Diagnosis and Management of Parkinsons Disease

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Diagnosis and Management of Parkinsons Disease

• Theresa A. Zesiewicz, MDAssociate Professor of
  Neurology
• University of South Florida

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What is Parkinsons Disease?

• Neurologic disease caused by degeneration of
  dopamine neurons
• Only neurodegenerative disease whose symptoms can
  so readily be treated by medication

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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

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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

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Parkinsons Disease Pathology

• The pathognomic hallmark of the disease is the
  Lewy Body
• It is found intracerebrally
• Also found in the autonomic nervous system

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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

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Parkinsons Disease Symptoms

• Secondary features of the disease
• Depression
• Dementia
• Dysphagia
• Anxiety
• Orthostatic hypotension
• Constipation

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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

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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

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Treatment of Parkinsons Disease

• Neurodegenerative disease whose symptoms can be
  readily treatable by medication
• Levodopa treatment of PD Breakthrough in the
  20th century

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Treatment of Parkinsons Disease

• Make correct diagnosis
• Differentiate between Parkinsons disease and
  Atypical Parkinsonism
• Atypical Parkinsonism
• Early speech and balance disorder
• Poor response to levodopa
• Less commonly characterized by tremor

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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

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Medications to Treat PD

• Artane (Trihexyphenidyl)
• Amantadine (Symmetrel)
• Dopamine Agonists (Requip (ropinirole), Mirapex
  (pramipexole), Parlodel (bromocriptine), Permax
  (pergolide), Apokyn

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Medications to Treat PD

• Eldepryl (Selegiline)
• Sinemet (carbidopa/levodopa)
• COMT inhibitors, Comtan, Tasmar

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Levodopa

• Chemical precursor of dopamine
• Can cause nausea and vomiting
• Sine emesis
• Regular (10/100, 25/100), CR (25/100, 50/200)

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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

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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

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Dopamine Agonists

• Non-ergots Requip and Mirapex
• Ergots Permax and Parlodel
• Apomorphine, Cabergoline
• Apokyn

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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

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Pramipexole (Mirapex)

• Pramipexole is a non-ergot D2/D3 agonist
• Synthetic amino-benzathiazol derivative
• Side effects somnolence, nausea, constipation,
  insomnia, hallucinations

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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

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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

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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

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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

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Ropinirole (Requip)

• The time to onset of dyskinesia was significantly
  longer in patients taking ropinirole than
  levodopa (p
• At 5 years, incidence of dyskinesia was 20 in
  the ropinirole group and 45 in the levodopa group

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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.

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Anticholinergics

• Artane (trihexyphenidyl)
• Used to reduce tremor
• One of the first antiparkinsonian medications
• Initial therapy or adjunct therapy

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Trihexyphenidyl (Artane)

• Side effects
• Confusion
• Memory Impairment
• Hallucinations
• Dry Mouth
• Blurred Vision

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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

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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

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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

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Stalevo

• Triple combination tablet of levodopa/carbidopa/en
  tacapone in PD patients
• Three strengths 50/12.5/200, 100/25/200 and
  150/37.5/200 mg

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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

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Complications of Long-term Therapy with Sinemet

• Motor Fluctuations, dyskinesia, predictable
  wearing-off
• On/Off states
• Dyskinesia involuntary abnormal movements
  associated with medication intake

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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

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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

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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

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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

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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 patients
  major problems are

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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

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Treatment of PD Cases

• 62 year old woman comes into clinic with slight
  rest tremor
• Diagnosed with PD
• If the tremor doesnt bother her, we may do
  nothing
• May use medication specifically for tremor, like
  artane

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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)

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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

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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

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Treatment of PD cases

• Will consider other options before Sinemet
• Eventually, PD patients will need to take Sinemet

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Treatment of PD cases

• We will ask you exact times you take your
  medication
• How much off time, dyskinesia, tremor you have
  between doses

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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