28 katz parkinsons - ucsf · pdf filetreatment at symptom onset, cerebellar signs, or non-...

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Parkinson’s Disease for the Primary Care Provider

Maya Katz, M.D.Assistant Professor of Neurology

Movement Disorder and Neuromodulation CenterUCSF Medical Center

Review of Parkinson’s Disease: Out line

� PD demographics� PD diagnostic criteria� Main PD motor symptoms� Non-motor PD symptoms� Cognition and PD� Clinical course of PD� Pathology of PD� Pathophysiology of PD� Etiology of PD� Review treatments for PD

Parkinson’s disease: Demographics

1Wickremaracthi et al. 2009. J Neurol Neurosurg Psych; Walker et al. 2010. Parkinsonism and Related Disorders2Lees et al. 2009. The Lancet

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)

Men are more likely to develop Parkinson’s disease compared to women

Typical life expectancy: 12-20 years (range: 12-40)

Parkinson’s disease Diagnostic Criteria : UK Brain Bank

Step 1 MOTOR SYMPTOMS

Bradykinesia and either rest tremor (4-6 Hz tremor), rigidity or postural instability

Step 2 EXCLUSION CRITERIA

e.g. history of repeated strokes or TBI, h/o neuroleptic treatment at symptom onset, cerebellar signs, or non-responsiveness to levodopa, early severe autonomic involvement, early and severe dementia

Step 3 SUPPORTIVE CRITERIA (at least 3)

e.g, history of unilateral onset and persistent asymmetry of symptoms, 70-100% responsiveness to levodopa, presence of dyskinesias, clinical course for > 10 years, levodopa response for 5 years or more

Hughes et al. 2001, Neurology

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Parkinson’s disease: NINDS Diagnostic Criteria

Possible Parkinson’s disease

At least 2 features in Group A, with one of them being either tremor or bradykinesia, no features in group B present, and sustained response to dopaminergic therapy

Probable Parkinson’s disease

At least 3 of 4 features in group A present, no features in group B for > 3 years, and sustained response to dopaminergic therapy

Definite Parkinson’s disease

All criteria met for Possible PD, plus histopathologic confirmation of diagnosis at autopsy

Group A: characteristic of PD

Resting tremor (4-6 Hz)

Bradykinesia

Rigidity

Asymmetric onset

Group B: suggestive of alternative diagnosis

Onset of the following symptoms < 3 years after PD onset:

postural instabilityfreezinghallucinationsdementia

Supranuclear gaze palsy (other than restriction of upgaze or slowed saccades)

Severe dysautonomia

Other condition known to cause parkinsonism Gelb et al. 1999, Archives Neurol

Cardinal motor symptoms: Tremor

Cardinal motor symptoms: Bradykinesia Cardinal motor symptoms: Gait Impairment

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Motor symptoms are Just the tip of the iceberg…

Langston, 2006, Ann Neurol

PD non-motor symptoms: Categories

� Autonomic� Orthostasis� Constipation� Urinary urgency� ED

� Sleep� RBD� Poor sleep

maintenance� Sensory� Loss of smell� Loss of taste� Pain

� Psychiatric� Fatigue� Depression� Anxiety� Apathy� Psychosis

� Cognitive� Executive dysfunction� Impaired attention� Impaired visuo-spatial

function� Relative preservation of

anterograde memory� Mild cognitive impairment� Dementia

Barrone et al. 2009, Mov Disord

PD non-motor symptoms: Prevalence

� Most PD patients report an average of 8 non-motor symptoms

� Non-motor symptoms are often:� more difficult to treat� impair quality of life more than

motor symptoms

Barrone et al. 2009, Mov Disord

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

PD-MCI

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

↓

↓

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Parkinson’s disease: Clinical course

Stage 5: ~2 yearsWheelchair bound or bedriddenCan only ambulate with another person assisting

Zhao et al. 2010, Mov Disord

Stage 4: ~2 yearsSevere 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 yearsUnilateral involvement

PD pathology: substantia nigra pars compacta degeneration

Scarr et al., 2013, Front. Cell. Neurosci.; Jenner 2002, Neurology

PD pathology: Lewy body PD pathology: prion like disease

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PD pathology: Braak Staging

Braak et al., 2004, Cell Tissue Research

PD pathology: Peripheral Lewy Bodies

Tolosa and Vilas, 2015, Brain

� DaTSCANs detect presnaptic 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. NeurologyPiggott 1998; Fang and Martin, 2015, Parkinsonism and Related

Disorders

PD imaging: DaTSCAN

� DAT can be used as an imaging biomarker for PD� Predictable change in Specific Binding Ratio (SBR)

annually, an average 7% SBR reduction annually, greater than 20 times the rate of signal loss seen in normal aging

Pigott 1998; Seibyl et al. 2016, presented at PPMI Investigator Conference

PD imaging: DaTSCAN

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PD pathophysiology: Rate Model

The basal ganglia has two major intrinsic pathways:

Direct and Indirect

• The direct pathway facilitates movement.

• The indirect pathway inhibits movement

• Striatal dopamine excites the direct pathway (increasing movement), and suppresses the indirect pathway (increasing movement)

PD pathophysiology: Rate Model

Basal Ganglia Direct and Indirect Pathways

PD pathophysiology: Brain Arrhythmia

Phase amplitude coupling� Increased bursting of

neuronal activity

� Increased synchronization in neuronal activity

� Increased oscillatory activity

de Hemptinne et al. 2013, PNAS

PD etiology: Multifactorial

• Complex interplay between • genetics (ingredients)• environment (recipe)

Tanner et al. 2011, Envi Health PerspectivesAbbott et al. 2015, Neurology

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PD Treatments: Role of exercise

Oguh et al. 2014, Parkinsonism and Related DisordersShu et al. 2014, PLOSYang et al. 2014, PLOSSharp and Hewitt, 2014, Neurosci Biobehav Rev

PD Treatments: Role of cognitive training

Paris et al. 2011, Movement Disorders

PD Treatment: MedicationsCarbidopa/Levodopa:Mechanism of Action

Cannas et al. 2010, Neuropsychiatr Dis Treat; Jenner, 2002, Neurology

PD Treatment: MedicationsCarbidopa/Levodopa:

Effects

� The most effective and generally well-tolerated medicine for PD

� Short half-life (~90 minutes), may need to be taken frequently as PD progresses

� Should be taken 30-60 minutes before or after a protein-rich meal

� Main side effects: nausea, lightheadedness, hallucinations, and dyskinesias

Cenci 2015, Frontiers in Neurology

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PD Treatment: Medications

Sinemet CR

Carbidopa/Levodopa:Formulations

Sinemet IR

Rytary

Parcopa

PD Treatment: MedicationsCarbidopa/Levodopa Extenders:

Mechanism of Action

• Rasagaline (Azilect)

• Selegiline (Eldepryl)

• Entacapone (Comtan)

• Tolcapone (Tasmar)

Najib 2001, Clinical Therapeutics, Youdim 2006, Nature Rev


Carbidopa/Levodopa Extenders:Effects

Entacapone (Comtan)

Rasagaline (Azilect)

Tolcapone (Tasmar)

Selegiline (Eldepryl)

1 HOUR INCREASED ON-TIMESide effects: drug interactions1 HOUR INCREASED ON-TIMESide effects: drug interactions, HTN, insomnia, delirium

Najib 2001, Clinical Therapeutics

1 HOUR INCREASED ON-TIMESide effects: diarrhea, orange urine

2-3 HOURS INCREASED ON-TIMESide effects: Liver failure

PD Treatment: MedicationsDopamine Agonist:

Mechanism of Action

• Pramipexole (Mirapex)

• Ropinirole (Requip)

• Rotigotine (Neupro)

Jenner, 2002, Neurology

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Dopamine Agonist:Effects

� Compared to carbidopa/levodopa� Lasts longer, half-life: ~6 hours� Lower risk of causing dyskinesias� More mild benefit

� Main side effects: sleep attacks, ICDs, sedation, confusion, hallucinations, cognitive deficits, dry mouth, lightheadedness

� Usually not prescribed to people over 70 years of age

Jenner, 2002, Neurology

PD Treatment: Motor Fluctuations & Dyskinesias

Cenci, 2014, Frontiers Neurology

PD Treatment: Motor Fluctuations

OFF MEDICATIONS ON MEDICATIONS

PD Treatments: Dyskinesias

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� The risk of dyskinesias is inversely proportional to the age of PD onsetAge of PD onset Percentage developing dyskinesia after 5 years of L-dopa

40-49 70%50-59 42%60-69 33%70-79 24%

Ku and Glass, 2010, Movement Disorders; PSG Study Group, NEJM, 2004

PD Treatments: Risk of dyskinesias� The risk of dyskinesias is inversely proportional t o the L-dopa dose

Dose of levodopa Percentage developing dyskinesia after 1 year of L-dopaPlacebo 3%150 mg/day 3%300 mg/day 2%600 mg/day 15%

Dopamine agonists

Trihexyphenidyl (Artane) MAO-B inhibitor(Selegiline or Rasagaline)

ZonisamidePD Treatments: Levodopa sparing therapy

Amantadine

PD Treatment: MedicationsLevodopa sparing therapy:

Effects

Trihexyphenidyl

Dopamine agonists

Zonisamide

Mild-moderate reduction in parkinsonism Side effects: ICD, sleep attacks, hallucinations, cognitive deficits


Reduces tremor, mild benefitSide effects: nephrolithiasis, somnolence, ataxia, confusion, cognitive deficits

Reduces tremor and dystoniaSide effects: sedation, delirium, hallucinations, increased risk of dementia, dry mouth, constipation

PD Treatment: MedicationsLevodopa sparing therapy:

Effects

MAO-B inhibitors


Amantadine

Very mild reduction in parkinsonism, Potential neuroprotective benefit Side effects: drug interactions, depends on whether rasagaline or selegiline are used

Mild to moderate reduction in parkinsonism, Reduces dyskinesiasSide effects: confusion, hallucinations, dry mouth, constipation,

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CALM-PD PSG Study Group, 2000, JAMA

� CALM-PD Clinical TrialDosing strategy Percentage developing dyskinesia

after 2 yearsImprovement in movement and function scale (UPDRS)

Pramipexole 10% 4.5 points

Levodopa 30% 9.2 points

PD Treatments: Risk of developing dyskinesias vs. quality of life � PD MED Clinical Trial

Age of PD onset

Percentage who discontinued allocated treatment due to side effects

Percentage who developed dyskinesias after 3 years

Domains of significant benefit (motor symptoms, QOL measures)

Dopamine agonist orMAO-B inhibitor

26% 33% None

Levodopa 2% 36% Overall QOL, Mobility,ADLs, Cognition, and Communication

PD MED Collaborative Group, 2014, The Lancet

PD Treatments: Risk of developing dyskinesias vs. quality of life

Amantadine

PD Treatments: Anti-dyskinetic medication

� Only medication that controls tremors, stiffness and slowness, AND also controls dyskinesias

� Could early amantadine prevent the development of dyskinesias?

PD Treatments: Duopa Infusion

Intestinal infusion of dopamine (levodopa)� Reduces off-medication time

� Can reduce dyskinesias

� Has been available in Europe for > 10 years

� Possible side effects:� Tubing issues� Otherwise same as oral L-dopa

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� Maintains consistent plasma levels of levodopa over a 16 hour infusion

Nyholm et al. MDS Conference abstract. 2012


The pump is worn throughout the day in a packThe pump is disconnected during sleep

PD Treatments: Deep brain stimulation (DBS)PD Treatments: Deep brain stimulation (DBS)

Permanently implanted brain pacemaker1. Lead2. Extension Wire

3. IPG

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DBS: video pre- and post-surgery

PRE-DBS POST-DBS


PRE-DBS POST-DBS


PRE-DBS POST-DBS

DBS: When to consider therapy?

Fasano & Deuschl 2012, Basal Ganglia

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DBS: Ideal candidates

• PD symptoms for at least 5 years

• Good levodopa response, but with motor fluctuations, dyskinesias, and/or adverse medication effects

• Freezing of gait and postural instability should not be the primary symptoms

• Ability to comply with lifelong and frequent follow-up

• Good social support

• Reasonable expectations for the surgery

• No medical contraindications for surgery

• No untreated severe psychiatric disease

• No dementiaMarks et al., Editor, 2015, Deep Brain Stimulation Management

DBS: What can DBS do?

• In general, only what levodopa can doExceptions: 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

DBS: What are the limitations of DBS?

• Less effective for midline symptoms

• Will not treat non-motor symptoms (lightheadedness, constipation, sleep)

• Can make certain symptoms worse (e.g. speech, falls, behavior and cognition)

Marks et al., Editor, 2015, Deep Brain Stimulation Management Slide courtesy of Susan Heath

DBS: Basic Programming

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Traditional DBS surgery: awake Interventional MRI (iMRI) DBS surgery: asleep

Deep Brain Stimulation: GPi vs. STN

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

� Anatomy:� The goal is to implant the electrode into

the sensorimotor portion of the nucleus


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

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Okun, Arch Neurol, 2005

� Anatomy:

� The GPi is a much larger target than the STN (~500mm3 vs. 200 mm3).

� The smaller STN target may make it more susceptible to adverse effects due to spread of current.

� The smaller size of STN is likely what allows for a lower average charge density (fewer battery replacements ).

� More neurosurgeons feel comfortable with STN targeting .


Miocinovic et al. 2006, J NeurophysOkun 2005, Arch NeurolRodriguez-Oroz 2005, Brain

• Paresthesias

• Dysarthria, dysphagia

• Increased falls

• Reduced verbal fluency

• Dyskinesias

• Behavioral changes

• Increased suicidality

• Hypomania

Benarroch, et al., 2008, Neurology

DBS: STNStimulation-induced adverse effects

• Paresthesias

• Dysarthria, dysphagia

• Visual phenomena

Gross et al. 2006

DBS: GPiStimulation-induced adverse effects

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Deep Brain StimulationGPi vs. STN

Williams et al., 2014, Movement Disorders

DBS: Mechanism of Action

• DBS is a permanently implanted brain pacemaker

• Phase amplitude coupling observed in PD is reversed with DBS

De Hemptinne et al., 2013, PNAS

PD Treatments: Palliative Care

…our most cruel failure in how we treat the sick and the aged is the failure to recognize that they have priorities beyond merely being safe and living longer.

Being Mortal: Medicine and What Matters in the EndAtul Gawande, M.D.

UCSF Parkinson’s Disease Supportive Care Clinic

Palliative Care for Parkinson’s Disease

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Clinical TeamPalliative care physician: Steve Pantilat, M.D.

Neurologist: Maya Katz, M.D. and Nick Galifianakis, M.D.

Nurse: Karen Merchant, RN

Chaplain: Judy Long, MS

Social worker: Monica Eisenhardt, LCSW


� Study design� Randomized Clinical Trial

� Study visits� Baseline, 3 months, 6 months, 9 months, 12 months

� Primary outcomes� QOL and caregiver distress at 6 months

� Secondary outcomes� Predictors of response, health service utilization, qualitative

interviews to optimize intervention

Study Summary


� Lorna Beccaria, Study Coordinator� 415-353-9453� [email protected]

� Maya Katz, Site Principal Investigator� 415-446-9396� [email protected]

Questions/Referrals

Palliative Care for Parkinson’s DiseaseParkinson’s Disease Clinical Trials

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

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

NeurologyJill L. Ostrem, M.D.Caroline Tanner, M.D., Ph.D.Nicholas Galifianakis,M.D.Marta San Luciano, M.D.Maya Katz, M.D.Jim Mass, M.D.Robert White, M.D.NeurosurgeryPhilip A. Starr, M.D.., Ph.D.Paul S. Larson, M.D.Edward F. Chang, M.D., Ph.D.Dan Lim, M.D., Ph.D.NeuropsychologyCaroline A. Racine, Ph.D.Johannes Rothlind, Ph.D.NursingMonica Volz, N.P.Susan Heath, M.S., R.N.Karen Merchant, RN

Clinical Support StaffShatara BlackmonYasmeen GonzalezChristine JiuntiMelissa ChenJanet AllenLori AnzaldoSarena PerezSocial WorkMonica Eisenhardt, L.C.S.W.Research StaffSarah Wang, Ph.D.Lorna Beccaria, R.N.Kristen Dodenhoff, B.A.Michael Dodge, B.A.FellowsNijee Luthra, M.D., Ph.D.Cameron Dietiker, M.D.Erica Byrd, M.D.Jennifer Chen, M.D.Svjetlana Miocinovic, M.D., Ph.D.Brian Lee, M.D., Ph.D.

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Parkinson’s Disease for the Primary Care ProviderAdvances in Internal Medicine

Self-Assessment Exam Question

Thank you

1 Need an acknowledgment pageMaya Katz, 2/27/2013

28 katz parkinsons - ucsf · pdf filetreatment at symptom onset, cerebellar signs, or non-...

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