Transcript Diagnosis and Management of Parkinson’s Disease

Diagnosis and Management
of Parkinson’s Disease
Theresa A. Zesiewicz, MD
Associate Professor of Neurology
University of South Florida
What is Parkinson’s
Disease?
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Neurologic disease caused by
degeneration of dopamine neurons
Only neurodegenerative disease whose
symptoms can so readily be treated by
medication
Pathophysiology
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Movement in the body is produced by
the MOTOR CORTEX
Main motor pathway consists of the
pyramidal system
The EXTRAPYRAMIDAL system (EPS)
modulates the pyramidal system
EPS: substantia nigra, striatum,
subthalamic nucleus, globus pallidus,
thalamus
Pathophysiology
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Normal movementdependent on
dopamine production in the substantia
nigra that innervates the striatum
PD is associated with massive
degeneration of dopamine-producing
neurons in substantia nigra
When 60 to 80% of these neurons are
lost, symptoms of PD appear
Parkinson’s Disease:
Pathology
The pathognomic hallmark of the
disease is the Lewy Body
 It is found intracerebrally
 Also found in the autonomic
nervous system
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Clinical Features of PD
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Resting Tremor (70%)
Bradykinesia
Rigidity
Postural Instability
– Signs start in one limb, usually an
arm, and spread to the other limb
on that side
Parkinson’s Disease
Symptoms
 Secondary
disease:
features of the
 Depression
 Dementia
 Dysphagia
 Anxiety
 Orthostatic
hypotension
 Constipation
Hoehn and Yahr Stages of
PD
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Stage I: unilateral symptoms of disease
Stage II: bilateral symptoms of disease
Stage III: all of above, plus postural
instability
Stage IV: all of above, plus patient need
assistance
Stage V: patient cannot function
independently
Prognosis
First 5 years are the “honeymoon
period”, and patients generally do
well
 Between 5 and 10 years, most
patients experience medicationrelated difficulty
 By 10 years, many develop poor
balance
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Treatment of Parkinson’s
Disease
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Neurodegenerative disease
whose symptoms can be readily
treatable by medication
Levodopa treatment of PD:
Breakthrough in the 20th century
Treatment of Parkinson’s
Disease
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Make correct diagnosis
Differentiate between Parkinson’s
disease and Atypical Parkinsonism
Atypical Parkinsonism:
– Early speech and balance disorder
– Poor response to levodopa
– Less commonly characterized by
tremor
Treatment of PD
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After diagnosis of PD is made, treatment
depends on:
– Functional disability of the symptoms
– Work status of the patient
– The presence or absence of cognitive
(mental) difficulties
– The financial situation of the patient
Medications to Treat PD
Artane (Trihexyphenidyl)
 Amantadine (Symmetrel)
 Dopamine Agonists (Requip
(ropinirole), Mirapex
(pramipexole), Parlodel
(bromocriptine), Permax
(pergolide), Apokyn
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Medications to Treat PD
 Eldepryl
(Selegiline)
 Sinemet (carbidopa/levodopa)
 COMT inhibitors, Comtan,
Tasmar
Levodopa
Chemical precursor of dopamine
 Can cause nausea and vomiting
 “Sine emesis”
 Regular (10/100, 25/100), CR
(25/100, 50/200)
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Levodopa/Carbidopa
(Sinemet)
A combination of carbidopa and
levodopa
 Carbidopa is a peripheral
decarboxylase inhibitor
 Carbidopa allows more levodopa
to pass through the blood brain
barrier
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Levodopa
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Most effective medication to reduce or
treat PD symptoms
PD patients will eventually need
levodopa in the form of Sinemet
Associated with higher incidence of
motor fluctuations
Associated with earlier onset of
dyskinesia
Dopamine Agonists
 Non-ergots:
Requip and
Mirapex
 Ergots: Permax and Parlodel
 Apomorphine, Cabergoline
 Apokyn
Dopamine Agonists
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Act like dopamine in the brain at
dopamine receptors
Do not need to be metabolized like
levodopa
Have longer half-lives than levodopa
More expensive the levodopa, more
cognitive side effects
Pramipexole (Mirapex)
 Pramipexole
is a non-ergot
D2/D3 agonist
 Synthetic amino-benzathiazol
derivative
 Side effects: somnolence,
nausea, constipation,
insomnia, hallucinations
Pramipexole (Mirapex)
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Effective is early MONOTHERAPY and
ADJUNCT therapy
Compared to placebo in early disease,
significantly improves motor function
and activities of daily living
In one study, “off” time was reduced
by 17% compared to 8% with placebo
Allows for the reduction of levodopa
Pramipexole (Mirapex)
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CALM-PD Study (Comparison of the agonist
pramipexole with levodopa on motor
complications of PD)
2 year study, 301 PD patients
Patients were randomized to receive
pramipexole or levodopa
At study conclusion, patients assigned to
levodopa had greater improvement in motor
function
CALM-PD study
Only 28% of patients on
pramipexole developed motor
fluctuations, compared to 51% of
patients on levodopa
 Somnolence, hallucinations,
peripheral edema were more
common in compared to 6% with
placebo
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Ropinirole (Requip)
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Non-ergot dopamine agonist
Double-blind, placebo-controlled trials
indicate that ropinirole is effective as
mono- and adjunct therapy in PD
5-year study by Rascol et al
Patients randomized to ropinirole or
levodopa
Ropinirole (Requip)
The time to onset of dyskinesia
was significantly longer in patients
taking ropinirole than levodopa (p
< 0.001)
 At 5 years, incidence of dyskinesia
was 20% in the ropinirole group
and 45% in the levodopa group
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Dopamine Agonists and
Somnolence
 Somnolence,
excessive
daytime sleepiness, and sleep
attacks are associated with
virtually all antiparkinsonian
medications
 Appear to be most common
with dopamine agonists.
Anticholinergics
 Artane
(trihexyphenidyl)
 Used to reduce tremor
 One of the first
antiparkinsonian medications
 Initial therapy or adjunct
therapy
Trihexyphenidyl (Artane)
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Side effects:
–Confusion
–Memory Impairment
–Hallucinations
–Dry Mouth
–Blurred Vision
Symmetrel (Amatadine)
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An anti-viral medication with
dopaminergic properties
Initial therapy or adjunct therapy
Provides mild to moderate benefit
Neuropsychiatric side effects:
confusion, hallucinations, nightmares,
insomnia
Leg swelling, livdeo reticularis
Withdraw gradually
Eldepryl (Selegiline)
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Irreversible MAO-B inhibitor
Developed as an anti-depressant;
metabolized to methamphetamine
Used as a Sinemet booster
No firm data to indicate that it slows
progression in PD
Should not be used in conjunction with
antidepressants
COMT inhibitors
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Entacapone (Comtan)
Tolcapone (Tasmar)hepatic toxicity
Allow more Sinemet to pass through
the blood brain barrier
Can only be used in combination with
Sinemet
Diarrhea, mandatory monitoring of
liver function enzymes with Tasmar
Stalevo
Triple combination tablet of
levodopa/carbidopa/entacapone in
PD patients
 Three strengths: 50/12.5/200,
100/25/200 and 150/37.5/200 mg
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Stalevo
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Reduces 3-OMD, a by-product of
Sinemet that may interfere with its
absorption
Allows for 35% to 40% of levodopa to
pass through the blood brain barrier
(BBB)
Without Comtan (Stalevo), only about
10% of Sinemet tablet passes through
BBB
Complications of Long-term
Therapy with Sinemet
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Motor Fluctuations, dyskinesia,
predictable wearing-off
On/Off states
Dyskinesia: involuntary abnormal
movements associated with
medication intake
Complications of
medications
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50% of patients treated for 5 years of
longer will develop motor fluctuations
90% will experience them by 15 years
after diagnosis
Therapeutic window: target zone to
treat patients
This window becomes narrower with
time
Continuous Dopaminergic
Stimulation (CDS)
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Dopamine neurons normally release
dopamine in a stable, continuous
manner
In early PD, remaining dopamine
neurons take up levodopa, convert it
to dopamine, store it, and slowly
release it
Over time, as more dopamine neurons
are lost, this storage and release
Continuous Dopamine
Stimulation (CDS)
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The loss of intraneuronal storage and
slow release capacity is expressed as a
SHORTENED duration of benefit from
levodopa
Once this capacity is lost, patients
fluctuate in concert with levodopa
fluctuations in the blood
Information to have
Ready for your doctor
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Know all doses of medications and
times they are taken
Know whether dose of PD medication
lasts from dose to dose
Know how much dyskinesia the patient
has, if any, during each dose interval
Know how long it takes for medication
to take effect
Information for your
doctor
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What percent of the day do you have
dyskinesia?
What percent of the day do you
experience “off” time?
This will help you determine what the
patient’s major problems are
Treatment of PD
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Disease of “timing”
Doctor will carefully assess your motor
and non-motor function during the day
Information comes from patient
history, diary
Treatment of PD: Cases
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62 year old woman comes into clinic
with slight rest tremor
Diagnosed with PD
If the tremor doesn’t bother her, we
may do nothing
May use medication specifically for
tremor, like artane
Treatment of PD: cases
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56 year old man who comes into the
office with stiffness of one arm,
slowness, tremor
Symptoms are bothering him
We would treat this patient
Options include dopamine agonist,
selegiline (usually hold Sinemet until
later)
Treatment of PD: cases
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We will ask you what your major
symptom is
If you are depressed, but motor
symptoms are well controlled, treat
depression
Treatment of PD: cases
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70 year old woman who has had PD
for 5 years
She is taking Mirapex maximum dose
Medication is not lasting from pill to
pill
At some point, it will be time to add
SINEMET
Treatment of PD: cases
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Will consider other options before
Sinemet
Eventually, PD patients will need to
take Sinemet
Treatment of PD: cases
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We will ask you exact times you take
your medication
How much off time, dyskinesia, tremor
you have between doses
Treatment of PD: cases
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As disease advanced, it may be more
difficult to treat patients medically
At some point, patients may be
referred to surgery