1. Diagnosis and Management of Parkinson’s Disease
Theresa A. Zesiewicz, MD Associate Professor of Neurology
University of South Florida

2. What is Parkinson’s Disease?
Neurologic disease caused by degeneration of dopamine neurons
Only neurodegenerative disease whose symptoms can so readily be treated by medication

3. Pathophysiology 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

4. Pathophysiology
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

5. 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

6. Clinical Features of PD
Resting Tremor (70%)
Bradykinesia
Rigidity
Postural Instability
Signs start in one limb, usually an arm, and spread to the other limb on that side

7. Parkinson’s Disease Symptoms
Secondary features of the disease:
Depression
Dementia
Dysphagia
Anxiety
Orthostatic hypotension
Constipation

8. Hoehn and Yahr Stages of PD
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

9. Prognosis
First 5 years are the “honeymoon period”, and patients generally do well
Between 5 and 10 years, most patients experience medication-related difficulty
By 10 years, many develop poor balance

10. Treatment of Parkinson’s Disease
Neurodegenerative disease whose symptoms can be readily treatable by medication
Levodopa treatment of PD: Breakthrough in the 20th century

11. Treatment of Parkinson’s Disease
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

12. Treatment of PD 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

13. Medications to Treat PD
Artane (Trihexyphenidyl)
Amantadine (Symmetrel)
Dopamine Agonists (Requip (ropinirole), Mirapex (pramipexole), Parlodel (bromocriptine), Permax (pergolide), Apokyn

14. Medications to Treat PD
Eldepryl (Selegiline)
Sinemet (carbidopa/levodopa)
COMT inhibitors, Comtan, Tasmar

15. Levodopa Chemical precursor of dopamine Can cause nausea and vomiting
“Sine emesis”
Regular (10/100, 25/100), CR (25/100, 50/200)

16. 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

17. Levodopa 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

18. Dopamine Agonists Non-ergots: Requip and Mirapex
Ergots: Permax and Parlodel
Apomorphine, Cabergoline
Apokyn

19. Dopamine Agonists 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

20. Pramipexole (Mirapex)
Pramipexole is a non-ergot D2/D3 agonist
Synthetic amino-benzathiazol derivative
Side effects: somnolence, nausea, constipation, insomnia, hallucinations

21. Pramipexole (Mirapex)
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

22. Pramipexole (Mirapex)
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

23. 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

24. Ropinirole (Requip) 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

25. 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

26. 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.

27. Anticholinergics Artane (trihexyphenidyl) Used to reduce tremor
One of the first antiparkinsonian medications
Initial therapy or adjunct therapy

28. Trihexyphenidyl (Artane)
Side effects:
Confusion
Memory Impairment
Hallucinations
Dry Mouth
Blurred Vision

29. Symmetrel (Amatadine)
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

30. Eldepryl (Selegiline)
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

31. COMT inhibitors 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

32. 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

33. Stalevo
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

34. Complications of Long-term Therapy with Sinemet
Motor Fluctuations, dyskinesia, predictable wearing-off
On/Off states
Dyskinesia: involuntary abnormal movements associated with medication intake

35. Complications of medications
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

36. Continuous Dopaminergic Stimulation (CDS)
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 capacity is lost

37. Continuous Dopamine Stimulation (CDS)
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

38. Information to have Ready for your doctor
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

39. Information for your doctor
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

40. Treatment of PD Disease of “timing”
Doctor will carefully assess your motor and non-motor function during the day
Information comes from patient history, diary

41. Treatment of PD: Cases
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

42. Treatment of PD: cases
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)

43. Treatment of PD: cases We will ask you what your major symptom is
If you are depressed, but motor symptoms are well controlled, treat depression

44. Treatment of PD: cases 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

45. Treatment of PD: cases Will consider other options before Sinemet
Eventually, PD patients will need to take Sinemet

46. Treatment of PD: cases
We will ask you exact times you take your medication
How much off time, dyskinesia, tremor you have between doses

47. Treatment of PD: cases
As disease advanced, it may be more difficult to treat patients medically
At some point, patients may be referred to surgery