Welcome To The World of Parkinson

1
Welcome To The World ofParkinsons Disease

• 
  Dr Anjum Qazi
• 
  Emory Family Medicine

2
OUTLINE

1. Epidemiology, Etiology, and Burden of Illness
2. Clinical Course of PD
3. Evolution of Assessment
4. Treatment Goals and Considerations
5. Pharmacologic Management
6. Conclusions

3
ORIGIN OF PARKINSONS DISEASE
First report of shaking palsy by Dr. J.
Parkinson in 1817 Involuntary tremulous
motion, with lessened muscular power, in parts
not in action and even when supported . . . the
senses and intellects being uninjured . . .
unsteadiness of his hand whilst writing or
employing. The fingers cannot be disposed of in
the proposed direction and applied with certainty
to any proposed joint. Harrassed by this
tormenting round, the patient has recourse to
walking, but as the disease progresses, the
propensity to lean forwards becomes invincible
4
Parkinsons Disease

• Definition
• Most prevalent type of parkinson presentation
• Caused by lesions in the basal ganglia,
  predominantly in the substantia nigra
• Clinical symptoms associated with a reduction in
  the number of neurons in the substantia nigra
• Manifests as deficits in motor behavior

5
Primary Parkinsons Disease

• Progressive and chronic
• Neurodegenerative disease
• Characterized by slow and relatively selective
  loss of substantia nigra dopaminergic neurons

Watts Koller. Movement Disorders Neurologic
Principles and Practice. 1997.
6
Epidemiology of PD

• 500,000 to 1 million patients in U.S.
• 40,000 to 60,000 new cases/year
• Male predominance (32)
• Average age of onset is 60 years
• Affects up to 0.3 of the general population but
  1 to 3 of those gt65 years
• Prevalence increasing as the population ages

7
Parkinsons Disease

• Categories of causes
• Primary or idiopathic (Parkinson disease)
• Secondary (associated with infections, drugs,
  toxins, infarcts, trauma, tumors)
• Parkinson-plus syndrome
• Heredodegenerative diseases

Waters CH. Diagnosis and Management of
Parkinsons Disease, 1999.
8
Etiology of PD

• Specific causative factors are unknown
• A complex interaction between genetic and
  environmental factors is probably involved
• Families with rare autosomal dominant and
  autosomal recessive inheritance patterns have
  been described

9
Potential Causes of Parkinsons Disease

• Genes
• ?-synuclein
• Parkin
• UCH-L1
• Susceptibility genes

• Environment
• Pesticides
• Rural living
• Other (?)

• Pathogenic Mechanisms
• Protein aggregation
• Mitochondrial dysfunction
• Oxidative stress
• Inflammation
• Excitotoxicity

Apoptosis (cell death)
UCH-L1 ubiquitin hydrolase L1.
10
Mechanisms inthe Pathogenesis of PD
CAUSE Genetic Abnormalities / Environmental
Toxins
PATHOGENETIC EVENTS Mitochondrial Damage
Oxidative Stress
Excessive Excitotoxicity Calcium
Dysregulation
NEURONAL DYSFUNCTION Protein Aggregation
CELL DEATH Apoptosis
11
Progressive Changes in P.D.
Adapted from Parkinsons Disease and Movement
Disorders, 1988.
12
Heredity Plays Larger Role in YOPD
Identical
Fraternal
1.5

• A major epidemiologic study suggests that
• Genetic factors play a larger role in YOPD
• Environmental insults play a larger role in PD
  onset after age 50

RR6.00
1.0
Pairwise Concordance
0.5
RR1.39
RR1.02
0.0
Overall
?50
gt50
Age at Diagnosis of First Twin (years)
Tanner et al. JAMA. 1999281341-346.
13
Genetic Factors

• Autosomal dominant and autosomal recessive
  patterns of inheritance have been identified
• None linked to majority of PD cases
• It is hypothesized that excessive protein
  accumulation due to genetic or environmental
  insults may be involved in the pathogenesis of PD

14
Risk Factors for PD

• Age is strongest predictor of increased risk of
  PD
• Other risk factors include
• Exposure to environmental toxins
• Genetic factors, family history of parkinsonism
• Male gender
• Premorbid parkinsonian personality characterized
  by traits of
• Introversion
• Rigidity
• Inflexibility

15
Role of Environmental Toxins

• Data are inconclusive
• PD may be more common in those who
• Have a history of exposure to
• Insecticides
• Herbicides
• Heavy metals
• Lived in rural areas for prolonged periods
• Drank well water for many years

16
Genetic Factors Autosomal Dominant

• Familial forms with autosomal dominant
  inheritance pattern identified with mutations in
  genes encoding 2 proteins
• Alpha-synuclein (SNCA)
• Presynaptic nerve terminal protein
• Also associated with Alzheimers disease
• Over expression can induce dopamine neuron
  degeneration
• Ubiquitin carboxy-terminal hydrolase L1 (UCH-L1)
• Ubiquitin pathway is important in protein
  degradation

Leroy et al. Nature. 1998395451-452. Polymeropou
los et al. Science. 19972762045-2047. Ueda et
al. Proc Natl Acad Sci USA. 19939011282-11286. Z
hou et al. Brain Res. 200086633-43.
17
Genetic Factors Autosomal Recessive

• An autosomal recessive form of parkinsonism has
  been associated with mutations in the parkin
  gene
• Relatively young-onset parkinsonism
• Early dystonia
• Symmetric involvement
• Good levodopa response
• Absence of Lewy bodies

Abbas et al. Hum Mol Genet. 19998567-574. Hattor
i et al. Ann Neurol. 199844935-941. Kitada et
al. Nature. 1998392605-608. Lucking et al. N
Engl J Med. 20003421560-1567.
18
Clinical Features of Parkinsons Disease
19
CLINICAL PRESENTATION OF PD

• Progressive neurodegenerative disease
• Loss of dopaminergic neurons
• Motor symptoms
• Non-motor symptoms

Colcher, et al. Med Clin North Am.
199983327-347.
20
Clinical Features of P.D.

• Motor abnormalities
• Extra-pyramidal
• Autonomic failure
• Constipation
• Impotence
• Neuro-psychiatric dysfunction
• Depression
• Dementia

21
Motor Abnormalities

• Bradykinesia, Akinesia
• Rigidity (cogwheel)
• Instability
• Tremor Resting Postural
• Gait Abnormalities

Watts Koller. Movement Disorders Neurologic
Principles and Practice. 1997.
22
Question TO MAKE THE DIAGNOSIS OF PARKINSONS,
YOU NEED ?

• A. 1 OF 3 CARDINAL SIGNS 2 LESSER SIGNS
• B. 2 OF THE 3 CARDINAL SIGNS
• C. 3 OF THE 3 CARDINAL SIGNS
• D. 2 OF THE 3 CARDINAL SIGNS 2 LESSER SIGNS

23
Diagnostic Criteria for PD

• At least 2 of these criteria are required
• Bradykinesia
• Muscular rigidity
• Resting tremor

Watts Koller. Movement Disorders Neurologic
Principles and Practice. 1997.
24
SLEEP DISTURBANCES

• Estimated prevalence varies across studies lt 98
• Common problems include
• Disorders of sleep initiation and maintenance
• Periodic limb movements in sleep (PLMS)
• REM behavior disorder (RBD)
• Excessive daytime sleepiness

Simuni. Neurol Clin. 200422S107-S126.
25
SENSORY SYMPTOMS

• gt60 of PD patients complain of pain1
• Muscle cramps
• Stiffness
• Dystonias
• Radiculopathies
• Arthralgias
• 40 of PD patients have sensory complaints2
• Burning
• Tingling
• Numbness

1. Mott, et al. Aust Fam Physician.
200433663-664. 2. Colcher, et al. Med Clin
North Am. 199983327-347.
26
Longitudinal Course of PD

• Insidious, often unilateral onset
• Resting tremor
• Loss of arm swing
• Slowing of movement
• Rate of progression varies
• Eventually symptoms worsen become bilateral
• Postural instability marks the beginning of more
  severe disease
• Treatment must be individualized

Watts Koller. Movement Disorders Neurologic
Principles and Practice. 1997.
27
TYPICAL PROGRESSION CLINICAL COURSE
Motor Complication Period
Preclinical Phase
Cognitive Decline
Resistant Symptoms
Honeymoon Period
0
3
8
15
20
-2 to -6
Years
Fahn. Ann NY Acad Sci. 20039911-14.
28
Stages of Parkinsons Disease

• STAGE I Unilateral
• STAGE II Bilateral
• STAGE III Postural reflexes impaired
• STAGE IV Significant impaired ADLs
• STAGE V Bedridden

29
Atypical Features Indicating a Non-PD Diagnosis

• Remitting course
• Oculogyric crisis
• Supranuclear down or lateral gaze palsy
• Cerebellar signs
• Severe autonomic dysfunction suggesting diagnosis
  other than PD

Watts Koller. Movement Disorders Neurologic
Principles and Practice. 1997.
30
Atypical Features Indicating a Non-PD Diagnosis

• Alzheimerslike dementia from onset
• Early change of personality
• Apathy
• Disinhibition
• Irritability
• Early word-finding deficits

Watts Koller. Movement Disorders Neurologic
Principles and Practice. 1997.
31
Atypical Features Indicating a Non-PD Diagnosis

• Abrupt onset of symptoms
• Stepwise course
• Motor neuron signs
• Lack of disease progression

Watts Koller. Movement Disorders Neurologic
Principles and Practice. 1997.
32
Atypical Features Indicating a Non-PD Diagnosis

• Cerebrovascular disease
• History of repeated head injury
• History of definite encephalitis
• Neuroleptic treatment
• Evidence of tumor or hydrocephalus
• Exposure to toxic substance

Watts Koller. Movement Disorders Neurologic
Principles and Practice. 1997.
33
Diagnostic Classification of PD

• Clinically Possible
• The presence of any one of the salient features
• Clinically Probable
• A combination of any 2 of the cardinal features
• Clinically Definite
• Any combination of 3 of the cardinal features

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Diagnostic Classification of PD

• Clinically Possible
• The presence of any one of the salient features
  tremor, rigidity, or bradykinesia
• Impairment of postural reflexes is not included
  because it is too nonspecific
• The tremor must be of recent onset, but may be
  postural or resting

Calne et al. Ann Neurol. 199232(suppl)S125-S127.
35
Diagnostic Classification of PD

• Clinically Probable
• A combination of any 2 of the cardinal features
  resting tremor, rigidity, bradykinesia, or
  impairment of postural reflexes
• Alternatively, asymmetrical resting tremor,
  asymmetrical rigidity, or asymmetrical
  bradykinesia are sufficient

36
Diagnostic Classification of PD

• Clinically Definite
• Any combination of 3 of the cardinal features
  resting tremor, rigidity, bradykinesia, or
  impairment of postural reflexes
• Alternatives sufficient are 2 of these features,
  with one of the first 3 displaying asymmetry

37
Parkinsons Disease

• Categories of causes
• Primary or idiopathic (Parkinson disease)
• Secondary
• Infections
• Drugs
• Toxins
• Infarcts
• Trauma
• Tumors
• Parkinson-plus syndrome
• Heredodegenerative diseases

38
Increased Diagnostic Accuracy in PD

• Clinical
• Resting tremor
• Unilateral onset
• Masked facies
• Pharmacologic
• Dramatic and sustained response to levodopa
  treatment

Watts Koller. Movement Disorders Neurologic
Principles and Practice. 1997.
39
Neurodegenerative Diseases With Parkinsonian
Features

• Progressive supranuclear palsy
• Multiple system atrophy
• Shy-Drager syndrome
• Olivopontocerebellar degeneration
• Striatonigral degeneration
• Corticobasal ganglionic degeneration

Watts Koller. Movement Disorders Neurologic
Principles and Practice. 1997.
40
Parkinsonism Other Causes

• Vascular
• Trauma
• Hydrocephalus
• Toxins

Watts Koller. Movement Disorders Neurologic
Principles and Practice. 1997.
41
Senile Parkinsonism

• No tremor
• Bradykinesia / akinesia
• Gait disturbance
• Stooped posture
• No response to levodopa

Watts Koller. Movement Disorders Neurologic
Principles and Practice. 1997.
42
Dementia and Parkinsonism

• Parkinsons disease
• Alzheimers disease
• Lewy bodyrelated dementia

Watts Koller. Movement Disorders Neurologic
Principles and Practice. 1997.
43
Dementia With Lewy Bodies

• Progressive cognitive decline
• Fluctuating cognition, attention, alertness
• Visual hallucinations
• Parkinsonism
• Supportive features
• Falls
• Syncope
• Transient loss of consciousness
• Neuroleptic sensitivity

McKeith et al. Neurology. 1996471113-1124.
44
Environmental Toxins in PD

• In rats, chronic systemic exposure to rotenone, a
  mitochondrial complex I inhibitor, resulted in
• Selective degeneration of the nigrostriatal
  system associated behaviorally with bradykinesia
  and rigidity
• Fibrillar cytoplasmic inclusions positive for
  ubiquitin and alpha-synuclein

Betarbet et al. Nat Neurosci. 200031301-1306.
45
TREATMENT GOALS AND CONSIDERATIONS
46
GOALS FOR THE TREATMENT OF PD

• CURRENT
• Enhance functioning ADLs Motor non-motor
  symptoms
• Maintain quality of life
• Delay need for levodopa
• Minimize and delay motor complications
• FUTURE
• Slow or halt disease progression

47
Management of PD

• Key Points
• Individualize therapy according to
• Age
• Cognitive status
• Symptoms
• Response to treatment
• Focus on wellness
• Exercise
• Stress reduction
• Well-balanced diet

48
Management of PD

• Key Points
• Monitor functional ability
• Introduce dopaminergic therapy when symptoms
  require treatment
• Evaluate response and modify treatment if
  necessary

49
Parkinsons Disease Treatment Algorithm
50
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51
Question WHICH OF THE FOLLOWING IS THE IST LINE
TREATMENT FOR PARKINSONS

• STIMULATE DOPAMINE RECEPTORS
• B. INHIBIT DOPAMINE METABOLISM
• C. ANTI- HISTAMINES/CHOLINERGICS
• D. INCREASES DOPAMINE LEVELS

52
INCREASE DOPAMINE LEVELS

• LEVODOPA-CARBIDOPA (SINEMET)
• AMANTADINE (SYMMETREL)

53
Pharmacologic Therapy
Blood-Brain Barrier
COMT catechol-O-methyltransferase DOPAC
dihydroxyphenylacetic acid DA dopamine
agonist HVA homovanillic acid DDC dopa
decarboxylase MAO-B monoamine oxidase, type b
54
Management of P. D.
Parkinsons Disease
Pharmacologic Therapy
Nonpharmacologic Therapy
Education
Neuroprotection (? Selegiline)
Support Service
Functional Impairment
Continue to Monitor
Exercise
Yes
No
Nutrition
Levodopa (/- COMT Inhibitor)
Dopamine Agonists
Dopamine Agonist Levodopa (/- COMT Inhibitor)
Add COMT Inhibitor If Not On
Motor Complications Use Strategy That ?
Likelihood of Occurrence
Unacceptable Control With Medical Therapy
Consider Surgical Management
55
Management of P. D.
Pharmacologic Therapy
Neuroprotection ? Selegiline
Continue to Monitor
Functional Impairment
No
Yes
Dopamine Agonists
Levodopa (/- COMT Inhibitor)
56
PHARMACOLOGIC MANAGEMENT
57
(No Transcript)
58
(No Transcript)
59
Dual Inhibition of the Two Major Levodopa
Degradation Pathways
Schematic of Dual Inhibition of DDC and COMT
Enzyme Pathways
With dual inhibition, significantly more levodopa
reaches the brain, with a 3540 increase in
bioavailability and a 3050 reduction in plasma
variability
Nutt et al 1994. Gordin et al 2003 Stalevo PI,
2003.
Dopa decarboxylase inhibitor
60
AGENTS COMMONLY USED IN THE MANAGEMENT OF PD

• LEVODOPA
• COMT INHIBITORS
• DOPA DECARBOXYLASE INHIBITORS
• Carbidopa
• Benserazide
• Tolcapone
• Entacapone
• MAO-B INHIBITORS
• Selegiline

• DOPAMINE AGONISTS
• Pramipexole
• Ropinirole
• Pergolide
• Bromocriptine
• ANTICHOLINERGICS
• Trihexyphenidyl
• Benztropine
• NMDA RECEPTOR ANTAGONISTS
• Amantadine

1. Deleu, et al. Clin Pharmacokinet.
200241261-309. 2. Stacy M. Pharmacotherapy.
200020(1 pt 2)8S-16S.
61
Levodopa Overview

• Highly effective drug for PD symptoms
• Used since late 1960s1
• Relatively rapid onset of action2

1. Tolosa E et al. Neurology. 199850(suppl
6)S2-S10. 2. Stacy M. Pharmacotherapy.
200020(suppl)8S-16S.
62
Evolution of Levodopa Therapy
Marked benefit with high doses of oral levodopa
Levodopa controlled-release formulations
introduced
StalevoTM (carbidopa, levodopa entacapone)
introduced
1990s
1980s
1960
1970s
2003
Striatal dopamine loss identified in PD
DDC inhibitors introduced
COMT inhibitors introduced
Dopa decarboxylase Catechol-O-methyl
transferase
Ehringer et al 1960 Cotzias et al 1967
63
Levodopa Overview

• Metabolized to dopamine to be effective1
• Carbidopa to limit peripheral side effects1
• Absorption delayed or diminished by large neutral
  amino acids or agents that slow transit time,
  antacids, and anticholinergics1,2
• Short half-life may induce pulsatile stimulation
  of dopamine receptors3

64
Pharmacologic Therapy
Blood-Brain Barrier
COMT catechol-O-methyltransferase DOPAC
dihydroxyphenylacetic acid DA dopamine
agonist HVA homovanillic acid DDC dopa
decarboxylase MAO-B monoamine oxidase, type b
65
Levodopa Strengths

• Most effective
• Use for almost 40 years
• Rapid onset of action
• Well tolerated
• ? Reduces mortality

66
Levodopa Weaknesses

• Must be converted to dopamine
• Needs dopa-decarboxylase inhibitor
• Absorption delayed with food
• Timing for introduction controversial
• Motor fluctuations
• Motor dyskinesias
• ? Increased risk of melanoma

67
Levodopa Overview

• Levodopa induces motor complications1-4
• Up to 80 of Parkinsons 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. 199669477-486. 2. Poewe
WH, Wenning GK. Neurology. 199647(suppl
3)S146-S152. 3. Parkinson Study Group. Ann
Neurol. 19963937-45. 4. Olanow CW, Stocchi F.
Eur J Neurol. 20007(suppl 1)3-8.
68
Levodopa Motor Complications

• May Occur in up to 80 of Patients
• Freezing
• Dyskinesias
• Choreo-athetoid movements
• Usually appear in middle of on period
• Occur months to years post-initiation
• End-of-dose wearing-off
• 1 to 3 years post-initiation of levodopa
• Response duration (4 h) becomes shorter

69
Risk Factors for Developing Motor Complications

• Duration of illness
• Duration of treatment
• Severity of illness
• Young age at onset
• Short half-life of dopaminergic agent, leading to
  pulsatile stimulation
• High dosage of levodopa

70
Reducing the Peripheral Metabolism of Levodopa
Levodopa/DDC Inhibitor
3-OMD
COMT
Dopamine
Levodopa
X
X
DDC
Dopamine
Central
Peripheral
DDC dopamine
decarboxylase 3-OMD 3-O-methyldopa
71
Carbidopa-Levodopa

• When to start therapy?
• How to administer t.i.d.?
• When do you make adjustments?
• Frequency of dosing
• Strength of dosage
• When to add Comtan
• When to add Dopa-Agonists

72
Wearing Off Nonmotor Symptoms

• Sensory pain, paresthesias, sensory loss,
  akathisia
• Psychiatric anxiety, paranoia, hallucinations,
  depression, panic, cognitive changes
• Autonomic pallor, BP changes, shortness of
  breath, tachycardia, sweating, laryngeal stridor,
  papillary dilation, drooling, dysphagia,
  belching, abdominal bloating, urinary frequency,
  and micturation disturbances

73
COMT INHIBITORS AS ADJUNCTS w/ LEVODOPA

• Inhibit enzymes that metabolize levodopa
  dopamine
• Reduce 3-O-methyldopa formation
• Allows more levodopa to reach the brain
• Used as adjuncts to levodopa
• Entacapone
• Tolcapone
• Stalevo (levodopa carbidopa entacapone)
• Limited data available from controlled trials
• No evidence that they reduce motor complications

Deleu, et al. Clin Pharmacokinet. 200241261-309.
74

• Efficacy of Entacapone

75
Effect of Entacapone on Levodopa Availability

• Blocks the COMT enzyme
• Allows more levodopa to enter the brain

18F-Dopa/carbidopa
18F-Dopa/carbidopa/entacapone
Images are scaled to activity in the occipital
cortex
PET images of 18F-Dopa accumulated in a patient
given a single dose of levodopa/carbidopa with
and without entacapone
76
Entacapone Dosing

• 200 mg tablet w/ Carbidopa/levodopa
• Maximum dosage is 8 tablets/day
• No titration required
• Effective from first dose
• Use with immediate and CR levodopa
• Levodopa dose may be decreased
• Average dosage decrease was 25
• No laboratory monitoring required
• Avoid rapid withdrawal/discontinuation

77
Entacapone Smoothes Plasma Levodopa Levels
Entacapone/Levodopa/DDCI
Levodopa Administration
Levodopa plasma levels in a single patient with
or without administration of entacapone. Entacapon
e administered with the second and subsequent
doses first dose is levodopa only. Olanow CW, et
al. Neurology. 2000 Swanson G, et al. Trends
Neurosci. 2000. (Courtesy of F. Stocchi)
78
Overview

• Role of levodopa therapy
• What is StalevoTM (carbidopa, levodopa and
  entacapone)?
• StalevoTM dosing and administration

79
Stalevo

• StalevoTM is a combination of levodopa, the DDCI
  carbidopa, and the COMT inhibitor entacapone, in
  one tablet
• Dual inhibition of the DDC and COMT pathways
• Extends the elimination half-life of levodopa
• Enhances the benefits of levodopa
• Provides greater control of PD symptoms
• The efficacy and safety of combining carbidopa /
  levodopa entacapone has been established in
  several clinical trials

80

• MAO-B INHIBITORS

81
MAO-B INHIBITORS

• SELEGILINE
• Non-competitive MAO-B1
• Selectivity lost after 10 mg1
• Concern over tyramine (cheese) effect1
• Active amphetamine-like metabolites1
• RASAGILINE2
• No amphetamine-like metabolites
• Pending FDA Approval
• Putative neuroprotective effect suggested by
  laboratory studies

1. Siderowf, et al. Med Clin North Am.
199983445-466. 2. Siddiqui, et al. Drugs
Aging. 20052283-91.
82
DOPAMINE AGONISTS
83
RATIONALE FOR EARLY USE OF DOPAMINE AGONISTS AS
INITIAL MONOTHERAPY

• Dopamine agonists improve motor symptoms in early
  PD1
• Monotherapy for up to 5 years2,3
• Risk of developing motor complications is reduced
  
• Putative neuroprotective effect suggested by
  laboratory studies5

1. Olanow, et al. Eur J Neurol. 20007(suppl
1)3-8. 2. Barone, et al. Poster presented at
53rd Annual American Academy of Neurology 2001
Philadelphia, PA. 3. Olanow. Neurology.
200258(suppl 1)S33-S41. 4. Parkinson Study
Group. JAMA. 20002841931-1938. 5. Schapira.
Eur J Neurol. 20029(suppl 3)7-14.
84
EARLY USE OF DOPAMINE AGONISTS RESULTS IN FEWER
MOTOR COMPLICATIONS THAN LEVODOPA
LEVODOPA
DOPAMINE AGONIST
Percent of Patients
Pramipexole Study
Cabergoline Study
Pergolide Study
Ropinirole Study
1. Rascol, et al. N Engl J Med.
20003421484-1491. 2. Parkinson Study Group.
JAMA. 20002841931-1938. 3. Parkinson Study
Group. Arch Neruol. 2004611044-1053. 4. Rinne,
et al. Drugs. 199855(suppl 1)23-30. 5. Oertel
W. Early dopamine agonists delay motor
complications (Abstract M86). Author
communication.
85
Events Leading to Motor Complicationsin
Parkinson Disease
Artists interpretation of dopamine
neurotransmission adapted from observations in
animal models. Chase TN. Drugs. 1998 Swanson G,
et al. eds. Basal Ganglia, Parkinsons Disease
and Levodopa Therapy (suppl to Trends Neurosci).
2000.
86
Consequences of Abnormal Motor Control

• Less on time
• More off time
• Increased Dyskinesias
• Increased Motor complications
• Repercussions
• Compromised mobility
• Compromised ADLs
• Restriction of social and physical activities
• Sense of loss of control confidence
• Increased dependence on caretakers

87
Continuous Dopaminergic Stimulation (CDS)
Hypothesis

• Pulsatile activation of striatal dopamine
  receptors may contribute to motor complications
• Short-acting levodopa leads to
• Fluctuating plasma levels of levodopa
• High and low levels of receptor activation
• Smoothing levodopa availability may
• Provide more CDS
• Prevent or delay the onset of motor complications

Olanow W, et al. Trends Neurosci. 2000.
88
CDS Leads to More Normal Motor Functioning in
Parkinson Disease
Artists interpretation of dopamine
neurotransmission adapted from observations in
animal models Chase TN. Drugs. 1998 Swanson G,
et al. eds. Basal Ganglia, Parkinsons Disease
and Levodopa Therapy (suppl to Trends Neurosci).
2000.
89
Features of Pramipexole (Mirapex), a Dopamine
Agonist

• Believed to provide direct stimulation of
  dopamine receptors in the striatum1
• Longer plasma half-life than levodopa1
• Reduced risk of motor complications compared
  with levodopa after 4 years2,3
• Improves dyskinesias2,3
• Improves wearing off2,3
• No difference in on-off2,3

1. Watts RL. Neurology. 199749724-728. 2.
Holloway RG. Neurology. 200258(suppl
3)A81-A82. 3. Data on file.
90
REQUIP

• D2/D3 dopamine agonist1,2
• Preclinical studies suggest neuroprotective
• Significantly reduce the incidence of dyskinesias
  in PD relative to L-dopa6
• May delay the progression of PD relative to
  L-dopa7

91
CONCLUSIONS

• Approach patients with goal of long-term disease
  management
• Appreciation of the impact of non-motor symptoms
  on quality of life and functional status
• Achieve symptomatic control with fewer long-term
  motor complications

92
CONCLUSIONS

• No evidence exists to suggest that withholding
  symptomatic therapy is better long term may
  even hasten deterioration
• Patients should be educated at disease onset
  about the potential long-term benefits of various
  therapies and be given the option of starting
  treatment

93
Thanks for your attention