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Challenges and Controversies in Movement Disorders Management: A Case-Based Approach

UCSF Weill Institute ofNeurosciences

Jill L. Ostrem, MDProfessor of Neurology

Caroline M. Tanner, MD, PhDProfessor of Neurology

February 9, 2017

DisclosuresCaroline Tanner, MD, PHD• Consultant: Neurocrine, Adamas, Apple, Biogen• DMC Member: Biotie, Voyager, Intec

Jill Ostrem, MD• Consultant and speaker: Allergan Inc., Medtronic Inc.• Educational grant support: Medtronic Inc, Allergan Inc,

AbbVie Inc, Boston Scientific Inc.• Clinical trial support: Ceregene Inc., St. Jude Medical,

Inc, Boston Scientific Inc, Cala Health Inc, Google Inc

Case 1: PD Motor Fluctuations

Off Medications On Medications

• 65 yo female with 8 year history of PD• Developed motor fluctuations 5 years ago – now with increasing “off time” and

peak dose dyskinesia• Current medications:

Carbidopa/Levodopa 25/100 1 ½ tabs 5 times a dayRasagiline 1mg QDPramipexole 0.25mg TIDDonepezil 10mg QD

Challenge: Medical Management of Motor Fluctuations• Many drug class options: Levodopa, dopamine agonist, MAO B

inhibitors, COMT inhibitors, others… • Levodopa

– Most effective and widely used treatment in PD– Improves function and QOL, reduces morbidity, and mortality– Dopa decarboxylase (carbidopa) inhibits peripheral LD

metabolism- more levodopa CNS availability (improves tolerability reducing nausea)

– Early PD simple dosing schedules, becomes more complex in advanced PD

– Short half-life (1.5 hours)– As PD progresses, conversion of LD to dopamine, storage, release,

becomes unpredictable– Intermittent/pulsatile release of dopamine in the striatum,

produces changes in the postsynaptic receptors leading to motor complications and dyskinesia (70% after 5 years)

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Motor Fluctuations

Typical Clinical Pattern of Wearing Off

Adapted from Hauser RA. Geriatrics. 2006;61:14-20.

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PD Medication PD Medication PD Medication

“Wearing off” period

Time

Other Levodopa Formulations• Controlled release or sustained release

– Slower release of LD in the gut (degradable polymer matrix)– No difference motor fluctuations and dyskinesia in a 5 year study

(moderate to severe PD)– Patient transferred to CR CD-LD from IR CD-LD do not experience

significant “off time” reduction– Absorption is delayed and symptom relief is less predictable

• CD-LD + Entacapone (CLE)– Entacapone inhibits peripheral conversion of LD and allows more LD to

enter CNS– Prolongs LD half-life to 2.4 hrs– CLE still has unpredictable plasma LD profile with high LD fluctuations

• New oral formulation of CD-LD (contains both IR and CR levodopa)

• Each Rytary capsule contains CD-LD (1:4) microbeads designed to dissolve at various rates allowing for release and absorption of LD over a longer timeframe

• FDA Approved- Jan 2015

Controversy: Is new extended-release carbidopa/levodopa (Rytary- IPX066) (Impax)

an advance for the field? Mean LD and CD Plasma Concentration Profiles

Hsu A, et al. J Clin Pharmacol 2015;55:995–1003.

• Healthy volunteers (n=24) assessed the PK of Rytary vs IR, CR, and CLE formulations

• Greater mean and sustained plasma concentrations with Rytary

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Rytary vs Placebo in Early PDMean UPDRS II +III over 30 weeks

Pahwa R, et al. Parkinsonism Relat Disord 2014;20:142–148.

• APEX-PD – N=381 early LD-naive PD, fixed titration schedule

• No SAE attributed to study treatment

• Best balance between efficacy and safety with Rytary 145 mg TID

Rytary vs IR CD-LD in Advanced PD

Hauser RA, et al. Lancet Neurol 2013;12:346–356

• Advance PD (N=450), randomized, DB, parallel- group trial

• Adjustment period to maximize treatment response to IR CD-LD followed by 6 week Rytary dose-conversion period

• Rytary TID could be adjusted to reduce off time

• Randomly assigned to Rytary or CD-LD for 13 wks

• Primary efficacy endpoint- % “off time” and reduced with Rytary (1.2 hours)

• Mean daily IR CD-LD dose was 825mg (5.2 doses)/ Rytary 1,621mg (3.6 doses)

• SAE- 3 pts on Rytary and 1 on IR CD-LD developed ICD

Rytary vs CD-LD-Entacapone in Advanced PD

Stocchi F, et al. Parkinsonism Relat Disord2014; 20:1335–1340.

• ASCEND-PD (n=84)• Pts previously treated on stable

dose of CLE > 4 times /day having > 2.5 hours of off time a day

• Open label dose conversion phase followed by 2 wk randomized crossover period of each treatment

• Rytary showed improved “off time” (34%) and increase in “on time” by 1.4 hours without increasing troublesome dyskinesia with reduced dosing frequency

Conversion to Rytary

750 mg

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Dose Conversion Clinical Pearls • Insurance approval more difficult unless

already “failed” IR and CR CD-LD formulations• Conversion guidelines likely will underdose

your patient• May need to go to 4X a day or even 5X a day• Can still be used with other forms of LD

Case 2: Unpredictable L-dopa BenefitMotor Fluctuations in Advanced PD

• 88 year old man Parkinson’s disease 20 years

• Unpredictable benefit from oral carbidopa\levodopa preparations; dyskinesia with disabling blepharospasm alternating with inability to stand and walk even with assistance; dopamine agonists caused paranoid delusions, resolved with discontinuation; frequent nocturnal awakening to move/urinate, excessive day time sleepiness

• Current regimen: carbidopa\levodopa 25\100 IR q 1.5 - 2 hours while awake, 1-2 doses at night

Pretreatment video here

Challenge: Medical Management of Motor Fluctuations

This patient: • Drug class options limited:

– Intolerable adverse effects: dopamine agonists– Inadequate benefit/dose limiting side effects:

• MAO B inhibitors, COMT inhibitors, oral levodopa preparations including Rytary

• Did not want to consider surgery

Considerations in Selecting TherapiesOral L-dopa preparations

DA agonists Jejunal infusion L-dopa gel

DBS

Motor fluctuations, mild +++ +++ - ++Motor fluctuations, severe + + +++ +++Dementia, mild ++ + ++ +Dementia, severe ++ - + +Psychosis, ICD ++ - + +Poor social support ++ + - -Wary of invasive intervention ++ ++ - -Reduced finances +++ ++ - +

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Levodopa-Carbidopa Intestinal Gel • Continuous intrajejunal infusion of C/L gel• Programmable pump to adjust dose • FDA approval 2015 – AbbVie

Efficacy of Carbidopa\Levodopa Enteral Infusion

Moderate to Large CID in most studies reported

Improved on time without dyskinesias compared to oral C\Ll

Olanow Lancet Neurology 2014; Palhagen 2012; Fernandez 2013

Safety Considerations – 4 Clinical Trials

Lang et al, Mov Disord 2016 20

Practical Considerations Dose titration: • Outpatient, but at least ½ day in office to initiate• Calculate based on current c\l dose• Infusion usually 16 hours • Morning dose a bolus • Continuous dose thereafter with option for extra dosesReturn in one week for re-adjustment of doseMonitor B12, B6 (peripheral neuropathy)

Costs: Est.~ $6000/month• Patient and caregiver understanding key to

success• Care of site• Handling of cassette• Pump program can be fixed or adjustable• Adjustable often better efficacy(Medical Letter 2015)

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Case 3 – Challenge: How to Manage Dystonia in PD?

• Often occurs in LE, with foot inversion and toe curling

• Often painful• Usually in the “off medication” state

• Usually in the “off medication” state• Can also have eye opening apraxia

Botulinum ToxinInjections

• Toxin temporarily weakens dystonic muscles, allowing for a more normal posture, function, reduction of pain

• Bleph: Moderate to marked improvement in 90% of patients– Complications: eyelid ptosis, dry mouth, visual impairment,

headache– Complications usually improve < two weeks, decrease with repeat

injections• Limb: Limited literature in PD

– Traditionally EMG or E-Stim used to help guide injections– Temporary muscle weakness can occur

Mechanism of Action Available Botulinum Toxins

• Neurotoxin products contains highly purified botulinum toxin protein refined from the bacterium Clostridium botulinum

• All toxins has a heavy chain and a light chain bound by a di-sulfide bound

Serotype Generic Name Trade Name Manufacturer

A onabotulinumtoxinA Botox® Allergan

A abobotulinumtoxinA Dysport™ Ipsen

A inco botulinumtoxinA XEOMIN® Merz

B rima botulinumtoxinB Myobloc® Solstice

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Controversy: Are botulinum toxin injections with ultrasound more effective? Also Useful for Sialorrhea in PD

Jost WH J Neural Transm 123:51-55, 2016

Caution of Use• BTX-should be used with extreme caution in patients:

– myasthenia gravis – amyotrophic lateral sclerosis (ALS) – taking anticoagulants– taking certain antibiotics – aminoglycosides

• Immunogenicity– Increased risk with larger doses and injections

administered < 3 months intervals– Controversial if newer Incobotulinum toxin may have less

immunogenicity– Clinicians often use in vivo tests: such as the frontalis test – If resistance occurs, replacing one serotype of BTX with

another may be effective.

Case 4: Drug-Induced Hallucinations

66 year old man, Parkinson’s disease for 4 yearsTreatment regimen: Carbidopa\L-dopa 25\100 6 doses, Ropinirole discontinued 6 weeks ago

Thanks to: Joseph Friedman for Video

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Psychosis in Parkinson’s Disease Characteristic features

Illusions / “minor” hallucinations:• Typically visual • Misperceptions of real stimuli • Sense of presence• Fleeting images in peripheral vision

Hallucinations:• Visual most common

• Vivid, people & animals most common, may be known• Low light, certain locations• Often nonthreatening

• Auditory less common • May be solitary or combined with visual• Solitary may be indistinct voices, music; Rarely threatening voices;

commands not described Thanks to: Joseph Friedman for Video

Psychosis in Parkinson’s Disease Characteristic features - 2

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Delusions:• False fixed beliefs • Commonly paranoid • Typical themes: • Spousal infidelity• Relatives plotting to steal finances• Sometimes Capgras – like delusions: spouse, home are imposters • Can be very complex, & hallucinations involved in content of the

delusion• Can be nonthreatening • Insight often retained but typically incompletely

Challenge: Treating Psychosis in Parkinson’s Disease

• Exclude delirium (concurrent medical problems) • Exclude psychotic depression • Determine severity and impact of symptoms • Evaluate PD medications: stop anticholinergics; stop

amantadine; reduce or stop agonists; reduce or stop hypnosedatives, anxiolytics, opiates; reduce non-essential PD therapies

• Consider anti-dementia therapy if cognitive impairment: rivastigmine > donepezil in modest reduction VH, not delusions; CAUTION: memantine may aggravate VH

• Consider specific antipsychotic therapy:

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Treating Psychosis in Parkinson’s Disease -2Consider specific antipsychotic therapy:

• CAUTION: BLACK BOX WARNING : all cause mortality, CVD • Baseline EKG for QTc prolongation• Atypical antipsychotics: Very low doses often effective

– Clozapine : • Efficacy without increased parkinsonism; • Rare agranulocytosis, not dose-related, requires regular

monitoring– Quetiapine:

• Efficacy less consistent; may worsen parkinsonism• No monitoring required

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Pimavanserin (ACP-103) (Nuplazid)• Treatment for Parkinson’s disease psychosis• An inverse agonist targeting serotonin receptor subtype 5-HT2A• Phase III pivotal trial was positive• Significant reductions in SAPS-PD (scale for assessment for positive symptom

scores) • FDA approved for hallucinations & delusions in PD psychosis w/o dementia,

2016• Acadia Pharmaceuticals

Pimavanserin: Efficacy

Improvement in psychosis vs. placebo

Reduced caregiver burden; Improved nighttime sleep, daytime wakefulness

Cummings et al, Lancet, 2014

Pimavanserin: Safety & Tolerability • QTc prolongation • “Black Box” anti-psychotic

effects• Concomittant use of

another antipsychotic may increase serious AEs (open label study)

Cummings et al, Lancet 2014

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Pimavanserin – Practical AspectsDose: 34 mg p.o. daily (2 x 17 mg)Cost: ~ $24,000/year• Only drug approved for hallucinations & delusions in PD • Most third parties require approval

Initiating treatment:• EKG for QTc at baseline, monitor for prolongation• Therapeutic efficacy may not be immediate; up to 2 weeks for

full effect• Abrupt discontinuation of other anti-psychotic treatments may

precipitate worsening of symptoms • May be used chronically with other antipsychotics, but possible

safety concerns

61 yo male with advanced PD with STN DBS

R STN DBS produced activation of internal capsule resulting in left facial pulling and tonic arm contractions

R STN DBS settings: C+0-, 1.8V, 60us, 130 Hz

Case 5: Challenge – How to manage low threshold for stimulation side effects with DBS?

Key Structures Surrounding STN

Thalamus

SubstantiaNigra

dorsal

lateralmedial

ventralParesthesias/ sensoryphenomena (medial lemniscus) (medial or posterior)

Diplopia, otheroculomotordisturbances,mydriasis (CNIII)(medial)

Affective/ impulsive changes (limbic STN or SNr) (medial and ventral)

Muscular contractions, dysarthria (corticobulbar/spinal tract) (or anterior)

Contralateral gaze deviation too lateral (frontal eye fields in IC)

Reduction of rigidity, tremor,akinesia/bradykinesia,induction of dyskinesia(dorsolateral)

GPi

Coronal view No side effects at high stimulation (> 10 V) lead too dorsal

STN

Spread of current to internal capsule• Lower thresholds right after surgery• Can occur with STN, GPi, VIM Targets

– STN - lead too lateral and/or anterior– GPi - lead too posterior or too medial– VIM- lead too lateral

• Programming strategies– Bipolar stimulation– Try other contacts

• Troubleshooting– Image brain to assess lead location, migration– May need lead revision

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Controversy: Will DBS directional leads be better?

Traditional Medtronic Lead(Four concentric ring electrodes)

Two concentric ring electrodes (outer) Six non-concentric directional electrodes (middle)

New leads Reker P, et al in press

Current Steering/Directional Stimulation• Allows for stimulation perpendicular to the lead axis/not circumferential• First temporary steering electrodes implanted - showed wider therapeutic

programming window at lower current (Pollo C, et al Brain 2014)

Will likely:• Allow for reduction in stimulation induced side effects• Lower number of lead revision surgeries• Lower energy requirements and extend battery longevity

St Jude Medical/Abbott DBS Infinity System

• Pivotal US PD clinical trial completed• FDA approved 2016 for PD and ET• Approved in Australia and Europe• Constant current device• BluetoothTM wireless communication• Upgradeable software option• Bilateral frequency control • Communicates with Apple digital devices

(iPad mini/iPod touch)• Directional lead to allow for current

“steering”• Not MRI compatible• Non-rechargable

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Boston Scientific Vercise™ DBS System likely coming to market soon

Currently available in Europe Rechargeable and non-rechargeable neurostimulatorsTablet based programmerCurrent steering and 8 electrode DBS leadsFractional current deliveryNot MRI Compatible

New software to localize and visualize shape of electrical stimulation field

• Computational modeling / volume of tissue activation (VTA) and individualized direct programming

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• 78 year old woman with Parkinson’s disease for 25 years• The first woman in her law school class• Divorced with two sons• Significant benefit from DBS, but postural instability progressed; she was

wheelchair bound for about 5 years • Highly intelligent, MoCA 27/30 • Many non-motor symptoms (depression, severe neuropathic pain, dysphagia) • Fairly good quality of life• End of life discussions with her & 2 sons: She was consistent in her request for

DNR status, no life-sustaining measures if there was no reasonable hope of recovery to a similar quality of life; did not want to be intubated, did not want any artificial means of nutrition.

• Progressive clinical worsening: dysphagia, sepsis, encephalopathy

Case 6

• Despite her verbalizing and documenting clear goals of care, her sons were conflicted regarding the decision not to intubate and not to start a feeding tube.

• Extensive discussions were held with the help of the palliative team, and her sons felt at peace carrying out the wishes she had clearly verbally stated and documented.

• At her funeral, her youngest son said, “I know it’s a strange thing to say, but my mom’s death was beautiful”. She was placed on a morphine drip and IV fluids, and her sons stayed with her for the week in a quiet large room with a beautiful view on the palliative care service. She was intermittently conscious and able to share in memories, videos and photos; both the patient and her youngest son are singers, and they were able to enjoy singing their favorite songs together that week. A few moments before her death, she opened her eyes, said ‘I love you’ to her son and then passed away quietly and peacefully.

• Her PD neurologist continues to have contact with her sons and daughter-in-law to share in her memory.

Case 6

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We’ve been wrong about what our job is in medicine. We think our job is to ensure health and survival. But really it is larger than that. It is to enable well-being. And well-being is about the reasons one wishes to be alive.

Being Mortal: Medicine and What Matters in the EndAtul Gawande

Parkinson’s Disease Palliative Care Model:

Palliative care principles address “ Total Pain”

The suffering that encompasses all of a person’s physical, psychological, social, spiritual and

practical struggles in the setting of serious illnessSaunders, 1996, BMJ

Neurologists as primary palliative providers

Palliative care principles address “Total Pain”• Optimize communication regarding serious news • Manage intractable symptoms• Alleviate suffering• Align treatment with patient preferences• Address end-of-life care

Palliative Care for Parkinson’s Disease:How to bring it up…

� Multiple studies have shown greater receptiveness to the term, “supportive” rather than, “palliative”

• “I would like to give you an extra layer of support to help with your symptoms and the stress of being sick”

Fadul et al. 2009, CancerRondali et al., 2013, Palliative and Supportive Care

UCSF Parkinson’s Disease Supportive Care Clinic

Study Coordinator 415-353- 9453

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UCSF Movement Disorders and Neuromodulation Center

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Movement Disorder and Neuromodulation CenterJill L. Ostrem, MD, Medical DirectorPhilip Starr, MD, PhD, Surgical Director

NeurosurgeryPhilip Starr, MD, PhDPaul S. Larson, MDEdward F. Chang, MDDaniel Lim, MD, PhDKrzysztof Bankiewicz, MD, PhDCoralie De Hemptinne, PhDNicki Swann, PhDAndrew Miller, BAWhitney Chen, PhDDoris Wang, MD, PhD

NeuropsychologyCaroline Racine Belkoura, PhD

NursingMonica Volz, FNP, MSKaren Merchant, MSNSusan Heath, MS, RNGina Bringas-Cinco, RNAnnie Li Wong, NP

NeurologyJill Ostrem, MDNicholas Galifianakis, MDCaroline Tanner, MD, PhDMarta San Luciano, MDMaya Katz, MDIan Bledsoe, MD,MSRobert White, MD, PhDJames Maas, MD, PHDChadwick Christine, MDMichael Aminoff, MDRobert Edwards, MDKen Nakamura, MD, PhDAlexandra Nelson, MD, PhDMichael Geschwind, MDAmy Viehoever, MD, PhD

FellowsCameron Dietiker, MDKyle Mitchell, MDNijee Luthra, MD, PhDEthan Brown, MDMitra Afshari, MDRory Murphy, MDIdit Tamir, MD, PhD

Research /Support StaffSarah Wang, PhDKristen Dodenhoff, BAMichael Dodge, BAJanet Allen, BAShatara BlackmonYasmeen GonzalezJeverly CalaunanKathleen Comyns, MPHSamantha Betheil, BACheryl Meng, MPH Farah KauserRhonda Lee

PsychiatryAndrea Seritan, MD

Social WorkMonica Eisenhardt, LCSW

ChaplinJudith Long

Physical TherapyNancy Byl, PT, PhDHeather Bhide, PT

2017 UCSF Movement Disorders Research Retreat

Psychosis in Parkinson’s DiseaseNINDS/NIMH Working Group Criteria:• Primary diagnosis of PD using UK brain bank criteria• Presence of at least one of: illusions, false sense of presence,

hallucinations, delusions• Symptoms begin after PD onset• Symptoms are recurrent or continuous for 1 month • No other cause

Ravina 2007; Chang 2016

Epidemiology: 16% - 75% prevalence• Illusions, minor visual hallucinations most common form• Minor visual hallucinations may precede motor signs, esp. in RBD• Most common in advanced disease, cognitive impairment

Tackling the Myths of “Palliative Care”

� Palliative care is “giving up”

� Palliative care means there is “nothing left to do”

� Palliative care means foregoing lifesaving therapies

� Palliative care shortens life expectancy

� Palliative care = hospice