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? 7/27/2008University Hospitals Neurological Institute2

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) 7/27/2008University Hospitals Neurological Institute3

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 7/27/2008University Hospitals Neurological Institute4

Parkinson’s disease is relatively common 2 nd 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 7/27/2008University Hospitals Neurological Institute5

People with Parkinson’s are like snowflakes 7/27/2008University Hospitals Neurological Institute6

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 7/27/2008University Hospitals Neurological Institute7

Lewy bodies form in the brain 7/27/2008University Hospitals Neurological Institute8

9 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, /27/2008University Hospitals Neurological Institute

10 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) 7/27/2008University Hospitals Neurological Institute

Progression of Parkinson’s Disease 7/27/2008University Hospitals Neurological Institute11 Preclinical Stage (-2 to -6 yrs) Symptom Onset Diagnosis & Treatment Honeymoon Period Motor Complications (3 to 8 yrs) Treatment Resistant Symptoms (8 to 15 yrs) Cognitive Decline (15 To 20 yrs)

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 7/27/2008University Hospitals Neurological Institute12

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 7/27/2008University Hospitals Neurological Institute13

Advanced Stage Motor complications persist and more challenging Emergence of treatment refractory symptoms –Balance Impairment –Cognitive Decline –Autonomic Dysfunction 7/27/2008University Hospitals Neurological Institute14

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 7/27/2008University Hospitals Neurological Institute15

Dyskinesia 6/10/2008University Hospitals Neurological Institute16 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 6/10/2008University Hospitals Neurological Institute17 GI System BloodBrain GI Dysmotility Protein 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

09/08/06University Hospitals Neurological Institute18 Pharmacological Approaches to Motor Complications

Comparison of Oral Dopaminergic Medications Relative Equivalence of Dopamimetic Medications Medication BrandGeneric Name Levodopa equavelence* Mirapex 1 mgpramipexole dihydrochloride100 Parlodel 5 mgbromocriptine100 Requip 1 mgropinerole20 Sinemet 10/100carbidopa/levodopa100 Sinemet 25/100carbidopa/levodopa100 Sinemet CR 25/100carbidopa/levodopa, controled release65 Sinemet CR 50/200carbidopa/levodopa, controled release130 Stalevo 100carbidopa/levodopa/entacapone130 * expressed in clinically equivalent milagrams levodopa 7/27/2008University Hospitals Neurological Institute19

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 7/27/2008University Hospitals Neurological Institute20

COMT Inhibition (entacapone, tolcapone) Blocks the breakdown of levodopa and increases the duration of action by minutes Comtan(entacapone) dosed frequently up to 8 times a day May be combined in 1 pill with levodopa/carbidopa as Stalevo 7/27/2008University Hospitals Neurological Institute21

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 7/27/2008University Hospitals Neurological Institute22

Dose Fractionation Can smooth levels and reduce off time and dyskinesia by reducing levodopa dose and increase frequency 7/27/2008University Hospitals Neurological Institute23

09/08/06University Hospitals Neurological Institute24 DBS for Movement Disorders Patient Selection and Evaluation

Deep Brain Stimulation Surgery Stage IStage II 7/27/2008University Hospitals Neurological Institute26

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. 7/27/2008University Hospitals Neurological Institute27

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? 7/27/2008University Hospitals Neurological Institute28

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 7/27/2008University Hospitals Neurological Institute29

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 7/27/2008University Hospitals Neurological Institute30

What are not realistic expectations from surgery? Improved “on-freezing” Improved balance Improved memory Improved swallowing, or bladder function 7/27/2008University Hospitals Neurological Institute31

Predictors of Good Outcome Good response to Sinemet or other dopaminergic therapies Early wearing off, fluctuations between on and off Dyskinesias Tremor 7/27/2008University Hospitals Neurological Institute32

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. 7/27/2008University Hospitals Neurological Institute33

What is most important! The patient gets from surgery what they anticipated from it 7/27/2008University Hospitals Neurological Institute34

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 7/27/2008University Hospitals Neurological Institute35

Sites for Stimulation Subthalamic Nucleus (STN) Globus Pallidus Internus (GPi) 7/27/2008University Hospitals Neurological Institute36

University Hospitals Movement Disorders Team 7/27/2008University Hospitals Neurological Institute37

09/08/06University Hospitals Neurological Institute38 Contact Us Appointment Line: (216) Office: (216) Questions about DBS: Christina Whitney, PhD, ACNS-BC (216)

09/08/06University Hospitals Neurological Institute39 Thank You.