The Science and Medicine of The Science and Medicine of Parkinson’s DiseaseParkinson’s Disease
The Science and Medicine of The Science and Medicine of Parkinson’s DiseaseParkinson’s Disease
Applying Science, Expert Analysis, Guidelines, and Landmark Applying Science, Expert Analysis, Guidelines, and Landmark Trials to the Front Lines of Clinical PracticeTrials to the Front Lines of Clinical Practice
Applying Science, Expert Analysis, Guidelines, and Landmark Applying Science, Expert Analysis, Guidelines, and Landmark Trials to the Front Lines of Clinical PracticeTrials to the Front Lines of Clinical Practice
Critical Challenges and Critical Challenges and Landmark Practice AdvancesLandmark Practice Advances
Lawrence W. Elmer, MD, PhD Lawrence W. Elmer, MD, PhD Program ChairmanProgram Chairman
Program ChairmanProgram ChairmanAssociate Professor of NeurologyAssociate Professor of Neurology
Director, The Center for Neurological DisordersDirector, The Center for Neurological DisordersUniversity of ToledoUniversity of Toledo
Toledo, OHToledo, OH
Lawrence W. Elmer, MD, PhD Lawrence W. Elmer, MD, PhD Program ChairmanProgram Chairman
Program ChairmanProgram ChairmanAssociate Professor of NeurologyAssociate Professor of Neurology
Director, The Center for Neurological DisordersDirector, The Center for Neurological DisordersUniversity of ToledoUniversity of Toledo
Toledo, OHToledo, OH
Program FacultyProgram Faculty
Lawrence W. Elmer, MD, PhDLawrence W. Elmer, MD, PhDProgram ChairmanProgram ChairmanAssociate Professor of NeurologyAssociate Professor of NeurologyDirector, The Center for Neurological Director, The Center for Neurological DisordersDisordersThe University of ToledoThe University of ToledoToledo, OHToledo, OH
William G. Ondo, MDWilliam G. Ondo, MDAssociate Professor of NeurologyAssociate Professor of NeurologyBaylor College of Medicine Baylor College of Medicine Houston, TXHouston, TX
Lawrence W. Elmer, MD, PhDLawrence W. Elmer, MD, PhDProgram ChairmanProgram ChairmanAssociate Professor of NeurologyAssociate Professor of NeurologyDirector, The Center for Neurological Director, The Center for Neurological DisordersDisordersThe University of ToledoThe University of ToledoToledo, OHToledo, OH
William G. Ondo, MDWilliam G. Ondo, MDAssociate Professor of NeurologyAssociate Professor of NeurologyBaylor College of Medicine Baylor College of Medicine Houston, TXHouston, TX
Mark F. Lew, MD, FAANMark F. Lew, MD, FAANProfessor of NeurologyProfessor of NeurologyDirector, Division of Movement Director, Division of Movement DisordersDisordersVice-Chair Department of NeurologyVice-Chair Department of NeurologyKeck/USC School of MedicineKeck/USC School of MedicineLos Angeles, CALos Angeles, CA
Andrew Siderowf, MD, MSCEAndrew Siderowf, MD, MSCEParkinson’s Disease and Movement Parkinson’s Disease and Movement Disorders CenterDisorders CenterAssociate Professor of NeurologyAssociate Professor of NeurologyUniversity of PennsylvaniaUniversity of PennsylvaniaPhiladelphia, PAPhiladelphia, PA
Mark F. Lew, MD, FAANMark F. Lew, MD, FAANProfessor of NeurologyProfessor of NeurologyDirector, Division of Movement Director, Division of Movement DisordersDisordersVice-Chair Department of NeurologyVice-Chair Department of NeurologyKeck/USC School of MedicineKeck/USC School of MedicineLos Angeles, CALos Angeles, CA
Andrew Siderowf, MD, MSCEAndrew Siderowf, MD, MSCEParkinson’s Disease and Movement Parkinson’s Disease and Movement Disorders CenterDisorders CenterAssociate Professor of NeurologyAssociate Professor of NeurologyUniversity of PennsylvaniaUniversity of PennsylvaniaPhiladelphia, PAPhiladelphia, PA
Faculty COI DisclosuresFaculty COI Disclosures
Lawrence W. Elmer, MD, PhD Lawrence W. Elmer, MD, PhD Research/Grant Support/Clinical TrialsResearch/Grant Support/Clinical Trials: GSK: GSKConsultantConsultant: Schwarz-Pharma, TEVA, GSK: Schwarz-Pharma, TEVA, GSKSpeakers BureauSpeakers Bureau: Boehringer-Ingelheim, GSK, Novartis, Pfizer, Teva, Valeant, Vernalis: Boehringer-Ingelheim, GSK, Novartis, Pfizer, Teva, Valeant, Vernalis
Mark F. Lew, MD, FAANMark F. Lew, MD, FAANGrant/Research Support:Grant/Research Support: Boehringer-Ingelheim, Eisai, GSK, Ipsen, Kyowa, Mentor, NIH, Boehringer-Ingelheim, Eisai, GSK, Ipsen, Kyowa, Mentor, NIH, Novartis, Schering Plough, Schwarz Pharma/UCB, Solstice, Solvay, TevaNovartis, Schering Plough, Schwarz Pharma/UCB, Solstice, Solvay, TevaConsultantConsultant: Boehringer-Ingelheim, GSK, Ipsen, Kyowa, Novartis, Prestwick, Schwarz : Boehringer-Ingelheim, GSK, Ipsen, Kyowa, Novartis, Prestwick, Schwarz Pharma, Solstice, TEVA, Valeant, VernalisPharma, Solstice, TEVA, Valeant, VernalisSpeaker’s Bureau:Speaker’s Bureau: Allergan, Boehringer-Ingelheim, GSK, Novartis, Solstice, Teva, UCB, Allergan, Boehringer-Ingelheim, GSK, Novartis, Solstice, Teva, UCB, ValeantValeant
Andrew D. Siderowf, MD, MSCEAndrew D. Siderowf, MD, MSCEGrant/Research Support:Grant/Research Support: Boehringer-Ingelheim Boehringer-IngelheimConsultant:Consultant: Boehringer-Ingelheim, TEVA Boehringer-Ingelheim, TEVASpeaker’s Bureau:Speaker’s Bureau: Boehringer-Ingelheim, Schwarz-Pharma, Teva Boehringer-Ingelheim, Schwarz-Pharma, Teva
William G. Ondo, MDWilliam G. Ondo, MDGrant/Research SupportGrant/Research Support: Forrest, UCB: Forrest, UCBSpeaker’s Bureau:Speaker’s Bureau: Boehringer-Ingelheim, GSK, TEVA, Valeant, UCB Boehringer-Ingelheim, GSK, TEVA, Valeant, UCB
Lawrence W. Elmer, MD, PhD Lawrence W. Elmer, MD, PhD Research/Grant Support/Clinical TrialsResearch/Grant Support/Clinical Trials: GSK: GSKConsultantConsultant: Schwarz-Pharma, TEVA, GSK: Schwarz-Pharma, TEVA, GSKSpeakers BureauSpeakers Bureau: Boehringer-Ingelheim, GSK, Novartis, Pfizer, Teva, Valeant, Vernalis: Boehringer-Ingelheim, GSK, Novartis, Pfizer, Teva, Valeant, Vernalis
Mark F. Lew, MD, FAANMark F. Lew, MD, FAANGrant/Research Support:Grant/Research Support: Boehringer-Ingelheim, Eisai, GSK, Ipsen, Kyowa, Mentor, NIH, Boehringer-Ingelheim, Eisai, GSK, Ipsen, Kyowa, Mentor, NIH, Novartis, Schering Plough, Schwarz Pharma/UCB, Solstice, Solvay, TevaNovartis, Schering Plough, Schwarz Pharma/UCB, Solstice, Solvay, TevaConsultantConsultant: Boehringer-Ingelheim, GSK, Ipsen, Kyowa, Novartis, Prestwick, Schwarz : Boehringer-Ingelheim, GSK, Ipsen, Kyowa, Novartis, Prestwick, Schwarz Pharma, Solstice, TEVA, Valeant, VernalisPharma, Solstice, TEVA, Valeant, VernalisSpeaker’s Bureau:Speaker’s Bureau: Allergan, Boehringer-Ingelheim, GSK, Novartis, Solstice, Teva, UCB, Allergan, Boehringer-Ingelheim, GSK, Novartis, Solstice, Teva, UCB, ValeantValeant
Andrew D. Siderowf, MD, MSCEAndrew D. Siderowf, MD, MSCEGrant/Research Support:Grant/Research Support: Boehringer-Ingelheim Boehringer-IngelheimConsultant:Consultant: Boehringer-Ingelheim, TEVA Boehringer-Ingelheim, TEVASpeaker’s Bureau:Speaker’s Bureau: Boehringer-Ingelheim, Schwarz-Pharma, Teva Boehringer-Ingelheim, Schwarz-Pharma, Teva
William G. Ondo, MDWilliam G. Ondo, MDGrant/Research SupportGrant/Research Support: Forrest, UCB: Forrest, UCBSpeaker’s Bureau:Speaker’s Bureau: Boehringer-Ingelheim, GSK, TEVA, Valeant, UCB Boehringer-Ingelheim, GSK, TEVA, Valeant, UCB
Questions We Will Attempt to Answer in Questions We Will Attempt to Answer in This Science-to-Strategy Summit on PD This Science-to-Strategy Summit on PD
Critical Issues in Parkinson's Disease► How do we make the diagnosis of Parkinson's Disease
(PD)? Criteria for diagnosis► What are the underlying causes and pathophysiology of
PD? Epidemiology? ► How do we stage patients with PD? What is the natural
history?► How early should pharmacologic therapy in PD begin?► What are the initial starting agents for PD? Why?► What do landmark trials tell us about early intervention? A
paradigm shift?
Critical Issues in Parkinson's Disease► How do we make the diagnosis of Parkinson's Disease
(PD)? Criteria for diagnosis► What are the underlying causes and pathophysiology of
PD? Epidemiology? ► How do we stage patients with PD? What is the natural
history?► How early should pharmacologic therapy in PD begin?► What are the initial starting agents for PD? Why?► What do landmark trials tell us about early intervention? A
paradigm shift?
Questions We Will Attempt to Answer in Questions We Will Attempt to Answer in This Science-to-Strategy Summit on PD This Science-to-Strategy Summit on PD
Critical Issues in Parkinson's Disease► Do patients do better with monotherapy or combination
therapy? Under what circumstances?► How should we sequence pharmacologic agents in PD?► How do we manage the side effects of drug therapy in
PD? Strategies?► What do studies suggest about disease modification? ► How do we manage the non-motor, co-morbid conditions
of PD? What are those conditions? ► How does receptor selectivity impact our approach to
drug therapy? Safety? ► What is the role of MAO-B inhibition in PD? Which
agents? Why?
Critical Issues in Parkinson's Disease► Do patients do better with monotherapy or combination
therapy? Under what circumstances?► How should we sequence pharmacologic agents in PD?► How do we manage the side effects of drug therapy in
PD? Strategies?► What do studies suggest about disease modification? ► How do we manage the non-motor, co-morbid conditions
of PD? What are those conditions? ► How does receptor selectivity impact our approach to
drug therapy? Safety? ► What is the role of MAO-B inhibition in PD? Which
agents? Why?
Parkinson’s Disease — BackgroundParkinson’s Disease — Background
A Clinical Diagnosis
► Cardinal Signs: Rest tremor, bradykinesia, rigidity and loss of postural reflexes
► Non-Motor Symptoms: Autonomic dysfunction, cognitive/ neurobehavioral abnormalities, sleep disorders and sensory abnormalities such as anosmia, paresthesias and pain
► Other Clinical Features and Secondary Motor Symptoms:— Hypomimia, dysarthria, dysphagia, sialorrhoea, micrographia, shuffling gait, festination, freezing, dystonia, glabellar reflexes)
A Clinical Diagnosis
► Cardinal Signs: Rest tremor, bradykinesia, rigidity and loss of postural reflexes
► Non-Motor Symptoms: Autonomic dysfunction, cognitive/ neurobehavioral abnormalities, sleep disorders and sensory abnormalities such as anosmia, paresthesias and pain
► Other Clinical Features and Secondary Motor Symptoms:— Hypomimia, dysarthria, dysphagia, sialorrhoea, micrographia, shuffling gait, festination, freezing, dystonia, glabellar reflexes)
Parkinson’s Disease — EpidemiologyParkinson’s Disease — Epidemiology
A Widespread Problem
► As many as one million Americans suffer from Parkinson's disease
► This is more than the combined number of people diagnosed with multiple sclerosis, muscular dystrophy and Lou Gehrig's disease (ALS)
► Incidence of Parkinson’s increases with age, but an estimated 15 percent of people with PD are diagnosed before the age of 50
► Approximately 40,000 Americans are diagnosed with Parkinson's disease each year: This number does not reflect the thousands of cases that go undetected.
Parkinson’s Disease Foundation, Inc. 2007
A Widespread Problem
► As many as one million Americans suffer from Parkinson's disease
► This is more than the combined number of people diagnosed with multiple sclerosis, muscular dystrophy and Lou Gehrig's disease (ALS)
► Incidence of Parkinson’s increases with age, but an estimated 15 percent of people with PD are diagnosed before the age of 50
► Approximately 40,000 Americans are diagnosed with Parkinson's disease each year: This number does not reflect the thousands of cases that go undetected.
Parkinson’s Disease Foundation, Inc. 2007
Parkinson’s Disease — CostsParkinson’s Disease — Costs
Staggering Resources Expended
► Combined direct and indirect cost of Parkinson’s, includingtreatment, social security payments and lost income from inability to work, is estimated to be more than $5.6 billion per year in the U.S. alone
Parkinson’s Disease Foundation, Inc. 2007
Staggering Resources Expended
► Combined direct and indirect cost of Parkinson’s, includingtreatment, social security payments and lost income from inability to work, is estimated to be more than $5.6 billion per year in the U.S. alone
Parkinson’s Disease Foundation, Inc. 2007
The Problem: Loss of Dopaminergic and The Problem: Loss of Dopaminergic and Non-Dopaminergic NeuronsNon-Dopaminergic Neurons
A Lang, Neurology 2007;68;948-952.
H. Braak, et al., Cell Tissue Res (2004) 318: 121–134.
Progressive Parkinson’s Disease PathologyProgressive Parkinson’s Disease Pathology
Stages of Parkinson’s DiseaseStages of Parkinson’s Disease
► Mild symptoms, no disabilityMild symptoms, no disability► Non-pharmacological approachesNon-pharmacological approaches
► Moderate symptoms with some disabilityModerate symptoms with some disability► Multiple treatments available including l-dopaMultiple treatments available including l-dopa
► Progression of symptomsProgression of symptoms► Levodopa required +/- other medsLevodopa required +/- other meds
EarlyEarly ModerateModerate AdvancedAdvanced
► Disease progressesDisease progresses► Non-motor complications mayNon-motor complications may outweigh motor disturbances outweigh motor disturbances
Adjunctive Drug Therapy for Advanced PD
Report of the Quality Standards Subcommittee of theAmerican Academy of Neurology 2006
Early Diagnosis andEarly Diagnosis andIntervention In Parkinson’s DiseaseIntervention In Parkinson’s Disease
Can We Affect Clinical Outcomes Can We Affect Clinical Outcomes with Early Therapy: What the Evidence Tells Uswith Early Therapy: What the Evidence Tells Us
Early Diagnosis andEarly Diagnosis andIntervention In Parkinson’s DiseaseIntervention In Parkinson’s Disease
Can We Affect Clinical Outcomes Can We Affect Clinical Outcomes with Early Therapy: What the Evidence Tells Uswith Early Therapy: What the Evidence Tells Us
Mark F. Lew, MDMark F. Lew, MDProfessor Of NeurologyProfessor Of Neurology
Director Division Of Movement DisordersDirector Division Of Movement DisordersVice-chair Department Of NeurologyVice-chair Department Of Neurology
Keck/USC School Of MedicineKeck/USC School Of MedicineLos Angeles, CaliforniaLos Angeles, California
Mark F. Lew, MDMark F. Lew, MDProfessor Of NeurologyProfessor Of Neurology
Director Division Of Movement DisordersDirector Division Of Movement DisordersVice-chair Department Of NeurologyVice-chair Department Of Neurology
Keck/USC School Of MedicineKeck/USC School Of MedicineLos Angeles, CaliforniaLos Angeles, California
The Science and Medicine of Parkinson’s DiseaseThe Science and Medicine of Parkinson’s Disease
Parkinson’s Disease: Old NewsParkinson’s Disease: Old News
► Chronic progressive neurodegenerative disorderChronic progressive neurodegenerative disorder
► Characterized by loss of dopaminergic neurons Characterized by loss of dopaminergic neurons in the substantia nigrain the substantia nigra
► Clinical features of Parkinson’s DiseaseClinical features of Parkinson’s Disease
● Tremor, rigidity and bradykinesiaTremor, rigidity and bradykinesia● Postural instability in later stagesPostural instability in later stages● Autonomic failure (constipation, orthostasis, impotence)Autonomic failure (constipation, orthostasis, impotence)● Neuropsychiatric dysfunction (depression, dementia) Neuropsychiatric dysfunction (depression, dementia)
► Chronic progressive neurodegenerative disorderChronic progressive neurodegenerative disorder
► Characterized by loss of dopaminergic neurons Characterized by loss of dopaminergic neurons in the substantia nigrain the substantia nigra
► Clinical features of Parkinson’s DiseaseClinical features of Parkinson’s Disease
● Tremor, rigidity and bradykinesiaTremor, rigidity and bradykinesia● Postural instability in later stagesPostural instability in later stages● Autonomic failure (constipation, orthostasis, impotence)Autonomic failure (constipation, orthostasis, impotence)● Neuropsychiatric dysfunction (depression, dementia) Neuropsychiatric dysfunction (depression, dementia)
Playfer. Postgrad Med. 1997;73:257-264; Olanow Et Al. Neurology. 2001;56 (Suppl 5):s1-s88; Barbosa Et Al. Psychiatr Clin North Am. 1997;20:769-790; .Bhatia Et Al. Hosp Med. 1998;59:469-480.
Parkinson’s Disease: EpidemiologyParkinson’s Disease: Epidemiology
► Approximately 1 million patients in USApproximately 1 million patients in US
► 40,000 to 60,000 new cases/year40,000 to 60,000 new cases/year
► Average age of onset is 60 years, predominantly Average age of onset is 60 years, predominantly malesmales● Affects up to 0.3% of general populationAffects up to 0.3% of general population● 1% to 3% of those older than 65 years1% to 3% of those older than 65 years
► Prevalence increasing as the population agesPrevalence increasing as the population ages
► Approximately 1 million patients in USApproximately 1 million patients in US
► 40,000 to 60,000 new cases/year40,000 to 60,000 new cases/year
► Average age of onset is 60 years, predominantly Average age of onset is 60 years, predominantly malesmales● Affects up to 0.3% of general populationAffects up to 0.3% of general population● 1% to 3% of those older than 65 years1% to 3% of those older than 65 years
► Prevalence increasing as the population agesPrevalence increasing as the population ages
Rajput Et Al. Ann Neurol. 1984;16:278-282. Barbosa Et Al. Psychiatr Clin North Am. 1997;20:769-790. Olanow Et Al. Neurology. 2001;56 (11 Suppl 5):s1-s88.Schrag Et Al. Bmj. 2000;321:21-22.
When to Start Therapy?When to Start Therapy?
► Wait until patient is simply bothered by symptoms?Wait until patient is simply bothered by symptoms?
► Wait until patient has functional disability?Wait until patient has functional disability?
► Wait until patient “really needs” treatment?Wait until patient “really needs” treatment?
► As soon asAs soon as a diagnosis is made? a diagnosis is made?
► Wait until patient is simply bothered by symptoms?Wait until patient is simply bothered by symptoms?
► Wait until patient has functional disability?Wait until patient has functional disability?
► Wait until patient “really needs” treatment?Wait until patient “really needs” treatment?
► As soon asAs soon as a diagnosis is made? a diagnosis is made?
Is the “Gold Standard” Really Golden?Is the “Gold Standard” Really Golden?
► Levodopa/carbidopa: Dopamine precursorLevodopa/carbidopa: Dopamine precursor
► Most effective therapy: Gold standard? Most effective therapy: Gold standard?
► Early side effects: Nausea and hypotensionEarly side effects: Nausea and hypotension
► Long term side effects: Dyskinesias and motor Long term side effects: Dyskinesias and motor fluctuations such as “wearing off”fluctuations such as “wearing off”
► Levodopa/carbidopa: Dopamine precursorLevodopa/carbidopa: Dopamine precursor
► Most effective therapy: Gold standard? Most effective therapy: Gold standard?
► Early side effects: Nausea and hypotensionEarly side effects: Nausea and hypotension
► Long term side effects: Dyskinesias and motor Long term side effects: Dyskinesias and motor fluctuations such as “wearing off”fluctuations such as “wearing off”
Olanow et al. Neurology. 2001;56 (suppl 5):S1-S88. Jankovic and Tolosa. Parkinson’s Disease and Movement Disorders. 3rd ed. Philadelphia: Lippincott Williams & Wilkins; 1998:177-190. Sinemet (carbidopa-levodopa). Complete prescribing information. Merck & Co. Inc.; Bristol-Myers Squibb Co.; April 2002.Barbosa et al. Psychiatr Clin North Am. 1997;20:769-790.
2004;351 (Dec 9):2498-2508
Landmark Trials in Parkinson’s DiseaseLandmark Trials in Parkinson’s Disease
Goal and Purpose of TrialGoal and Purpose of Trial
To determine if levodopa alters the natural To determine if levodopa alters the natural history of PD. Does it hasten it, slow it down, history of PD. Does it hasten it, slow it down,
or does it have no effect? or does it have no effect?
Corollary:Corollary: Should levodopa be started earlier Should levodopa be started earlier or later in the natural history of this disease?or later in the natural history of this disease?
To determine if levodopa alters the natural To determine if levodopa alters the natural history of PD. Does it hasten it, slow it down, history of PD. Does it hasten it, slow it down,
or does it have no effect? or does it have no effect?
Corollary:Corollary: Should levodopa be started earlier Should levodopa be started earlier or later in the natural history of this disease?or later in the natural history of this disease?
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THE ELLDOPA STUDYCHANGE IN TOTAL UPDRS FROM BASELINE
NEJM 2004;351 (Dec 9):2498-2508
Dopaminergic AES ELLDOPA TrialDopaminergic AES ELLDOPA Trial
PlaceboPlacebo 150mg/d150mg/d 300mg/d300mg/d 600mg/d600mg/d p-Valuep-Value
ENROLLEDENROLLED 9090 9292 8888 9191
AnyAny 33 / 37%33 / 37% 33 / 36%33 / 36% 27 / 31%27 / 31% 37 / 41%37 / 41% 0.5177 0.5177
Wearing-offWearing-off 12 / 13%12 / 13% 15 / 16%15 / 16% 16 / 18%16 / 18% 27 / 30%27 / 30% 0.0596 0.0596
DyskinesiaDyskinesia 3 / 3%3 / 3% 3 / 3%3 / 3% 2 / 2%2 / 2% 15 / 16%15 / 16% 0.00010.0001
On-offOn-off 3 / 3%3 / 3% 1 / 1%1 / 1% 0 / 0%0 / 0% 3 / 3%3 / 3% 0.2602 0.2602
DystoniaDystonia 19 / 21%19 / 21% 19 / 21%19 / 21% 14 / 16%14 / 16% 12 / 13%12 / 13% 0.3001 0.3001
FreezingFreezing 1313 / 14%/ 14% 99 / 10%/ 10% 66 / 7%/ 7% 55 / 5%/ 5% 0.14970.1497
N / Percent
NEJM 2004;351 (Dec 9):2498-2508
Dopamine Agonists vs. Levodopa Dopamine Agonists vs. Levodopa
4545
2020
3434
2323
Rascol et al. N Engl J Med 2000;342:1484-1491; Parkinson Study Group. Arch Neurol 2004; 61:1044-1053.
(%)(%) (%)(%) 7474
52526363
47475454
2525
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2020
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6060
8080
100100
1st 1st ComplicationComplication Wearing offWearing off DyskinesiaDyskinesia
Levodopa (n=89)Levodopa (n=89)
Ropinirole (n=179)Ropinirole (n=179)
Levodopa (n=150)Levodopa (n=150)
Pramipexole (n=151)Pramipexole (n=151)
00
2020
4040
6060
8080
100100
Wearing offWearing offDyskinesiaDyskinesia
Courtesy K. Lyons, PhD. 2006
Side Effects of Dopamine Agonists Side Effects of Dopamine Agonists vs. Levodopavs. Levodopa
Rascol O et al. (2000), N Engl J Med 342(20):1484-1491; Parkinson Study Group (2000), JAMA 284(15):1931-1938; PSG (2004), Arch Neurol 61(7):1044-1053
LevodopaLevodopa RopiniroleRopinirole LevodopaLevodopa PramipexolePramipexoleSomnolenceSomnolence 19%19% 27%27% 21.3%21.3% 36.4%36.4%
Peripheral Peripheral edemaedema 5.6%5.6% 14%14% 14.7%14.7% 42.4%42.4%
HallucinationsHallucinations 5.6%5.6% 17%17% 8%8% 14.6%14.6%
NauseaNausea 49%49% 49%49% 38%38% 38.4%38.4%
Postural Postural hypotensionhypotension 12%12% 12%12% 15%15% 9%9%
Old School ThinkingOld School Thinking
Does Early Diagnosis = Early Treatment?Does Early Diagnosis = Early Treatment?
► IfIf we had a therapy that was shown to be . . . we had a therapy that was shown to be . . .
1) 1) EfficaciousEfficacious compared to placebo compared to placebo 2) 2) SafeSafe and and well toleratedwell tolerated 3) Potentially 3) Potentially disease modifyingdisease modifying
This would compelling argument that This would compelling argument that everyoneeveryone with PD with PD should take this medication should take this medication as soon asas soon as they were they were diagnosed without delay.diagnosed without delay.
► IfIf we had a therapy that was shown to be . . . we had a therapy that was shown to be . . .
1) 1) EfficaciousEfficacious compared to placebo compared to placebo 2) 2) SafeSafe and and well toleratedwell tolerated 3) Potentially 3) Potentially disease modifyingdisease modifying
This would compelling argument that This would compelling argument that everyoneeveryone with PD with PD should take this medication should take this medication as soon asas soon as they were they were diagnosed without delay.diagnosed without delay.
Initiating Treatment for Parkinson’s DiseaseInitiating Treatment for Parkinson’s Disease
Double-Blind Double-Blind Active Treatment PhaseActive Treatment Phase
Double-Blind Double-Blind Placebo-Controlled PhasePlacebo-Controlled Phase
Delayed Rasagiline 2 mg/dayDelayed Rasagiline 2 mg/day
Rasagiline 1 mg/dayRasagiline 1 mg/day Rasagiline 1mg/dayRasagiline 1mg/day
6 Months6 Months 6 Months6 Months
Parkinson Study Group.Parkinson Study Group. Arch Neurol Arch Neurol 2002; 59:1937-43.2002; 59:1937-43.
N=404N=404
Parkinson Study Group. Parkinson Study Group. Arch Neurol. Arch Neurol. 2004; 61:561-5662004; 61:561-566..Parkinson Study Group. Parkinson Study Group. Arch Neurol. Arch Neurol. 2004; 61:561-5662004; 61:561-566..
RandomizationRandomization
Rasagiline 2 mg/dayRasagiline 2 mg/day Rasagiline 2mg/dayRasagiline 2mg/day
TEMPO: Delayed-Start DesignTEMPO: Delayed-Start Design
N=138 N=138 At 6 months in Delayed At 6 months in Delayed Start:Start: PlaceboPlacebo group receives group receives 2mg2mg
N=132N=132
N=134N=134 N=124N=124
PlaceboPlaceboXX
N=124N=124
N=132N=132
Baseline Demographics and Baseline Demographics and Clinical CharacteristicsClinical Characteristics
ParameterParameterPatients ever TreatedPatients ever Treated
with Rasagiline in TEMPOwith Rasagiline in TEMPO(N = 398)(N = 398)
Age, y ± SDAge, y ± SD 60.9 ± 10.860.9 ± 10.8
Caucasian, n (%)Caucasian, n (%) 377 (94.7%)377 (94.7%)
Male, n (%)Male, n (%) 253 (63.6%)253 (63.6%)
PD duration, years ± SDPD duration, years ± SD 1.2 ± 1.21.2 ± 1.2
Total UPDRS, mean ± SDTotal UPDRS, mean ± SD 26.1 ± 11.526.1 ± 11.5
Hoehn & Yahr stage ± SDHoehn & Yahr stage ± SD 1.9 ± 0.51.9 ± 0.5
Parkinson Study Group. Parkinson Study Group. Arch Neurol. Arch Neurol. 2002; 59:1937-43.2002; 59:1937-43.
TEMPO: Primary Efficacy Measure—TEMPO: Primary Efficacy Measure—Treatment Effect on Total UPDRS at 6 MonthsTreatment Effect on Total UPDRS at 6 Months
(Primary Analysis: Adjusted Mean (Primary Analysis: Adjusted Mean ± ± SE) SE)
0.510.51
-0.13-0.13
4.074.075.05.0
0.00.0
1.01.0
2.02.0
3.03.0
4.04.0
PP << 0.00010.0001
PlaceboPlacebo
Rasagiline 2 mgRasagiline 2 mg
Rasagiline 1 mgRasagiline 1 mg
P < 0.0001P < 0.0001
Parkinson Study Group. Parkinson Study Group. Arch Neurol. Arch Neurol. 2002; 59:1937-43.2002; 59:1937-43.
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TEMPO: 12-Month ResultsTEMPO: 12-Month Results Mean Change in Total UPDRSMean Change in Total UPDRS
Parkinson Study Group. Parkinson Study Group. Arch Neurol.Arch Neurol. 2004; 61:561-566. 2004; 61:561-566.
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Rasagiline 1 mgRasagiline 1 mgRasagiline 2 mgRasagiline 2 mg
Delayed-rasagiline 2 mgDelayed-rasagiline 2 mg
Symptomatic versus Symptomatic versus Disease-Modifying EffectsDisease-Modifying Effects
Delayed-startDelayed-start
Symptom Symptom improvemeimprovementnt
TimeTime
TimeTime
Delayed-startDelayed-start
Delayed-start Delayed-start does not catch updoes not catch up
Symptom Symptom improvemeimprovementnt
Delayed-start Delayed-start catches upcatches up
Design contributed by R. HauserDesign contributed by R. Hauser
TEMPO: Adverse Event Frequency TEMPO: Adverse Event Frequency Similar To PlaceboSimilar To Placebo
% of patients reporting
Parkinson Study Group. Parkinson Study Group. Arch Neurol. Arch Neurol. 2002; 59:1937-43.2002; 59:1937-43.
0 2 4 6 8 10 12 14 16 18
Pain
Back Pain
Arthralgia
Nausea
Asthenia
Dizziness
Accidental Injury
Headache
Infection
Rasagiline 1mg
Rasagiline 2mgPlacebo
TEMPO: Study ConclusionsTEMPO: Study Conclusions
► In early PD patients:In early PD patients:
● Rasagiline effectively manages symptoms over 1 yearRasagiline effectively manages symptoms over 1 year● Frequency of AEs similar to placeboFrequency of AEs similar to placebo
Results from delayed start design suggests:Results from delayed start design suggests:● “…“…Effects of rasagiline on the progression of disability Effects of rasagiline on the progression of disability
in patients with PD cannot be fully explained by its in patients with PD cannot be fully explained by its symptomatic effect and may be due to disease symptomatic effect and may be due to disease modifying activity of the drug.”modifying activity of the drug.”
► In early PD patients:In early PD patients:
● Rasagiline effectively manages symptoms over 1 yearRasagiline effectively manages symptoms over 1 year● Frequency of AEs similar to placeboFrequency of AEs similar to placebo
Results from delayed start design suggests:Results from delayed start design suggests:● “…“…Effects of rasagiline on the progression of disability Effects of rasagiline on the progression of disability
in patients with PD cannot be fully explained by its in patients with PD cannot be fully explained by its symptomatic effect and may be due to disease symptomatic effect and may be due to disease modifying activity of the drug.”modifying activity of the drug.”
Parkinson Study Group. Arch Neurol. 2004; 61:561-566
Old School RevisitedOld School Revisited
TEMPO TEMPO Long Term, Open Label Follow Up Long Term, Open Label Follow Up
To examine the effect of early- versus delayed-start rasagiline on long-term PD symptom progression
To examine the effect of early- versus delayed-start rasagiline on long-term PD symptom progression
—Some patients have been followed for up to 8.5 years—Some patients have been followed for up to 8.5 years
Lew Et Al Submitted For Publication European Journal Of Neurology
TEMPO: 2 Years MonotherapyTEMPO: 2 Years Monotherapy
M. Lew Presented 9/2005 EFNS
Change From Baseline: Total UPDRS Long-term Rasagiline Therapy Without Dopaminergics
Change From Baseline: Total UPDRS Long-term Rasagiline Therapy Without Dopaminergics
M. Lew Presented 9/2005 EFNS
Percent Change From Baseline UPDRS For Early versus Delayed Rasagiline
Percent Change From Baseline UPDRS For Early versus Delayed Rasagiline
M.Lew Presented EFNS 9/2005
Conclusions: Early TreatmentConclusions: Early Treatment
► Early versus delayed rasagiline therapy is Early versus delayed rasagiline therapy is associated with less PD symptom progression at associated with less PD symptom progression at 1 year1 year11
► Current long-term analysis shows this advantage Current long-term analysis shows this advantage persists in patients treated for up to 6 yearspersists in patients treated for up to 6 years22
► Treating early with rasagiline is beneficial for PD Treating early with rasagiline is beneficial for PD patientspatients
1Parkinson Study Group. Arch Neurol. 2004;61:561-566 2Lew EFNS 2005
Adjunctive Drug TherapyAdjunctive Drug Therapy for Advanced Parkinson’s Disease for Advanced Parkinson’s Disease
Combination Strategies andCombination Strategies and
Sequencing PharmacotherapySequencing Pharmacotherapy
Adjunctive Drug TherapyAdjunctive Drug Therapy for Advanced Parkinson’s Disease for Advanced Parkinson’s Disease
Combination Strategies andCombination Strategies and
Sequencing PharmacotherapySequencing Pharmacotherapy
Lawrence Elmer, MD, PhDProgram Chairman
Associate ProfessorDepartment of Neurology
University of ToledoCollege of Medicine
Lawrence Elmer, MD, PhDProgram Chairman
Associate ProfessorDepartment of Neurology
University of ToledoCollege of Medicine
The Science and Medicine The Science and Medicine of Parkinson’s Diseaseof Parkinson’s Disease
Stages of Parkinson’s DiseaseStages of Parkinson’s Disease
► Mild symptoms, no disabilityMild symptoms, no disability► Non-pharmacological approachesNon-pharmacological approaches
► Moderate symptoms with some disabilityModerate symptoms with some disability► Multiple treatments available including l-dopaMultiple treatments available including l-dopa
► Progression of symptomsProgression of symptoms► Levodopa required +/- other medsLevodopa required +/- other meds
EarlyEarly ModerateModerate AdvancedAdvanced
► Disease progressesDisease progresses► Non-motor complications mayNon-motor complications may outweigh motor disturbances outweigh motor disturbances
Adjunctive Drug Therapy for Advanced PD
Report of the Quality Standards Subcommittee of theAmerican Academy of Neurology 2006
Early or Moderate Stage Management of PDEarly or Moderate Stage Management of PD
► Level A – MAO-B inhibitors – selegiline, Level A – MAO-B inhibitors – selegiline, rasagilinerasagiline► Level A – Dopamine agonists – pramipexole, ropinirole, Level A – Dopamine agonists – pramipexole, ropinirole,
rotigotinerotigotine – – caution in elderly, cognitive impairment, young caution in elderly, cognitive impairment, young males (?)males (?)
► Level A - Carbidopa/levodopa – immediate releaseLevel A - Carbidopa/levodopa – immediate release► Level B - Carbidopa/levodopa – controlled releaseLevel B - Carbidopa/levodopa – controlled release
RecommendedRecommended
Years 1-5 (possibly more?)Years 1-5 (possibly more?)
QuestionableQuestionable ► Co-enzyme Q10Co-enzyme Q10► AmantadineAmantadine
Therapeutic Agents
Adjunctive Drug Therapy for Advanced PD
Miyasaki, JM, et al., Neurology 2002;58:11–17O. Suchowersky, et al., Neurology 2006; 66: 976-982
Long-term Treatment of Parkinson’s Disease Long-term Treatment of Parkinson’s Disease Associated with Motor ComplicationsAssociated with Motor Complications
Adjunctive Drug Therapy for Advanced PD
Goals of Current Therapeutic StrategiesGoals of Current Therapeutic Strategies
Adjunctive Drug Therapy for Advanced PD
DADA GABAGABA
AChACh
StriatumStriatum
Substantia NigraSubstantia NigraSubstantia NigraSubstantia Nigra
LevodopaLevodopaLevodopaLevodopa
AnticholinergicsAnticholinergics
Sites of Action of PD Drugs: 1960’sSites of Action of PD Drugs: 1960’s
Adjunctive Drug Therapy for Advanced PD
DADA GABAGABA
AChACh
StriatumStriatum
LevodopaLevodopa
AmantadineAmantadine
SelegilineSelegiline
Dopamine agonistsDopamine agonists BromocriptineBromocriptine PergolidePergolide
AnticholinergicsAnticholinergics
BBBBBB CarbidopaCarbidopa BenserazideBenserazide
MAO-BMAO-B
Sites of Action of PD Drugs: 1990’sSites of Action of PD Drugs: 1990’s
Adjunctive Drug Therapy for Advanced PD
DADA GABAGABA
AChACh
StriatumStriatum
Substantia NigraSubstantia Nigra
LevodopaLevodopa
AmantadineAmantadine
SelegilineSelegiline Dopamine agonistsDopamine agonists BromocriptineBromocriptine PergolidePergolide PramipexolePramipexole PopinirolePopinirole
BaclofenBaclofen
AnticholinergicsAnticholinergics
BBBBBB CarbidopaCarbidopa BenserazideBenserazide TolcaponeTolcapone EntacaponeEntacapone
MAO-BMAO-B
Sites of Action of PD Drugs: 2000Sites of Action of PD Drugs: 2000
Adjunctive Drug Therapy for Advanced PD
DADA GABAGABA
AChACh
StriatumStriatum
Substantia NigraSubstantia Nigra
LevodopaLevodopaAmantadineAmantadine
SelegilineSelegilineZydis selegilineZydis selegilineRasagilineRasagiline
Dopamine agonistsDopamine agonists ApomorphineApomorphine BromocriptineBromocriptine PergolidePergolide PramipexolePramipexole RopiniroleRopinirole RotigotineRotigotine
BaclofenBaclofen
AnticholinergicsAnticholinergics
BBBBBB CarbidopaCarbidopa BenserazideBenserazide TolcaponeTolcapone EntacaponeEntacapone
MAO-BMAO-BStalevo®Stalevo®(carbidopa/levodopa/entacapone)(carbidopa/levodopa/entacapone)
Parcopa®Parcopa®
Sites of Action of PD Drugs: 2008Sites of Action of PD Drugs: 2008
Adjunctive Drug Therapy for Advanced PD
Singh, et al, Progress in Neurobiology, 81:29-44 (2007).
Sites of Action of Pharmacological Sites of Action of Pharmacological Therapies Currently Prescribed for PDTherapies Currently Prescribed for PD
Sites of Action of PD Drug Treatment: EmergingSites of Action of PD Drug Treatment: Emerging
Adjunctive Drug Therapy for Advanced PD
DAGABA
ACh
StriatumStriatum
Substantia NigraSubstantia Nigra
Other Receptor TargetsOther Receptor TargetsSerotonergic AntagonistsSerotonergic AntagonistsAdenosine AntagonistsAdenosine Antagonists
AMPA AntagonistsAMPA AntagonistsAdrenergic AntagonistsAdrenergic Antagonists
Dopamine agonistsDopamine agonistsControlled-releaseControlled-releaseNovel DA’sNovel DA’sNasal spraysNasal spraysOther transdermalOther transdermal
MAO-B
Extended levodopaExtended levodopadelivery systemsdelivery systems
Advanced Management of PDAdvanced Management of PDTreating Motor FluctuationsTreating Motor Fluctuations
► Level A – entacapone, rasagilineLevel A – entacapone, rasagiline► Level B – pramipexole, ropinirole, tolcapone - Level B – pramipexole, ropinirole, tolcapone - caution caution
hepatotoxicityhepatotoxicity► Level C – apomorphine, cabergoline, and selegilineLevel C – apomorphine, cabergoline, and selegiline► Level C (surgical) – STN deep brain stimulationLevel C (surgical) – STN deep brain stimulation► Level C (dyskinesias) - amantadineLevel C (dyskinesias) - amantadine► Disregarded – bromocriptine, sustained release Disregarded – bromocriptine, sustained release
carbidopa/levodopacarbidopa/levodopa
EvidenceEvidence
Years 1-3 and followingYears 1-3 and following
Adjunctive Drug Therapy for Advanced PD Pahwa, R., et al., Neurology 2006;66:983–995
Published Reductions in “OFF” Time:Published Reductions in “OFF” Time:Moderate to Advanced PDModerate to Advanced PD
Pahwa, R., et al., Neurology 2006;66:983–995 Appendix E-1
DrugDrug DurationDuration ActiveActive PlaceboPlacebo Treatment EffectTreatment Effect
pramipexolepramipexole 32 week32 week 31%* (1.8 h)31%* (1.8 h) 7% (0.2 h)7% (0.2 h) 24% (1.6 h)24% (1.6 h)
pramipexolepramipexole 40 week40 week 15%*15%* 3%3% 12%12%
ropiniroleropinirole 12 week12 week 23%*23%* 4%4% 19%19%
ropiniroleropinirole 26 week26 week 11.7%*11.7%* 5%5% 6.7%6.7%
ODT selegilineODT selegiline 12 week12 week 32% (2.2 h)*32% (2.2 h)* 9% (0.6 h)9% (0.6 h) 23% (1.6 h)23% (1.6 h)
rasagiline (0.5mg)rasagiline (0.5mg) 26 week26 week 23% (1.4h)*23% (1.4h)* 15% (0.9 h)15% (0.9 h) 8% (0.5 h)8% (0.5 h)
rasagiline (1.0mg)rasagiline (1.0mg) 26 week26 week 29% (1.8h)*29% (1.8h)* 15% (0.9 h)15% (0.9 h) 14% (0.9 h)14% (0.9 h)
rasagilinerasagiline 18 week18 week 21% (1.2 hr)*21% (1.2 hr)* 7% (0.4 h)7% (0.4 h) 14% (0.8 h)14% (0.8 h)
tolcapone (100mg tid)tolcapone (100mg tid) 12 week12 week 32% (2.3 h)32% (2.3 h) 20% (1.4 h)20% (1.4 h) 12% (0.9 h)12% (0.9 h)
tolcapone (200mg tid)tolcapone (200mg tid) 12 week12 week 48% (3.2 h)*48% (3.2 h)* 20% (1.4 h)20% (1.4 h) 28% (1.8 h)28% (1.8 h)
tolcapone (100mg tid)tolcapone (100mg tid) 12 week12 week 31.5%*31.5%* 11%11% 20.5%20.5%
entacaponeentacapone 18 week18 week 21% (1.2 h)*21% (1.2 h)* 7% (0.4 h)7% (0.4 h) 14% (0.8 h)14% (0.8 h)
entacaponeentacapone 24 week24 week 25.8% (1.6 h)*25.8% (1.6 h)* 13.4% (0.9 h)13.4% (0.9 h) 12.4% (0.7 h)12.4% (0.7 h)
entacaponeentacapone 24 week24 week 23.6% (1.3 h)*23.6% (1.3 h)* 1.9% (0.1 h)1.9% (0.1 h) 21.7% (1.2 h)21.7% (1.2 h)
Goals of Current Therapeutic StrategiesGoals of Current Therapeutic Strategies
Adjunctive Drug Therapy for Advanced PD
Plasma Levels – Rotigitine CDSPlasma Levels – Rotigitine CDS
Adjunctive Drug Therapy for Advanced PD
Adjunctive Transdermal SystemAdjunctive Transdermal System
Adjunctive Drug Therapy for Advanced PD
UPDRS Motor Scores Following UPDRS Motor Scores Following Intermittent SC ApomorphineIntermittent SC Apomorphine
R. Pfeiffer, L. Gutmann, K. Hull, Jr., P. Bottini, J. Sherry; Parkinsonism & Related Disorders, 13:93-100 (2007).
Effect Of Tolcapone On Levodopa- Effect Of Tolcapone On Levodopa- Induced Improvement In PDInduced Improvement In PD
Mot
or s
core
impr
ovem
ent
Mot
or s
core
impr
ovem
ent
MinutesMinutes
Roberts et al, 1994.
LD doseLD dose
0
2
4
6
8
10
12
14
16
0 60 120 180 240
TolcaponePlacebo
Percentage Reduction in Off-time and Percentage Reduction in Off-time and Levodopa with COMT InhibitionLevodopa with COMT Inhibition
Rajput, A. H. et al. Neurology. 1997 Oct;49(4):1066-71.
22
-20-20-21-21
-32-32-24-24
-48-48-60-60
-50-50
-40-40
-30-30
-20-20
-10-10
00
1010
% Reduction in off time% Reduction in off time % Reduction in Ldopa dose% Reduction in Ldopa dose
PlaceboPlacebo Tolcapone 100 mg tidTolcapone 100 mg tid Tolcapone 200 m tidTolcapone 200 m tid
Adjunctive Drug Therapy for Advanced PD
Lew M, Kricorian G., World Congress of Neurology 2005
Long-term Surveillance of Long-term Surveillance of Tolcapone HepatotoxicityTolcapone Hepatotoxicity
► Entacapone prolongs the half-life of levodopa by Entacapone prolongs the half-life of levodopa by 85%,85%,with no change in Cwith no change in Cmaxmax or T or Tmaxmax
► Increases levodopa exposure by Increases levodopa exposure by 35%35%
Effect of Entacapone onEffect of Entacapone onLevodopa PharmacokineticsLevodopa Pharmacokinetics
Buottinen HM, et al. J Neurol Neurosurg Psychiatry. 1996. Diagnosis and Treatment of Parkinson’s Disease: Update 2004
Entacapone in Fluctuating PDEntacapone in Fluctuating PD
► Five (5) pivotal randomized, placebo-Five (5) pivotal randomized, placebo-controlled, double blind studiescontrolled, double blind studies● Increase in “on” time of approximatelyIncrease in “on” time of approximately
1 to 2 hours1 to 2 hours● Reduction in “off” time 1 to 1.5 hoursReduction in “off” time 1 to 1.5 hours● Reduction in daily levodopa dose ofReduction in daily levodopa dose of
33 to 140 mg33 to 140 mg● Improvement in UPDRS “on” scoreImprovement in UPDRS “on” score
► Five (5) pivotal randomized, placebo-Five (5) pivotal randomized, placebo-controlled, double blind studiescontrolled, double blind studies● Increase in “on” time of approximatelyIncrease in “on” time of approximately
1 to 2 hours1 to 2 hours● Reduction in “off” time 1 to 1.5 hoursReduction in “off” time 1 to 1.5 hours● Reduction in daily levodopa dose ofReduction in daily levodopa dose of
33 to 140 mg33 to 140 mg● Improvement in UPDRS “on” scoreImprovement in UPDRS “on” score
Ruottinen 1996; PSG 1997; Rinne 1998; Poewe 2002; Brooks 2003.
Zydis Selegiline: Zydis Selegiline: Reduction in “Off” Time at 12 WeeksReduction in “Off” Time at 12 Weeks
BaselineWeeks 10-12
Zel
apar
Pla
cebo0
5
10
15
20
25
30
35
40
45%
Wa
kin
g H
ou
rs "
OF
F"
Time
Reduction in % Waking Hours "OFF"
Zelapar
Placebo
32%*
*p<0.001 Observation Period
Adjunctive Drug Therapy for Advanced PD Waters CH, et al., Mov Disord 2004;19:426-32
Adjunctive Drug Therapy for Advanced PD
Lew M, Kricorian G. Long-term treatment of Parkinson's disease with a novel MAO-B inhibitor: analysis of safety and efficacy J Neurol Sci 2005;238 Suppl 1:S363
Zydis Selegiline: Zydis Selegiline: Long-term Follow-upLong-term Follow-up
Adjunctive Drug Therapy for Advanced PD
Lew M, Kricorian G. Long-term treatment of Parkinson's disease with a novel MAO-B inhibitor: analysis of safety and efficacy J Neurol Sci 2005;238 Suppl 1:S363
Zydis Selegiline: Zydis Selegiline: Long-term Follow-up – Concomitant MedsLong-term Follow-up – Concomitant Meds
Zydis SelegilineZydis Selegiline
CharacteristicCharacteristic Continuing Continuing (n=171),n (%)(n=171),n (%)
Prior PlaceboPrior Placebo(n=83),n (%)(n=83),n (%)
All PatientsAll Patients(n=254) ),n (%)(n=254) ),n (%)
Dopamine agonists Dopamine agonists AnticholinergicsAnticholinergics
4 (2.3)4 (2.3)3 (1.8)3 (1.8)
2 (2.4)2 (2.4)0 (0)0 (0)
6 (2.4)6 (2.4)3 (1.2)3 (1.2)
Rasagiline: Reduction in “OFF” Time Rasagiline: Reduction in “OFF” Time Similar to EntacaponeSimilar to Entacapone
Ch
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e fr
om
Bas
elin
e C
han
ge
fro
m B
asel
ine
( Ho
urs
)H
ou
rs)
-1.20-1.20-1.18-1.18
-0.40-0.40
Rasagiline 1 mgRasagiline 1 mgRasagiline 1 mgRasagiline 1 mg
Entacapone 200 mgEntacapone 200 mg Entacapone 200 mgEntacapone 200 mg
Placebo-LD/DDIPlacebo-LD/DDIPlacebo-LD/DDIPlacebo-LD/DDI
-0.2-0.2-0.2-0.2
-0.7-0.7-0.7-0.7
-2.2-2.2-2.2-2.2
-1.2-1.2-1.2-1.2
-1.0-1.0-1.0-1.0
P = 0.0001P = 0.0001P < 0.0001P < 0.0001
Adjusted Means ±SE
Rascol. Lancet. 2005; 365:947-54.Rascol. Lancet. 2005; 365:947-54.
All patients on LD/DDI
Impr
ovem
ent
Adjunctive Drug Therapy for Advanced PD
22 44 66 88 1010 1212 1616 2020 24241414 1818 2222 2626
PRESTO: Change From Baseline in Total PRESTO: Change From Baseline in Total Daily “OFF” (Hours) by VisitDaily “OFF” (Hours) by Visit
0.50.5
0.00.0
-0.5-0.5
-1.0-1.0
-1.5-1.5
-2.0-2.0
-2.5-2.5
WeekWeek
Rasagiline 0.5 mgRasagiline 0.5 mgRasagiline 1 mgRasagiline 1 mg
PlaceboPlacebo
00
Ho
urs
Adjunctive Drug Therapy for Advanced PD
Heinz Reichmann, Wolfgang JostWorld Congress on Parkinson’s Disease and Related Disorders, 2007
Open Label Study of Rasagiline in Open Label Study of Rasagiline in Fluctuating Patients: Delayed Benefit?Fluctuating Patients: Delayed Benefit?
0
20
40
60
80
100
120
140
BaselineBaseline 4 weeks4 weeks 4 months4 months
Med
ian
tota
l dai
ly O
FF
tim
e (D
iary
)M
edia
n to
tal d
aily
OF
F ti
me
(Dia
ry)
******
N=545N=545
******##
*** p< 0.001 vs. baseline*** p< 0.001 vs. baseline
# p<0.001 vs. 4 weeks# p<0.001 vs. 4 weeks
Concomitant Medication Concomitant Medication Usage in PRESTOUsage in PRESTO
RasagilineRasagiline
CharacteristicCharacteristic PlaceboPlacebo(n=159)(n=159)
0.5 mg/day0.5 mg/day (n=164)(n=164)
1 mg/day 1 mg/day (n=149)(n=149)
Dopamine agonists Dopamine agonists
EntacaponeEntacapone
AmantadineAmantadine
111 (69.8)111 (69.8)
61 (38.4)61 (38.4)
38 (23.9)38 (23.9)
113 (68.9)113 (68.9)
55 (33.5)55 (33.5)
34 (20.7)34 (20.7)
106 (71.1)106 (71.1)
49 (32.9)49 (32.9)
26 (17.4)26 (17.4)
Data = N (%)Data = N (%)
Elmer, L and the Parkinson Study Group. MDS, 2005
-1.95-1.78
-1.67
-1.27-1.05
-0.83
-2.4
-2
-1.6
-1.2
-0.8
-0.4
0
Rasagiline 1.0 mg/dayRasagiline 1.0 mg/day
Rasagiline 0.5 mg/dayRasagiline 0.5 mg/day
PlaceboPlacebo
Without COMT-IWithout COMT-I(n=307)(n=307)
With COMT-IWith COMT-I(n=165)(n=165)
All patients on LD/CDAll patients on LD/CD*p<0.05; ***p<0.001 vs placebo*p<0.05; ***p<0.001 vs placebo
Cha
nge
from
bas
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e in
mea
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ine
in m
ean
Tot
al d
aily
OF
F t
ime
(hou
rs)
Tot
al d
aily
OF
F t
ime
(hou
rs)
Rasagiline with and without Rasagiline with and without Concomitant COMT-IConcomitant COMT-I
Adjunctive Drug Therapy for Advanced PD Elmer, L and the Parkinson Study Group. MDS, 2005
******
**
-1.89-1.75
-0.85
-1.06
-2
-1.6
-1.2
-0.8
-0.4
0
Rasagiline 1.0 mg/dayRasagiline 1.0 mg/day
PlaceboPlacebo
All patients on LD/DDIAll patients on LD/DDI
Cha
nge
from
bas
elin
e in
mea
nC
hang
e fr
om b
asel
ine
in m
ean
Tot
al d
aily
OF
F t
ime
(hou
rs)
Tot
al d
aily
OF
F t
ime
(hou
rs)
Without DAsWithout DAs(n=91)(n=91)
With DAsWith DAs(n=217)(n=217)
***p<0.001 vs placebo***p<0.001 vs placebo
Rasagiline with and without Rasagiline with and without Concomitant DAConcomitant DA
Adjunctive Drug Therapy for Advanced PD Elmer, L and the Parkinson Study Group. MDS, 2005
******
Cognitive and Behavioral Adverse Events Cognitive and Behavioral Adverse Events Comparison of Rasagiline with Other AgentsComparison of Rasagiline with Other Agents
% Incidence of CBAE’s above placebo % Incidence of CBAE’s above placebo
(from package inserts)(from package inserts)
% Incidence of CBAE’s % Incidence of CBAE’s above placebo (from above placebo (from TEMPO and PRESTOTEMPO and PRESTO))
EntacaponeEntacapone PramipexolePramipexole RopiniroleRopinirole RasagilineRasagiline
As MonotherapyAs Monotherapy
Sleep disorderSleep disorder 55 N/AN/A N/AN/A
SomnolenceSomnolence 1313 3434 N/AN/A
DepressionDepression N/AN/A N/AN/A 33
Abnormal dreamsAbnormal dreams N/AN/A N/AN/A >1>1
HallucinationsHallucinations 66 44 N/AN/A
ConfusionConfusion 33 44 N/AN/A
As Adjunctive TherapyAs Adjunctive Therapy
Sleep disorderSleep disorder N/AN/A 11 N/AN/A 11
SomnolenceSomnolence 22 33 1212 1.61.6
DepressionDepression N/AN/A N/AN/A N/AN/A N/AN/A
Abnormal dreamsAbnormal dreams N/AN/A 11 11 2.72.7
HallucinationsHallucinations N/AN/A 1313 66 11
ConfusionConfusion N/AN/A 33 77 >1>1Elmer L, et al., J Neurol Sci 2006;248(1-2):78-83.
Deep Brain Stimulation: Deep Brain Stimulation: Reduction in “Off” TimeReduction in “Off” Time
The Deep-Brain Stimulation for Parkinson’s Disease Study Group. N Engl J Med 2001;345:956-963.
BaselineBaseline
Six MonthsSix Months27% ON 27% ON
50% OFF50% OFF
23%23%ON w/dyskON w/dysk
74% ON74% ON
19% OFF19% OFF
7% 7% ON w/dyskON w/dysk
All P values < 0.001
Conclusions: Advanced TreatmentConclusions: Advanced Treatment
► Combination therapy reasonable to consider Combination therapy reasonable to consider before before levodopa introducedlevodopa introduced
► Adjunctive therapy with multiple agents from different Adjunctive therapy with multiple agents from different classes has been demonstrated to be effective and well-classes has been demonstrated to be effective and well-toleratedtolerated
► Entacapone, zydis selegiline, and rasagiline have lower Entacapone, zydis selegiline, and rasagiline have lower incidence of cognitive and behavioral side effects incidence of cognitive and behavioral side effects compared to dopamine agonists as adjunctive agents. compared to dopamine agonists as adjunctive agents. Long-acting dopamine agonists are promising options for Long-acting dopamine agonists are promising options for advanced management of Parkinson’s disease.advanced management of Parkinson’s disease.
Andrew Siderowf, MD, MSCEAndrew Siderowf, MD, MSCEParkinson’s Disease and Movement Parkinson’s Disease and Movement
Disorders CenterDisorders CenterAssociate Professor of NeurologyAssociate Professor of Neurology
University of PennsylvaniaUniversity of PennsylvaniaPhiladelphia, PAPhiladelphia, PA
Andrew Siderowf, MD, MSCEAndrew Siderowf, MD, MSCEParkinson’s Disease and Movement Parkinson’s Disease and Movement
Disorders CenterDisorders CenterAssociate Professor of NeurologyAssociate Professor of Neurology
University of PennsylvaniaUniversity of PennsylvaniaPhiladelphia, PAPhiladelphia, PA
MAO SelectivityMAO Selectivity“From Prozac to Parmesan”“From Prozac to Parmesan”
MAO SelectivityMAO Selectivity“From Prozac to Parmesan”“From Prozac to Parmesan”
The Science and Medicine The Science and Medicine of Parkinson’s Diseaseof Parkinson’s Disease
Physiological BackgroundPhysiological Background
► Monoamine oxidase (MAO)Monoamine oxidase (MAO)● Enzyme responsible for degradation of catecholamines Enzyme responsible for degradation of catecholamines
(dopamine, noradrenaline) and serotonin(dopamine, noradrenaline) and serotonin
► Two isoformsTwo isoforms ● MAO-A: Primarily in the liver and GI tract MAO-A: Primarily in the liver and GI tract ● MAO-B: Primarily in the brainMAO-B: Primarily in the brain
► The selectivity of MAO-B inhibition is dose-relatedThe selectivity of MAO-B inhibition is dose-related● At low doses, only MAO-B is inhibitedAt low doses, only MAO-B is inhibited● At higher doses, MAO-A is also inhibitedAt higher doses, MAO-A is also inhibited
► Monoamine oxidase (MAO)Monoamine oxidase (MAO)● Enzyme responsible for degradation of catecholamines Enzyme responsible for degradation of catecholamines
(dopamine, noradrenaline) and serotonin(dopamine, noradrenaline) and serotonin
► Two isoformsTwo isoforms ● MAO-A: Primarily in the liver and GI tract MAO-A: Primarily in the liver and GI tract ● MAO-B: Primarily in the brainMAO-B: Primarily in the brain
► The selectivity of MAO-B inhibition is dose-relatedThe selectivity of MAO-B inhibition is dose-related● At low doses, only MAO-B is inhibitedAt low doses, only MAO-B is inhibited● At higher doses, MAO-A is also inhibitedAt higher doses, MAO-A is also inhibited
Mendelsohn MJ. In: Ford M et al (eds). Mendelsohn MJ. In: Ford M et al (eds). Clinical ToxicologyClinical Toxicology. 2001. . 2001. Youdim MBH et al. Youdim MBH et al. Br J PharmacolBr J Pharmacol. 2001;132:500-506.. 2001;132:500-506.
Relative Functions of MAO-A and MAO-BRelative Functions of MAO-A and MAO-B
► Functions via deaminationFunctions via deamination
► Type AType A● Predominates in the gutPredominates in the gut
• Serotonin (5-HT) and noradrenaline (NA)Serotonin (5-HT) and noradrenaline (NA)• Inhibitors are active as antidepressants: Phenelzine Inhibitors are active as antidepressants: Phenelzine
(Nardil); transylcypromine (Parnate)(Nardil); transylcypromine (Parnate)• Tyramine in the intestineTyramine in the intestine
► Type BType B ● 80% located within CNS80% located within CNS● Dopamine in the CNSDopamine in the CNS● Inhibitors have anti-PD effectsInhibitors have anti-PD effects
► Functions via deaminationFunctions via deamination
► Type AType A● Predominates in the gutPredominates in the gut
• Serotonin (5-HT) and noradrenaline (NA)Serotonin (5-HT) and noradrenaline (NA)• Inhibitors are active as antidepressants: Phenelzine Inhibitors are active as antidepressants: Phenelzine
(Nardil); transylcypromine (Parnate)(Nardil); transylcypromine (Parnate)• Tyramine in the intestineTyramine in the intestine
► Type BType B ● 80% located within CNS80% located within CNS● Dopamine in the CNSDopamine in the CNS● Inhibitors have anti-PD effectsInhibitors have anti-PD effects
Rasagiline vs. SelegilineRasagiline vs. Selegiline
► In vitroIn vitro studies studies● Both are selective and highly potentBoth are selective and highly potent● MAO-B ICMAO-B IC5050 in human and rat brain 20-90 fold lower than in human and rat brain 20-90 fold lower than
for MAO-A inhibitionfor MAO-A inhibition
► In vivo In vivo studiesstudies● Oral acute administration in rodentsOral acute administration in rodents● Rasagiline more potent that selegilineRasagiline more potent that selegiline
• Ratio of MAO-B ED50 in brain or liver from 1/3 to 1/13Ratio of MAO-B ED50 in brain or liver from 1/3 to 1/13• Selectivity maintained over treatmentSelectivity maintained over treatment
► Irreversible inhibition studiesIrreversible inhibition studies• Recovery of MAO activity following chronic drug Recovery of MAO activity following chronic drug
administrationadministration
► In vitroIn vitro studies studies● Both are selective and highly potentBoth are selective and highly potent● MAO-B ICMAO-B IC5050 in human and rat brain 20-90 fold lower than in human and rat brain 20-90 fold lower than
for MAO-A inhibitionfor MAO-A inhibition
► In vivo In vivo studiesstudies● Oral acute administration in rodentsOral acute administration in rodents● Rasagiline more potent that selegilineRasagiline more potent that selegiline
• Ratio of MAO-B ED50 in brain or liver from 1/3 to 1/13Ratio of MAO-B ED50 in brain or liver from 1/3 to 1/13• Selectivity maintained over treatmentSelectivity maintained over treatment
► Irreversible inhibition studiesIrreversible inhibition studies• Recovery of MAO activity following chronic drug Recovery of MAO activity following chronic drug
administrationadministration
Concurrent Antidepressant and MAOI Use Concurrent Antidepressant and MAOI Use
► SSRIs are commonly used antidepressants SSRIs are commonly used antidepressants that enhance serotonin levels in the CNSthat enhance serotonin levels in the CNS
► MAO-A inhibition increases levels of serotoninMAO-A inhibition increases levels of serotonin
► TheoreticallyTheoretically, patients receiving rasagiline or , patients receiving rasagiline or selegiline concurrently with SSRIs may be at selegiline concurrently with SSRIs may be at increased risk of developing serotonin increased risk of developing serotonin syndromesyndrome
► SSRIs are commonly used antidepressants SSRIs are commonly used antidepressants that enhance serotonin levels in the CNSthat enhance serotonin levels in the CNS
► MAO-A inhibition increases levels of serotoninMAO-A inhibition increases levels of serotonin
► TheoreticallyTheoretically, patients receiving rasagiline or , patients receiving rasagiline or selegiline concurrently with SSRIs may be at selegiline concurrently with SSRIs may be at increased risk of developing serotonin increased risk of developing serotonin syndromesyndrome
Role of SerotoninRole of Serotonin
FunctionsFunctions
► SleepSleep
► EmotionEmotion
► Appetite Appetite
► ThermoregulationThermoregulation
► EmesisEmesis
► PainPain
► BehaviorBehavior
► Vascular toneVascular tone
► GI motilityGI motility
FunctionsFunctions
► SleepSleep
► EmotionEmotion
► Appetite Appetite
► ThermoregulationThermoregulation
► EmesisEmesis
► PainPain
► BehaviorBehavior
► Vascular toneVascular tone
► GI motilityGI motility
Sites of ActionSites of Action
► Cardiovascular Cardiovascular systemsystem
► GI tractGI tract
► BrainBrain
Sites of ActionSites of Action
► Cardiovascular Cardiovascular systemsystem
► GI tractGI tract
► BrainBrain
Boyer EW, et al. N Eng J Med, 2005; 352 (11):1112-1120.
Symptoms of Serotonin ToxicitySymptoms of Serotonin ToxicityA Life Threatening SyndromeA Life Threatening Syndrome
► Cognitive Cognitive SymptomsSymptoms
► Cognitive Cognitive SymptomsSymptoms
► ConfusionConfusion► AgitationAgitation► AnxietyAnxiety
► ConfusionConfusion► AgitationAgitation► AnxietyAnxiety
► Autonomic Autonomic SymptomsSymptoms
► Autonomic Autonomic SymptomsSymptoms
► HyperthermiaHyperthermia► DiaphoresisDiaphoresis► TachycardiaTachycardia► HypertensionHypertension
► HyperthermiaHyperthermia► DiaphoresisDiaphoresis► TachycardiaTachycardia► HypertensionHypertension
► Somatic Somatic SymptomsSymptoms
► Somatic Somatic SymptomsSymptoms
► MyoclonusMyoclonus► HyperreflexiaHyperreflexia► Muscle rigidityMuscle rigidity► TremorTremor
► MyoclonusMyoclonus► HyperreflexiaHyperreflexia► Muscle rigidityMuscle rigidity► TremorTremor
Sorenson, Susan, Pharm D. Utox Update, 2002; 4(4):1-2.Boyer EW, et al. N Eng J Med, 2005; 352(11):1112-1120.
Mechanism of Serotonin ToxicityMechanism of Serotonin Toxicity
SynapticSynapticgapgap
ReceptorReceptor
TryptophanTryptophanSynaptic Synaptic terminalterminal
5-HTP5-HTP
5-HT5-HT
5-HT 5-HT
TrpHTrpH
AADCAADC
5-HT 5-HT
5-HT5-HT
5-HIAA5-HIAA
5-HT 5-HT
Waitlling, KJ. The RBI Handbook of Receptor Classification and Signal Transduction. RBI. Fifth Edition, 2001: 72-Waitlling, KJ. The RBI Handbook of Receptor Classification and Signal Transduction. RBI. Fifth Edition, 2001: 72-73.73.Boyer EW, et al. Boyer EW, et al. N Eng J Med, N Eng J Med, 2005; 352 (11):1112-1120.2005; 352 (11):1112-1120.
AntidepressantsAntidepressants5-HT 5-HT 5-HT 5-HT
5-HT 5-HT
XX
XX
MAOIsMAOIs
► 5-HT= Serotonin5-HT= Serotonin► TrpH= Tryptophan TrpH= Tryptophan
hydroxylase hydroxylase ► 5-HTP= 5-hydroxy-5-HTP= 5-hydroxy-
tryptophantryptophan► AADC= Aromatic AADC= Aromatic
acid decarboxylaseacid decarboxylase► MAO-A= MAO-A=
Monoamine Monoamine oxidase type Aoxidase type A
► 5-HIAA=5-Hydroxy-5-HIAA=5-Hydroxy-indoleacetic acidindoleacetic acid
Antidepressant Use (%) inAntidepressant Use (%) inParkinson’s PatientsParkinson’s Patients
36%
32%
18%
36%
28%
14%
0
5
10
15
20
25
30
35
40
Early Moderate Advanced
2005
2006
36%
32%
18%
36%
28%
14%
0
5
10
15
20
25
30
35
40
Early Moderate Advanced
2005
2006
Source: 2006 Scientific Advisory Meeting Summary.
Parkinson’s Disease StageParkinson’s Disease Stage
MedicationsMedications Number of Number of PatientsPatients
Total Years of Total Years of Exposure*Exposure*
All AntidepressantsAll Antidepressants 275 (20.2%)275 (20.2%) 349.2349.2
SSRIsSSRIs 141 (10.4%)141 (10.4%) 161.3161.3
TricyclicsTricyclics 115 (8.4%)115 (8.4%) 138.5138.5
OtherOther†† 61 (4.5%)61 (4.5%) 66.266.2
*Range: 1 day to 6.2 years*Range: 1 day to 6.2 years†† Other: bupropion, mianserin, mirtazapine, nefazodone, Other: bupropion, mianserin, mirtazapine, nefazodone, trazodonetrazodone
Antidepressants That Were Used inAntidepressants That Were Used inRasagiline Clinical Trials Rasagiline Clinical Trials
n=1361 subjects exposed to rasagilinen=1361 subjects exposed to rasagiline
SSRIs (n)SSRIs (n)► CitalopramCitalopram (26)(26)
► EscitalopramEscitalopram (6)(6)
► FluoxetineFluoxetine (7)(7)
► FluvoxamineFluvoxamine (2)(2)
► ParoxetineParoxetine (59)(59)
► SertralineSertraline (69)(69)
► VenalfaxineVenalfaxine (2)(2)
SSRIs (n)SSRIs (n)► CitalopramCitalopram (26)(26)
► EscitalopramEscitalopram (6)(6)
► FluoxetineFluoxetine (7)(7)
► FluvoxamineFluvoxamine (2)(2)
► ParoxetineParoxetine (59)(59)
► SertralineSertraline (69)(69)
► VenalfaxineVenalfaxine (2)(2)
Tricyclics (n)Tricyclics (n)► Amitriptyline (106)Amitriptyline (106)
► Clomipramine (4)Clomipramine (4)
► Doxepin (1)Doxepin (1)
► Nortriptyline (5)Nortriptyline (5)
Tricyclics (n)Tricyclics (n)► Amitriptyline (106)Amitriptyline (106)
► Clomipramine (4)Clomipramine (4)
► Doxepin (1)Doxepin (1)
► Nortriptyline (5)Nortriptyline (5)
Other (n)Other (n)► Buprion (5)Buprion (5)
► Mianserin (2)Mianserin (2)
► Mirtazapine (13)Mirtazapine (13)
► Nefazodone (2)Nefazodone (2)
► Trazodone (45)Trazodone (45)
Other (n)Other (n)► Buprion (5)Buprion (5)
► Mianserin (2)Mianserin (2)
► Mirtazapine (13)Mirtazapine (13)
► Nefazodone (2)Nefazodone (2)
► Trazodone (45)Trazodone (45)
Specific Antidepressants Used inSpecific Antidepressants Used inRasagiline Clinical Trials Rasagiline Clinical Trials
Serotonin Syndrome and the Combined Use of Serotonin Syndrome and the Combined Use of
Selegiline and an AntidepressantSelegiline and an Antidepressant
Aim:Aim: To better estimate the frequency of serotonin syndrome To better estimate the frequency of serotonin syndrome in patients with PD treated with deprenyl and an in patients with PD treated with deprenyl and an antidepressantantidepressant
► Surveyed all investigators in Parkinson’s Study Group (PSG)Surveyed all investigators in Parkinson’s Study Group (PSG)
► 47 (75%) of investigators responded47 (75%) of investigators responded
► 4568 patients treated with combination of Deprenyl and 4568 patients treated with combination of Deprenyl and antidepressantsantidepressants
Results:Results:
► 11 patients (0.24%) reported to have experienced symptoms possibly 11 patients (0.24%) reported to have experienced symptoms possibly consistent with serotonin syndromeconsistent with serotonin syndrome
► 2 patients (0.04%) experienced symptoms considered to be serious (no 2 patients (0.04%) experienced symptoms considered to be serious (no deaths)deaths)
► The constellation of symptoms reported did not seem to meet The constellation of symptoms reported did not seem to meet Sternbach’s criteria for serotonin syndrome Sternbach’s criteria for serotonin syndrome
Aim:Aim: To better estimate the frequency of serotonin syndrome To better estimate the frequency of serotonin syndrome in patients with PD treated with deprenyl and an in patients with PD treated with deprenyl and an antidepressantantidepressant
► Surveyed all investigators in Parkinson’s Study Group (PSG)Surveyed all investigators in Parkinson’s Study Group (PSG)
► 47 (75%) of investigators responded47 (75%) of investigators responded
► 4568 patients treated with combination of Deprenyl and 4568 patients treated with combination of Deprenyl and antidepressantsantidepressants
Results:Results:
► 11 patients (0.24%) reported to have experienced symptoms possibly 11 patients (0.24%) reported to have experienced symptoms possibly consistent with serotonin syndromeconsistent with serotonin syndrome
► 2 patients (0.04%) experienced symptoms considered to be serious (no 2 patients (0.04%) experienced symptoms considered to be serious (no deaths)deaths)
► The constellation of symptoms reported did not seem to meet The constellation of symptoms reported did not seem to meet Sternbach’s criteria for serotonin syndrome Sternbach’s criteria for serotonin syndrome Richard, et al. Neurology 1997; 48(4):1070-78.
Serotonin Syndrome and the Combined Use of Serotonin Syndrome and the Combined Use of Selegiline and an Antidepressant Selegiline and an Antidepressant
Richard, et al. Neurology 1997; 48(4):1070-78.
► Also analyzed all published case reports and FDA data regarding possible serotonin syndrome in patients treated with Deprenyl and antidepressants
► Results Case Reports:● 5 separate published cases from PSG survey● Only 1 case met Sternbach’s criteria for serotonin syndrome,
though had atypical aspects associated too● All cases associated with fluoxetine but one (marprotiline)
► Results FDA:● Only 2 of 48 potential cases appeared to satisfy Sternbach’s
criteria for serotonin syndrome
► Also analyzed all published case reports and FDA data regarding possible serotonin syndrome in patients treated with Deprenyl and antidepressants
► Results Case Reports:● 5 separate published cases from PSG survey● Only 1 case met Sternbach’s criteria for serotonin syndrome,
though had atypical aspects associated too● All cases associated with fluoxetine but one (marprotiline)
► Results FDA:● Only 2 of 48 potential cases appeared to satisfy Sternbach’s
criteria for serotonin syndrome
Schwid, et al. American Academy of Neurology National Meeting 2005.
Safety of Rasagiline in Combination with Safety of Rasagiline in Combination with Serotonin Reuptake InhibitorsSerotonin Reuptake Inhibitors
► Results from PRESTO adjunct study in 472 subjects with advanced PD
► 77 patients treated with SSRIs
► No adverse events differed significantly between SSRI + and SSRI – patients other than vomiting (5% vs 1%)
● SSRI patients with greater impairment at baseline, however
► Among SSRI receiving patients, no difference in adverse events between those taking rasagiline vs. placebo
► Conclusions: ● “This study showed no deleterious interactions between SSRIs
and rasagiline in patients with advanced PD.”
● “Rasagiline was safe and effective.”
► Results from PRESTO adjunct study in 472 subjects with advanced PD
► 77 patients treated with SSRIs
► No adverse events differed significantly between SSRI + and SSRI – patients other than vomiting (5% vs 1%)
● SSRI patients with greater impairment at baseline, however
► Among SSRI receiving patients, no difference in adverse events between those taking rasagiline vs. placebo
► Conclusions: ● “This study showed no deleterious interactions between SSRIs
and rasagiline in patients with advanced PD.”
● “Rasagiline was safe and effective.”
Rasagiline and Dietary TyramineRasagiline and Dietary Tyramine
Issues, Studies, and ResultsIssues, Studies, and Results
Rasagiline and Dietary TyramineRasagiline and Dietary Tyramine
Issues, Studies, and ResultsIssues, Studies, and Results
The Science and Medicine of Parkinson’s DiseaseThe Science and Medicine of Parkinson’s Disease
Tyramine InteractionTyramine Interaction
► Non-selective MAOINon-selective MAOI● Well recognizedWell recognized● Potentiated in patients taking LDPotentiated in patients taking LD
► Reversible MAOIsReversible MAOIs● Does not occur at clinically relevant dosagesDoes not occur at clinically relevant dosages● High dosage or high tyramineHigh dosage or high tyramine
► Irreversible MAOIsIrreversible MAOIs● Theoretical riskTheoretical risk● Exceptional dosage or high tyramineExceptional dosage or high tyramine
► Non-selective MAOINon-selective MAOI● Well recognizedWell recognized● Potentiated in patients taking LDPotentiated in patients taking LD
► Reversible MAOIsReversible MAOIs● Does not occur at clinically relevant dosagesDoes not occur at clinically relevant dosages● High dosage or high tyramineHigh dosage or high tyramine
► Irreversible MAOIsIrreversible MAOIs● Theoretical riskTheoretical risk● Exceptional dosage or high tyramineExceptional dosage or high tyramine
Pharmacology of theTyramine ReactionPharmacology of theTyramine Reaction
TyramineTyramineTyramineTyramine Hydroxyphenylacetic acid Hydroxyphenylacetic acid (inactive)(inactive)
MAO-AMAO-A
SympathomimeticSympathomimetic ResponseResponse
( Blood Pressure)( Blood Pressure)
Norepinephrine (NE) displacement
Norepinephrine (NE) displacement
TyramineTyramineTyramineTyramine
Non-Selective MAO InhibitorNon-Selective MAO Inhibitor
MAO-AMAO-A NENE
NENE NENENE
NE
NE
X
A Tyramine-Rich MealA Tyramine-Rich Meal
Da Prada M et al. J Neural Transm 1988:(Suppl)26;31-56.
2.5 13Parma ham
14.1 3Soup, minestrone
5.3 0.6Spinach
10.6 9Filet of beef
5.3 3Pepper sauce
3.5 7Cheese, Gorgonzola
3.5 0.4Dessert, Tiramisu
11.8 0.1Red wine, Brunello
Total Tyramine: 36.1
Portion size (oz) Tyramine (mg)
Tyramine Interaction Studies Tyramine Interaction Studies with Rasagilinewith Rasagiline
1.1. Tyramine challenge in 27 healthy subjectsTyramine challenge in 27 healthy subjects11 ● Rasagiline 1mg, 2mg with up to 800 mg tyramine HCl Rasagiline 1mg, 2mg with up to 800 mg tyramine HCl
2.2. Tyramine challenge in 20 PD patientsTyramine challenge in 20 PD patients22
● Rasagiline 1mg, 2mg with up to 75 mg tyramine HCl Rasagiline 1mg, 2mg with up to 75 mg tyramine HCl
3.3. PRESTO home BP monitoring in 443 PD patientsPRESTO home BP monitoring in 443 PD patients33
● Rasagiline 0.5mg, 1.0mg + CD/LD with usual dietRasagiline 0.5mg, 1.0mg + CD/LD with usual diet
4.4. PPRRESTO tyramine challenge in 55 PD patientsESTO tyramine challenge in 55 PD patients44
● Rasagiline 0.5mg, 1mg + CD/LD with 50 mg tyramine HCl Rasagiline 0.5mg, 1mg + CD/LD with 50 mg tyramine HCl
5.5. TEMPO tyramine challenge in 55 PD patientsTEMPO tyramine challenge in 55 PD patients44
● Rasagiline 1mg, 2mg with 75mg tyramine HClRasagiline 1mg, 2mg with 75mg tyramine HCl
1.1. Tyramine challenge in 27 healthy subjectsTyramine challenge in 27 healthy subjects11 ● Rasagiline 1mg, 2mg with up to 800 mg tyramine HCl Rasagiline 1mg, 2mg with up to 800 mg tyramine HCl
2.2. Tyramine challenge in 20 PD patientsTyramine challenge in 20 PD patients22
● Rasagiline 1mg, 2mg with up to 75 mg tyramine HCl Rasagiline 1mg, 2mg with up to 75 mg tyramine HCl
3.3. PRESTO home BP monitoring in 443 PD patientsPRESTO home BP monitoring in 443 PD patients33
● Rasagiline 0.5mg, 1.0mg + CD/LD with usual dietRasagiline 0.5mg, 1.0mg + CD/LD with usual diet
4.4. PPRRESTO tyramine challenge in 55 PD patientsESTO tyramine challenge in 55 PD patients44
● Rasagiline 0.5mg, 1mg + CD/LD with 50 mg tyramine HCl Rasagiline 0.5mg, 1mg + CD/LD with 50 mg tyramine HCl
5.5. TEMPO tyramine challenge in 55 PD patientsTEMPO tyramine challenge in 55 PD patients44
● Rasagiline 1mg, 2mg with 75mg tyramine HClRasagiline 1mg, 2mg with 75mg tyramine HCl
1. Guillaume JJ, et al. Mov Disord. 2006;21(Suppl 15):S594.2. Data on file. TVP 1012/132. Manuscript in preparation.3. White WB, et al. Neurology. 2006; 66 (Suppl 2): A314-A315. 4. deMarcaida, JA. et al. Movement Disord. 2006;21(10):1716-1721.
• TEVA has conducted 5 tyramine studies showing no interaction at approved dosesTEVA has conducted 5 tyramine studies showing no interaction at approved doses– Two possible cases on 2mg during developmentTwo possible cases on 2mg during development
1.1. Tyramine challenge in 27 healthyTyramine challenge in 27 healthy subjects subjects11
● Rasagiline 1mg, 2mg with up to 800 mg tyramine HCl Rasagiline 1mg, 2mg with up to 800 mg tyramine HCl
● No significant differences between selegiline and rasagiline in No significant differences between selegiline and rasagiline in the studythe study
2.2. Tyramine challenge in 20 PD patientsTyramine challenge in 20 PD patients22
3.3. PRESTO home BP monitoring in 443 PD patientsPRESTO home BP monitoring in 443 PD patients33
4.4. PPRRESTO tyramine challenge in 55 PD patientsESTO tyramine challenge in 55 PD patients44
5.5. TEMPO tyramine challenge in 55 PD patientsTEMPO tyramine challenge in 55 PD patients44
1.1. Tyramine challenge in 27 healthyTyramine challenge in 27 healthy subjects subjects11
● Rasagiline 1mg, 2mg with up to 800 mg tyramine HCl Rasagiline 1mg, 2mg with up to 800 mg tyramine HCl
● No significant differences between selegiline and rasagiline in No significant differences between selegiline and rasagiline in the studythe study
2.2. Tyramine challenge in 20 PD patientsTyramine challenge in 20 PD patients22
3.3. PRESTO home BP monitoring in 443 PD patientsPRESTO home BP monitoring in 443 PD patients33
4.4. PPRRESTO tyramine challenge in 55 PD patientsESTO tyramine challenge in 55 PD patients44
5.5. TEMPO tyramine challenge in 55 PD patientsTEMPO tyramine challenge in 55 PD patients44
Tyramine Interaction StudiesTyramine Interaction Studies
1. Guillaume JJ, et al. Mov Disord. 2006;21(Suppl 15):S594.2. Data on file. TVP 1012/132. Manuscript in preparation.3. White WB, et al. Neurology. 2006; 66 (Suppl 2): A314-A315. 4. deMarcaida, JA. et al. Movement Disord. 2006;21(10):1716-1721.
1.1. Tyramine challenge in 27 healthy subjectsTyramine challenge in 27 healthy subjects11
2.2. Tyramine challenge in 20 PD patientsTyramine challenge in 20 PD patients22
● Chronic levodopa usageChronic levodopa usage
● Rasagiline 1mg, 2mg Rasagiline 1mg, 2mg
● Fasting (which increases tyramine bioavailability)Fasting (which increases tyramine bioavailability)
● 75-225 mg tyramine75-225 mg tyramine
● At 2 mg, two patients demonstrated increased BP based on these unrealistic At 2 mg, two patients demonstrated increased BP based on these unrealistic conditionsconditions
3.3. PRESTO home BP monitoring in 443 PD patientsPRESTO home BP monitoring in 443 PD patients33
4.4. PPRRESTO tyramine challenge in 55 PD patientsESTO tyramine challenge in 55 PD patients44
5.5. TEMPO tyramine challenge in 55 PD patientsTEMPO tyramine challenge in 55 PD patients44
1.1. Tyramine challenge in 27 healthy subjectsTyramine challenge in 27 healthy subjects11
2.2. Tyramine challenge in 20 PD patientsTyramine challenge in 20 PD patients22
● Chronic levodopa usageChronic levodopa usage
● Rasagiline 1mg, 2mg Rasagiline 1mg, 2mg
● Fasting (which increases tyramine bioavailability)Fasting (which increases tyramine bioavailability)
● 75-225 mg tyramine75-225 mg tyramine
● At 2 mg, two patients demonstrated increased BP based on these unrealistic At 2 mg, two patients demonstrated increased BP based on these unrealistic conditionsconditions
3.3. PRESTO home BP monitoring in 443 PD patientsPRESTO home BP monitoring in 443 PD patients33
4.4. PPRRESTO tyramine challenge in 55 PD patientsESTO tyramine challenge in 55 PD patients44
5.5. TEMPO tyramine challenge in 55 PD patientsTEMPO tyramine challenge in 55 PD patients44
Tyramine Interaction StudiesTyramine Interaction Studies
1. Guillaume JJ, et al. Mov Disord. 2006;21(Suppl 15):S594.2. Data on file. TVP 1012/132. Manuscript in preparation.3. White WB, et al. Neurology. 2006; 66 (Suppl 2): A314-A315. 4. deMarcaida, JA. et al. Movement Disord. 2006;21(10):1716-1721.
1.1. Tyramine challenge in 27 healthy subjectsTyramine challenge in 27 healthy subjects11
2.2. Tyramine challenge in 20 PD patientsTyramine challenge in 20 PD patients22
3.3. PRESTO home BP monitoring in 443 PD patientsPRESTO home BP monitoring in 443 PD patients33
● Rasagiline 0.5mg, 1.0mg + CD/LD with usual dietRasagiline 0.5mg, 1.0mg + CD/LD with usual diet
● No pressor effectsNo pressor effects
4.4. PPRRESTO tyramine challenge in 55 PD patientsESTO tyramine challenge in 55 PD patients44
5.5. TEMPO tyramine challenge in 55 PD patientsTEMPO tyramine challenge in 55 PD patients44
1.1. Tyramine challenge in 27 healthy subjectsTyramine challenge in 27 healthy subjects11
2.2. Tyramine challenge in 20 PD patientsTyramine challenge in 20 PD patients22
3.3. PRESTO home BP monitoring in 443 PD patientsPRESTO home BP monitoring in 443 PD patients33
● Rasagiline 0.5mg, 1.0mg + CD/LD with usual dietRasagiline 0.5mg, 1.0mg + CD/LD with usual diet
● No pressor effectsNo pressor effects
4.4. PPRRESTO tyramine challenge in 55 PD patientsESTO tyramine challenge in 55 PD patients44
5.5. TEMPO tyramine challenge in 55 PD patientsTEMPO tyramine challenge in 55 PD patients44
Tyramine Interaction StudiesTyramine Interaction Studies
1. Guillaume JJ, et al. Mov Disord. 2006;21(Suppl 15):S594.2. Data on file. TVP 1012/132. Manuscript in preparation.3. White WB, et al. Neurology. 2006; 66 (Suppl 2): A314-A315. 4. deMarcaida, JA. et al. Movement Disord. 2006;21(10):1716-1721.
1.1. Tyramine challenge in 27 healthy subjectsTyramine challenge in 27 healthy subjects11 2.2. Tyramine challenge in 20 PD patientsTyramine challenge in 20 PD patients22
3.3. PRESTO home BP monitoring in 443 PD patientsPRESTO home BP monitoring in 443 PD patients33
4.4. PPRRESTO tyramine challenge in 55 PD patientsESTO tyramine challenge in 55 PD patients44
ANDAND
5.5. TEMPO tyramine challenge in 55 PD patientsTEMPO tyramine challenge in 55 PD patients44
● Rasagiline 1mg, 2mg with 75mg tyramine HClRasagiline 1mg, 2mg with 75mg tyramine HCl
● Substudy of pivotal trialSubstudy of pivotal trial
● Following six months therapy to demonstrate selectivity was Following six months therapy to demonstrate selectivity was maintained LTmaintained LT
● Tyramine given with light mealTyramine given with light meal
● No pressor effectsNo pressor effects
1.1. Tyramine challenge in 27 healthy subjectsTyramine challenge in 27 healthy subjects11 2.2. Tyramine challenge in 20 PD patientsTyramine challenge in 20 PD patients22
3.3. PRESTO home BP monitoring in 443 PD patientsPRESTO home BP monitoring in 443 PD patients33
4.4. PPRRESTO tyramine challenge in 55 PD patientsESTO tyramine challenge in 55 PD patients44
ANDAND
5.5. TEMPO tyramine challenge in 55 PD patientsTEMPO tyramine challenge in 55 PD patients44
● Rasagiline 1mg, 2mg with 75mg tyramine HClRasagiline 1mg, 2mg with 75mg tyramine HCl
● Substudy of pivotal trialSubstudy of pivotal trial
● Following six months therapy to demonstrate selectivity was Following six months therapy to demonstrate selectivity was maintained LTmaintained LT
● Tyramine given with light mealTyramine given with light meal
● No pressor effectsNo pressor effects
Tyramine Interaction StudiesTyramine Interaction Studies
1. Guillaume JJ, et al. Mov Disord. 2006;21(Suppl 15):S594.2. Data on file. TVP 1012/132. Manuscript in preparation.3. White WB, et al. Neurology. 2006; 66 (Suppl 2): A314-A315. 4. deMarcaida, JA. et al. Movement Disord. 2006;21(10):1716-1721.
Summary: Serotonin SyndromeSummary: Serotonin Syndrome and Cheese Effect and Cheese Effect
► Both related to excess catecholaminesBoth related to excess catecholamines
► May be precipitated by non-selective MAO inhibitionMay be precipitated by non-selective MAO inhibition
► Selectivity for MAO-BSelectivity for MAO-B
● Not absolute; may diminish at higher dosesNot absolute; may diminish at higher doses● Studies ongoing to establish, characterizeStudies ongoing to establish, characterize
in humansin humans
► Both related to excess catecholaminesBoth related to excess catecholamines
► May be precipitated by non-selective MAO inhibitionMay be precipitated by non-selective MAO inhibition
► Selectivity for MAO-BSelectivity for MAO-B
● Not absolute; may diminish at higher dosesNot absolute; may diminish at higher doses● Studies ongoing to establish, characterizeStudies ongoing to establish, characterize
in humansin humans
Summary: MAO-B InhibitionSummary: MAO-B Inhibition
Tyramine reaction: A theoretical riskTyramine reaction: A theoretical risk
● NoNo potential for “cheese reaction” at defined low potential for “cheese reaction” at defined low doses of selective MAO-B inhibitors doses of selective MAO-B inhibitors
● At recommended doses, At recommended doses, no confirmed tyramine no confirmed tyramine reactions to date reactions to date
• More than 30,000 patients treatedMore than 30,000 patients treated• No tyramine restriction in 3 pivotal studies or ADAGIO trialNo tyramine restriction in 3 pivotal studies or ADAGIO trial• Five tyramine challenge studiesFive tyramine challenge studies
● Relatively easy to avoid foods/beverages Relatively easy to avoid foods/beverages highhigh in in tyramine, per labeltyramine, per label
Tyramine reaction: A theoretical riskTyramine reaction: A theoretical risk
● NoNo potential for “cheese reaction” at defined low potential for “cheese reaction” at defined low doses of selective MAO-B inhibitors doses of selective MAO-B inhibitors
● At recommended doses, At recommended doses, no confirmed tyramine no confirmed tyramine reactions to date reactions to date
• More than 30,000 patients treatedMore than 30,000 patients treated• No tyramine restriction in 3 pivotal studies or ADAGIO trialNo tyramine restriction in 3 pivotal studies or ADAGIO trial• Five tyramine challenge studiesFive tyramine challenge studies
● Relatively easy to avoid foods/beverages Relatively easy to avoid foods/beverages highhigh in in tyramine, per labeltyramine, per label
Non-Motor Aspects ofNon-Motor Aspects ofParkinson’s DiseaseParkinson’s Disease
Assessment and ManagementAssessment and Management
Sleep, Depression, and DementiaSleep, Depression, and Dementia
Non-Motor Aspects ofNon-Motor Aspects ofParkinson’s DiseaseParkinson’s Disease
Assessment and ManagementAssessment and Management
Sleep, Depression, and DementiaSleep, Depression, and Dementia
William G. Ondo, MDWilliam G. Ondo, MDAssociate Professor of NeurologyAssociate Professor of Neurology
Baylor College of Medicine Baylor College of Medicine Houston, TexasHouston, Texas
William G. Ondo, MDWilliam G. Ondo, MDAssociate Professor of NeurologyAssociate Professor of Neurology
Baylor College of Medicine Baylor College of Medicine Houston, TexasHouston, Texas
The Science and Medicine The Science and Medicine of Parkinson’s Diseaseof Parkinson’s Disease
Parkinson’s DiseaseParkinson’s Disease Cardinal Motor FeaturesCardinal Motor Features
► Bradykinesia and hypokinesiaBradykinesia and hypokinesia● Slow and smallSlow and small
► RigidityRigidity
► TremorTremor● Rest>actionRest>action
► +/- Postural instability+/- Postural instability
► Bradykinesia and hypokinesiaBradykinesia and hypokinesia● Slow and smallSlow and small
► RigidityRigidity
► TremorTremor● Rest>actionRest>action
► +/- Postural instability+/- Postural instability
Non-Motor Complications of PDNon-Motor Complications of PD
► In his original essay, James Parkinson In his original essay, James Parkinson alluded to the non-motor problems in alluded to the non-motor problems in advancing disease in the following terms:advancing disease in the following terms:
“ “In this stage, the In this stage, the sleepsleep becomes much becomes much disturbed. The disturbed. The bowelsbowels, which had been all along , which had been all along torpid,now in most cases, demand stimulating torpid,now in most cases, demand stimulating medicines of considerable power: the expulsion medicines of considerable power: the expulsion of faeces from the rectum sometimes requiring of faeces from the rectum sometimes requiring mechanical aid.”mechanical aid.”
► In his original essay, James Parkinson In his original essay, James Parkinson alluded to the non-motor problems in alluded to the non-motor problems in advancing disease in the following terms:advancing disease in the following terms:
“ “In this stage, the In this stage, the sleepsleep becomes much becomes much disturbed. The disturbed. The bowelsbowels, which had been all along , which had been all along torpid,now in most cases, demand stimulating torpid,now in most cases, demand stimulating medicines of considerable power: the expulsion medicines of considerable power: the expulsion of faeces from the rectum sometimes requiring of faeces from the rectum sometimes requiring mechanical aid.”mechanical aid.”
Non-Motor Features in PDNon-Motor Features in PD
► Sleep disruptionSleep disruption
► Psychiatric and/or cognitive Psychiatric and/or cognitive disturbancesdisturbances
► Autonomic dysfunction and Autonomic dysfunction and related findingsrelated findings
► Sensory symptomsSensory symptoms
► Sleep disruptionSleep disruption
► Psychiatric and/or cognitive Psychiatric and/or cognitive disturbancesdisturbances
► Autonomic dysfunction and Autonomic dysfunction and related findingsrelated findings
► Sensory symptomsSensory symptoms
Spectrum of Sleep DisturbancesSpectrum of Sleep Disturbances
► Excessive Daytime SleepinessExcessive Daytime Sleepiness
► Fractionate Nocturnal SleepFractionate Nocturnal Sleep
► REM Behavioral DisorderREM Behavioral Disorder
► Periodic Limb Movements of SleepPeriodic Limb Movements of Sleep
► Restless Legs SyndromeRestless Legs Syndrome
► Sleep ApneaSleep Apnea
► Excessive Daytime SleepinessExcessive Daytime Sleepiness
► Fractionate Nocturnal SleepFractionate Nocturnal Sleep
► REM Behavioral DisorderREM Behavioral Disorder
► Periodic Limb Movements of SleepPeriodic Limb Movements of Sleep
► Restless Legs SyndromeRestless Legs Syndrome
► Sleep ApneaSleep Apnea
Spectrum of Neuropsychiatric and Spectrum of Neuropsychiatric and Cognitive SymptomsCognitive Symptoms
► DepressionDepression
► AnxietyAnxiety
► PsychosisPsychosis
► DementiaDementia
► ApathyApathy
► FatigueFatigue
► DepressionDepression
► AnxietyAnxiety
► PsychosisPsychosis
► DementiaDementia
► ApathyApathy
► FatigueFatigue
Autonomic Symptoms in PDAutonomic Symptoms in PD
► ConstipationConstipation
► Hyperhidrosis (sweating dysfunction)Hyperhidrosis (sweating dysfunction)
► Urinary dysfunction (urgency, frequency Urinary dysfunction (urgency, frequency incontinence)incontinence)
► Sexual dysfunctionSexual dysfunction
► SialorrheaSialorrhea
► ConstipationConstipation
► Hyperhidrosis (sweating dysfunction)Hyperhidrosis (sweating dysfunction)
► Urinary dysfunction (urgency, frequency Urinary dysfunction (urgency, frequency incontinence)incontinence)
► Sexual dysfunctionSexual dysfunction
► SialorrheaSialorrhea
Sensory Symptoms in PDSensory Symptoms in PD
► PainPain
► NumbnessNumbness
► Tingling Tingling
► BurningBurning
► Smell lossSmell loss
► Discriminant VisionDiscriminant Vision
► DiplopiaDiplopia
► PainPain
► NumbnessNumbness
► Tingling Tingling
► BurningBurning
► Smell lossSmell loss
► Discriminant VisionDiscriminant Vision
► DiplopiaDiplopia
PD NMS: Patient Questionnaire Pilot StudyPD NMS: Patient Questionnaire Pilot Study(UK, USA, Germany, Spain)(UK, USA, Germany, Spain)
► Parkinson’s DiseaseParkinson’s Disease● N = 123N = 123● Age: 68.1 Age: 68.1 ± 10.3 yrs (41-87)± 10.3 yrs (41-87)● 59.3% Male59.3% Male● 51% mixed, 28% AD, , 20% TD51% mixed, 28% AD, , 20% TD● PD Duration: 6.4 PD Duration: 6.4 ± 4.3 y (0.5-22 yrs)± 4.3 y (0.5-22 yrs)● 84% levodopa, 60% DA84% levodopa, 60% DA
► ControlsControls● N = 89N = 89● Age: 62.7 ± 12.8 yrs (27-81)Age: 62.7 ± 12.8 yrs (27-81)● 42.7% Male42.7% Male
► Parkinson’s DiseaseParkinson’s Disease● N = 123N = 123● Age: 68.1 Age: 68.1 ± 10.3 yrs (41-87)± 10.3 yrs (41-87)● 59.3% Male59.3% Male● 51% mixed, 28% AD, , 20% TD51% mixed, 28% AD, , 20% TD● PD Duration: 6.4 PD Duration: 6.4 ± 4.3 y (0.5-22 yrs)± 4.3 y (0.5-22 yrs)● 84% levodopa, 60% DA84% levodopa, 60% DA
► ControlsControls● N = 89N = 89● Age: 62.7 ± 12.8 yrs (27-81)Age: 62.7 ± 12.8 yrs (27-81)● 42.7% Male42.7% Male
Chaudhuri R, et al. The NMSQuest study (p NA)Chaudhuri R, et al. The NMSQuest study (p NA) Mov Disord Mov Disord 2006:21(7):916-923. 2006:21(7):916-923.
PD NMS Patient Questionnaire StudyPD NMS Patient Questionnaire StudyGU/GI Tract SymptomsGU/GI Tract Symptoms
0
10
20
30
40
50
60
70
80
Per
cent
yes
Yes Pt
Yes C
p = 0.000
p = 0.0001p = 0.0007
p = 0.0000
p = 0.3 p = 0.2
p = 0.2
p = 0.001p = 0.01
Vomiting, fecal incontinence, incomplete bowelemptying not significantly different from controlsVomiting, fecal incontinence, incomplete bowelemptying not significantly different from controls
PD NMS Patient Questionnaire StudyPD NMS Patient Questionnaire StudyCognition/Neuropsychiatric FeaturesCognition/Neuropsychiatric Features
0
10
20
30
40
50
60
Per
cent
yes
Yes Pt
Yes C
p = 0.9
p = 0.001
p = 0.06
p = 0.0001
p = 0.01
p = 0.004
p = 0.01p = 0.0000
Cognition + Neuropsychiatry
p = 0.006
Pain and memory problems were not significantly different from controls
PD NMS Patient Questionnaire StudyPD NMS Patient Questionnaire StudyAutonomic FeaturesAutonomic Features
0
10
20
30
40
50
60
Per
cent
yes
Yes Pt
Yes C
p = 0.1
p = 0.05
p = 0.0007
p = 0.25p = 0.0000
p = 0.003p = 0.0000
Autonomic
Ankle swelling and sex drive not significantly different from controls
PD NMS Patient Questionnaire StudyPD NMS Patient Questionnaire StudySleep DisturbancesSleep Disturbances
0
10
20
30
40
50
60
Per
cent
yes
Yes Pt
Yes C
p = 0.001
p = 0.2p = 0.04
p = 0.003p = 0.0005
Sleep + Somnolence
Insomnia not significantly different from controls
Sleep Disorders InSleep Disorders InParkinson’s DiseaseParkinson’s Disease
The Science and Medicine The Science and Medicine of Parkinson’s Diseaseof Parkinson’s Disease
Sleep Disorders in PDSleep Disorders in PD
► Excessive Daytime SomnolenceExcessive Daytime Somnolence● Insomnia/Fractionated SleepInsomnia/Fractionated Sleep● Daytime soporific driveDaytime soporific drive
► REM Behavioral DisorderREM Behavioral Disorder► Restless Legs Syndrome (RLS)Restless Legs Syndrome (RLS)► Sleep ApneaSleep Apnea
● 20%20%● Not associated with weightNot associated with weight
► Excessive Daytime SomnolenceExcessive Daytime Somnolence● Insomnia/Fractionated SleepInsomnia/Fractionated Sleep● Daytime soporific driveDaytime soporific drive
► REM Behavioral DisorderREM Behavioral Disorder► Restless Legs Syndrome (RLS)Restless Legs Syndrome (RLS)► Sleep ApneaSleep Apnea
● 20%20%● Not associated with weightNot associated with weight
Excessive Daytime Sleepiness (EDS)Excessive Daytime Sleepiness (EDS)and “Sleep Attacks” and “Sleep Attacks”
► First reported with pramipexoleFirst reported with pramipexole
► Subsequent reports with other agonistsSubsequent reports with other agonistsand other PD medicationsand other PD medications
► Numerous studies demonstrate EDSNumerous studies demonstrate EDS
► First reported with pramipexoleFirst reported with pramipexole
► Subsequent reports with other agonistsSubsequent reports with other agonistsand other PD medicationsand other PD medications
► Numerous studies demonstrate EDSNumerous studies demonstrate EDS
Daytime Sleepiness in PDDaytime Sleepiness in PD
► Poor Nocturnal SleepPoor Nocturnal Sleep● DiseaseDisease● MedicationsMedications
► DirectDirect Daytime SomnolenceDaytime Somnolence● DiseaseDisease● MedicationsMedications
► Poor Nocturnal SleepPoor Nocturnal Sleep● DiseaseDisease● MedicationsMedications
► DirectDirect Daytime SomnolenceDaytime Somnolence● DiseaseDisease● MedicationsMedications
Baylor PD Sleep SurveyBaylor PD Sleep Survey
► 303/320 consecutive patients included303/320 consecutive patients included● 11 (Not PD), 4 (unknown drugs), 2 (incomplete data)11 (Not PD), 4 (unknown drugs), 2 (incomplete data)
► Age: 67.1 ± 10.7Age: 67.1 ± 10.7
► Duration: 9.1 ± 5.7 yearsDuration: 9.1 ± 5.7 years
► Gender: 60.4 % maleGender: 60.4 % male
► Hoehn and Yahr: 2.5 ± 0.9Hoehn and Yahr: 2.5 ± 0.9
Neurology, 2001 Oct 23;57(8):1392-6
Nocturnal Sleep ProblemsNocturnal Sleep Problems
► REM Behavioral Disorder REM Behavioral Disorder 42.8 % 42.8 %
► SomniloquismSomniloquism 50.8 % 50.8 %
► SomnambulismSomnambulism 5.3 % 5.3 %
► SnoringSnoring 38.8 % 38.8 %
► RLSRLS 19.5 % 19.5 %
► Number of AwakeningsNumber of Awakenings 2.7 ± 2.5 2.7 ± 2.5
► REM Behavioral Disorder REM Behavioral Disorder 42.8 % 42.8 %
► SomniloquismSomniloquism 50.8 % 50.8 %
► SomnambulismSomnambulism 5.3 % 5.3 %
► SnoringSnoring 38.8 % 38.8 %
► RLSRLS 19.5 % 19.5 %
► Number of AwakeningsNumber of Awakenings 2.7 ± 2.5 2.7 ± 2.5
Neurology, 2001 Oct 23;57(8):1392-6
Daytime Sleepiness in PDDaytime Sleepiness in PD
► Epworth Score: 11.1 ± 5.9, 43% > 10 Epworth Score: 11.1 ± 5.9, 43% > 10 ► Daytime sleepiness correlates withDaytime sleepiness correlates with::
● Duration of PDDuration of PD● Severity of PDSeverity of PD● Male GenderMale Gender● All dopamine agonistsAll dopamine agonists
• Pergolide Pergolide 12.5 ± 5.412.5 ± 5.4• Ropinirole Ropinirole 12.1 ± 5.712.1 ± 5.7• PramipexolePramipexole 11.7 ± 5.411.7 ± 5.4
► Epworth Score: 11.1 ± 5.9, 43% > 10 Epworth Score: 11.1 ± 5.9, 43% > 10 ► Daytime sleepiness correlates withDaytime sleepiness correlates with::
● Duration of PDDuration of PD● Severity of PDSeverity of PD● Male GenderMale Gender● All dopamine agonistsAll dopamine agonists
• Pergolide Pergolide 12.5 ± 5.412.5 ± 5.4• Ropinirole Ropinirole 12.1 ± 5.712.1 ± 5.7• PramipexolePramipexole 11.7 ± 5.411.7 ± 5.4
Neurology, 2001 Oct 23;57(8):1392-6
Falling Asleep While DrivingFalling Asleep While Driving
► Falling Asleep: 63/279 (20.8 %)Falling Asleep: 63/279 (20.8 %)► Correlates withCorrelates with::
● AgeAge● Dopamine agonistsDopamine agonists● LevodopaLevodopa
► Independently correlates only with levodopaIndependently correlates only with levodopa► All DA had similar % of falling asleepAll DA had similar % of falling asleep
► Falling Asleep: 63/279 (20.8 %)Falling Asleep: 63/279 (20.8 %)► Correlates withCorrelates with::
● AgeAge● Dopamine agonistsDopamine agonists● LevodopaLevodopa
► Independently correlates only with levodopaIndependently correlates only with levodopa► All DA had similar % of falling asleepAll DA had similar % of falling asleep
Neurology, 2001 Oct 23;57(8):1392-6
Adjusted M
ean (95% C
I) Epw
orth Score
Mean (S
D) E
pworth S
core
04
812
1620
24
04
812
1620
24
Levodopa MonotherapyLevodopa Monotherapy (N = 100)(N = 100)
Pramipexole and LevodopaPramipexole and Levodopa (N =85)(N =85)Pergolide and LevodopaPergolide and Levodopa (N = 32)(N = 32)Ropinirole and LevodopaRopinirole and Levodopa (N =22)(N =22)
Dopamine Agonist MonotherapyDopamine Agonist Monotherapy (N = 34)(N = 34)
No Dopaminergic TherapyNo Dopaminergic Therapy (N = 18)(N = 18)
PD Therapy and Sleep DisturbancesPD Therapy and Sleep Disturbances
Sleep Studies in PDSleep Studies in PD
► Two trials have failed to correlate nocturnal Two trials have failed to correlate nocturnal sleep problems with EDSsleep problems with EDS● ApneaApnea● Total sleep timeTotal sleep time● AwakeningsAwakenings
► One showed that more nocturnal total sleep One showed that more nocturnal total sleep correlated with EDScorrelated with EDS
► Two trials have failed to correlate nocturnal Two trials have failed to correlate nocturnal sleep problems with EDSsleep problems with EDS● ApneaApnea● Total sleep timeTotal sleep time● AwakeningsAwakenings
► One showed that more nocturnal total sleep One showed that more nocturnal total sleep correlated with EDScorrelated with EDS
Rye et al. J Sleep Res. 2000;9:63 Arnulf et al. Neurology 2002;58:1019.
CSF Orexin-ACSF Orexin-A
Lower levels correlated with disease severity.
Drouot, 03
Lower levels correlated with disease severity.
Drouot, 03
Normal levels in small sample.
Overeem, 02
Normal levels in small sample.
Overeem, 02
Thannickal, T. C. et al. Brain 2007 130:1586-1595.
Distribution of Hcrt Cells inDistribution of Hcrt Cells inNormal and Across PD StagesNormal and Across PD Stages
Management of Daytime SleepinessManagement of Daytime Sleepiness
► Optimize nocturnal sleepOptimize nocturnal sleep
► Minimize offending agentsMinimize offending agents
► Stimulant medications?Stimulant medications?
► Modafinil?Modafinil?
► Sodium Oxybate?Sodium Oxybate?
► Optimize nocturnal sleepOptimize nocturnal sleep
► Minimize offending agentsMinimize offending agents
► Stimulant medications?Stimulant medications?
► Modafinil?Modafinil?
► Sodium Oxybate?Sodium Oxybate?
EDS ConclusionsEDS Conclusions
► Caused by PD and dopaminergic medicationsCaused by PD and dopaminergic medications● Role of dopamine on sleep poorly Role of dopamine on sleep poorly
understoodunderstood
► Not associated with nocturnal sleep problemsNot associated with nocturnal sleep problems
► Some physiologic similarities to narcolepsySome physiologic similarities to narcolepsy
► Treatments often not satisfactoryTreatments often not satisfactory
► Caused by PD and dopaminergic medicationsCaused by PD and dopaminergic medications● Role of dopamine on sleep poorly Role of dopamine on sleep poorly
understoodunderstood
► Not associated with nocturnal sleep problemsNot associated with nocturnal sleep problems
► Some physiologic similarities to narcolepsySome physiologic similarities to narcolepsy
► Treatments often not satisfactoryTreatments often not satisfactory
Rapid Eye MovementRapid Eye MovementBehavioral Disorder (RBD)Behavioral Disorder (RBD)
Rapid Eye MovementRapid Eye MovementBehavioral Disorder (RBD)Behavioral Disorder (RBD)
Parasomnia: Vigorous movements /w dream Parasomnia: Vigorous movements /w dream content associated with loss of REM atoniacontent associated with loss of REM atonia
Parasomnia: Vigorous movements /w dream Parasomnia: Vigorous movements /w dream content associated with loss of REM atoniacontent associated with loss of REM atonia
The Science and Medicine The Science and Medicine of Parkinson’s Diseaseof Parkinson’s Disease
Sleep HypnogramSleep Hypnogram
REM Behavioral DisorderREM Behavioral Disorder
► Lack of REM sleep atoniaLack of REM sleep atonia
► Dream behaviorDream behavior
► Lack of REM sleep atoniaLack of REM sleep atonia
► Dream behaviorDream behavior
Male > Female PrevalenceMale > Female Prevalence
► Not predicted by testosteroneNot predicted by testosterone
► May result from dream contentMay result from dream content
► Not predicted by testosteroneNot predicted by testosterone
► May result from dream contentMay result from dream content
MaleMale(n=75)(n=75)
Female Female (n=45)(n=45)
Defense from attackDefense from attack 18.7%18.7% 0.0%0.0%
AggressionAggression 9.3%9.3% 0.0%0.0%
Work RelatedWork Related 32.0%32.0% 6.3%6.3%
Sports/AdventureSports/Adventure 17.3%17.3% 4.4%4.4%
DomesticDomestic 32.0%32.0% 66.7%66.7%
Borek, 2006.
RBD and SynucleinopathiesRBD and Synucleinopathies
► SynucleinopathiesSynucleinopathies● PD, MSA, DLBPD, MSA, DLB
► Schenck et al 1996Schenck et al 1996● 38% of 29 RBD patients developed AS38% of 29 RBD patients developed AS
• 3.7 years after RBD Dx3.7 years after RBD Dx● 65% of 26 RBD patients developed AS65% of 26 RBD patients developed AS
• 13.3 years after RBD Dx13.3 years after RBD Dx
► RBD seen in PD, MSA, DLB in 30-70% of casesRBD seen in PD, MSA, DLB in 30-70% of cases► RBD preceded parkinsonismRBD preceded parkinsonism
● MSA: 1-2 yearsMSA: 1-2 years● PD: 3-4 yearsPD: 3-4 years
● DLB: 9 yearsDLB: 9 years
► SynucleinopathiesSynucleinopathies● PD, MSA, DLBPD, MSA, DLB
► Schenck et al 1996Schenck et al 1996● 38% of 29 RBD patients developed AS38% of 29 RBD patients developed AS
• 3.7 years after RBD Dx3.7 years after RBD Dx● 65% of 26 RBD patients developed AS65% of 26 RBD patients developed AS
• 13.3 years after RBD Dx13.3 years after RBD Dx
► RBD seen in PD, MSA, DLB in 30-70% of casesRBD seen in PD, MSA, DLB in 30-70% of cases► RBD preceded parkinsonismRBD preceded parkinsonism
● MSA: 1-2 yearsMSA: 1-2 years● PD: 3-4 yearsPD: 3-4 years
● DLB: 9 yearsDLB: 9 years
Eisensehr, I. et al. Brain 2000 123:1155-1160.
The [123I]IPT-SPECT of One Patient With RBD,The [123I]IPT-SPECT of One Patient With RBD,One Patient with Parkinson's Disease (H&Y I)One Patient with Parkinson's Disease (H&Y I)
and One Control Subjectand One Control Subject
RBD PathophysiologyRBD Pathophysiology
► Brainstem involvementBrainstem involvement● Pons: Locus coeruleus, laterodoasal and Pons: Locus coeruleus, laterodoasal and
pedunculopontine tegmental nucleipedunculopontine tegmental nuclei● Medulla: Magnocellularis, gigantocellularis, Medulla: Magnocellularis, gigantocellularis,
paramedianus nucleiparamedianus nuclei
► Dorsal pontine lesions results in RBDDorsal pontine lesions results in RBD● Animal modelsAnimal models● Human lesionsHuman lesions
► Single autopsy: Lewy bodies in pons and medullaSingle autopsy: Lewy bodies in pons and medulla
► Brainstem involvementBrainstem involvement● Pons: Locus coeruleus, laterodoasal and Pons: Locus coeruleus, laterodoasal and
pedunculopontine tegmental nucleipedunculopontine tegmental nuclei● Medulla: Magnocellularis, gigantocellularis, Medulla: Magnocellularis, gigantocellularis,
paramedianus nucleiparamedianus nuclei
► Dorsal pontine lesions results in RBDDorsal pontine lesions results in RBD● Animal modelsAnimal models● Human lesionsHuman lesions
► Single autopsy: Lewy bodies in pons and medullaSingle autopsy: Lewy bodies in pons and medulla
REM SleepREM Sleep
Braak PD Pathology StagingBraak PD Pathology Staging
Pre-Motor Features of PDPre-Motor Features of PD
► RBDRBD
► Olfaction lossOlfaction loss
► Autonomic Dysfunction Autonomic Dysfunction ● Cardiac, constipationCardiac, constipation
► RBDRBD
► Olfaction lossOlfaction loss
► Autonomic Dysfunction Autonomic Dysfunction ● Cardiac, constipationCardiac, constipation
RBD: ConclusionsRBD: Conclusions
► This is probably a “form fruste” of PD and other This is probably a “form fruste” of PD and other synucleinopathiessynucleinopathies● No overt pathological or physiological No overt pathological or physiological
differencedifference
► Sex difference may reflect dream contentSex difference may reflect dream content
► No treatment trials in PD but benzodiazepines, No treatment trials in PD but benzodiazepines, melatonin, or cholinesterase inhibitors may helpmelatonin, or cholinesterase inhibitors may help
► This is probably a “form fruste” of PD and other This is probably a “form fruste” of PD and other synucleinopathiessynucleinopathies● No overt pathological or physiological No overt pathological or physiological
differencedifference
► Sex difference may reflect dream contentSex difference may reflect dream content
► No treatment trials in PD but benzodiazepines, No treatment trials in PD but benzodiazepines, melatonin, or cholinesterase inhibitors may helpmelatonin, or cholinesterase inhibitors may help
Restless Legs Syndrome (RLS) Restless Legs Syndrome (RLS) and Parkinson’s Diseaseand Parkinson’s Disease
Restless Legs Syndrome (RLS) Restless Legs Syndrome (RLS) and Parkinson’s Diseaseand Parkinson’s Disease
The Science and Medicine The Science and Medicine of Parkinson’s Diseaseof Parkinson’s Disease
Restless Leg SyndromeRestless Leg Syndrome
► Urge to move the legsUrge to move the legs
► Improves during movementImproves during movement
► Worsens with inactivityWorsens with inactivity
► Worse in evening/nightWorse in evening/night
► Urge to move the legsUrge to move the legs
► Improves during movementImproves during movement
► Worsens with inactivityWorsens with inactivity
► Worse in evening/nightWorse in evening/night
Restless Leg SyndromeRestless Leg Syndrome
Original Original PD/No RLS PD/No RLS
(n=240)(n=240)
Original Original PD/RLS PD/RLS (n=63)(n=63)
Total Total PD/RLS PD/RLS (n=109)(n=109)
Total “RLS Total “RLS Only” Only”
(n=146)(n=146)
““RLS Only” RLS Only” (+) Fam. (+) Fam.
Hist. of RLS Hist. of RLS (n=96)(n=96)
““RLS Only” RLS Only” (-) Fam. (-) Fam.
Hist. of RLS Hist. of RLS (n=50)(n=50)
AgeAge 67.5 67.5 ± ± 1111 67.0 67.0 ± 10± 10 67.9 67.9 ± 10± 10 59.8 59.8 ± 15± 15 59.3 59.3 ± 15± 15 60.9 60.9 ± 16± 16
Age Onset Age Onset of RLSof RLS N/AN/A 62.5 62.5 ± 12.8± 12.8 56.6 56.6 ± 18.6± 18.6 35.6 35.6 ± 19.8± 19.8 29.8 29.8 ± 17.5± 17.5 46.5 46.5 ± 19.5± 19.5
% with (+) % with (+) Fam. Fam.
History of History of RLSRLS
---- 17.517.5 20.220.2 65.865.8 100100 00
% Male% Male 62.562.5 52.452.4 48.648.6 37.037.0 35.435.4 40.040.0
Ferritin Ferritin (Mg/ml)(Mg/ml)
88.4 88.4 ± 68± 68(n=32)(n=32)
50.7 50.7 ± 47± 47(n=25)(n=25)
58.8 58.8 ± 51± 51(n=46)(n=46)
86.3 86.3 ± 63± 63(n=90)(n=90)
96.4 96.4 ± 65± 65(n=64)(n=64)
61.5 61.5 ± 51± 51(n=26)(n=26)
Ondo WG, at al. Ondo WG, at al. Arch Neurol Arch Neurol 2002:59:421-424. 2002:59:421-424.
PD/RLS ConclusionsPD/RLS Conclusions
► Symptoms of RLS are common in PD (20%)Symptoms of RLS are common in PD (20%)
► RLS does not contribute to PD sleepinessRLS does not contribute to PD sleepiness
► RLS/PD: associated with lower serum RLS/PD: associated with lower serum ferritinsferritins
► PD symptoms precede RLS symptoms PD symptoms precede RLS symptoms unless there is a (+) family history of RLSunless there is a (+) family history of RLS
► RLS is RLS is notnot a form fruste of PD a form fruste of PD
► RLS pathology much different than PDRLS pathology much different than PD
► Symptoms of RLS are common in PD (20%)Symptoms of RLS are common in PD (20%)
► RLS does not contribute to PD sleepinessRLS does not contribute to PD sleepiness
► RLS/PD: associated with lower serum RLS/PD: associated with lower serum ferritinsferritins
► PD symptoms precede RLS symptoms PD symptoms precede RLS symptoms unless there is a (+) family history of RLSunless there is a (+) family history of RLS
► RLS is RLS is notnot a form fruste of PD a form fruste of PD
► RLS pathology much different than PDRLS pathology much different than PD
DepressionDepression
The Science and Medicine The Science and Medicine of Parkinson’s Diseaseof Parkinson’s Disease
Depression ScreeningDepression Screeningand Assessmentand Assessment
► Assessment toolsAssessment tools● 1-question screen 1-question screen ● Geriatric Depression Scale (GDS-15) Geriatric Depression Scale (GDS-15) ● Hamilton Depression Scale (HDRS)Hamilton Depression Scale (HDRS)● SCID depression module (DSM-IV diagnosis)SCID depression module (DSM-IV diagnosis)
► 42% patients GDS-15 + (≥5)42% patients GDS-15 + (≥5)
but . . .but . . .► 26% reported depression on 1-question 26% reported depression on 1-question
screenscreen ● Problem with perception or instrument?Problem with perception or instrument?
► Assessment toolsAssessment tools● 1-question screen 1-question screen ● Geriatric Depression Scale (GDS-15) Geriatric Depression Scale (GDS-15) ● Hamilton Depression Scale (HDRS)Hamilton Depression Scale (HDRS)● SCID depression module (DSM-IV diagnosis)SCID depression module (DSM-IV diagnosis)
► 42% patients GDS-15 + (≥5)42% patients GDS-15 + (≥5)
but . . .but . . .► 26% reported depression on 1-question 26% reported depression on 1-question
screenscreen ● Problem with perception or instrument?Problem with perception or instrument?
Shulman LM, at al. Mvmt Disord 2001;16(3):507-510
Nonrecognition of Depression and Other Nonrecognition of Depression and Other Non-motor Symptoms in PDNon-motor Symptoms in PD
4439 42 43
21 1914
30
0102030405060708090
100
Depression Anxiety Fatigue Sleep Disorders
4439 42 43
21 1914
30
0102030405060708090
100
Depression Anxiety Fatigue Sleep Disorders
Results of validated screening instruments Results of validated screening instruments The physician’s impression following a routine office visitThe physician’s impression following a routine office visitResults of validated screening instruments Results of validated screening instruments The physician’s impression following a routine office visitThe physician’s impression following a routine office visit
Pa
tient
s (%
)P
atie
nts
(%)
Shulman LM, at al. Mvmt Disord 2001;16(3):507-510
Impact of Depression on FunctionImpact of Depression on Function (Schwab and England Score) (Schwab and England Score)
Explained 54% of varianceExplained 54% of variance
VariableVariable Coefficient bCoefficient b Standard Standard error se (b)error se (b) tt PP
ConstantConstant 56.056.0 17.117.1 3.33.3 .002.002
Hoehn Hoehn and Yahrand Yahr -11.0-11.0 1.91.9 -5.8-5.8 <.001<.001
HDRSHDRS -0.7-0.7 0.20.2 -4.0-4.0 <.001<.001
MMSEMMSE 1.91.9 0.50.5 3.63.6 .001.001
Shulman LM, at al. Mvmt Disord 2001;16(3):507-510
Impact of Depression on FunctionImpact of Depression on Function (UPDRS ADL Score) (UPDRS ADL Score)
Explained 37% of varianceExplained 37% of variance
VariableVariable Coefficient bCoefficient b Standard error Standard error se (b)se (b) tt PP
ConstantConstant 47.547.5 9.19.1 5.25.2 <.001<.001
HDRSHDRS 0.50.5 0.10.1 4.44.4 <.001<.001
MMSEMMSE -1.4-1.4 0.30.3 -4.2-4.2 <.001<.001
Shulman LM, at al. Mvmt Disord 2001;16(3):507-510
FrequencyFrequency
► 34% with DSM-IV depression34% with DSM-IV depression● 21% with major depression21% with major depression● 13% with minor depression or dysthymia13% with minor depression or dysthymia
● Caveat is using inclusive criteriaCaveat is using inclusive criteria
► GDS-15 good screening instrument for DSM-GDS-15 good screening instrument for DSM-IV diagnosis of depression at cutoff ofIV diagnosis of depression at cutoff of 5 5● Sensitivity = 89% Sensitivity = 89%
● Specificity = 80%Specificity = 80%
► 34% with DSM-IV depression34% with DSM-IV depression● 21% with major depression21% with major depression● 13% with minor depression or dysthymia13% with minor depression or dysthymia
● Caveat is using inclusive criteriaCaveat is using inclusive criteria
► GDS-15 good screening instrument for DSM-GDS-15 good screening instrument for DSM-IV diagnosis of depression at cutoff ofIV diagnosis of depression at cutoff of 5 5● Sensitivity = 89% Sensitivity = 89%
● Specificity = 80%Specificity = 80%
Treatment of DepressionTreatment of Depression
► Antidepressant propertiesAntidepressant properties● SerotonergicSerotonergic● AdrenergicAdrenergic● AnticholinergicAnticholinergic● Dopamine re-uptakeDopamine re-uptake● HistaminicHistaminic
► Antidepressant propertiesAntidepressant properties● SerotonergicSerotonergic● AdrenergicAdrenergic● AnticholinergicAnticholinergic● Dopamine re-uptakeDopamine re-uptake● HistaminicHistaminic
Treatment of Depression in PDTreatment of Depression in PD
► Antidepressant medicationsAntidepressant medications● 4 small controlled trials4 small controlled trials● Large NIH trial ongoingLarge NIH trial ongoing
► MAO-B inhibitors?MAO-B inhibitors?
► Dopamine agonistsDopamine agonists? ?
► Antidepressant medicationsAntidepressant medications● 4 small controlled trials4 small controlled trials● Large NIH trial ongoingLarge NIH trial ongoing
► MAO-B inhibitors?MAO-B inhibitors?
► Dopamine agonistsDopamine agonists? ?
DementiaDementia
Lewy Body Dementia (LBD)Lewy Body Dementia (LBD)
Parkinson’s Disease with Dementia (PDD) Parkinson’s Disease with Dementia (PDD)
Lewy Body Dementia (LBD)Lewy Body Dementia (LBD)
Parkinson’s Disease with Dementia (PDD) Parkinson’s Disease with Dementia (PDD)
The Science and Medicine The Science and Medicine of Parkinson’s Diseaseof Parkinson’s Disease
Dementia in PDDementia in PD
► Prevalence of PDDPrevalence of PDD
● Cross-sectional prevalence of dementia is 40% in Cross-sectional prevalence of dementia is 40% in patients with PDpatients with PD11
● 78% of a population-based, representative cohort 78% of a population-based, representative cohort of patients with PD developed dementia during anof patients with PD developed dementia during an8-year study period8-year study period22
► Best predictor of mortalityBest predictor of mortality
► Prevalence of PDDPrevalence of PDD
● Cross-sectional prevalence of dementia is 40% in Cross-sectional prevalence of dementia is 40% in patients with PDpatients with PD11
● 78% of a population-based, representative cohort 78% of a population-based, representative cohort of patients with PD developed dementia during anof patients with PD developed dementia during an8-year study period8-year study period22
► Best predictor of mortalityBest predictor of mortality
Cummings JL. J Geriatr Psychiatry Neurol. 1988;1:24-36.Hughes TA, et al. Neurology. 2000;54:1596-1602.
Dementia in PDDementia in PD
Emre M. Lancet Neurol. 2003;2:229-237.
► Impaired memory (retrieval > amnestic patternImpaired memory (retrieval > amnestic pattern))● Benefit from external cuesBenefit from external cues● Preserved recognitionPreserved recognition
► Executive dysfunctionExecutive dysfunction● Concepts, problem solving, set shifting Concepts, problem solving, set shifting ● Internally cued behavior Internally cued behavior ● Tasks that require planning and sequencingTasks that require planning and sequencing
► Attentional impairmentAttentional impairment● Reaction times and vigilanceReaction times and vigilance● FluctuationsFluctuations
► HallucinationsHallucinations
► Impaired memory (retrieval > amnestic patternImpaired memory (retrieval > amnestic pattern))● Benefit from external cuesBenefit from external cues● Preserved recognitionPreserved recognition
► Executive dysfunctionExecutive dysfunction● Concepts, problem solving, set shifting Concepts, problem solving, set shifting ● Internally cued behavior Internally cued behavior ● Tasks that require planning and sequencingTasks that require planning and sequencing
► Attentional impairmentAttentional impairment● Reaction times and vigilanceReaction times and vigilance● FluctuationsFluctuations
► HallucinationsHallucinations
Clinical Symptoms of PDD vs ADClinical Symptoms of PDD vs AD
82%
71%74%
100%
28%
8%4%
7%
16%21%
0%
20%
40%
60%
80%
100%
Parkinson’s Disease Dementia (N=34)Parkinson’s Disease Dementia (N=34) Alzheimer’s Disease (N=92)Alzheimer’s Disease (N=92)
Major Major DepressionDepression FluctuationFluctuation FallsFalls VisualVisual
HallucinationsHallucinations ParkinsonismParkinsonism
Ballard C, et al. Am J Psych. 1999;156:1039-1045.Ballard C, et al. J Clin Psych. 2001;62:46-49.
PD DementiaPD Dementia
► Diffuse loss of Cholinergic function (imaging Diffuse loss of Cholinergic function (imaging and pathology)and pathology)● Worse than Alzheimer’s diseaseWorse than Alzheimer’s disease
► Marked reduction in Nucleus Basalis of Meynert Marked reduction in Nucleus Basalis of Meynert (basal forebrain)(basal forebrain)
► Pathology is mostly Lewy bodiesPathology is mostly Lewy bodies
► Responds to cholinesterase inhibitors Responds to cholinesterase inhibitors
► Diffuse loss of Cholinergic function (imaging Diffuse loss of Cholinergic function (imaging and pathology)and pathology)● Worse than Alzheimer’s diseaseWorse than Alzheimer’s disease
► Marked reduction in Nucleus Basalis of Meynert Marked reduction in Nucleus Basalis of Meynert (basal forebrain)(basal forebrain)
► Pathology is mostly Lewy bodiesPathology is mostly Lewy bodies
► Responds to cholinesterase inhibitors Responds to cholinesterase inhibitors
Treatment of DementiaTreatment of Dementia
► Acetylcholinesterase inhibitorsAcetylcholinesterase inhibitors
● Rivastigmine (Exelon)*Rivastigmine (Exelon)*● Galantamine (Razadyne)Galantamine (Razadyne)● Donepezil (Aricept)Donepezil (Aricept)
► Memantine (Namenda)Memantine (Namenda)
► Acetylcholinesterase inhibitorsAcetylcholinesterase inhibitors
● Rivastigmine (Exelon)*Rivastigmine (Exelon)*● Galantamine (Razadyne)Galantamine (Razadyne)● Donepezil (Aricept)Donepezil (Aricept)
► Memantine (Namenda)Memantine (Namenda)
177 (83.9%) completed 96 (78.0%) completed
211 to Riv-Rivastigmine 123 to Plc-Rivastigmine
Rivastigmine PD StudyRivastigmine PD Study
Extension studyExtension study 334 patients entered O-L study
263 (72.7%) completed
147 (82.1%) completed
99 (27.3%)discontinued
32 (17.9%)discontinued
362 Rivastigmine 179 placebo
Core studyCore study
24 weeks24 weeks
541 randomized to core study
650 screened
ADAS-Cog Results ADAS-Cog Results
2
1
0
-1
-2
-3
-4
-5
PlaceboPlaceboRivastigmineRivastigmine
n=284P<0.001
n=256P<0.001
n=150
n=139
16 240
Weeks During TreatmentWeeks During Treatment
ImprovementImprovement
DeclineDecline
Mea
n (±
SE
M)
Cha
nge
Fro
m B
asel
ine
Mea
n (±
SE
M)
Cha
nge
Fro
m B
asel
ine
AD
AS
-Cog
Rat
ing
AD
AS
-Cog
Rat
ing
* OC analysis
Adverse EventsAdverse EventsCore and Extension StudiesCore and Extension Studies
CoreCore
RivastigRivastigN=362N=362n (%) n (%)
PlaceboPlaceboN=179 N=179 n (%) n (%)
Total patients with AE(s) Total patients with AE(s) 303 (83.7) 303 (83.7) 127 (70.9) 127 (70.9)
Nausea Nausea 105 (29.0) 105 (29.0) 20 (11.2) 20 (11.2)
Vomiting Vomiting 60 (16.6) 60 (16.6) 3 (1.7) 3 (1.7)
Tremor Tremor 37 (10.2) 37 (10.2) 7 (3.9) 7 (3.9)
Diarrhea Diarrhea 26 (7.2) 26 (7.2) 8 (4.5) 8 (4.5)
Anorexia Anorexia 22 (6.1) 22 (6.1) 5 (2.8) 5 (2.8)
Fall Fall 21 (5.8) 21 (5.8) 11 (6.1) 11 (6.1)
Dizziness Dizziness 21 (5.8) 21 (5.8) 2 (1.1) 2 (1.1)
Hypotension Hypotension 19 (5.2) 19 (5.2) 14 (7.8) 14 (7.8)
Hallucination Hallucination 17 (4.7) 17 (4.7) 17 (9.5) 17 (9.5)
Constipation Constipation 17 (4.7) 17 (4.7) 12 (6.7) 12 (6.7)
Confusional state Confusional state 13 (3.6) 13 (3.6) 10 (5.6) 10 (5.6)
Orthostatic Hyp Orthostatic Hyp 6 (1.7) 6 (1.7) 9 (5.0) 9 (5.0)
ExtensionExtensionRiv-RivastigRiv-Rivastig
N=211 N=211 n (%) n (%)
Pl-RivastigPl-Rivastig N=123 N=123 n (%) n (%)
159 (75.4) 93 (75.6)
29 (13.7) 33 (26.8)
17 (8.1) 20 (16.3)
8 (3.8) 15 (12.2)
4 (1.9) 4 (3.3)
6 (2.8) 6 (4.9)
7 (3.3) 9 (7.3)
5 (2.4) 3 (2.4)
8 (3.8) 5 (4.1)
9 (4.3) 7 (5.7)
4 (1.9) 2 (1.6)
10 (4.7) 7 (5.7)
5 (2.4) 4 (3.3)
Psychosis in PDPsychosis in PD
► Visual hallucinationsVisual hallucinations
► Paranoid delusionsParanoid delusions
► Main risk factor for NHPMain risk factor for NHP
► Risk factorsRisk factors● Age, dementia, multiple medications, vision loss, Age, dementia, multiple medications, vision loss,
Apo E, reduced occipitotemporoparietal activity Apo E, reduced occipitotemporoparietal activity
► Visual hallucinationsVisual hallucinations
► Paranoid delusionsParanoid delusions
► Main risk factor for NHPMain risk factor for NHP
► Risk factorsRisk factors● Age, dementia, multiple medications, vision loss, Age, dementia, multiple medications, vision loss,
Apo E, reduced occipitotemporoparietal activity Apo E, reduced occipitotemporoparietal activity
PET Imaging of PD Hallucination PET Imaging of PD Hallucination
Treatment of PsychosisTreatment of Psychosis
► Clozapine (12.5-100 mg)Clozapine (12.5-100 mg)
► Quetiapine (25 - 400 mg)Quetiapine (25 - 400 mg)
► Olanzapine (1.25 - 5 mg)Olanzapine (1.25 - 5 mg)
► Risperidone (1 - 2 mg)Risperidone (1 - 2 mg)
► Ziprasidone (20-80 mg)Ziprasidone (20-80 mg)
► Aripiprizole (?)Aripiprizole (?)
► Ondansetron (8 - 32 mg)Ondansetron (8 - 32 mg)
► Cholinesterase inhibitorsCholinesterase inhibitors
► Clozapine (12.5-100 mg)Clozapine (12.5-100 mg)
► Quetiapine (25 - 400 mg)Quetiapine (25 - 400 mg)
► Olanzapine (1.25 - 5 mg)Olanzapine (1.25 - 5 mg)
► Risperidone (1 - 2 mg)Risperidone (1 - 2 mg)
► Ziprasidone (20-80 mg)Ziprasidone (20-80 mg)
► Aripiprizole (?)Aripiprizole (?)
► Ondansetron (8 - 32 mg)Ondansetron (8 - 32 mg)
► Cholinesterase inhibitorsCholinesterase inhibitors
ConclusionsConclusions
► Non-motor features are common in PD and may Non-motor features are common in PD and may be more problematic than motor symptomsbe more problematic than motor symptoms
► Recognition historically poor, but improvingRecognition historically poor, but improving
► Pathology is heterogeneous and variably related Pathology is heterogeneous and variably related to dopaminergic function to dopaminergic function
► Non-motor features are common in PD and may Non-motor features are common in PD and may be more problematic than motor symptomsbe more problematic than motor symptoms
► Recognition historically poor, but improvingRecognition historically poor, but improving
► Pathology is heterogeneous and variably related Pathology is heterogeneous and variably related to dopaminergic function to dopaminergic function
Case StudiesCase Studies
The Science and Medicine The Science and Medicine of Parkinson’s Diseaseof Parkinson’s Disease
Case #1Case #1
► A 56-year-old male in good health presents with rest A 56-year-old male in good health presents with rest tremor of the right (dominant) hand. Tremor worse tremor of the right (dominant) hand. Tremor worse with stress and when he walks. Handwriting has with stress and when he walks. Handwriting has become slightly smaller but all words are legible. Wife become slightly smaller but all words are legible. Wife has noticed decreased arm swing on the right.has noticed decreased arm swing on the right.
► He is complaining of severe constipation and stiffness He is complaining of severe constipation and stiffness
in right side, He states that symptoms are only in right side, He states that symptoms are only minimally interfering with job and home life. More minimally interfering with job and home life. More importantly, the couple is troubled that condition will importantly, the couple is troubled that condition will become apparent to coworkers and interfere with become apparent to coworkers and interfere with career.career.
► A 56-year-old male in good health presents with rest A 56-year-old male in good health presents with rest tremor of the right (dominant) hand. Tremor worse tremor of the right (dominant) hand. Tremor worse with stress and when he walks. Handwriting has with stress and when he walks. Handwriting has become slightly smaller but all words are legible. Wife become slightly smaller but all words are legible. Wife has noticed decreased arm swing on the right.has noticed decreased arm swing on the right.
► He is complaining of severe constipation and stiffness He is complaining of severe constipation and stiffness
in right side, He states that symptoms are only in right side, He states that symptoms are only minimally interfering with job and home life. More minimally interfering with job and home life. More importantly, the couple is troubled that condition will importantly, the couple is troubled that condition will become apparent to coworkers and interfere with become apparent to coworkers and interfere with career.career.
Case #1Case #1
► Family History:Family History: No family history of Parkinson’s No family history of Parkinson’s diseasedisease
► Medical History/Medications:Medical History/Medications: Wife noticed that for the Wife noticed that for the past three years the patient thrashes around during past three years the patient thrashes around during sleep and fell out of bed twice.sleep and fell out of bed twice.No current medicationsNo current medications
► Examination:Examination: R Reveals normal mental status and eye eveals normal mental status and eye movements. He has mild bradykinesia on repetitive movements. He has mild bradykinesia on repetitive alternating movements in the right hand and a rest alternating movements in the right hand and a rest tremor is noted. tremor is noted.
► Decision making:Decision making: Making the diagnosis of PD; early Making the diagnosis of PD; early non-motor features of PD; when to initiate therapynon-motor features of PD; when to initiate therapy
► Family History:Family History: No family history of Parkinson’s No family history of Parkinson’s diseasedisease
► Medical History/Medications:Medical History/Medications: Wife noticed that for the Wife noticed that for the past three years the patient thrashes around during past three years the patient thrashes around during sleep and fell out of bed twice.sleep and fell out of bed twice.No current medicationsNo current medications
► Examination:Examination: R Reveals normal mental status and eye eveals normal mental status and eye movements. He has mild bradykinesia on repetitive movements. He has mild bradykinesia on repetitive alternating movements in the right hand and a rest alternating movements in the right hand and a rest tremor is noted. tremor is noted.
► Decision making:Decision making: Making the diagnosis of PD; early Making the diagnosis of PD; early non-motor features of PD; when to initiate therapynon-motor features of PD; when to initiate therapy
Case #2Case #2
► 58-year-old male in good health presents with 58-year-old male in good health presents with resting tremor of the right (dominant) hand resting tremor of the right (dominant) hand and difficulty with simple tasks such as and difficulty with simple tasks such as brushing teeth and combing hair. He works brushing teeth and combing hair. He works as a desk clerk and has noticed significant as a desk clerk and has noticed significant problems with writing. Also has trouble problems with writing. Also has trouble buttoning and at times has trouble cutting buttoning and at times has trouble cutting food.food.
► Complains of fatigue, lack of motivation and Complains of fatigue, lack of motivation and disinterest. He tends to fall asleep easily disinterest. He tends to fall asleep easily during the day.during the day.
► 58-year-old male in good health presents with 58-year-old male in good health presents with resting tremor of the right (dominant) hand resting tremor of the right (dominant) hand and difficulty with simple tasks such as and difficulty with simple tasks such as brushing teeth and combing hair. He works brushing teeth and combing hair. He works as a desk clerk and has noticed significant as a desk clerk and has noticed significant problems with writing. Also has trouble problems with writing. Also has trouble buttoning and at times has trouble cutting buttoning and at times has trouble cutting food.food.
► Complains of fatigue, lack of motivation and Complains of fatigue, lack of motivation and disinterest. He tends to fall asleep easily disinterest. He tends to fall asleep easily during the day.during the day.
Case #2Case #2
► Family HistoryFamily History: Father died with Parkinson Disease : Father died with Parkinson Disease and a cousin diagnosed with Parkinson’s disease 2 and a cousin diagnosed with Parkinson’s disease 2 years ago is responding well to levodopayears ago is responding well to levodopa
► Medical History/Medications:Medical History/Medications: No significant medical or No significant medical or surgical history. No current medicationssurgical history. No current medications
► Examination:Examination: Bilateral bradykinesia and asymmetric Bilateral bradykinesia and asymmetric rest tremor right greater than left. Gait is slow but there rest tremor right greater than left. Gait is slow but there is no problem turning. Pull Test is negative. Rest of the is no problem turning. Pull Test is negative. Rest of the examination is normalexamination is normal
► Decision making:Decision making: Patient diagnosed with Parkinson’s Patient diagnosed with Parkinson’s disease with some disability and he wishes to start disease with some disability and he wishes to start treatment.treatment.
► Family HistoryFamily History: Father died with Parkinson Disease : Father died with Parkinson Disease and a cousin diagnosed with Parkinson’s disease 2 and a cousin diagnosed with Parkinson’s disease 2 years ago is responding well to levodopayears ago is responding well to levodopa
► Medical History/Medications:Medical History/Medications: No significant medical or No significant medical or surgical history. No current medicationssurgical history. No current medications
► Examination:Examination: Bilateral bradykinesia and asymmetric Bilateral bradykinesia and asymmetric rest tremor right greater than left. Gait is slow but there rest tremor right greater than left. Gait is slow but there is no problem turning. Pull Test is negative. Rest of the is no problem turning. Pull Test is negative. Rest of the examination is normalexamination is normal
► Decision making:Decision making: Patient diagnosed with Parkinson’s Patient diagnosed with Parkinson’s disease with some disability and he wishes to start disease with some disability and he wishes to start treatment.treatment.
Case #3Case #3
► 68-year-old woman with a 4-year history of 68-year-old woman with a 4-year history of Parkinson’s disease. She initially presented with Parkinson’s disease. She initially presented with asymmetric tremor involving the left hand. asymmetric tremor involving the left hand. Subsequently, she progressed to have tremor both Subsequently, she progressed to have tremor both sides and significant slowness bilaterally. Was started sides and significant slowness bilaterally. Was started on levodopa 3 years ago.on levodopa 3 years ago.
► Currently takes carbidopa-levodopa 25/100 one tablet Currently takes carbidopa-levodopa 25/100 one tablet 4 times per day. She is experiencing return of tremor 4 times per day. She is experiencing return of tremor and slowness and sweating and abdominal pain as the and slowness and sweating and abdominal pain as the medication is wearing off. During off periods, and in medication is wearing off. During off periods, and in the early morning hours and she has painful dystonia the early morning hours and she has painful dystonia of the left foot. She has abnormal movements while of the left foot. She has abnormal movements while the medication is working. the medication is working.
► 68-year-old woman with a 4-year history of 68-year-old woman with a 4-year history of Parkinson’s disease. She initially presented with Parkinson’s disease. She initially presented with asymmetric tremor involving the left hand. asymmetric tremor involving the left hand. Subsequently, she progressed to have tremor both Subsequently, she progressed to have tremor both sides and significant slowness bilaterally. Was started sides and significant slowness bilaterally. Was started on levodopa 3 years ago.on levodopa 3 years ago.
► Currently takes carbidopa-levodopa 25/100 one tablet Currently takes carbidopa-levodopa 25/100 one tablet 4 times per day. She is experiencing return of tremor 4 times per day. She is experiencing return of tremor and slowness and sweating and abdominal pain as the and slowness and sweating and abdominal pain as the medication is wearing off. During off periods, and in medication is wearing off. During off periods, and in the early morning hours and she has painful dystonia the early morning hours and she has painful dystonia of the left foot. She has abnormal movements while of the left foot. She has abnormal movements while the medication is working. the medication is working.
Case #3Case #3
► Family HistoryFamily History: no relatives with PD: no relatives with PD
► Medical HistoryMedical History: : No significant medical or No significant medical or surgical history surgical history
► Medications:Medications: Amitriptyline 50 mg. q.h.s for Amitriptyline 50 mg. q.h.s for depression in addition to carbidopa-levodopadepression in addition to carbidopa-levodopa
► Decision makingDecision making: treatment of motor : treatment of motor fluctuations, non-motor features of PDfluctuations, non-motor features of PD
► Family HistoryFamily History: no relatives with PD: no relatives with PD
► Medical HistoryMedical History: : No significant medical or No significant medical or surgical history surgical history
► Medications:Medications: Amitriptyline 50 mg. q.h.s for Amitriptyline 50 mg. q.h.s for depression in addition to carbidopa-levodopadepression in addition to carbidopa-levodopa
► Decision makingDecision making: treatment of motor : treatment of motor fluctuations, non-motor features of PDfluctuations, non-motor features of PD
Case #4Case #4
► 82-year-old woman has a history of Parkinson’s 82-year-old woman has a history of Parkinson’s disease for 12 years. She presented with disease for 12 years. She presented with shuffling gait, masked facies, postural instability, shuffling gait, masked facies, postural instability, and a pill-rolling tremor of the right hand.and a pill-rolling tremor of the right hand.
► Initially responded well to carbidopa-levodopa. Initially responded well to carbidopa-levodopa. Then she developed mild wearing off and Then she developed mild wearing off and dyskinesia. Over the past two years she has dyskinesia. Over the past two years she has been experiencing visual hallucinations, been experiencing visual hallucinations, paranoia, and vivid dreams. She has become paranoia, and vivid dreams. She has become more forgetful and gets lost easily around familiar more forgetful and gets lost easily around familiar places. She falls frequently.places. She falls frequently.
► 82-year-old woman has a history of Parkinson’s 82-year-old woman has a history of Parkinson’s disease for 12 years. She presented with disease for 12 years. She presented with shuffling gait, masked facies, postural instability, shuffling gait, masked facies, postural instability, and a pill-rolling tremor of the right hand.and a pill-rolling tremor of the right hand.
► Initially responded well to carbidopa-levodopa. Initially responded well to carbidopa-levodopa. Then she developed mild wearing off and Then she developed mild wearing off and dyskinesia. Over the past two years she has dyskinesia. Over the past two years she has been experiencing visual hallucinations, been experiencing visual hallucinations, paranoia, and vivid dreams. She has become paranoia, and vivid dreams. She has become more forgetful and gets lost easily around familiar more forgetful and gets lost easily around familiar places. She falls frequently.places. She falls frequently.
Case #4Case #4
► Family History:Family History: 87-year-old sister diagnosed with 87-year-old sister diagnosed with Alzheimer’s disease and Pakinson’s diseaseAlzheimer’s disease and Pakinson’s disease
► Medical History:Medical History: Mild stroke 3 years ago; has minimal Mild stroke 3 years ago; has minimal residual effects of right-sided weakness. residual effects of right-sided weakness.
► MedicationsMedications: She takes 1 aspirin daily in addition to : She takes 1 aspirin daily in addition to carbidopa-levodopacarbidopa-levodopa
► Decision makingDecision making: management of advanced PD : management of advanced PD motor and non-motor featuresmotor and non-motor features
► Family History:Family History: 87-year-old sister diagnosed with 87-year-old sister diagnosed with Alzheimer’s disease and Pakinson’s diseaseAlzheimer’s disease and Pakinson’s disease
► Medical History:Medical History: Mild stroke 3 years ago; has minimal Mild stroke 3 years ago; has minimal residual effects of right-sided weakness. residual effects of right-sided weakness.
► MedicationsMedications: She takes 1 aspirin daily in addition to : She takes 1 aspirin daily in addition to carbidopa-levodopacarbidopa-levodopa
► Decision makingDecision making: management of advanced PD : management of advanced PD motor and non-motor featuresmotor and non-motor features