PARKINSON’S DISEASEDiagnosis & Treatment Options

University of South CarolinaSchool of Medicine

March 27, 2014

Dale R.Hamrick, MDPO Box 23656

Columbia, SC 29224(803) 422-2985

Cardinal Characteristics

Resting tremor

Bradykinesia

Rigidity

Postural instability

Beware the Old Man (or woman)Difficulty initiating movement (akinesia)Small amplitude movements (hypokinesia)Reduced motor velocity (bradykinesia)Loss of postural reflexesStooped body posture

Additional Signs & SymptomsMicrographia

Masked face

Slowing of ADLs

Stooped, shuffling gait

Decreased arm swing when walking

Additional Signs and SymptomsDifficulty arising from a chair

Difficulty turning in bed

Hypophonic speech

Non-Motor SymptomsNeuropsychiatric

DepressionAnhedoniaAttention deficitHallucinationsDelusionsObsessional behaviorCognitive disorder

Sleep disordersRestless legsPeriodic limb

movementsREM behavior disorderExcessive daytime

somnolenceVivid dreamingNon-REM sleep-related

movement disordersInsomnia

Non-Motor SymptomsAutonomic symptoms

Bladder urgency, nocturia, frequency

SweatingOrthostatic hypotensionHypersexualityErectile impotence

hypotestosterone state

GI symptomsSialorrheaAgeusiaDysphagiaRefluxVomitingNauseaConstipationFecal incontinence

Non-Motor SymptomsSensory

PainParesthesiaOlfactory disturbance

OtherFatigueDiplopiaBlurred visionSeborrheaWeight loss

Epidemiology Incidence

5-24/ 105 worldwide (USA: 20.5/105)Incidence of PS/PD rising slowly with aging

populationPrevalence

57-371/105 worldwide (USA/Canada 300/105)35%-42% of cases undiagnosed at any time

Onsetmean PS 61.6 years; PD 62.4 yearsrare before age 30; 4-10% cases before age 40

What Happened?

Mortality in PSReduced life expectancy

Mean survival after onset ~ 15 yearslonger in non-demented PD caseslonger with L-dopa use

PD survival >MSA, PSPThe most common causes of death:

pulmonary infection/aspiration, urinary tract infection, pulmonary embolism and complications of falls and fractures

Atypical ParkinsonismEarly onset of, or rapidly progressing,

dementiaRapidly progressive courseSupranuclear gaze palsyUpper motor neuron signsCerebellar signs—dysmetria, ataxiaUrinary incontinenceEarly symptomatic postural hypotension

Progressive supranuclear palsySupranuclear downgaze palsy, square wave

jerksUpright posture/frequent fallsPseudobulbar emotionalityFurrowed brow/stare

Corticobasal degenerationUnilateral, coarse tremorLimb apraxia/limb dystonia/alien limb

Multiple system atrophyShy-Drager syndrome

Autonomic insufficiency—orthostasis, impotenceStriatonigral degeneration

Tremor less prominentOlivopontocerebellar atrophy

Cerebellar signs

Diffuse Lewy Body DiseaseEarly onset of dementiaDelusions and hallucinationsAgitation

Alzheimer’s diseaseDementia is the primary clinical syndromeRest tremor is rare

Hydrocephalus-induced ParkinsonismNormal pressure hydrocephalusClinical triad:

parkinsonism/gait disorderurinary/fecal incontinencedementia

Drug Classes in PDDopaminergic agents

LevodopaDopamine agonists

COMT inhibitors MAO-B inhibitorsAnticholinergicsAmantadine

LevodopaMost effective drug for parkinsonian

symptomsFirst developed in the late 1960s; rapidly

became the drug of choice for PDLarge neutral amino acid; requires active

transport across the gut and blood-brain barriers

Levodopa (cont’d)Rapid peripheral decarboxylation to

dopamine without a decarboxylase inhibitor (DCIs: carbidopa, benserazide)

Side effects: nausea, postural hypotension, dyskinesias, motor fluctuations

AmantadineAntiviral agent; PD benefit found accidentallyTremor, bradykinesia, rigidity & dyskinesiasExact mechanism unknown; possibly:

enhancing release of stored dopamineinhibiting presynaptic reuptake of

catecholaminesdopamine receptor agonismNMDA receptor blockade

Side effects —autonomic, psychiatric200-300 mg/day

Treatment OptionsPreventive treatment

No definitive treatment availableSymptomatic treatment

PharmacologicalSurgical

Non-motor managementRestorative—experimental only

TransplantationNeurotrophic factors

Levodopa-Induced DyskinesiasMost common is “peak dose” dyskinesia

disappears with dose reductionChoreiform, ballistic and dystonic movementsMost patients prefer some dyskinesias over

the alternative of akinesia and rigidity

COMT InhibitorsNewest class of antiparkinsonian drugs:

tolcapone, entacaponePotentiate LD: prevent peripheral

degradation by inhibiting catechol O-methyl transferase

Reduces LD dose necessary for a given clinical effect

COMT Inhibitors (cont’d)Helpful for both early and fluctuating

Parkinson’s diseaseMay be particularly useful for patients with

“brittle” PD, who fluctuate between off and on states frequently throughout the day

Dopamine Agonists: Distinguishing FeaturesDirectly stimulate dopamine receptorsNo competition with dietary amino acidsLonger half-life than levodopaMonotherapy or adjunct therapyMay delay or reduce motor fluctuations &

dyskinesias associated with levodopaMay be neuroprotective“The Patch” – rotigotine (Neupro)

DAs: Common Adverse EffectsNausea, vomitingDizziness, postural hypotensionHeadacheDrowsiness & somnolenceDyskinesiasConfusion, hallucinations, paranoia

Clinical Decision-Making in Early PDDisease severity

degree of functional impairmentimpact on quality of life

Age of patientcomorbiditiesrisk of acute drug intolerancerisk of long-term complications

Neuroprotection

Initial Therapy: The Elderly PatientShorter treatment horizonLower risk of long-term complicationsHigher likelihood of comorbiditiesCarbidopa/Levodopa: well tolerated, effectiveUse adjunctive medications cautiouslyAvoid sedating medications

Initial Therapy: The Young PatientLong-term treatment horizonIncreased risk of long-term complicationsIncreased patient responsibilitiesDopamine agonist monotherapyLevodopa-sparing strategiesPutative neuroprotective strategiesRole of levodopa is not adequately defined

Levodopa: Guidelines in Early PDStart low and increase slowlyTitrate dosage to efficacy (~200-600 mg/day)Immediate releaseControlled releaseAcute side effects: nausea, dizziness,

somnolence

Managing Early Complications: Wearing Off/Mild DyskinesiaFor pts on DA monotherapy:

elevate dosage of agonistadd LD, w/ or w/o COMT inhibitor

For pts on LD:add DA, COMT inhibitor, or MAO inhibitorreduce LD dosageuse combination of immediate and CR

Managing Early Complications: Altered Mental StatesConfusion, sedation, dizziness, hallucinations,

delusionsReduce or eliminate CNS-active drugs of

lesser priorityanticholinergics – sedativesamantadine – muscle relaxantshypnotics – urinary spasmodics

Reduce dosage of DA, COMT inhibitor, or LD

Surgical Treatments for Parkinson’s DiseaseAblative

thalamotomypallidotomy

Electrical stimulationVIM thalamus, globus pallidus internus, sub-

thalamic nucleusTransplant

autologous adrenal, human fetal, xenotransplants, genetically engineered transplants

Deep Brain Stimulation (DBS)High frequency,

pulsatile, bipolar electrical stimulation

Stereotactically placed into target nucleus

Exact physiology unknown, but higher frequencies mimic cellular ablation, not stimulation

Psycho-Social Aspects of Parkinson's diseaseChronic, progressive,

incurableOff the wall curesDepression (like

stroke, assume they all are depressed)

Housing – the move to the NH

Children and their fears

Resuscitation issues

Artificial nutrition issues

Other Parkinson’s Meds

MAO Inhibitorsrasagaline selegilene

zydis carbidopa/levodopa

rotigotine patch

Hoehn and Yahr Staging

1. Unilateral disease only2. Bilateral mild disease,

with or without axial involvement

3. Mild-to-moderate bilateral disease, with first signs of deteriorating balance

4. Severe disease requiring considerable assistance

5. Confinement to wheelchair or bed unless aided