Treatment of Parkinson s Disease in the Geriatric Population Yvette M. Bordelon, MD, PhD
TREATMENT OF PARKINSON DISEASE IN THE GERIATRIC POPULATION Yvette M. Bordelon, MD, PhD Associate Clinical Professor UCLA Neurology, Movement Disorders Program Disclosures: Speakers Bureau, Teva Pharmaceuticals
Parkinson Disease Second most common neurodegenerative disease next to Alzheimer disease Estimated to affect 1-2% of the population over 65; 1 million people in the US Affects men:women in a 2:1 ratio Mean age of onset 60 Young onset PD <50 Juvenile onset PD <18: rare Longevity not affected in mean onset PD Heterogeneous: no two people with PD are alike. Treatment must be individualized
Parkinson Disease Diagnosis Clinical Diagnosis UK PDS Brain Bank Criteria- Probable PD Bradykinesia + at least one of the following: rigidity, 4-6 Hz rest tremor, postural instability Exclude other causes of parkinsonism At least 3 of the following supportive criteria: unilateral onset, rest tremor, progressive persistent asymmetry, L- dopa responsive, L-dopa effective > 5 yrs, L-dopa induced dyskinesias, clinical course > 10 yrs Potential PD subtypes Tremor-dominant; postural instability/gait disorder (PIGD)
PD Differential Diagnosis Essential Tremor Atypical Parkinsonian Disorders Progressive Supranuclear Palsy Corticobasal Syndrome Dementia with Lewy Body disease Multiple System Atrophy Drug-Induced Parkinsonism (neuroleptics, antiemetics) Vascular parkinsonism Normal Pressure Hydrocephalus
PD Pathology Degeneration of the striatonigral dopaminergic pathway Substantia nigra pars compacta (melanin containing cells) projecting to caudate and putamen (striatum) Pathologic hallmark is the Lewy body: dense cytoplasmic inclusion of alphasynuclein Normal PD Lewy body
PD Pathology Location of Lewy bodies and Lewy neurites- Braak staging Not only confined to the substantia nigra: widespread brain disease Braak et al., Staging of brain pathology related to sporadic Parkinson s disease. Neurobiology of Aging 2003; 24: 197-211.
PD Imaging Imaging of striatal dopaminergic terminal loss can support a clinical diagnosis; may be useful in distinguishing between PD and essential tremor but not in differentiating among parkinsonisms DaT scan FDA approved; ioflupane-dopamine transporter ligand Normal PD [ 123 I]Ioflupane SPECT scan (DaTscan)
Parkinson Disease Treatment Symptoms Early PD Which meds? Start of meds? Disease modification? Late PD Wearing Off Dyskinesias Which meds?
Parkinson Disease Treatment Levodopa Dopaminergic Synapse HVA MAO-B Inhibitors MAO-B 3MT COMT DOPAC COMT Inhibitors Post-synaptic Medium-sized GABAergic Striatal neuron Pre-synaptic SNc AADC Dopamine COMT MAO-B Dopamine Dopamine Agonists Dopamine Receptor Increase dopamine release Inhibit synaptic dopamine degradation Activate post-synaptic dopamine receptors
PD Medical Management MAO-B inhibitors - rasagiline (Azilect) - selegiline (Eldepryl) - orally disintegrating selegiline (Zelapar) Dopamine agonists pramipexole (Mirapex) pramipexole ER ropinirole (Requip) ropinirole XL rotigotine (Neupro) patch Levodopa- gold standard provides greatest symptomatic benefit Carbidopa-levodopa (Sinemet) IR, CR, Rytary Carbidopa-levodopaentacapone (Stalevo) Duopa (intestinal infusion) Anticholinergics Amantadine
Early PD Management Clinical Practice Medications started when function impaired Different threshold for every patient May change as neuroprotective agents are identified Choice dependent on patient age, med tolerability, symptom pattern and severity Patients under 70 consider starting with dopamine agonists or MAO-B inhibitors, older than 70 with levodopa Tremor may respond better to anticholinergics if not controlled by other meds
Medication Options MAO-B inhibitors Selegiline and Rasagiline Mild symptomatic benefit and possibly diseasemodifying Dopamine Agonists Ropinirole, ropinirole XL, pramipexole, pramipexole ER, rotigotine (patch) Symptomatic benefit Delays motor complications More side effects than levodopa
Early PD Medications Levodopa Most effective medication for PD motor symptoms Consider as first-line agent in patients >70 due to side effect profile of dopamine agents With disease progression, levodopa can lead to motor complications of wearing OFF of medication benefit and dyskinesias 50% of patients develop motor complication after 5 years More likely in young onset (<40) Many options available for initiating levodopa; no strong evidence for or against one strategy; practitioner dependent
Early PD Medications Levodopa Many options available for initiating levodopa; general considerations carbidopa-levodopa (Sinemet) IR 25/100 C-L-entacapone (Stalevo) 50, 75, 100, 125, 150, 200 C-L (Sinemet) CR 25/100, 50/200 70% bioavailable, not as predictable onset and duration; used at bedtime C-L (Rytary) new formulation of mixture or shortacting and long-acting C-L beads: 95, 145, 195, 245; titration and conversion VERY challenging; perhaps 1/3 or 1/2 potency of Sinemet IR
Early PD Management American Academy of Neurology Practice Parameter Initiation with either dopamine agonist (DA) or levodopa (Level A evidence-established efficacy) Levodopa: superior motor benefit but higher risk of dyskinesias No evidence of improved outcome initiating with sustained-release forms of levodopa (Sinemet CR) Rytary not yet studied Practice Parameter: Initiation of treatment for Parkinson s disease: An evidence-based review. Neurology 2002 58: 11-17.
Early PD Management Clinical Practice Medications started when function impaired Different threshold for every patient May change as neuroprotective agents are identified Choice dependent on patient age, med tolerability, symptom pattern and severity Patients under 70 consider starting with dopamine agonists or MAO-B inhibitors, older than 70 with levodopa; amantadine sometimes useful but short-lived Tremor may repond better to anticholinergics if not controlled by other meds
Early PD Management Medication Doses Rasagiline 1 mg qam Selegiline 5mg bid; 2 nd dose no later than 2pm Pramipexole 0.25mg tid to start, titrate up to 3-4.5mg/day divided tid or qid; Pramipexole ER titrate up by 0.375 mg to 3-4.5 mg/day Ropinirole 0.5 tid to start, titrate up to 9-16mg/day divided tid or qid; Ropinirole XL titrate up by 2mg to 10-16 mg/day Rotigotine patch titrate up by 2mg to 8mg/day Agonist equivalents: pramipexole:ropinirole:rotigotine= 1:4:4 Amantadine 100 mg up to tid-qid Trihexyphenidyl 1mg to start, titrate up to 2mg tid or higher if tolerated Carbidopa/levodopa titrate up by 25/100 increments to the dose best tolerated and most effective Rytary is newest formulation titration not yet well established
Early PD Management Medication Side Effects Selegiline Metabolized through methamphetamine path. Insomnia, cognitive side effects Rasagiline 1 mg qam Well tolerated. No need to keep tyramine restricted diet Pramipexole, Ropinirole short-acting and controlled release Nausea, somnolence (rarely sleep attacks), leg swelling, hallucinations, hypotension, impulse control disorders Rotigotine Same as pramipexole and ropinirole but less nausea and with skin irritation possibly Amantadine Hallucinations, livedo reticularis, leg swelling, constipation Trihexyphenidyl Dry mouth, confusion, blurry vision, urinary retention Carbidopa/levodopa Nausea, cognitive side effects, hypotension
Dopamine Agonist Side Effects Impulse Control Disorders Greater recognition of this side effect. Estimated frequency of 13.6% (Weintraub et al., 2010). Also present with levodopa but lower incidence Uncontrolled compulsion for an activity: gambling, sex, shopping, eating, computer use, etc. More common with younger onset PD Typically requires cessation of agonist.
FIGURE 1. Suggested guideline for the treatment of Parkinson's disease from early to advanced staged. DA, dopamine; DAT, dopamine transporter; DBS, deep brain stimulation; MAO, monoamine oxidase; VMAT2, vesicular monoamine transporter type 2. Therapies in Parkinson's disease. Jankovic, Joseph; Poewe, Werner. Current Opinion in Neurology. 25(4):433-447, August 2012. 2012 Lippincott Williams & Wilkins, Inc. Published by Lippincott Williams & Wilkins, Inc. 2
PD Progression MOTOR COMPLICATIONS ON Dyskinesia Threshold DYSKINESIAS L-Dopa Doses Therapeutic Window Narrows with Progression 6-8 h 3-5 h.5-2 h OFF Efficacy Threshold WEARING OFF Early Mid Late Adapted from Jankovic
Treatment of Motor Complications Treatment of Wearing OFF Increase frequency of PD med dosing or individual doses Add MAO-B inhibitor if not already used Add dopamine agonist if not already used For severe or sudden OFF consider apomorphine SC Add controlled release carbidopa/levodopa if not already used Add COMT inhibitor Entacapone (200 mg always given with levodopa dose) Increases serum transport of levodopa and prolongs half-life Tolcapone requires LFT monitoring Treatment of Dyskinesias Add amantadine Decrease frequency of PD med dosing or individual doses Decrease or remove MAO-B inhibitors, dopamine agonists or COMT inhibitors if being used
Motor Complications Pulsatile stimulation of dopamine receptors believed to underlie development of motor complications. Goals have been to develop continuous medication delivery systems Ropinirole XL Pramipexole ER Rotigotine patch Duopa- intraduodenal levodopa infusion pump Rytary-longer-acting carbidopa-levodopa No data yet to support that these medications delay motor complications
Late PD Management American Academy of Neurology Practice Parameter Treatment of wearing off Level A evidence: Rasagiline and entacapone Level B evidence: Pramipexole, ropinirole, tolcapone (pergolide) Level C evidence: Selegiline, apomorphine (cabergoline) No benefit: sustained release levodopa and bromocriptine Treatment of dykinesias Level C evidence: Amantadine Practice Parameter: Treatment of Parkinson disease with motor fluctuations and Dyskinesia (an evidence-based review) Pahwa et al., Neurology 2006 66: 983-995.
Late PD Management Clinical Practice Treatment of wearing off Add-on MAO-B inhibitors, COMT inhibitors and/or dopamine agonists More frequent levodopa dosing Treatment of dyskinesias Add-on Amantadine Decrease individual doses of PD meds Consideration of DBS If not a surgical candidate, consider Duopa: intestinal levodopa infusion
Late PD Management DBS Targets: GPi, STN Patient selection is critical: Advanced PD with wearing off and dyskinesias Good levodopa response (exception: tremor dominant) If gait/balance are primary problems then DBS not likely to be helpful No significant cognitive impairment May worsen after surgery Neuropsychological testing performed to evaluate Management of expectations
Motor Complications Assessment is difficult Day to day variation Difficult for patients/families to describe Written diaries or logs are timeintensive New Devices under development to track motor symptoms PKG: watch-- monitor motor symptoms with data downloaded at end of study period and analyzed. UCLA study underway in PD patients with motor fluctuations and dyskinesias preparing for DBS
DBS in PD Patient Selection Accurate PD diagnosis. Disabling motor fluctuations, dyskinesias or tremor. Or difficulty tolerating med side effects Age: no strict cut-off for consideration; chronological age vs physiological age Cognitive function Detailed neuropsychological testing performed in all cases Impairment may worsen with surgery
DBS in PD Patient Selection Levodopa responsiveness: best predictor for DBS response (tremor excluded) L-dopa response approximates DBS efficacy Threshold of 30% improvement between OFF and ON exams non L-dopa responsive symptoms (axialspeech/gait/balance) generally not improved with DBS Psychiatric disease: severe depression or anxiety Psychosocial support
DBS in PD Patient Selection No consensus on how to measure these criteria nor what thresholds should be established for inclusion/exclusion of DBS consideration Deep Brain Stimulation for Parkinson Disease. An Expert Consensus and Review of Key Issues. Bronstein et al., Arch Neurology 2011 68: 165-171.
Goal of DBS in PD: More time in best on condition Nutt and Burchiel: Neurology 57:1835, 2001
Parkinson s Disease DBS Two Targets Subthalamic Nucleus Globus Pallidus Internus EQUAL motor efficacy STN results in greater medication reduction STN has increased neurocognitive complications Mood and cognitive problems, impulse control disorders
GPi vs STN Rematch + slight advantage ++ definite advantage Adapted from Williams et al. 2014 Mov Disord Clin Pract 1: 24-35 GPi STN Tremor + + Rigidity + Bradykinesia + L-dopa responsive Gait and + balance Dyskinesias ++ Cognition + Med Flexibility and Stability ++ Programming Ease ++ Med Reduction ++ Overall Quality of Life + + Ability to use 1 lead ++ Off period motor symptoms + + Mood/Behavior +
FIGURE 2. Suggested guideline for the treatment of levodopa-related motor fluctuations and dyskinesias. COMT, catechol-o-methyl transferase; CR, controlled release; DA, dopamine; ER, extended release; GPi, globus pallidus interna; MAO, monoamine oxidase; STN, subthalamic nucleus. Therapies in Parkinson's disease. Jankovic, Joseph; Poewe, Werner. Current Opinion in Neurology. 25(4):433-447, August 2012. 2012 Lippincott Williams & Wilkins, Inc. Published by Lippincott Williams & Wilkins, Inc. 2
PD Treatment Motor Symptoms Tremor Rigidity (muscle stiffness) Bradykinesia (slowness of movement) Walking difficulties Postural Instability Speech problems Motor complications (wearing off of meds, dyskinesias) Non-Motor Symptoms Depression, Anxiety Sleep Disorders Cognitive decline Autonomic nervous system dysfunction (gastrointestinal complaints, orthostasis, incontinence, erectile dysfunction)
PD Management Exercise Improves muscle strength, flexibility, joint ROM The only treatment for gait and balance impairment Animal data suggest neuroprotection Also improves non-motor PD symptoms No specific exercise plan yet recommended although several are under study Often Physical, Occupation and Speech Therapy helpful in designing treatments BIG and LOUD therapies Rock-Steady Boxing, Yoga, Tai Chi.
Essential Tremor Diagnostic Criteria- Consensus Statement of the Movement Disorder Society on Tremor Bilateral postural tremor with or without kinetic tremor, involving hands and forearms, that is visible and persistent Duration > 5 years No other neurologic deficits or exposure to tremorogenic drugs and not of abrupt onset
Essential Tremor The most prevalent movement disorder. Approximately 4-5% of the population over age 40, an estimated 10 million people in the US, many more worldwide; 10 times more common than PD Risk Factors: Age (prevalence of 9% over age 60) Family History Typically alcohol responsive
Essential Tremor Etiology No cause yet clearly identified Strongly familial but no gene mutations yet identified-recent association with LINGO1 Pathology only recently reported through autopsy studies 2/3 cases with cerebellar changes 1/3 with Lewy bodies (seen in Parkinson disease) but in different brainstem nucleus May provide clues as to why ET can be seen more commonly in families with PD
ET Treatment American Academy of Neurology Practice Parameter First-line Medications (Level A evidence) Propranolol and propranolol LA Primidone Either Medication may reduce tremor by as much as 50% Propranolol + Primidone may increase efficacy by another 10-15% Second-line Medications (Level B evidence) Gabapentin Topiramate Atenolol Alprazolam Sotalol Evidence-based guideline update: Treatment of essential tremor., Zesiewicz et al., Neurology 2011 77: 1752-55.
ET Management In addition to medications consider botulinum toxin injections Occupational Therapy/assist devices including weighted utensils, etc. Deep Brain Stimulation when medications not adequately effective or not tolerated Target: Vim nucleus of the thalamus Other surgical interventions when DBS not desired or too risky and only unilateral treatment necessary Thalamotomy, focused ultrasound (investigational)
ET Management Consideration of Deep Brain Stimulation Patient Selection Accurate ET diagnosis. Must distinguish between ET and tremordominant PD Consideration of DAT or F-DOPA imaging to establish diagnosis Age Tremor refractory to medications or side effects not tolerated Cognitive function
Atypical Parkinsonian Disorders Variants of Parkinson Disease Parkinsonism (characteristic stiffness and slowness) with additional signs or symptoms Parkinson s Plus Syndromes Atypical Parkinsonian Disorders Parkinsonism not levodopa responsive If so, small percentage of patients and benefit not usually sustained DBS usually not effective
Atypical Parkinsonian Disorders Parkinsonism plus. Dementia and hallucinations Dementia with Lewy Body Disease (DLB) Autonomic nervous system dysfunction-fainting, Incontinence Multiple System Atrophy (MSA) Eye movement limitations and falls Progressive Supranuclear Palsy (PSP) Asymmetric apraxia, myoclonus and dystonia Corticobasal Degeneration/Syndrome (CBD/CBS)
Classification by Pathology Pathologic Cause: protein misfolding and aggregation Synucleinopathies (Lewy bodies) Parkinson Disease Dementia with Lewy Body disease MSA Tauopathies (tau neurofibrillary tangles) PSP CBD Frontotemporal Dementias (FTD)
Atypical Parkinsonian Syndromes Other Parkinsonisms Vascular Parkinsonism: moderate-severe white matter small vessel ischemic disease Drug-Induced Parkinsonism Dopamine Receptor Blockers: Neuroleptics (except quetiapine and clozapine) and the anti-emetics metoclopramide (Reglan) and prochlorperazine (Compazine) Normal Pressure Hydrocephalus Classic Triad: memory impairment, magnetic gait, incontinence. Parkinsonism may be seen and improves with shunting
Dementia with Lewy Bodies Synucleinopathy Clinical criteria for probable DLB: Dementia plus 2 of the following: Parkinsonism (onset concurrent or after dementia) Fluctuating cognition Visual hallucinations Pathology reveals LB throughout cortex and brainstem FDG-PET: decreased metabolism in occipital cortex
Dementia with Lewy Bodies Difficult to distinguish from PD dementia (PDD). Clinical criteria for probable PDD: preceding PD diagnosis and Dementia plus 2 of the following Reduced attention Memory impairment Language impairment Visuospatial dysfunction Executive dysfunction Treatment Levodopa as tolerated by cognitive impairment and hallucinations Quetiapine or clozapine for psychosis as these are generally free of parkinsonian side effects Cholinesterase inhibitors for cognitve and behavioral symptoms
MSA Clinical Diagnosis-updated Clinical Criteria for Probable MSA Age of onset >30 and sporadic, progressive disorder characterized by: Autonomic dysfunction involving urinary incontinence plus erectile dysfunction in males, or an orthostatic decrease in 3 min of SBP by 30 mmhg or DBP by 15 and Poor levodopa response or A cerebellar syndrome (gait ataxia with cerebellar dysarthria, limb ataxia or cerebellar oculomotor dysfunction) Subtypes: MSA-P (parkinsonism- previously striatonigral degeneration) MSA-C (cerebellar- previously olivopontocerebellar atrophy) (Autonomic predominance- previously Shy-Drager) Mean onset age 50s; prevalence 3-4 per 100,000; average duration 10 years Gilman et al., Second consensus statement on the diagnosis of multiple system atrophy. Neurology 2008; 71: 670-676.
MSA Clinical Diagnosis Clinically possible Additional features also include: Atrophy on MRI of putamen, MCP, pons or cerebellum, dopamine deficiency by SPECT or PET, or hypometabolism in putamen, brainstem or cerebellum by FDG-PET. Treatment Levodopa is tried and may be responsive for a short period Fludrocortisone, midodrine for hypotension Botulinum Toxin for dystonia Amantadine trial
PSP Clinical Diagnosis NINDS-SPSP Criteria for PSP Clinically Probable Gradually progressive disorder Onset age 40 or above No features suggestive of alternative diagnosis Vertical supranuclear gaze palsy Slowing of vertical saccades and prominent postural instability with falls within the first year Sensitivity 50%; Specificity 100% Clinically Possible 1-3 above and Vertical supranuclear gaze palsy OR slowing of vertical saccades and falls within the first year Sensitivity 83%; Specificity 93% Age of onset mid-60s, prevalence 5-6 per 100,000 average duration 5-9 years 4R Tauopathy Litvan I et al., Neurology 1996; 47: 1-9.
PSP: Clinical Features Cardinal: Vertical gaze palsy (down>up) > horizontal Axial>appendicular rigidity Prominent postural instability with frequent falls Supportive: Eyelid opening apraxia, blepharospasm, diplopia, photosensitivity, square wave jerks, absent OKN Frontalis, corrugator overactivity-psp stare Spastic/ataxic dysarthria, stuttering, tachyphemia, dysphagia Reckless gait, hyperextended posture, falls backward, freezing of gait, rocket sign Dystonia, retrocollis Emotional incontinence Impulsive behavior Executive dysfunction, apathy, bradyphrenia Applause sign, repeated motor behaviors, perseveration Urinary incontinence, constipation Insomnia, daytime somnolence
PSP Treatment Levodopa- some mild responsiveness in a portion of patients; CoQ10, amantadine and amitryptilline can be tried No other adequate symptomatic therapies available currently Clinical Trials underway
CBD Clinical Diagnosis 4R Tauopathy The most difficult diagnosis to establish among Atypical Parkinsonisms due to Overlap and variability of clinical symptoms Overlap of pathological contributions to similar clinical syndromes Williams and Lees Lancet Neurology 2009 8:270-279.
Revision of CBD Diagnostic Criteria Clinical Criteria for Possible CBD-Broader definition Gradual onset and progression; Duration of at least 1 year Possible CBS: May be symmetric; 1 of: a) limb rigidity or akinesia, b) limb dystonia, c) limb myoclonus plus 1 of: d) orobuccal or limb apraxia, e) cortical sensory deficit, f) alien limb phenomena Or Fronto-behavioral-spatial syndrome (FBS): 2 of: executive dysfunction; behavioral or personality changes; visuospatial deficits; + 1 CBS feature Or Nonfluent/agrammatic variant (NAV) of primary progressive aphasia: effortful, agrammatic speech plus at least 1 of: impaired grammar/sentence comprehension; apraxia of speech; + 1 CBS feature Or Progressive Supranuclear Palsy syndrome (PSPS): 3 of: axial or symmetric limb rigidity or akinesia, postural instability with falls, urinary incontinence, behavioral changes, supranuclear vertical gaze palsy or slow saccades; + 1 CBS feature Armstrong et al., 2013 Criteria for the diagnosis of corticobasal degeneration. Neurology 80: 496-503.
CBD Clinical Diagnosis Marked asymmetry of: Limb rigidity or akinesia Limb dystonia and myoclonus Ideomotor apraxia, cortical sensory deficits, alien limb phenomenon Poor levodopa responsiveness Gait and balance impairment Often from rigidity/dystonia/apraxia of legs/arms Speech changes Dysarthia, language impairment, apraxia of speech in combination with dysphagia
CBD Treatment Levodopa-some mild responsiveness in a portion of patients Levetiracetam for myoclonus Trihexyphenidyl, baclofen, benzodiazepines for dystonia Cholinesterase inhibitors for cognitive impairment Botulinum toxin injections for dystonia
PSP clinical trials Observational ARTFL: Advancing Research and Treatment for Frontotemporal Lobar Degeneration FTLD syndromes (bvftd, PPA, FTD-ALS, PSP, CBS) Rating scales, cognitive battery, CSF, MRI for biomarker development FamPSP Genetic testing on PSP probands with a first degree relative with any neurological or psychiatric disorder
PSP clinical trials Interventional Tau Antibody Based Therapies C2N-8E12 (ABBV-8E12) anti-tau antibody infused intravenously Single Dose Phase 1 study ongoing; Multiple Dose Study planned for late 2016 BMS-986168 anti-tau antibody infused intravenously; Multiple Dose Phase 1 study ongoing. Salsalate: Phase 1 open label study of oral salsalate
Support: Parkinsonism UCLA Monthly Support Group First Friday of the month 2-4pm 300 medical plaza- Marisa Leif conference room Now available on Amazon
Summary Diagnosis of PD and variants remains a clinical one Arsenal of treatment options continues to grow DBS effective in carefully selected patients ET more common than PD and responsive to meds and DBS Atypical Parkinsonian Syndromes should be considered and require different treatment approaches
UCLA MOVEMENT DISORDERS Faculty Coordinators Jeff Bronstein Dolly West Indu Subramanian Henrietta Salazar Allan Wu Liz Quintero Carlos Portera-Cailliau Diane Yang Yvette Bordelon Paula Ravin Adrienne Keener Neurosurgery: Nader Pouratian Psychology: Arik Johnson Fellows Monica Skordilis Tammy Pham