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33rd Annual UCLA Intensive Course in Geriatric Medicine + Pharmacy & Board Review
TREATMENT OF PARKINSON DISEASE IN THE GERIATRIC
POPULATIONYvette M. Bordelon, MD, PhDAssociate Clinical Professor
UCLA Neurology, Movement Disorders Program
Disclosures: Speakers Bureau, Teva Pharmaceuticals
Notes:
33rd Annual UCLA Intensive Course in Geriatric Medicine + Pharmacy & Board Review
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
Notes:
33rd Annual UCLA Intensive Course in Geriatric Medicine + Pharmacy & Board Review
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)
Notes:
33rd Annual UCLA Intensive Course in Geriatric Medicine + Pharmacy & Board Review
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, anti-emetics)
• Vascular parkinsonism• Normal Pressure Hydrocephalus
Notes:
33rd Annual UCLA Intensive Course in Geriatric Medicine + Pharmacy & Board Review
PD Pathology• Degeneration of the striatonigraldopaminergic pathway• Substantia nigra pars compacta
(melanin containing cells) projecting to caudate and putamen (striatum)
• Pathologic hallmark is the Lewy body: dense cytoplasmic inclusion of alpha-synuclein
Normal PD
Lewybody
Notes:
33rd Annual UCLA Intensive Course in Geriatric Medicine + Pharmacy & Board Review
PD Pathology
Location of Lewy bodies and Lewy neurites- Braak stagingNot 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.
Notes:
33rd Annual UCLA Intensive Course in Geriatric Medicine + Pharmacy & Board Review
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
[123I]Ioflupane SPECT scan (DaTscan)
Notes:
33rd Annual UCLA Intensive Course in Geriatric Medicine + Pharmacy & Board Review
Sym
ptom
sParkinson Disease Treatment
Early PD• Which meds?• Start of meds?• Disease modification?
Late PD• Wearing Off• Dyskinesias• Which meds?
Notes:
33rd Annual UCLA Intensive Course in Geriatric Medicine + Pharmacy & Board Review
Parkinson Disease Treatment
Levodopa
HVA
3MT
MAO-BCOMT
DOPAC
COMTMAO-B
Dopamine Agonists
MAO-B Inhibitors COMT Inhibitors
DopamineDopamine
Pre-synapticSNc
Post-synapticMedium-sized GABAergic
Striatal neuron
Increase dopamine releaseInhibit synaptic dopamine degradationActivate post-synaptic dopamine receptors
Dopamine Receptor
AADC
Dopaminergic Synapse
Notes:
33rd Annual UCLA Intensive Course in Geriatric Medicine + Pharmacy & Board Review
• 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 standardprovides greatest symptomatic benefit
• Carbidopa-levodopa (Sinemet) IR, CR, Rytary
• Carbidopa-levodopa-entacapone (Stalevo)
• Duopa (intestinal infusion)
• Anticholinergics
• Amantadine
PD Medical Management
Notes:
33rd Annual UCLA Intensive Course in Geriatric Medicine + Pharmacy & Board Review
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
Notes:
33rd Annual UCLA Intensive Course in Geriatric Medicine + Pharmacy & Board Review
Medication Options
• MAO-B inhibitors• Selegiline and Rasagiline• Mild symptomatic benefit and possibly disease-
modifying• Dopamine Agonists• Ropinirole, ropinirole XL, pramipexole, pramipexole ER,
rotigotine (patch)• Symptomatic benefit• Delays motor complications• More side effects than levodopa
Notes:
33rd Annual UCLA Intensive Course in Geriatric Medicine + Pharmacy & Board Review
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
Notes:
33rd Annual UCLA Intensive Course in Geriatric Medicine + Pharmacy & Board Review
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 short-acting 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
Notes:
33rd Annual UCLA Intensive Course in Geriatric Medicine + Pharmacy & Board Review
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 (SinemetCR) Rytary not yet studied
Practice Parameter: Initiation of treatment for Parkinson’s disease: An evidence-based review. Neurology 2002 58: 11-17.
Notes:
33rd Annual UCLA Intensive Course in Geriatric Medicine + Pharmacy & Board Review
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
Notes:
33rd Annual UCLA Intensive Course in Geriatric Medicine + Pharmacy & Board Review
Early PD Management• Medication Doses
• Rasagiline 1 mg qam• Selegiline 5mg bid; 2nd 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
Notes:
33rd Annual UCLA Intensive Course in Geriatric Medicine + Pharmacy & Board Review
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
Notes:
33rd Annual UCLA Intensive Course in Geriatric Medicine + Pharmacy & Board Review
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.
Notes:
33rd Annual UCLA Intensive Course in Geriatric Medicine + Pharmacy & Board Review
© 2012 Lippincott Williams & Wilkins, Inc. Published by Lippincott Williams & Wilkins, Inc. 2
Therapies in Parkinson's disease. Jankovic, Joseph; Poewe, Werner. Current Opinion in Neurology. 25(4):433-447, August 2012.
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.
Notes:
33rd Annual UCLA Intensive Course in Geriatric Medicine + Pharmacy & Board Review
Early Mid Late
Dyskinesia Threshold
Efficacy Threshold
L-DopaDoses
OFF
ON
6-8 h 3-5 h .5-2 h
Adapted from Jankovic
PD Progression
WEARING OFF
DYSKINESIAS
MOTOR COMPLICATIONS
Therapeutic Window Narrows with Progression
Notes:
33rd Annual UCLA Intensive Course in Geriatric Medicine + Pharmacy & Board Review
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
Notes:
33rd Annual UCLA Intensive Course in Geriatric Medicine + Pharmacy & Board Review
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
Notes:
33rd Annual UCLA Intensive Course in Geriatric Medicine + Pharmacy & Board Review
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.
Notes:
33rd Annual UCLA Intensive Course in Geriatric Medicine + Pharmacy & Board Review
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
Notes:
33rd Annual UCLA Intensive Course in Geriatric Medicine + Pharmacy & Board Review
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
Notes:
33rd Annual UCLA Intensive Course in Geriatric Medicine + Pharmacy & Board Review
Motor Complications
• Assessment is difficult• Day to day variation• Difficult for patients/families to
describe• Written diaries or logs are time-
intensive• 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
Notes:
33rd Annual UCLA Intensive Course in Geriatric Medicine + Pharmacy & Board Review
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
Notes:
33rd Annual UCLA Intensive Course in Geriatric Medicine + Pharmacy & Board Review
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 (axial-
speech/gait/balance) generally not improved with DBS
• Psychiatric disease: severe depression or anxiety• Psychosocial support
Notes:
33rd Annual UCLA Intensive Course in Geriatric Medicine + Pharmacy & Board Review
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.
Notes:
33rd Annual UCLA Intensive Course in Geriatric Medicine + Pharmacy & Board Review
Nut
t and
Bur
chie
l: N
euro
logy
57:
1835
, 200
1
Goal of DBS in PD:More time in best “on” condition
Notes:
33rd Annual UCLA Intensive Course in Geriatric Medicine + Pharmacy & Board Review
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
Notes:
33rd Annual UCLA Intensive Course in Geriatric Medicine + Pharmacy & Board Review
GPi vs STN Rematch
Adapted from Williams et al. 2014 Mov DisordClin Pract 1: 24-35
GPi STNTremor + +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 +
+ slight advantage++ definite advantage
Notes:
33rd Annual UCLA Intensive Course in Geriatric Medicine + Pharmacy & Board Review
© 2012 Lippincott Williams & Wilkins, Inc. Published by Lippincott Williams & Wilkins, Inc. 2
Therapies in Parkinson's disease. Jankovic, Joseph; Poewe, Werner. Current Opinion in Neurology. 25(4):433-447, August 2012.
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, globuspallidus interna; MAO, monoamine oxidase; STN, subthalamic nucleus.
Notes:
33rd Annual UCLA Intensive Course in Geriatric Medicine + Pharmacy & Board Review
Motor Symptoms Non-Motor Symptoms• Tremor• Rigidity (muscle stiffness)• Bradykinesia (slowness
of movement)• Walking difficulties• Postural Instability• Speech problems• Motor complications
(wearing off of meds,dyskinesias)
• Depression, Anxiety• Sleep Disorders• Cognitive decline• Autonomic nervous systemdysfunction (gastrointestinal complaints, orthostasis,incontinence, erectile dysfunction)
PD Treatment
Notes:
33rd Annual UCLA Intensive Course in Geriatric Medicine + Pharmacy & Board Review
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….
Notes:
33rd Annual UCLA Intensive Course in Geriatric Medicine + Pharmacy & Board Review
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
Notes:
33rd Annual UCLA Intensive Course in Geriatric Medicine + Pharmacy & Board Review
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
Notes:
33rd Annual UCLA Intensive Course in Geriatric Medicine + Pharmacy & Board Review
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
Notes:
33rd Annual UCLA Intensive Course in Geriatric Medicine + Pharmacy & Board Review
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.
Notes:
33rd Annual UCLA Intensive Course in Geriatric Medicine + Pharmacy & Board Review
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)
Notes:
33rd Annual UCLA Intensive Course in Geriatric Medicine + Pharmacy & Board Review
ET Management
• Consideration of Deep Brain Stimulation• Patient Selection• Accurate ET diagnosis. •Must distinguish between ET and tremor-dominant PD•Consideration of DAT or F-DOPA imaging to establish diagnosis
• Age• Tremor refractory to medications or side effects not tolerated
• Cognitive function
Notes:
33rd Annual UCLA Intensive Course in Geriatric Medicine + Pharmacy & Board Review
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
Notes:
33rd Annual UCLA Intensive Course in Geriatric Medicine + Pharmacy & Board Review
Atypical Parkinsonian DisordersParkinsonism 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)
Notes:
33rd Annual UCLA Intensive Course in Geriatric Medicine + Pharmacy & Board Review
Classification by PathologyPathologic 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)
Notes:
33rd Annual UCLA Intensive Course in Geriatric Medicine + Pharmacy & Board Review
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
Notes:
33rd Annual UCLA Intensive Course in Geriatric Medicine + Pharmacy & Board Review
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
Notes:
33rd Annual UCLA Intensive Course in Geriatric Medicine + Pharmacy & Board Review
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
Notes:
33rd Annual UCLA Intensive Course in Geriatric Medicine + Pharmacy & Board Review
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.
Notes:
33rd Annual UCLA Intensive Course in Geriatric Medicine + Pharmacy & Board Review
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
Notes:
33rd Annual UCLA Intensive Course in Geriatric Medicine + Pharmacy & Board Review
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 TauopathyLitvan I et al., Neurology 1996; 47: 1-9.
Notes:
33rd Annual UCLA Intensive Course in Geriatric Medicine + Pharmacy & Board Review
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
Notes:
33rd Annual UCLA Intensive Course in Geriatric Medicine + Pharmacy & Board Review
• 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
PSP Treatment
Notes:
33rd Annual UCLA Intensive Course in Geriatric Medicine + Pharmacy & Board Review
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.
Notes:
33rd Annual UCLA Intensive Course in Geriatric Medicine + Pharmacy & Board Review
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; visuospatialdeficits; + 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.
Notes:
33rd Annual UCLA Intensive Course in Geriatric Medicine + Pharmacy & Board Review
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
Notes:
33rd Annual UCLA Intensive Course in Geriatric Medicine + Pharmacy & Board Review
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
Notes:
33rd Annual UCLA Intensive Course in Geriatric Medicine + Pharmacy & Board Review
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
Notes:
33rd Annual UCLA Intensive Course in Geriatric Medicine + Pharmacy & Board Review
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
Notes:
33rd Annual UCLA Intensive Course in Geriatric Medicine + Pharmacy & Board Review
Support: Parkinsonism
• UCLA Monthly Support Group• First Friday of the month 2-4pm• 300 medical plaza- Marisa Leif conference room
Now available on Amazon
Notes:
33rd Annual UCLA Intensive Course in Geriatric Medicine + Pharmacy & Board Review
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
Summary
Notes:
33rd Annual UCLA Intensive Course in Geriatric Medicine + Pharmacy & Board Review
UCLA MOVEMENT DISORDERS
FacultyJeff BronsteinIndu SubramanianAllan WuCarlos Portera-CailliauYvette BordelonPaula RavinAdrienne KeenerNeurosurgery: Nader PouratianPsychology: Arik Johnson
CoordinatorsDolly WestHenrietta SalazarLiz QuinteroDiane Yang
FellowsMonica SkordilisTammy Pham
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