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Diagnosis and Management of Parkinson’s Disease. Theresa A. Zesiewicz, MD Associate Professor of Neurology University of South Florida. What is Parkinson’s Disease?. Neurologic disease caused by degeneration of dopamine neurons

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diagnosis and management of parkinson s disease

Diagnosis and Management of Parkinson’s Disease

Theresa A. Zesiewicz, MDAssociate Professor of Neurology

University of South Florida

what is parkinson s disease
What is Parkinson’s Disease?
  • Neurologic disease caused by degeneration of dopamine neurons
  • Only neurodegenerative disease whose symptoms can so readily be treated by medication
pathophysiology
Pathophysiology
  • Movement in the body is produced by the MOTOR CORTEX
  • Main motor pathway consists of the pyramidal system
  • The EXTRAPYRAMIDAL system (EPS) modulates the pyramidal system
  • EPS: substantia nigra, striatum, subthalamic nucleus, globus pallidus, thalamus
pathophysiology4
Pathophysiology
  • Normal movementdependent on dopamine production in the substantia nigra that innervates the striatum
  • PD is associated with massive degeneration of dopamine-producing neurons in substantia nigra
  • When 60 to 80% of these neurons are lost, symptoms of PD appear
parkinson s disease pathology
Parkinson’s Disease: Pathology
  • The pathognomic hallmark of the disease is the Lewy Body
  • It is found intracerebrally
  • Also found in the autonomic nervous system
clinical features of pd
Clinical Features of PD
  • Resting Tremor (70%)
  • Bradykinesia
  • Rigidity
  • Postural Instability
    • Signs start in one limb, usually an arm, and spread to the other limb on that side
parkinson s disease symptoms
Parkinson’s Disease Symptoms
  • Secondary features of the disease:
      • Depression
      • Dementia
      • Dysphagia
      • Anxiety
      • Orthostatic hypotension
      • Constipation
hoehn and yahr stages of pd
Hoehn and Yahr Stages of PD
  • Stage I: unilateral symptoms of disease
  • Stage II: bilateral symptoms of disease
  • Stage III: all of above, plus postural instability
  • Stage IV: all of above, plus patient need assistance
  • Stage V: patient cannot function independently
prognosis
Prognosis
  • First 5 years are the “honeymoon period”, and patients generally do well
  • Between 5 and 10 years, most patients experience medication-related difficulty
  • By 10 years, many develop poor balance
treatment of parkinson s disease
Treatment of Parkinson’s Disease
  • Neurodegenerative disease whose symptoms can be readily treatable by medication
  • Levodopa treatment of PD: Breakthrough in the 20th century
treatment of parkinson s disease11
Treatment of Parkinson’s Disease
  • Make correct diagnosis
  • Differentiate between Parkinson’s disease and Atypical Parkinsonism
  • Atypical Parkinsonism:
    • Early speech and balance disorder
    • Poor response to levodopa
    • Less commonly characterized by tremor
treatment of pd
Treatment of PD
  • After diagnosis of PD is made, treatment depends on:
    • Functional disability of the symptoms
    • Work status of the patient
    • The presence or absence of cognitive (mental) difficulties
    • The financial situation of the patient
medications to treat pd
Medications to Treat PD
  • Artane (Trihexyphenidyl)
  • Amantadine (Symmetrel)
  • Dopamine Agonists (Requip (ropinirole), Mirapex (pramipexole), Parlodel (bromocriptine), Permax (pergolide), Apokyn
medications to treat pd14
Medications to Treat PD
  • Eldepryl (Selegiline)
  • Sinemet (carbidopa/levodopa)
  • COMT inhibitors, Comtan, Tasmar
levodopa
Levodopa
  • Chemical precursor of dopamine
  • Can cause nausea and vomiting
  • “Sine emesis”
  • Regular (10/100, 25/100), CR (25/100, 50/200)
levodopa carbidopa sinemet
Levodopa/Carbidopa (Sinemet)
  • A combination of carbidopa and levodopa
  • Carbidopa is a peripheral decarboxylase inhibitor
  • Carbidopa allows more levodopa to pass through the blood brain barrier
levodopa17
Levodopa
  • Most effective medication to reduce or treat PD symptoms
  • PD patients will eventually need levodopa in the form of Sinemet
  • Associated with higher incidence of motor fluctuations
  • Associated with earlier onset of dyskinesia
dopamine agonists
Dopamine Agonists
  • Non-ergots: Requip and Mirapex
  • Ergots: Permax and Parlodel
  • Apomorphine, Cabergoline
  • Apokyn
dopamine agonists19
Dopamine Agonists
  • Act like dopamine in the brain at dopamine receptors
  • Do not need to be metabolized like levodopa
  • Have longer half-lives than levodopa
  • More expensive the levodopa, more cognitive side effects
pramipexole mirapex
Pramipexole (Mirapex)
  • Pramipexole is a non-ergot D2/D3 agonist
  • Synthetic amino-benzathiazol derivative
  • Side effects: somnolence, nausea, constipation, insomnia, hallucinations
pramipexole mirapex21
Pramipexole (Mirapex)
  • Effective is early MONOTHERAPY and ADJUNCT therapy
  • Compared to placebo in early disease, significantly improves motor function and activities of daily living
  • In one study, “off” time was reduced by 17% compared to 8% with placebo
  • Allows for the reduction of levodopa
pramipexole mirapex22
Pramipexole (Mirapex)
  • CALM-PD Study (Comparison of the agonist pramipexole with levodopa on motor complications of PD)
  • 2 year study, 301 PD patients
  • Patients were randomized to receive pramipexole or levodopa
  • At study conclusion, patients assigned to levodopa had greater improvement in motor function
calm pd study
CALM-PD study
  • Only 28% of patients on pramipexole developed motor fluctuations, compared to 51% of patients on levodopa
  • Somnolence, hallucinations, peripheral edema were more common in compared to 6% with placebo
ropinirole requip
Ropinirole (Requip)
  • Non-ergot dopamine agonist
  • Double-blind, placebo-controlled trials indicate that ropinirole is effective as mono- and adjunct therapy in PD
  • 5-year study by Rascol et al
  • Patients randomized to ropinirole or levodopa
ropinirole requip25
Ropinirole (Requip)
  • The time to onset of dyskinesia was significantly longer in patients taking ropinirole than levodopa (p < 0.001)
  • At 5 years, incidence of dyskinesia was 20% in the ropinirole group and 45% in the levodopa group
dopamine agonists and somnolence
Dopamine Agonists and Somnolence
  • Somnolence, excessive daytime sleepiness, and sleep attacks are associated with virtually all antiparkinsonian medications
  • Appear to be most common with dopamine agonists.
anticholinergics
Anticholinergics
  • Artane (trihexyphenidyl)
  • Used to reduce tremor
  • One of the first antiparkinsonian medications
  • Initial therapy or adjunct therapy
trihexyphenidyl artane
Trihexyphenidyl (Artane)
  • Side effects:
    • Confusion
    • Memory Impairment
    • Hallucinations
    • Dry Mouth
    • Blurred Vision
symmetrel amatadine
Symmetrel (Amatadine)
  • An anti-viral medication with dopaminergic properties
  • Initial therapy or adjunct therapy
  • Provides mild to moderate benefit
  • Neuropsychiatric side effects: confusion, hallucinations, nightmares, insomnia
  • Leg swelling, livdeo reticularis
  • Withdraw gradually
eldepryl selegiline
Eldepryl (Selegiline)
  • Irreversible MAO-B inhibitor
  • Developed as an anti-depressant; metabolized to methamphetamine
  • Used as a Sinemet booster
  • No firm data to indicate that it slows progression in PD
  • Should not be used in conjunction with antidepressants
comt inhibitors
COMT inhibitors
  • Entacapone (Comtan)
  • Tolcapone (Tasmar)hepatic toxicity
  • Allow more Sinemet to pass through the blood brain barrier
  • Can only be used in combination with Sinemet
  • Diarrhea, mandatory monitoring of liver function enzymes with Tasmar
stalevo
Stalevo
  • Triple combination tablet of levodopa/carbidopa/entacapone in PD patients
  • Three strengths: 50/12.5/200, 100/25/200 and 150/37.5/200 mg
stalevo33
Stalevo
  • Reduces 3-OMD, a by-product of Sinemet that may interfere with its absorption
  • Allows for 35% to 40% of levodopa to pass through the blood brain barrier (BBB)
  • Without Comtan (Stalevo), only about 10% of Sinemet tablet passes through BBB
complications of long term therapy with sinemet
Complications of Long-term Therapy with Sinemet
  • Motor Fluctuations, dyskinesia, predictable wearing-off
  • On/Off states
  • Dyskinesia: involuntary abnormal movements associated with medication intake
complications of medications
Complications of medications
  • 50% of patients treated for 5 years of longer will develop motor fluctuations
  • 90% will experience them by 15 years after diagnosis
  • Therapeutic window: target zone to treat patients
  • This window becomes narrower with time
continuous dopaminergic stimulation cds
Continuous Dopaminergic Stimulation (CDS)
  • Dopamine neurons normally release dopamine in a stable, continuous manner
  • In early PD, remaining dopamine neurons take up levodopa, convert it to dopamine, store it, and slowly release it
  • Over time, as more dopamine neurons are lost, this storage and release capacity is lost
continuous dopamine stimulation cds
Continuous Dopamine Stimulation (CDS)
  • The loss of intraneuronal storage and slow release capacity is expressed as a SHORTENED duration of benefit from levodopa
  • Once this capacity is lost, patients fluctuate in concert with levodopa fluctuations in the blood
information to have ready for your doctor
Information to have Ready for your doctor
  • Know all doses of medications and times they are taken
  • Know whether dose of PD medication lasts from dose to dose
  • Know how much dyskinesia the patient has, if any, during each dose interval
  • Know how long it takes for medication to take effect
information for your doctor
Information for your doctor
  • What percent of the day do you have dyskinesia?
  • What percent of the day do you experience “off” time?
  • This will help you determine what the patient’s major problems are
treatment of pd40
Treatment of PD
  • Disease of “timing”
  • Doctor will carefully assess your motor and non-motor function during the day
  • Information comes from patient history, diary
treatment of pd cases
Treatment of PD: Cases
  • 62 year old woman comes into clinic with slight rest tremor
  • Diagnosed with PD
  • If the tremor doesn’t bother her, we may do nothing
  • May use medication specifically for tremor, like artane
treatment of pd cases42
Treatment of PD: cases
  • 56 year old man who comes into the office with stiffness of one arm, slowness, tremor
  • Symptoms are bothering him
  • We would treat this patient
  • Options include dopamine agonist, selegiline (usually hold Sinemet until later)
treatment of pd cases43
Treatment of PD: cases
  • We will ask you what your major symptom is
  • If you are depressed, but motor symptoms are well controlled, treat depression
treatment of pd cases44
Treatment of PD: cases
  • 70 year old woman who has had PD for 5 years
  • She is taking Mirapex maximum dose
  • Medication is not lasting from pill to pill
  • At some point, it will be time to add SINEMET
treatment of pd cases45
Treatment of PD: cases
  • Will consider other options before Sinemet
  • Eventually, PD patients will need to take Sinemet
treatment of pd cases46
Treatment of PD: cases
  • We will ask you exact times you take your medication
  • How much off time, dyskinesia, tremor you have between doses
treatment of pd cases47
Treatment of PD: cases
  • As disease advanced, it may be more difficult to treat patients medically
  • At some point, patients may be referred to surgery