10/10/18 Outline Parkinsons Disease Demographics PARKINSONS - PDF document

10/10/18 Outline — Parkinson’s Disease Demographics PARKINSON’S DISEASE PRIMER — Parkinson’s Disease Motor Symptoms — Parkinson’s Disease Progression — Parkinson’s Disease Pathophysiology Maya Katz, M.D. Assistant Professor of Neurology — Parkinson’s Disease Treatment Motor Symptoms UCSF Medical Center May 2018 — Parkinson’s Disease Treatment Non-motor Symptoms — Addressing the Total Pain of Parkinson’s Disease Parkinson’s disease: Demographics 1-2% of people 60 years of age or older (~130-140 per 100,000) I have no disclosures to report 2 nd most common neurodegenerative disorder Average age of onset: 60 years old (range 20-95) Males are 1.5 times more likely to develop Parkinson’s disease Typical life expectancy: 12-20 years (range: 12-40) Wickremaratchi et al. 2009. J Neurol Neurosurg Psych; Walker et al. 2010. Parkinsonism and Related Disorders Lees et al. 2009. The Lancet; Moisan et al. 2015, Journal of Neurology, Neurosurgery, & Psychiatry 1

10/10/18 Cardinal PD Motor Symptoms: Essential Tremor Tremor Cardinal PD Motor Symptoms: Cardinal PD Motor Symptoms: Bradykinesia Gait Impairment 2

10/10/18 Parkinson’s Disease: Parkinson’s Disease: Motor Fluctuations Motor Fluctuations OFF MEDICATIONS ON MEDICATIONS Parkinson’s Disease Progression: Parkinson’s Disease: Motor Fluctuations Dyskinesias Cenci, 2014, Frontiers Neurology 3

10/10/18 Parkinson’s Disease Progression: Hoehn & Yahr Staging Cognitive deficits: Prevalence and clinical course Stage 1: ~2 years Stage 3: ~2 years Unilateral involvement Mild to moderate Normal à PD-MCI à PD Dementia (PDD) bilateral involvement, Postural instability, Stage 2: ~7 years Still independent Mild bilateral PD-MCI: primarily nonamnestic single domain impairment involvement Stage 4: ~2 years Severe disability, Stage 5: ~2 years ~30% meet criteria for PD-MCI within 3 years after diagnosis • Needs an assistive ~50% meet criteria for PD-MCI after 5 years device to walk or stand • Wheelchair bound or bedridden Can only ambulate with another person assisting Zhao et al. 2010, Mov Disord Litvan et al., 2011, Mov Disord; Litvan et al., 2012, Mov Disord; Marras et al. 2013, Mov Disord Parkinson’s disease pathology: Substantia nigra pars compacta degeneration PD pathology: Peripheral Lewy Bodies Parkinson’s disease Normal Tolosa and Vilas, 2015, Brain UCSF Department of Pathology Scarr et al., 2013, Front. Cell. Neurosci. 4

10/10/18 Parkinson’s disease pathology: PD pathology: Braak Staging DaTSCAN § DaTSCANs detect presynaptic dopaminergic neuronal loss using SPECT imaging Measures Ioflupane ( 123 I), which is a DAT § ligand that binds to presynaptic dopamine transporters in the striatum Braak et al., 2004, Cell Tissue Research de la Feunte-Fernandez 2012. Neurology; Fang and Martin, 2015, Parkinsonism and Related Disorders; Parkinson’s Disease Motor Symptoms: Parkinson’s Disease Motor Symptoms: Medications Medications Carbidopa/Levodopa: Carbidopa/Levodopa: Formulations Effects Sinemet IR Short half-life (45-90 minutes) Orally disintegrating tablets (dysphagia) Not sublingually absorbed, similar time to — The most effective and generally well-tolerated medicine for PD Parcopa peak concentration compared to sinemet IR. Used in setting of dysphagia. — Short half-life (~45 to 90 minutes), needs to be taken frequently as PD progresses ~60 minutes increase in sustained Sinemet CR concentration compared to sinemet IR — Ideally should be taken 1 hour before or 2 hours after a protein-rich meal Impaired bioavailability, lower peak dose, time to peak concentration can be up to 120 — Main side effects: nausea, lightheadedness, hallucinations, and dyskinesias minutes longer than sinemet IR Rytary ~2 to 2.5 hours increase in sustained concentration compared to sinemet IR 5

10/10/18 Parkinson’s Disease Motor Symptoms: Parkinson’s Disease Motor Symptoms: Medications Medications Carbidopa/Levodopa Carbidopa/Levodopa ER: (Rytary) Dosing Guidelines Initial Dosing Guidelines — Start with sinemet 25/100mg IR: ½ tab three times per day — Increase to sinemet 25/100mg IR: 1 tab three times per day after 2 weeks — Increase to sinemet 25/100mg IR: 1.5 tabs three times per day after 2 weeks — Increase to sinemet 25/100mg IR: 2 tabs three times per day after 2 weeks Increase the dose until motor symptoms are significantly improved or there are side effects Parkinson’s Disease Motor Symptoms: Parkinson’s Disease Motor Symptoms: Medications Medications Carbidopa/Levodopa Extenders: Dopamine Agonists (ropinirole, pramipexole, rotigotine): Effects Effects 1 hour increased on-time Rasagaline (Azilect) — Compared to carbidopa/levodopa Side effects: drug interactions — More mild benefit 1 hour increased on-time — Lasts longer, half-life: ~6 hours Selegiline (Eldepryl) Side effects: drug interactions, HTN, — Lower risk of causing dyskinesias insomnia, delirium 1 hour increased on-time Entacapone (Comtan) — Main side effects: sleep attacks, Side effects: diarrhea, orange urine impulse control disorders (ICDs), sedation, confusion, hallucinations, 2-3 hours increased on-time Tolcapone (Tasmar) cognitive deficits, lightheadedness Side effects: Liver failure — Usually not prescribed to people over 70 years of age Najib 2001, Clinical Therapeutics Jenner, 2002, Neurology 6

10/10/18 Parkinson’s Disease Motor Symptoms: Parkinson’s Disease Motor Symptoms: Medications Medications Levodopa sparing therapy: Levodopa sparing therapy: Effects Effects Mild-moderate reduction in parkinsonism Dopamine agonists Side effects: ICD, sleep attacks, MAO-B inhibitors Very mild reduction in parkinsonism, if any hallucinations, cognitive deficits Side effects: drug interactions, depends on whether rasagaline or selegiline are used Reduces tremor, mild benefit Side effects: nephrolithiasis, somnolence, Zonisamide ataxia, confusion, cognitive deficits Mild reduction in parkinsonism, Reduces tremor and dystonia Amantadine Reduces dyskinesias Side effects: sedation, delirium, Trihexyphenidyl Side effects: confusion, hallucinations, hallucinations, increased risk of dementia, dry mouth, constipation, dry mouth, constipation Najib 2001, Clinical Therapeutics Najib 2001, Clinical Therapeutics Parkinson’s Disease Motor Symptoms: Risk of Developing Dyskinesias PD Treatments: Anti-dyskinetic medication Amantadine § CALM-PD Clinical Trial § Only medication that controls tremors, stiffness and slowness, Dosing Percentage developing Improvement in strategy dyskinesia after 2 years movement and function AND also controls dyskinesias scale (UPDRS) Pramipexole 10% 4.5 points § Side effects: confusion, hallucinations, rash, dry mouth, constipation Levodopa 30% 9.2 points § Could early amantadine prevent the development of dyskinesias? CALM-PD PSG Study Group, 2000, JAMA 7

10/10/18 PD Treatments: Botulinum Toxin Parkinson’s Disease Clinical Trials — Commercially available Neurotoxins — Botulinum Toxin A — Botox — Xeomin — Dysport — Botulinum Toxin B — Myobloc Parkinson’s Disease Motor Symptoms: Parkinson’s Disease Motor Symptoms: Non-pharmacological Treatments Non-pharmacological Treatments REHABILITATION REHABILITATION OUTPATIENT PHYSICAL THERAPY HOME SAFETY EV ALUATION • Refer to outpatient physical therapy early in the disease course • Refer for home safety evaluation: • Parkinson W ellness Recovery (PWR!) • skilled nursing • Lee Silverman Voice Training (LSVT) • physical therapy • Balance vest • occupational therapy • custodial non-skilled care 8

10/10/18 Parkinson’s Disease Motor Symptoms: Parkinson’s Disease Motor Symptoms: Non-pharmacological Treatments Non-pharmacological Treatments REHABILITATION IMBALANCE PHARMACOLOGICAL TREATMENTS MEDICARE COVERS ’SKILLED MAINTENANCE’ • Donepezil 10mg daily was shown to reduce falls in PD by almost 50% in a small • Medicare covers rehab services to maintain or manage a patient’s current condition clinical trial [Chung et al. 2010] when no functional improvement is possible • Vitamin D supplementation 1200 units daily was shown to reduce decline in balance in a small clinical trial [Suzuki et al. 2013] • Therapy services to maintain a patient’s current condition or slow decline are covered • Cyanocobalamin supplementation 1000mcg daily if a deficiency is identified • Check a DEXA scan and start a bisphosphonate (if needed) to reduce fracture risk Parkinson’s Disease Motor Symptoms: Parkinson’s Disease Motor Symptoms: Non-pharmacological Treatments Role of Exercise IMBALANCE Physical activity must be challenging to have a benefit USE OF ASSISTIVE DEVICES • Need to make sure that patients are not using progressives or bifocal glasses • Cane, walking sticks, walker ( U-step walker preferred ) • Consider knee protectors for frequent fallers • Recommend MedAlert System • Wheelchair optimization 9