Diagnosis and Diagnosis and Management of Management of Parkinson’s DiseaseParkinson’s Disease

Theresa A. Zesiewicz, MDTheresa A. Zesiewicz, MDAssociate Professor of Associate Professor of NeurologyNeurologyUniversity of South FloridaUniversity of South Florida

What is Parkinson’s What is Parkinson’s Disease?Disease? Neurologic disease caused by Neurologic disease caused by

degeneration of dopamine degeneration of dopamine neuronsneurons

Only neurodegenerative disease Only neurodegenerative disease whose symptoms can so readily whose symptoms can so readily be treated by medicationbe treated by medication

PathophysiologyPathophysiology

Movement in the body is produced Movement in the body is produced by the by the MOTOR CORTEXMOTOR CORTEX

Main motor pathway consists of the Main motor pathway consists of the pyramidal systempyramidal system

The The EXTRAPYRAMIDAL system (EPS)EXTRAPYRAMIDAL system (EPS) modulates the pyramidal systemmodulates the pyramidal system

EPS: substantia nigra, striatum, EPS: substantia nigra, striatum, subthalamic nucleus, globus subthalamic nucleus, globus pallidus, thalamuspallidus, thalamus

PathophysiologyPathophysiology

Normal movementNormal movementdependent on dependent on dopamine production in the dopamine production in the substantia nigra that innervates the substantia nigra that innervates the striatumstriatum

PD is associated with PD is associated with massive massive degenerationdegeneration of dopamine-producing of dopamine-producing neurons in substantia nigraneurons in substantia nigra

When 60 to 80% of these neurons are When 60 to 80% of these neurons are lost, symptoms of PD appear lost, symptoms of PD appear

Parkinson’s Disease: Parkinson’s Disease: PathologyPathology

The pathognomic hallmark of The pathognomic hallmark of the disease is the Lewy Bodythe disease is the Lewy Body

It is found intracerebrallyIt is found intracerebrally Also found in the autonomic Also found in the autonomic

nervous systemnervous system

Clinical Features of PDClinical Features of PD

Resting Tremor (70%)Resting Tremor (70%) BradykinesiaBradykinesia RigidityRigidity Postural InstabilityPostural Instability

– Signs start in one limb, usually Signs start in one limb, usually an arm, and spread to the an arm, and spread to the other limb on that sideother limb on that side

Parkinson’s Disease Parkinson’s Disease SymptomsSymptoms

Secondary features of the Secondary features of the disease:disease:

DepressionDepressionDementiaDementiaDysphagiaDysphagiaAnxietyAnxietyOrthostatic hypotensionOrthostatic hypotensionConstipationConstipation

Hoehn and Yahr Hoehn and Yahr Stages of PDStages of PD Stage I: unilateral symptoms of diseaseStage I: unilateral symptoms of disease Stage II: bilateral symptoms of diseaseStage II: bilateral symptoms of disease Stage III: all of above, plus postural Stage III: all of above, plus postural

instabilityinstability Stage IV: all of above, plus patient need Stage IV: all of above, plus patient need

assistance assistance Stage V: patient cannot function Stage V: patient cannot function

independentlyindependently

PrognosisPrognosis

First 5 years are the “honeymoon First 5 years are the “honeymoon period”, and patients generally period”, and patients generally do well do well

Between 5 and 10 years, most Between 5 and 10 years, most patients experience medication-patients experience medication-related difficultyrelated difficulty

By 10 years, many develop poor By 10 years, many develop poor balancebalance

Treatment of Parkinson’s Treatment of Parkinson’s DiseaseDisease

Neurodegenerative disease Neurodegenerative disease whose symptoms can be whose symptoms can be readily treatable by readily treatable by medicationmedication

Levodopa treatment of PD: Levodopa treatment of PD: Breakthrough in the 20Breakthrough in the 20thth centurycentury

Treatment of Parkinson’s Treatment of Parkinson’s DiseaseDisease

Make correct diagnosisMake correct diagnosis Differentiate between Parkinson’s Differentiate between Parkinson’s

disease and Atypical Parkinsonismdisease and Atypical Parkinsonism Atypical Parkinsonism:Atypical Parkinsonism:

– Early speech and balance disorderEarly speech and balance disorder– Poor response to levodopaPoor response to levodopa– Less commonly characterized by Less commonly characterized by

tremortremor

Treatment of PDTreatment of PD

After diagnosis of PD is made, After diagnosis of PD is made, treatment depends on:treatment depends on:

– Functional disability of the symptomsFunctional disability of the symptoms– Work status of the patient Work status of the patient – The presence or absence of cognitive The presence or absence of cognitive

(mental) difficulties(mental) difficulties– The financial situation of the patientThe financial situation of the patient

Medications to Treat Medications to Treat PDPD Artane (Trihexyphenidyl)Artane (Trihexyphenidyl) Amantadine (Symmetrel)Amantadine (Symmetrel) Dopamine Agonists (Requip Dopamine Agonists (Requip

(ropinirole), Mirapex (ropinirole), Mirapex (pramipexole), Parlodel (pramipexole), Parlodel (bromocriptine), Permax (bromocriptine), Permax (pergolide), Apokyn(pergolide), Apokyn

Medications to Treat Medications to Treat PDPD

Eldepryl (Selegiline)Eldepryl (Selegiline) Sinemet Sinemet

(carbidopa/levodopa)(carbidopa/levodopa) COMT inhibitors, Comtan, COMT inhibitors, Comtan,

TasmarTasmar

LevodopaLevodopa

Chemical precursor of Chemical precursor of dopaminedopamine

Can cause nausea and Can cause nausea and vomitingvomiting

““Sine emesis”Sine emesis” Regular (10/100, 25/100), CR Regular (10/100, 25/100), CR

(25/100, 50/200)(25/100, 50/200)

Levodopa/Carbidopa Levodopa/Carbidopa (Sinemet)(Sinemet)

A combination of carbidopa A combination of carbidopa and levodopaand levodopa

Carbidopa is a peripheral Carbidopa is a peripheral decarboxylase inhibitordecarboxylase inhibitor

Carbidopa allows more Carbidopa allows more levodopa to pass through the levodopa to pass through the blood brain barrierblood brain barrier

LevodopaLevodopa

Most effective medication to Most effective medication to reduce or treat PD symptomsreduce or treat PD symptoms

PD patients will eventually need PD patients will eventually need levodopa in the form of Sinemetlevodopa in the form of Sinemet

Associated with higher incidence Associated with higher incidence of motor fluctuationsof motor fluctuations

Associated with earlier onset of Associated with earlier onset of dyskinesiadyskinesia

Dopamine AgonistsDopamine Agonists

Non-ergots: Requip and Non-ergots: Requip and MirapexMirapex

Ergots: Permax and Ergots: Permax and ParlodelParlodel

Apomorphine, CabergolineApomorphine, Cabergoline ApokynApokyn

Dopamine AgonistsDopamine Agonists

Act like dopamine in the brain at Act like dopamine in the brain at dopamine receptorsdopamine receptors

Do not need to be metabolized like Do not need to be metabolized like levodopalevodopa

Have longer half-lives than Have longer half-lives than levodopalevodopa

More expensive the levodopa, More expensive the levodopa, more cognitive side effectsmore cognitive side effects

Pramipexole (Mirapex)Pramipexole (Mirapex)

Pramipexole is a non-ergot Pramipexole is a non-ergot D2/D3 agonistD2/D3 agonist

Synthetic amino-benzathiazol Synthetic amino-benzathiazol derivativederivative

Side effects: somnolence, Side effects: somnolence, nausea, constipation, nausea, constipation, insomnia, hallucinationsinsomnia, hallucinations

Pramipexole (Mirapex)Pramipexole (Mirapex)

Effective is early MONOTHERAPY and Effective is early MONOTHERAPY and ADJUNCT therapyADJUNCT therapy

Compared to placebo in early disease, Compared to placebo in early disease, significantly improves motor function significantly improves motor function and activities of daily livingand activities of daily living

In one study, “off” time was reduced In one study, “off” time was reduced by 17% compared to 8% with placeboby 17% compared to 8% with placebo

Allows for the reduction of levodopaAllows for the reduction of levodopa

Pramipexole (Mirapex)Pramipexole (Mirapex)

CALM-PD Study (Comparison of the CALM-PD Study (Comparison of the agonist pramipexole with levodopa on agonist pramipexole with levodopa on motor complications of PD)motor complications of PD)

2 year study, 301 PD patients2 year study, 301 PD patients Patients were randomized to receive Patients were randomized to receive

pramipexole or levodopapramipexole or levodopa At study conclusion, patients assigned At study conclusion, patients assigned

to levodopa had greater improvement to levodopa had greater improvement in motor functionin motor function

CALM-PD studyCALM-PD study

Only 28% of patients on Only 28% of patients on pramipexole developed motor pramipexole developed motor fluctuations, compared to 51% of fluctuations, compared to 51% of patients on levodopapatients on levodopa

Somnolence, hallucinations, Somnolence, hallucinations, peripheral edema were more peripheral edema were more common in compared to 6% with common in compared to 6% with placeboplacebo

Ropinirole (Requip)Ropinirole (Requip)

Non-ergot dopamine agonistNon-ergot dopamine agonist Double-blind, placebo-controlled Double-blind, placebo-controlled

trials indicate that ropinirole is trials indicate that ropinirole is effective as mono- and adjunct effective as mono- and adjunct therapy in PDtherapy in PD

5-year study by Rascol et al5-year study by Rascol et al Patients randomized to ropinirole Patients randomized to ropinirole

or levodopaor levodopa

Ropinirole (Requip)Ropinirole (Requip)

The time to onset of dyskinesia The time to onset of dyskinesia was significantly longer in was significantly longer in patients taking ropinirole than patients taking ropinirole than levodopa (p < 0.001)levodopa (p < 0.001)

At 5 years, incidence of At 5 years, incidence of dyskinesia was 20% in the dyskinesia was 20% in the ropinirole group and 45% in the ropinirole group and 45% in the levodopa grouplevodopa group

Dopamine Agonists Dopamine Agonists and Somnolenceand Somnolence Somnolence, excessive Somnolence, excessive

daytime sleepiness, and sleep daytime sleepiness, and sleep attacks are associated with attacks are associated with virtually all antiparkinsonian virtually all antiparkinsonian medicationsmedications

Appear to be most common Appear to be most common with dopamine agonists.with dopamine agonists.

AnticholinergicsAnticholinergics

Artane (trihexyphenidyl)Artane (trihexyphenidyl) Used to reduce tremorUsed to reduce tremor One of the first One of the first

antiparkinsonian medicationsantiparkinsonian medications Initial therapy or adjunct Initial therapy or adjunct

therapytherapy

Trihexyphenidyl Trihexyphenidyl (Artane)(Artane) Side effects:Side effects:

– ConfusionConfusion– Memory ImpairmentMemory Impairment– HallucinationsHallucinations– Dry MouthDry Mouth– Blurred VisionBlurred Vision

Symmetrel Symmetrel (Amatadine)(Amatadine) An anti-viral medication with An anti-viral medication with

dopaminergic propertiesdopaminergic properties Initial therapy or adjunct therapyInitial therapy or adjunct therapy Provides mild to moderate benefitProvides mild to moderate benefit Neuropsychiatric side effects: Neuropsychiatric side effects:

confusion, hallucinations, confusion, hallucinations, nightmares, insomnianightmares, insomnia

Leg swelling, livdeo reticularisLeg swelling, livdeo reticularis Withdraw graduallyWithdraw gradually

Eldepryl (Selegiline)Eldepryl (Selegiline)

Irreversible MAO-B inhibitorIrreversible MAO-B inhibitor Developed as an anti-depressant; Developed as an anti-depressant;

metabolized to methamphetamine metabolized to methamphetamine Used as a Sinemet boosterUsed as a Sinemet booster No firm data to indicate that it No firm data to indicate that it

slows progression in PDslows progression in PD Should not be used in conjunction Should not be used in conjunction

with antidepressantswith antidepressants

COMT inhibitorsCOMT inhibitors

Entacapone (Comtan)Entacapone (Comtan) Tolcapone (Tasmar)Tolcapone (Tasmar)hepatic hepatic

toxicitytoxicity Allow more Sinemet to pass through Allow more Sinemet to pass through

the blood brain barrierthe blood brain barrier Can only be used in combination Can only be used in combination

with Sinemetwith Sinemet Diarrhea, mandatory monitoring of Diarrhea, mandatory monitoring of

liver function enzymes with Tasmarliver function enzymes with Tasmar

StalevoStalevo

Triple combination tablet of Triple combination tablet of levodopa/carbidopa/entacapone levodopa/carbidopa/entacapone in PD patientsin PD patients

Three strengths: 50/12.5/200, Three strengths: 50/12.5/200, 100/25/200 and 150/37.5/200 100/25/200 and 150/37.5/200 mgmg

StalevoStalevo

Reduces 3-OMD, a by-product of Reduces 3-OMD, a by-product of Sinemet that may interfere with its Sinemet that may interfere with its absorptionabsorption

Allows for 35% to 40% of levodopa to Allows for 35% to 40% of levodopa to pass through the blood brain barrier pass through the blood brain barrier (BBB)(BBB)

Without Comtan (Stalevo), only about Without Comtan (Stalevo), only about 10% of Sinemet tablet passes 10% of Sinemet tablet passes through BBBthrough BBB

Complications of Long-term Complications of Long-term Therapy with SinemetTherapy with Sinemet

Motor Fluctuations, dyskinesia, Motor Fluctuations, dyskinesia, predictable wearing-offpredictable wearing-off

On/Off statesOn/Off states DyskinesiaDyskinesia: involuntary abnormal : involuntary abnormal

movements associated with movements associated with medication intakemedication intake

Complications of Complications of medicationsmedications 50% of patients treated for 5 years 50% of patients treated for 5 years

of longer will develop motor of longer will develop motor fluctuationsfluctuations

90% will experience them by 15 90% will experience them by 15 years after diagnosisyears after diagnosis

Therapeutic windowTherapeutic window: target zone : target zone to treat patientsto treat patients

This window becomes narrower This window becomes narrower with timewith time

Continuous Dopaminergic Continuous Dopaminergic Stimulation (CDS)Stimulation (CDS) Dopamine neurons normally release Dopamine neurons normally release

dopamine in a stable, continuous dopamine in a stable, continuous mannermanner

In early PD, remaining dopamine In early PD, remaining dopamine neurons take up levodopa, convert it to neurons take up levodopa, convert it to dopamine, store it, and slowly release itdopamine, store it, and slowly release it

Over time, as more dopamine neurons Over time, as more dopamine neurons are lost, this storage and release are lost, this storage and release capacity is lostcapacity is lost

Continuous Dopamine Continuous Dopamine Stimulation (CDS)Stimulation (CDS) The loss of intraneuronal storage The loss of intraneuronal storage

and slow release capacity is and slow release capacity is expressed as a SHORTENED expressed as a SHORTENED duration of benefit from levodopaduration of benefit from levodopa

Once this capacity is lost, patients Once this capacity is lost, patients fluctuate in concert with levodopa fluctuate in concert with levodopa fluctuations in the bloodfluctuations in the blood

Information to have Information to have Ready for your doctorReady for your doctor Know all doses of medications and Know all doses of medications and

times they are takentimes they are taken Know whether dose of PD Know whether dose of PD

medication lasts from dose to dosemedication lasts from dose to dose Know how much dyskinesia the Know how much dyskinesia the

patient has, if any, during each patient has, if any, during each dose intervaldose interval

Know how long it takes for Know how long it takes for medication to take effectmedication to take effect

Information for your Information for your doctordoctor What percent of the day do you What percent of the day do you

have dyskinesia?have dyskinesia?

What percent of the day do you What percent of the day do you experience “off” time?experience “off” time?

This will help you determine what This will help you determine what the patient’s major problems arethe patient’s major problems are

Treatment of PDTreatment of PD

Disease of “timing”Disease of “timing” Doctor will carefully assess your Doctor will carefully assess your

motor and non-motor function motor and non-motor function during the dayduring the day

Information comes from patient Information comes from patient history, diaryhistory, diary

Treatment of PD: Treatment of PD: CasesCases 62 year old woman comes into 62 year old woman comes into

clinic with slight rest tremorclinic with slight rest tremor Diagnosed with PDDiagnosed with PD If the tremor doesn’t bother her, If the tremor doesn’t bother her,

we may do nothingwe may do nothing May use medication specifically May use medication specifically

for tremor, like artanefor tremor, like artane

Treatment of PD: Treatment of PD: casescases 56 year old man who comes into 56 year old man who comes into

the office with stiffness of one the office with stiffness of one arm, slowness, tremorarm, slowness, tremor

Symptoms are bothering himSymptoms are bothering him We would treat this patientWe would treat this patient Options include dopamine Options include dopamine

agonist, selegiline (usually hold agonist, selegiline (usually hold Sinemet until later)Sinemet until later)

Treatment of PD: Treatment of PD: casescases We will ask you what your major We will ask you what your major

symptom issymptom is If you are depressed, but motor If you are depressed, but motor

symptoms are well controlled, symptoms are well controlled, treat depressiontreat depression

Treatment of PD: Treatment of PD: casescases 70 year old woman who has had 70 year old woman who has had

PD for 5 yearsPD for 5 years She is taking Mirapex maximum She is taking Mirapex maximum

dosedose Medication is not lasting from pill Medication is not lasting from pill

to pillto pill At some point, it will be time to At some point, it will be time to

add SINEMETadd SINEMET

Treatment of PD: Treatment of PD: casescases Will consider other options before Will consider other options before

SinemetSinemet Eventually, PD patients will need Eventually, PD patients will need

to take Sinemetto take Sinemet

Treatment of PD: Treatment of PD: casescases We will ask you exact times you We will ask you exact times you

take your medicationtake your medication How much off time, dyskinesia, How much off time, dyskinesia,

tremor you have between dosestremor you have between doses

Treatment of PD: Treatment of PD: casescases As disease advanced, it may be As disease advanced, it may be

more difficult to treat patients more difficult to treat patients medicallymedically

At some point, patients may be At some point, patients may be referred to surgeryreferred to surgery