Management of Moderate to Severe Parkinson’s Disease
Benjamin L. Walter M.D.
Medical Director, Deep Brain Stimulation Program
Neurological Institute
University Hospitals Case Medical Center
WHAT IS PARKINSON’S
DISEASE?
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Not all that look like Parkinson’s
is Parkinson’s
• Idiopathic Parkinson’s disease = “typical
Parkinson's disease”
• Secondary Parkinsonism
• Parkinson’s Plus = parkinsonism + … some
other features
– PSP (Progressive Supranuclear Palsy)
– MSA (Multiple Systems Atrophy)
– DLB (Diffuse Lewy Body Disease)
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The symptoms of Parkinson’s
Disease vary from patient to patient
•
Must have 2 of the following:
1.
2.
3.
4.
•
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Stiffness
Tremor at rest
Slowness
Postural Changes or Gait Changes (for example, shuffling or
freezing)
And should be responsive to dopamine
medications
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Parkinson’s disease is relatively
common
• 2nd most common neurodegenerative
disease
• 1/500 live with Parkinson’s disease
• Over the age of 60, 1/100 people have
PD
• May be more common in men
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People with Parkinson’s are like
snowflakes
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Tests for Parkinson’s Disease
• Genetic tests for only 10% of patients
• MRI, CT scans—do not make diagnosis
• When suspicion of another cause other
laboratory tests may be ordered
• The best test is the expert clinical
examination by a movement disorders
specialist
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Lewy bodies form in the brain
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Progression of Pathology in PD
Braak H, Del Tredici K, Bratzke H, et al: Staging of the intracerebral inclusion body pathology associated with idiopathic Parkinson's disease
(preclinical and clinical stages). J Neurol 249 Suppl 3:III/1-5, 2002
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Classes of Drugs For Parkinson’s
Disease
• Levodopa Compounds
– Carbidopa/levodopa
(Sinemet)
– Controlled Release
Carbidopa/levodopa
(Sinemet CR)
– Carbidopa/levodopa/
entacapone (Stalevo)
• Dopamine Agonists
–
–
–
–
–
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Pramipexole (Mirapex)
Ropinerole (Requip)
Pergolide (Permax)
Apomorpine (Apokyn)
Rotigitine (Neupro) Patch
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• Anticholinergics
–
–
–
–
Trihexaphenedyl (Artane)
Benztropine (Cogentin)
Parsitan
Kemadrin
• NMDA Antagonists
– Amantadine (Symmetrel)
• MAOB Inhibitors
– Selegeline (Eldepryl)
– Zelopar (Eldepryl Zydis)
– Rasagaline (Azilect)
• COMT Inhibitors
– Entacapone (Comtan)
– Tolcapone (Tasmar)
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Progression of Parkinson’s Disease
Preclinical
Stage
(-2 to -6 yrs)
Diagnosis &
Treatment
Symptom
Onset
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Motor
Complications
(3 to 8 yrs)
Honeymoon
Period
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Cognitive
Decline
(15 To 20 yrs)
Treatment
Resistant
Symptoms
(8 to 15 yrs)
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Early Stage
• Diagnosis
• Initiation of Therapy
– Dopaminergic
•
Choice between dopamine Agonists and Levodopa based therapy
– Other
•
MAOB-I, Amantadine, Anticholinergics
• Education and Counseling
• Identification and Treatment of Non-Motor
Symptoms
Patients generally do very well with medications
given ~3X daily
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Moderate Stage
• Emergence of motor complications
–
–
–
–
–
Early Wearing off
Morning Akinesia (hard to turn on in the morning)
On/Off Fluctuations
Dose Failures
Dyskinesia
• Good control possible but more challenging
and requires utilization of different
medications and strategies
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Advanced Stage
• Motor complications persist and more
challenging
• Emergence of treatment refractory symptoms
– Balance Impairment
– Cognitive Decline
– Autonomic Dysfunction
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Early Wearing Off
• Brain cells in substantia nigra - Cells that make and
store dopamine in the brain are progressively lost in
PD
• 70% are lost before symptoms are obvious
• Half-life of Levodopa is 90 minutes
– But in early disease even levodopa based medications last 6-8 hours—
Why?
• Levodopa is recycled by the brain – in substantia
nigra
• With loss of these cells, duration of response to
levodopa becomes shorter and shorter
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Dyskinesia
• Intermittent dosing of levodopa leads to
pulsatile stimulation of brain dopamine
receptors
Dopamine
Levels
Dose
• Pulsatile stimulation is believed to lead to the
development of dyskinesia
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Dose Failures
•
•
•
Levodopa’s PK profile is characterized by
very short plasma half-life due to rapid metabolism
variability in GI absorption due to:
•
GI dysmotility secondary to PD, delayed gastric emptying
• Inhibition of transport across the gut–blood barrier
•
potential delays in blood–brain barrier transport
Blood
GI System
GI Dysmotility
Protein Interference
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Brain
Protein Interference
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Pharmacological Approaches to
Motor Complications
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Comparison of Oral Dopaminergic Medications
Relative Equivalence of Dopamimetic Medications
Medication Brand
Mirapex 1 mg
Parlodel 5 mg
Requip 1 mg
Sinemet 10/100
Sinemet 25/100
Sinemet CR 25/100
Sinemet CR 50/200
Stalevo 100
Generic Name
pramipexole dihydrochloride
bromocriptine
ropinerole
carbidopa/levodopa
carbidopa/levodopa
carbidopa/levodopa, controled release
carbidopa/levodopa, controled release
carbidopa/levodopa/entacapone
Levodopa
equavelence*
100
100
20
100
100
65
130
130
* expressed in clinically equivalent milagrams levodopa
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Oral Dopamine Agonists (ropinerole,
pramipexole)
levodopa/carbidopa  levodopa/carbidopa +
dopamine agonist
• Much longer half life — 5-8hrs vs. 90 min
• Allows for smoother control with milder offs
• May reduce levodopa dose
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COMT Inhibition (entacapone, tolcapone)
• Blocks the breakdown of levodopa and
increases the duration of action by 30-60
minutes
• Comtan(entacapone) dosed frequently up to
8 times a day
• May be combined in 1 pill with
levodopa/carbidopa as Stalevo
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MAO-B Inhibitors (selegeline, rasagiline)
• Blocks breakdown of dopamine
• Increases effect of own dopamine
• Increases effect and smoothes therapeutic
effect of levodopa/carbidopa
• Effect of medication lasts several days but
requires daily dosing
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Dose Fractionation
• Can smooth levels and reduce off time and
dyskinesia by reducing levodopa dose and
increase frequency
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DBS for Movement Disorders
Patient Selection and Evaluation
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Deep Brain Stimulation Surgery
Stage I
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Stage II
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Who is a candidate?

 “Idiopathic” Parkinson’s disease

 Originally good response to Sinemet

 No longer satisfied with response from medication
due to any of the following:
•
•
•
•
•
Shortened or unpredictable medication response
Tremor
Stiffness
Slowness
Dyskinesia
.

 No significant depression, anxiety or memory loss
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Our thought process . . .
1. Does the patient have “Idiopathic PD”
2. What does the patient expect to get from
surgery? – Is it something surgery will help?
3. Have medications been tried adequately?
4. How do the predictors for good and bad
outcome weigh in the patient?
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When are medications not enough?
• Despite medication adjustments patient still
has:
–
–
–
–
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Early wearing off before next dose of medication
Frequent cycling between on and off
Tremor refractory to medication
Troubling dyskinesias
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What are realistic expectations from surgery?
•
•
•
•
•
•
•
•
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Improved Tremor
Improved Dyskinesia
Less ups and downs
Longer lasting benefit through the day
Improved slowness
Improved dystonia (cramps)
Some reduction in medication
Improved off freezing
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What are not realistic expectations from
surgery?
•
•
•
•
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Improved “on-freezing”
Improved balance
Improved memory
Improved swallowing, or bladder function
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Predictors of Good Outcome
• Good response to Sinemet or other
dopaminergic therapies
• Early wearing off, fluctuations between on
and off
• Dyskinesias
• Tremor
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Predictors of Poor Outcome
• Poor response to Sinemet (except tremor)
• Hallucinations
• Significant memory loss, depression or
anxiety
• Early problems with memory, low blood
pressure, swallowing, bladder control or
hallucinations.
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What is most important!
• The patient gets from surgery what they
anticipated from it
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What can be done to optimize the outcome?
• Multi-specialty evaluation
– Identify patients with significant memory loss
– Identify and treat untreated or undertreated depression and anxiety
• Weigh risks and benefits of implanting one
side or both
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Sites for Stimulation
• Subthalamic Nucleus (STN)
• Globus Pallidus Internus (GPi)
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University Hospitals
Movement Disorders Team
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Contact Us
Appointment Line: (216) 844-3192
Office: (216) 368-5247
Questions about DBS:
Christina Whitney, PhD, ACNS-BC
(216) 844-8542
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Thank You.
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