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

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

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10/10/18 Outline Parkinsons Disease Demographics PARKINSONS DISEASE PRIMER Parkinsons Disease Motor Symptoms Parkinsons Disease Progression Parkinsons Disease Pathophysiology Maya Katz, M.D. Assistant Professor of

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Maya Katz, M.D. Assistant Professor of Neurology UCSF Medical Center May 2018

PARKINSON’S DISEASE PRIMER

— Parkinson’s Disease Demographics — Parkinson’s Disease Motor Symptoms — Parkinson’s Disease Progression — Parkinson’s Disease Pathophysiology — Parkinson’s Disease Treatment Motor Symptoms — Parkinson’s Disease Treatment Non-motor Symptoms — Addressing the Total Pain of Parkinson’s Disease

Outline

I have no disclosures to report

Parkinson’s disease: Demographics

Wickremaratchi et al. 2009. J Neurol Neurosurg Psych; Walker et al. 2010. Parkinsonism and Related Disorders Lees et al. 2009. The Lancet; Moisan et al. 2015, Journal of Neurology, Neurosurgery, & Psychiatry

1-2% of people 60 years of age or older (~130-140 per 100,000) 2nd most common neurodegenerative disorder Average age of onset: 60 years old (range 20-95) Males are 1.5 times more likely to develop Parkinson’s disease Typical life expectancy: 12-20 years (range: 12-40)

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Cardinal PD Motor Symptoms: Tremor Essential Tremor Cardinal PD Motor Symptoms: Bradykinesia Cardinal PD Motor Symptoms: Gait Impairment

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OFF MEDICATIONS ON MEDICATIONS

Parkinson’s Disease: Motor Fluctuations Parkinson’s Disease: Motor Fluctuations

Cenci, 2014, Frontiers Neurology

Parkinson’s Disease Progression: Motor Fluctuations Parkinson’s Disease: Dyskinesias

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Stage 5: ~2 years

Wheelchair bound or bedridden Can only ambulate with another person assisting

Zhao et al. 2010, Mov Disord

Stage 4: ~2 years

Severe disability, Needs an assistive device to walk or stand

Stage 3: ~2 years

Mild to moderate bilateral involvement, Postural instability, Still independent

Stage 2: ~7 years

Mild bilateral involvement

Stage 1: ~2 years

Unilateral involvement

Parkinson’s Disease Progression: Hoehn & Yahr Staging

Cognitive deficits: Prevalence and clinical course

Litvan et al., 2011, Mov Disord; Litvan et al., 2012, Mov Disord; Marras et al. 2013, Mov Disord

Normal à PD-MCI à PD Dementia (PDD) PD-MCI: primarily nonamnestic single domain impairment

  • ~30% meet criteria for PD-MCI within 3 years after diagnosis
  • ~50% meet criteria for PD-MCI after 5 years

Parkinson’s disease pathology: Substantia nigra pars compacta degeneration

UCSF Department of Pathology

Parkinson’s disease Normal

Scarr et al., 2013, Front. Cell. Neurosci.

PD pathology: Peripheral Lewy Bodies

Tolosa and Vilas, 2015, Brain

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PD pathology: Braak Staging

Braak et al., 2004, Cell Tissue Research §

DaTSCANs detect presynaptic dopaminergic neuronal loss using SPECT imaging

§

Measures Ioflupane (123I), which is a DAT ligand that binds to presynaptic dopamine transporters in the striatum

de la Feunte-Fernandez 2012. Neurology; Fang and Martin, 2015, Parkinsonism and Related Disorders;

Parkinson’s disease pathology: DaTSCAN

Carbidopa/Levodopa: Effects

— The most effective and generally well-tolerated medicine for PD — Short half-life (~45 to 90 minutes), needs to be taken frequently as PD progresses — Ideally should be taken 1 hour before or 2 hours after a protein-rich meal — Main side effects: nausea, lightheadedness, hallucinations, and dyskinesias

Parkinson’s Disease Motor Symptoms: Medications

Sinemet CR Carbidopa/Levodopa: Formulations Sinemet IR Rytary Parcopa

~2 to 2.5 hours increase in sustained concentration compared to sinemet IR ~60 minutes increase in sustained concentration compared to sinemet IR Impaired bioavailability, lower peak dose, time to peak concentration can be up to 120 minutes longer than sinemet IR Orally disintegrating tablets (dysphagia) Not sublingually absorbed, similar time to peak concentration compared to sinemet IR. Used in setting of dysphagia. Short half-life (45-90 minutes)

Parkinson’s Disease Motor Symptoms: Medications

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Carbidopa/Levodopa

Initial Dosing Guidelines

— Start with sinemet 25/100mg IR: ½ tab three times per day — Increase to sinemet 25/100mg IR: 1 tab three times per day after 2 weeks — Increase to sinemet 25/100mg IR: 1.5 tabs three times per day after 2 weeks — Increase to sinemet 25/100mg IR: 2 tabs three times per day after 2 weeks

Parkinson’s Disease Motor Symptoms: Medications

Increase the dose until motor symptoms are significantly improved or there are side effects

Carbidopa/Levodopa ER: (Rytary) Dosing Guidelines

Parkinson’s Disease Motor Symptoms: Medications

Carbidopa/Levodopa Extenders: Effects Entacapone (Comtan) Rasagaline (Azilect)

Tolcapone (Tasmar)

Selegiline (Eldepryl)

1 hour increased on-time Side effects: drug interactions 1 hour increased on-time Side effects: drug interactions, HTN, insomnia, delirium Najib 2001, Clinical Therapeutics 1 hour increased on-time Side effects: diarrhea, orange urine 2-3 hours increased on-time Side effects: Liver failure

Parkinson’s Disease Motor Symptoms: Medications

— Compared to carbidopa/levodopa — More mild benefit — Lasts longer, half-life: ~6 hours — Lower risk of causing dyskinesias — Main side effects: sleep attacks,

impulse control disorders (ICDs), sedation, confusion, hallucinations, cognitive deficits, lightheadedness

— Usually not prescribed to people over

70 years of age Dopamine Agonists (ropinirole, pramipexole, rotigotine): Effects

Jenner, 2002, Neurology

Parkinson’s Disease Motor Symptoms: Medications

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Levodopa sparing therapy: Effects Trihexyphenidyl Dopamine agonists Zonisamide

Mild-moderate reduction in parkinsonism Side effects: ICD, sleep attacks, hallucinations, cognitive deficits Najib 2001, Clinical Therapeutics Reduces tremor, mild benefit Side effects: nephrolithiasis, somnolence, ataxia, confusion, cognitive deficits Reduces tremor and dystonia Side effects: sedation, delirium, hallucinations, increased risk of dementia, dry mouth, constipation

Parkinson’s Disease Motor Symptoms: Medications

Levodopa sparing therapy: Effects MAO-B inhibitors

Najib 2001, Clinical Therapeutics

Amantadine

Very mild reduction in parkinsonism, if any Side effects: drug interactions, depends on whether rasagaline or selegiline are used Mild reduction in parkinsonism, Reduces dyskinesias Side effects: confusion, hallucinations, dry mouth, constipation,

Parkinson’s Disease Motor Symptoms: Medications

CALM-PD PSG Study Group, 2000, JAMA

§ CALM-PD Clinical Trial Dosing strategy Percentage developing dyskinesia after 2 years Improvement in movement and function scale (UPDRS) Pramipexole 10% 4.5 points Levodopa 30% 9.2 points

Parkinson’s Disease Motor Symptoms: Risk of Developing Dyskinesias

Amantadine

PD Treatments: Anti-dyskinetic medication

§ Only medication that controls tremors, stiffness and slowness,

AND also controls dyskinesias

§ Side effects: confusion, hallucinations,

rash, dry mouth, constipation

§ Could early amantadine prevent

the development of dyskinesias?

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PD Treatments: Botulinum Toxin

— Commercially available Neurotoxins — Botulinum Toxin A — Botox — Xeomin — Dysport — Botulinum Toxin B — Myobloc

Parkinson’s Disease Clinical Trials

OUTPATIENT PHYSICAL THERAPY

  • Refer to outpatient physical therapy early in the disease course
  • Parkinson W

ellness Recovery (PWR!)

  • Lee Silverman Voice Training (LSVT)
  • Balance vest

REHABILITATION

Parkinson’s Disease Motor Symptoms: Non-pharmacological Treatments

HOME SAFETY EV ALUATION

  • Refer for home safety evaluation:
  • skilled nursing
  • physical therapy
  • ccupational therapy
  • custodial non-skilled care

REHABILITATION

Parkinson’s Disease Motor Symptoms: Non-pharmacological Treatments

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MEDICARE COVERS ’SKILLED MAINTENANCE’

  • Medicare covers rehab services to maintain or manage a patient’s current condition

when no functional improvement is possible

  • Therapy services to maintain a patient’s current condition or slow decline are covered

REHABILITATION

Parkinson’s Disease Motor Symptoms: Non-pharmacological Treatments

PHARMACOLOGICAL TREATMENTS

  • Donepezil 10mg daily was shown to reduce falls in PD by almost 50% in a small

clinical trial [Chung et al. 2010]

  • Vitamin D supplementation 1200 units daily was shown to reduce decline in balance in a

small clinical trial [Suzuki et al. 2013]

  • Cyanocobalamin supplementation 1000mcg daily if a deficiency is identified
  • Check a DEXA scan and start a bisphosphonate (if needed) to reduce fracture risk

IMBALANCE

Parkinson’s Disease Motor Symptoms: Non-pharmacological Treatments

USE OF ASSISTIVE DEVICES

  • Need to make sure that patients are not using progressives or bifocal glasses
  • Cane, walking sticks, walker (U-step walker preferred)
  • Consider knee protectors for frequent fallers
  • Recommend MedAlert System
  • Wheelchair optimization

IMBALANCE

Parkinson’s Disease Motor Symptoms: Non-pharmacological Treatments

Physical activity must be challenging to have a benefit

Parkinson’s Disease Motor Symptoms: Role of Exercise

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Intestinal infusion of carbidopa/levodopa (Duopa)

Olanow et al. 2014, The Lancet Neurology

Parkinson’s Disease Motor Symptoms: Advanced Treatments

Nyholm et al. MDS Conference abstract. 2012; Olanow et al. 2014, The Lancet Neurology

Parkinson’s Disease Motor Symptoms: Advanced Treatments

Levodopa plasma concentration Duopa Sinemet

Possible side effects:

§ Post-surgical complications § Tubing issues § Cases of severe neuropathy

Olanow et al. 2014, The Lancet Neurology

Intestinal infusion of carbidopa/levodopa (Duopa)

Parkinson’s Disease Motor Symptoms: Advanced Treatments Parkinson’s Disease Motor Symptoms: Advanced Treatments

Deep Brain Stimulation

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PRE-DBS POST-DBS

Deep Brain Stimulation

Parkinson’s Disease Motor Symptoms: Advanced Treatments

Deep Brain Stimulation

PRE-DBS POST-DBS

Parkinson’s Disease Motor Symptoms: Advanced Treatments

  • In general, only what levodopa can do

Exceptions: tremor and peak dose dyskinesias

  • Increases the best “on-medication” state by 4-5

hours daily

  • Improves motor function by 25-50%
  • Raises the ceiling for off-medication times
  • Reduction in medication dosing (30-50%)

Marks et al., Editor, 2015, Deep Brain Stimulation Management

What can DBS do?

Parkinson’s Disease Motor Symptoms: Deep Brain Stimulation

Marks et al., Editor, 2015, Deep Brain Stimulation Management

What are the limitations of DBS?

  • Less effective for midline symptoms
  • Will not treat non-motor symptoms
  • Can make certain symptoms worse

(e.g. speech, falls, behavior and cognition)

Parkinson’s Disease Motor Symptoms: Deep Brain Stimulation

What are the limitations of DBS?

  • 1/200 risk of stroke
  • 3-5% risk of infection
  • 2-3% risk of post-op seizure and/or post-op delirium
  • Can make verbal fluency and working memory worse
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  • Parkinson’s disease for at least 5 years
  • Robust improvement in motor symptoms with dopaminergic therapy
  • Consider as soon as motor symptoms are no longer easily managed with

medications alone

  • Freezing of gait and postural instability should not be the primary symptoms
  • Good social support
  • Ability to comply with complex life-long therapy
  • Reasonable expectations for the surgery
  • No medical contraindications for surgery
  • No untreated severe psychiatric disease
  • No dementia (PD-MCI can still be considered for unilateral, staged surgery)

Ideal Candidate for DBS

Parkinson’s Disease Motor Symptoms: Deep Brain Stimulation

Deep Brain Stimulation Awake Surgery Deep Brain Stimulation Asleep Surgery

physiology-guided implantation iMRI-guided implantation

Deep Brain Stimulation: Implantation Techniques

Fasano & Deuschl 2012, Basal Ganglia

Deep Brain Stimulation: Timing of Implantation

The goal is to implant the electrode into the sensorimotor portion of the nucleus

Deep Brain Stimulation: GPi vs. STN

Marks et al., Editor, 2015, Deep Brain Stimulation Management

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Okun, Arch Neurol, 2005

Deep Brain Stimulation: GPi vs. STN

San Luciano et al., 2015, Movement Disorders

Palliative Thalamotomy

Parkinson’s Disease Motor Symptoms: Advanced Treatments

Most PD patients report at least 8 non-motor symptoms

Langston , 2016, Annals of Neurology, Weintraub et al. 2004, J Am Geriatr Soc.; Shulman et al., 2002, Parkinsonism and Rel Disorders; Bostantjopoulou et al. 2013, Hippokratia; Miyasaki et al., 2012, Parkinsonism and Rel Disorders

Parkinson’s Disease Motor Symptoms:

Just the Tip of the Iceberg… Common Parkinson’s Disease Non-motor Symptoms

§ Autonomic dysfunction § Cognitive dysfunction § Fatigue § Gastrointestinal symptoms § Pain disorders § Psychiatric symptoms § Sleep disorders § Sensory deficits § Skin abnormalities § Speech impairment § Swallowing impairment

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Common Parkinson’s Disease Non-motor Symptoms

§ Autonomic dysfunction § Cognitive dysfunction § Fatigue § Gastrointestinal symptoms § Pain disorders § Psychiatric symptoms § Sleep disorders § Sensory deficits § Skin abnormalities § Speech impairment § Swallowing impairment EYELID OPENING APRAXIA DEFINITION

  • Inability to voluntarily raise the eyelids due to ideomotor apraxia
  • Can cause misinterpretation that the patient is asleep when they are

actually wide awake TREATMENTS

  • Typically responds very well to botulinum toxin administered to the muscles

around the eye every 3 months

Cummings and Winblad, 2007, Expert Review of Neurotherapeutics; Stubndorff et al., 2014, BMJ Open; Miyasaki et al., 2006, Neurology

Non-motor symptoms: Cognitive Deficits

PSEUDOBULBAR AFFECT (PBA) DEFINITION

  • Involuntary emotional expression disorder
  • Emotional incontinence

Expert Review of Neurotherapeutics; Stubndorff et al., 2014

Non-motor symptoms: Psychiatric disorders

TREATMENTS

  • SSRI
  • Nuedexta

Non-motor symptoms: Sleep Disorders

REM BEHAVIOR DISORDER (RBD) PREV ALENCE

  • Highly specific prodromal symptom predicting future Parkinson’s disease
  • Effects 50% of individuals with Parkinson’s disease

DEFINITION

  • Lack of paralysis while dreaming (REM phase of sleep)
  • One of the most dangerous symptoms in PD

Aurora et al., 2010, Journal of Clinical Sleep Medicine

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Non-motor symptoms: Sleep Disorders

REM BEHAVIOR DISORDER (RBD) PHARMACOLOGICAL TREATMENTS

  • Melatonin (3-15mg, ideally taken 2 hours before bedtime)
  • Clonazepam (start at 0.25mg at bedtime)
  • Anecdotal reports of benefit with cannabidiol (CBD) oil
  • Quetiapine (start at 12.5mg at bedtime, can increase by 12.5mg as needed)

NON-PHARMACOLOGICAL TREATMENTS

  • Maintain a safe sleep environment to prevent injuries
  • Move furniture away from the bed and place padding on corners of furniture
  • Consider placing a mattress on the floor near the bed
  • Bed-partner may need to sleep in a separate bed until RBD is well controlled with

pharmacological treatments

Aurora et al., 2010, Journal of Clinical Sleep Medicine

Parkinson’s Disease Neuroprotection: Nutrition Tips

Fried and Processed foods Non-organic dairy Simple carbohydrates Animal meats and fats Limit alcoholic beverages

Parkinson’s Disease: Nutrition Tips Parkinson’s Disease : Prevention Tips

BONE HEALTH COGNITIVE LESIURE ACTIVITIES STAY SOCIAL ORTHOSTATIC HYPOTENSION DENTAL HEALTH ANNUAL DERMATOLOGY EVALUATION SLEEP QUALITY VASCULAR RISK FACTORS

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Parkinson’s Disease : Prevention Tips

§ Prochlorperazine (Compazine) § Promethazine (Phenergan) § Metoclopramide (Reglan) § Most anticholinergics (e.g. benadryl or oxybutynin) § Most antipsychotics (only quetiapine, clozaril and pimavanserin are safe)

Parkinson’s Disease Motor Symptoms: Medication Tips

Parkinson’s disease palliative care model:

Palliative care principles address “Total Pain”

The suffering that encompasses all of a person’s physical, emotional, social, spiritual and practical struggles in the setting of serious illness

Dame Cicely Saunders, M.D., R.N., M.S.W . The Symptomatic Treatment of Incurable Malignant Disease. Prescriber’s J. 1964 Miyasaki et al., 2012, Parkinsomism and Related Dis

Similar rates of symptom burden in PD as in ALS and cancer

Symptom Burden

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Sir William Richard Gowers, 1886

SYMPTOMS

§ Isolation § Change in family dynamics § Loss of autonomy

Psychosocial Distress Spiritual Distress

SYMPTOMS

§ Grief § Guilt § Existential crisis § Death Anxiety

Planning and Preparing for the Future

T uck et al., 2015, Am J Hosp Palliat Care; T uck et al., 2015, Park Related Disorders Pantilat, 2016, Life after the diagnosis; T emel et al. 2010, NEJM, Zimmerman et al., 2014, Lancet

SYMPTOMS

§ Low rates of hospice use (<5%) § High rates of hospital deaths § Low rates of advance care planning

Reducing Care-Partner Stress SYMPTOMS

§ Grief, guilt, and isolation are

commonly expressed

§ High rates of care-partner burnout § Increased rates of illness and

hospitalizations among care-partners

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UCSF MOVEMENT DISORDER AND NEUROMODULATION CENTER (MDNC) SFV A PARKINSON’S DISEASE RESEARCH, EDUCATION AND CLINICAL CENTER (PADRECC)

Jill L. Ostrem, M.D. – MDNC Medical Director Philip A. Starr, M.D., Ph.D. – MDNC Surgical Director Caroline M. Tanner, M.D., Ph.D. – PADRECC Director

Neurology Jill L. Ostrem, M.D. Caroline Tanner, M.D., Ph.D. Ian Bledsoe, M.D., M.S. Nicholas Galifianakis, M.D., M.P.H. Marta San Luciano, M.D., M.S. Maya Katz, M.D. Jim Mass, M.D., Ph.D. Nijee Luthra, M.D., Ph.D. Cameron Dietiker, M.D. Ethan Brown, M.D.. Neurosurgery Philip A. Starr, M.D., Ph.D. Paul S. Larson, M.D. Edward F. Chang, M.D., Ph.D. Dan Lim, M.D., Ph.D. Coralie de Hemptinne, Ph.D. Roee Gilron, Ph.D. Witney Chen, Ph.D. candidate Psychiatry Andreea Seritan, M.D. Tobias Marton, M.D. Occupational and Environmental Medicine Samuel Goldman, M.D., M.P.H.

Clinical Fellows Jennifer Choi, M.D. Melissa Heiry, M.D. Fay Gao, M.D. Lauren Spiegel, M.D.

Physical Therapy Heather Bhide, P.T. Social Work Monica Eisenhardt, LCSW Chaplain Judy Long, M.S., M.A. Carolyn Talmadge, M.Div. Research Staff Sarah Wang, Ph.D Kathleen Comyns, M.P.H Cheryl Meng, M.P.H. Jana Guenther, B.A. Raisa Syed, B.A. Farah Kausar, B.A. Kanchi Mehta, B.A. Clinic Support Staff Yasmeen Gonzalez Christine Jiunti Jeverly Calaunan Janet Allen Lorraine Anzaldo

Neuropsychology Caroline A. Racine, Ph.D. Johannes Rothlind, Ph.D. Nursing Monica Volz, N.P. Rigzin Lama, R.N. Gina Bringas-Cinco, R.N.