Disclosures. Case 1: PD Motor Fluctuations. Challenge: Medical Management of Motor Fluctuations. On Medications. Off Medications

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1 Disclosures Caroline Tanner, MD, PHD Consultant: Neurocrine, Adamas, Apple, Biogen DMC Member: Biotie, Voyager, Intec Challenges and Controversies in Movement Disorders Management: A Case-Based Approach Jill L. Ostrem, MD Professor of Neurology Caroline M. Tanner, MD, PhD Professor of Neurology February 9, 2017 UCSF Weill Institute of Neurosciences 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 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 day Rasagiline 1mg QD Pramipexole 0.25mg TID Donepezil 10mg QD Off Medications On Medications 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) 1

2 Motor Fluctuations Other Levodopa Formulations Symptoms adequately controlled ( on time ) Symptoms not adequately controlled ( off time ) Typical Clinical Pattern of Wearing Off Wearing off period PD Medication PD Medication PD Medication Time 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 Adapted from Hauser RA. Geriatrics. 2006;61: Controversy: Is new extended-release carbidopa/levodopa (Rytary- IPX066) (Impax) an advance for the field? 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 Mean LD and CD Plasma Concentration Profiles Healthy volunteers (n=24) assessed the PK of Rytary vs IR, CR, and CLE formulations Greater mean and sustained plasma concentrations with Rytary Hsu A, et al. J Clin Pharmacol 2015;55:

3 Rytary vs Placebo in Early PD Mean UPDRS II +III over 30 weeks 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 Advance PD (N=450), randomized, DB, parallel- group trial Adjustment period to maximize treatment response to IR CD-LD followed by 6 week Rytary doseconversion 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 Pahwa R, et al. Parkinsonism Relat Disord 2014;20: Hauser RA, et al. Lancet Neurol 2013;12: Rytary vs CD-LD-Entacapone in Advanced PD Conversion to Rytary 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 750 mg Stocchi F, et al. Parkinsonism Relat Disord 2014; 20:

4 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 Benefit Motor 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 Pretreatment video here Current regimen: carbidopa\levodopa 25\100 IR q hours while awake, 1-2 doses at night 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 Therapies Oral L-dopa preparations DA agonists Jejunal infusion L-dopa gel Motor fluctuations, mild Motor fluctuations, severe DBS Dementia, mild Dementia, severe Psychosis, ICD Poor social support Wary of invasive intervention Reduced finances

5 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 Improved on time without dyskinesias compared to oral C\Ll Moderate to Large CID in most studies reported Olanow Lancet Neurology 2014; Palhagen 2012; Fernandez 2013 Safety Considerations 4 Clinical Trials 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 doses Return in one week for re-adjustment of dose Monitor 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) Lang et al, Mov Disord

6 Case 3 Challenge: How to Manage Dystonia in PD? Botulinum Toxin Injections Usually in the off medication state Can also have eye opening apraxia Often occurs in LE, with foot inversion and toe curling Often painful Usually in the off medication state 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 Serotype Generic Name Trade Name Manufacturer A onabotulinumtoxina Botox Allergan A abobotulinumtoxina Dysport Ipsen A incobotulinumtoxina XEOMIN Merz B rimabotulinumtoxinb Myobloc Solstice 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 6

7 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 Thanks to: Joseph Friedman for Video 66 year old man, Parkinson s disease for 4 years Treatment regimen: Carbidopa\L-dopa 25\100 6 doses, Ropinirole discontinued 6 weeks ago 7

8 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 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 nonessential 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: 31 8

9 Treating Psychosis in Parkinson s Disease -2 Consider 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 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 33 Pimavanserin: Efficacy Pimavanserin: Safety & Tolerability QTc prolongation Black Box anti-psychotic effects Concomittant use of another antipsychotic may increase serious AEs (open label study) Improvement in psychosis vs. placebo Reduced caregiver burden; Improved nighttime sleep, daytime wakefulness Cummings et al, Lancet, 2014 Cummings et al, Lancet

10 Pimavanserin Practical Aspects Dose: 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 Case 5: Challenge How to manage low threshold for stimulation side effects with DBS? 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 Key Structures Surrounding STN Spread of current to internal capsule Paresthesias/ sensory phenomena (medial lemniscus) (medial or posterior) Diplopia, other oculomotor disturbances, mydriasis (CNIII) (medial) Affective/ impulsive changes (limbic STN or SNr) (medial and ventral) Thalamus STN Substantia Nigra Coronal view medial GPi dorsal ventral lateral 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) No side effects at high stimulation (> 10 V) lead too dorsal 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 40 M D V L 10

11 Controversy: Will DBS directional leads be better? Traditional Medtronic Lead (Four concentric ring electrodes) New leads Reker P, et al in press Two concentric ring electrodes (outer) Six non-concentric directional electrodes (middle) 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 Bluetooth TM 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 11

12 Boston Scientific Vercise DBS System likely coming to market soon New software to localize and visualize shape of electrical stimulation field Computational modeling / volume of tissue activation (VTA) and individualized direct programming Currently available in Europe Rechargeable and non-rechargeable neurostimulators Tablet based programmer Current steering and 8 electrode DBS leads Fractional current delivery Not MRI Compatible 46 Case 6 Case 6 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 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. 12

13 Parkinson s Disease Palliative Care Model: 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 wellbeing is about the reasons one wishes to be alive. Being Mortal: Medicine and What Matters in the End Atul Gawande 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 illness Saunders, 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 UCSF Parkinson s Disease Supportive Care Clinic Fadul et al. 2009, Cancer Rondali et al., 2013, Palliative and Supportive Care Study Coordinator

14 UCSF Movement Disorders and Neuromodulation Center Neurosurgery Philip Starr, MD, PhD Paul S. Larson, MD Edward F. Chang, MD Daniel Lim, MD, PhD Krzysztof Bankiewicz, MD, PhD Coralie De Hemptinne, PhD Nicki Swann, PhD Andrew Miller, BA Whitney Chen, PhD Doris Wang, MD, PhD Neuropsychology Caroline Racine Belkoura, PhD Nursing Monica Volz, FNP, MS Karen Merchant, MSN Susan Heath, MS, RN Gina Bringas-Cinco, RN Annie Li Wong, NP Movement Disorder and Neuromodulation Center Jill L. Ostrem, MD, Medical Director Philip Starr, MD, PhD, Surgical Director Neurology Jill Ostrem, MD Nicholas Galifianakis, MD Caroline Tanner, MD, PhD Marta San Luciano, MD Maya Katz, MD Ian Bledsoe, MD,MS Robert White, MD, PhD James Maas, MD, PHD Chadwick Christine, MD Michael Aminoff, MD Robert Edwards, MD Ken Nakamura, MD, PhD Alexandra Nelson, MD, PhD Michael Geschwind, MD Amy Viehoever, MD, PhD Fellows Cameron Dietiker, MD Kyle Mitchell, MD Nijee Luthra, MD, PhD Ethan Brown, MD Mitra Afshari, MD Rory Murphy, MD Idit Tamir, MD, PhD Research /Support Staff Sarah Wang, PhD Kristen Dodenhoff, BA Michael Dodge, BA Janet Allen, BA Shatara Blackmon Yasmeen Gonzalez Jeverly Calaunan Kathleen Comyns, MPH Samantha Betheil, BA Cheryl Meng, MPH Farah Kauser Rhonda Lee Psychiatry Andrea Seritan, MD Social Work Monica Eisenhardt, LCSW Chaplin Judith Long Physical Therapy Nancy Byl, PT, PhD Heather Bhide, PT UCSF Movement Disorders Research Retreat Psychosis in Parkinson s Disease Tackling the Myths of Palliative Care NINDS/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 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 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 Ravina 2007; Chang