Benjamin L. Walter M.D.

Medical Director, Deep Brain Stimulation Program

Neurological Institute

University Hospitals Case Medical Center

Management of Moderate to Severe Parkinson’s Disease

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. Stiffness

2. Tremor at rest

3. Slowness

4. 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– Pramipexole (Mirapex)– Ropinerole (Requip)– Pergolide (Permax)– Apomorpine (Apokyn)– Rotigitine (Neupro) Patch

• 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

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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

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Dose

Dopamine

Levels

• Pulsatile stimulation is believed to lead to the development of dyskinesia

• Intermittent dosing of levodopa leads to pulsatile stimulation of brain dopamine receptors

Dose Failures

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GI System Blood Brain

GI Dysmotility

Protein InterferenceProtein Interference

• 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

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Pharmacological Approaches to Motor Complications

Comparison of Oral Dopaminergic Medications

Relative Equivalence of Dopamimetic Medications

Medication Brand Generic Name Levodopa equavelence*Mirapex 1 mg pramipexole dihydrochloride 100Parlodel 5 mg bromocriptine 100Requip 1 mg ropinerole 20Sinemet 10/100 carbidopa/levodopa 100Sinemet 25/100 carbidopa/levodopa 100Sinemet CR 25/100 carbidopa/levodopa, controled release 65Sinemet CR 50/200 carbidopa/levodopa, controled release 130Stalevo 100 carbidopa/levodopa/entacapone 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 DisordersPatient Selection and Evaluation

Deep Brain Stimulation Surgery

Stage I 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:– 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?

• 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?

• 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 UsAppointment 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.