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

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Presentation on theme: "Diagnosis and Management of Parkinson’s Disease Theresa A. Zesiewicz, MD Associate Professor of Neurology University of South Florida."— Presentation transcript:

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 Neurologic disease caused by degeneration of dopamine neurons Only neurodegenerative disease whose symptoms can so readily be treated by medication Only neurodegenerative disease whose symptoms can so readily be treated by medication

3 Pathophysiology Movement in the body is produced by the MOTOR CORTEX Movement in the body is produced by the MOTOR CORTEX Main motor pathway consists of the pyramidal system Main motor pathway consists of the pyramidal system The EXTRAPYRAMIDAL system (EPS) modulates the pyramidal system The EXTRAPYRAMIDAL system (EPS) modulates the pyramidal system EPS: substantia nigra, striatum, subthalamic nucleus, globus pallidus, thalamus 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 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 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 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 The pathognomic hallmark of the disease is the Lewy Body It is found intracerebrally It is found intracerebrally Also found in the autonomic nervous system Also found in the autonomic nervous system

6 Clinical Features of PD Resting Tremor (70%) Resting Tremor (70%) Bradykinesia Bradykinesia Rigidity Rigidity Postural Instability 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: Secondary features of the disease: Depression Depression Dementia Dementia Dysphagia Dysphagia Anxiety Anxiety Orthostatic hypotension Orthostatic hypotension Constipation Constipation

8 Hoehn and Yahr Stages of PD Stage I: unilateral symptoms of disease Stage I: unilateral symptoms of disease Stage II: bilateral symptoms of disease Stage II: bilateral symptoms of disease Stage III: all of above, plus postural instability Stage III: all of above, plus postural instability Stage IV: all of above, plus patient need assistance Stage IV: all of above, plus patient need assistance Stage V: patient cannot function independently Stage V: patient cannot function independently

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

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

11 Treatment of Parkinson’s Disease Make correct diagnosis Make correct diagnosis Differentiate between Parkinson’s disease and Atypical Parkinsonism Differentiate between Parkinson’s disease and Atypical Parkinsonism 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: 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) Artane (Trihexyphenidyl) Amantadine (Symmetrel) Amantadine (Symmetrel) Dopamine Agonists (Requip (ropinirole), Mirapex (pramipexole), Parlodel (bromocriptine), Permax (pergolide), Apokyn Dopamine Agonists (Requip (ropinirole), Mirapex (pramipexole), Parlodel (bromocriptine), Permax (pergolide), Apokyn

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

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

16 Levodopa/Carbidopa (Sinemet) A combination of carbidopa and levodopa A combination of carbidopa and levodopa Carbidopa is a peripheral decarboxylase inhibitor Carbidopa is a peripheral decarboxylase inhibitor Carbidopa allows more levodopa to pass through the blood brain barrier Carbidopa allows more levodopa to pass through the blood brain barrier

17 Levodopa Most effective medication to reduce or treat PD symptoms Most effective medication to reduce or treat PD symptoms PD patients will eventually need levodopa in the form of Sinemet PD patients will eventually need levodopa in the form of Sinemet Associated with higher incidence of motor fluctuations Associated with higher incidence of motor fluctuations Associated with earlier onset of dyskinesia Associated with earlier onset of dyskinesia

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

19 Dopamine Agonists Act like dopamine in the brain at dopamine receptors Act like dopamine in the brain at dopamine receptors Do not need to be metabolized like levodopa Do not need to be metabolized like levodopa Have longer half-lives than levodopa Have longer half-lives than levodopa More expensive the levodopa, more cognitive side effects More expensive the levodopa, more cognitive side effects

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

21 Pramipexole (Mirapex) Effective is early MONOTHERAPY and ADJUNCT therapy Effective is early MONOTHERAPY and ADJUNCT therapy Compared to placebo in early disease, significantly improves motor function and activities of daily living 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 In one study, “off” time was reduced by 17% compared to 8% with placebo Allows for the reduction of levodopa Allows for the reduction of levodopa

22 Pramipexole (Mirapex) CALM-PD Study (Comparison of the agonist pramipexole with levodopa on motor complications of PD) CALM-PD Study (Comparison of the agonist pramipexole with levodopa on motor complications of PD) 2 year study, 301 PD patients 2 year study, 301 PD patients Patients were randomized to receive pramipexole or levodopa Patients were randomized to receive pramipexole or levodopa At study conclusion, patients assigned to levodopa had greater improvement in motor function 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 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 Somnolence, hallucinations, peripheral edema were more common in compared to 6% with placebo

24 Ropinirole (Requip) Non-ergot dopamine agonist Non-ergot dopamine agonist Double-blind, placebo-controlled trials indicate that ropinirole is effective as mono- and adjunct therapy in PD Double-blind, placebo-controlled trials indicate that ropinirole is effective as mono- and adjunct therapy in PD 5-year study by Rascol et al 5-year study by Rascol et al Patients randomized to ropinirole or levodopa 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) 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 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 Somnolence, excessive daytime sleepiness, and sleep attacks are associated with virtually all antiparkinsonian medications Appear to be most common with dopamine agonists. Appear to be most common with dopamine agonists.

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

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

29 Symmetrel (Amatadine) An anti-viral medication with dopaminergic properties An anti-viral medication with dopaminergic properties Initial therapy or adjunct therapy Initial therapy or adjunct therapy Provides mild to moderate benefit Provides mild to moderate benefit Neuropsychiatric side effects: confusion, hallucinations, nightmares, insomnia Neuropsychiatric side effects: confusion, hallucinations, nightmares, insomnia Leg swelling, livdeo reticularis Leg swelling, livdeo reticularis Withdraw gradually Withdraw gradually

30 Eldepryl (Selegiline) Irreversible MAO-B inhibitor Irreversible MAO-B inhibitor Developed as an anti-depressant; metabolized to methamphetamine Developed as an anti-depressant; metabolized to methamphetamine Used as a Sinemet booster Used as a Sinemet booster No firm data to indicate that it slows progression in PD No firm data to indicate that it slows progression in PD Should not be used in conjunction with antidepressants Should not be used in conjunction with antidepressants

31 COMT inhibitors Entacapone (Comtan) Entacapone (Comtan) Tolcapone (Tasmar)  hepatic toxicity Tolcapone (Tasmar)  hepatic toxicity Allow more Sinemet to pass through the blood brain barrier Allow more Sinemet to pass through the blood brain barrier Can only be used in combination with Sinemet Can only be used in combination with Sinemet Diarrhea, mandatory monitoring of liver function enzymes with Tasmar Diarrhea, mandatory monitoring of liver function enzymes with Tasmar

32 Stalevo Triple combination tablet of levodopa/carbidopa/entacapone in PD patients 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 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 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) 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 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 Motor Fluctuations, dyskinesia, predictable wearing-off On/Off states On/Off states Dyskinesia: involuntary abnormal movements associated with medication intake 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 50% of patients treated for 5 years of longer will develop motor fluctuations 90% will experience them by 15 years after diagnosis 90% will experience them by 15 years after diagnosis Therapeutic window: target zone to treat patients Therapeutic window: target zone to treat patients This window becomes narrower with time This window becomes narrower with time

36 Continuous Dopaminergic Stimulation (CDS) Dopamine neurons normally release dopamine in a stable, continuous manner 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 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 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 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 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 all doses of medications and times they are taken Know whether dose of PD medication lasts from dose to dose 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 much dyskinesia the patient has, if any, during each dose interval Know how long it takes for medication to take effect 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 have dyskinesia? What percent of the day do you experience “off” time? What percent of the day do you experience “off” time? This will help you determine what the patient’s major problems are This will help you determine what the patient’s major problems are

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

41 Treatment of PD: Cases 62 year old woman comes into clinic with slight rest tremor 62 year old woman comes into clinic with slight rest tremor Diagnosed with PD Diagnosed with PD If the tremor doesn’t bother her, we may do nothing If the tremor doesn’t bother her, we may do nothing May use medication specifically for tremor, like artane 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 56 year old man who comes into the office with stiffness of one arm, slowness, tremor Symptoms are bothering him Symptoms are bothering him We would treat this patient We would treat this patient Options include dopamine agonist, selegiline (usually hold Sinemet until later) Options include dopamine agonist, selegiline (usually hold Sinemet until later)

43 Treatment of PD: cases We will ask you what your major symptom is We will ask you what your major symptom is If you are depressed, but motor symptoms are well controlled, treat depression 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 70 year old woman who has had PD for 5 years She is taking Mirapex maximum dose She is taking Mirapex maximum dose Medication is not lasting from pill to pill Medication is not lasting from pill to pill At some point, it will be time to add SINEMET At some point, it will be time to add SINEMET

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

46 Treatment of PD: cases We will ask you exact times you take your medication We will ask you exact times you take your medication How much off time, dyskinesia, tremor you have between doses 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 As disease advanced, it may be more difficult to treat patients medically At some point, patients may be referred to surgery At some point, patients may be referred to surgery


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