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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?. Neurologic disease caused by degeneration of dopamine neurons

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Diagnosis and Management of Parkinson’s Disease

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  1. Diagnosis and Management of Parkinson’s Disease Theresa A. Zesiewicz, MDAssociate 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

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