

axial

coronal

(134)

Stimulation

-

induced effects

(

(135)

(136)

(137)

(138)

Cell Transplants

Autologous adrenal transplantsAutologous adrenal transplants

No efficacyNo efficacy

Allogenic human fetal transplantsAllogenic human fetal transplants

Initial encouraging clinical resultsInitial encouraging clinical results

Xenogenic fetal transplant (porcine and Xenogenic fetal transplant (porcine and

bovine)

Preliminary results pendingPreliminary results pending

Genetically engineered cellsGenetically engineered cells

(139)

Human Fetal Transplants

EfficacyEfficacy

Encouraging preliminary results in young PD ptsEncouraging preliminary results in young PD pts

PET studies consistent with cell functioningPET studies consistent with cell functioning

Autopsies (2) show cell survivalAutopsies (2) show cell survival

ProblemsProblems

44--10 embryos < 10 weeks gestation needed10 embryos < 10 weeks gestation needed

Immunosuppression requirements unknownImmunosuppression requirements unknown

(140)

Nonpharmacologic Treatments (1)

Patient/caregiver education

Physical therapy

Exercise

(141)

Nonpharmacologic Treatments (2)

<

Management in Parkinson s Disease

Management

overview

Pathology of Parkinson

overview

feet, fluctuation of symptoms (YOPD)

Additional Signs and Symptoms

Clues Suggesting

dementia

Criteria for Diagnosis

Definitive diagnosis can only be made

Parkinson

overview

Secondary

Antiemetics

Treatment: Stop offending medications

Metabolic Causes of Parkinsonism

Toxin

 MPTPMPTP

Vascular Parkinsonism

Normal pressure hydrocephalus—

Diffused Lewy body disease

Young

242 medical records were enrolled

Demographic data

Current concept in treating PD

(post synaptic change) resulting in

overview

Symptomatic treatment

medical therapies to treat PD

American Academy of Neurology, 2001 American Academy of Neurology, 2001

Levodopa

to maintain employment and independent

and non

ELLDOPA study

Levodopa

Levodopa/Carbidopa Formulations

levodopa

Control

DB RANDOMIZED

L--DopaDopa--ArmArm Agonist

a: Lee et all 1971,

65 65--80%80% 35 35--58%58% Motor fluctuations Motor fluctuations >950 mg/d >950 mg/dbb 400 400--800mg/d800mg/daa

Levodopa Overview

Dykinesias

Schrag

Mortality of Parkinson

Mechanism of developing dyskinesia

Dopamine Receptor Subtypes

Carbergoline

Antiparkinsonian effect superior to

provides clinical benefits comparable

Headache

DAs: Common Adverse Effects

Pulmonary & retroperitoneal fibrosis, pleural

Cabergoline 0.25

Assessment of Dopamine Agonists for the

± Likely efficacious

Dopamine agonist

Apomorphine (2)

COMT inhibitor

Anticholinergics

confusion, hallucinations,

May be neuroprotective (DATATOP,

As adjunct to levodopa, provides reduced

overview

Late Complications

Response Fluctuations: Treatment

period Dystonia

off Response

Freezing and Falls

Depression

Anxiety/Restlessness

Sleep Disorders (1)

Orthostatic Hypotension

Urinary Incontinence/Frequency

Sexual Dysfunction

Excessive Sweating

Surgical Treatment

Surgical Treatments for Parkinson

MPTPMPTP