Parkinson's Disease 2009

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      Parkinson’s Disease 2009                                                                      • Identify and reinforce the spectrum of motor and
                                                                                                      nonmotor symptoms associated with early PD.
        Redefining Treatment Success in                                                             • Illustrate specific early red-flags used by generalists to
       Patients With Parkinson’s Disease                                                              differentiate early PD from other disorders.
                                                                                                    • Discuss treatment strategies for the management of
                                                                                                      early PD in a primary care setting.
               G. Barry Robbins, Jr. D.O., FACN
           Chair Dept. of Neurobehavioral Sciences                                                  • Outline and discuss the medications available for
                         ATSU/KCOM                                                                    management of early PD, their indications, and
                                                                                                      adverse effects.
                                                                                                    • Summarize approaches to advancing disease and end-
                                                                                                      of-life issues.

           Parkinson’s Disease:
                                                                                                                    PD Introduction
• Progressive neurodegenerative disorder that                                                       • Early diagnosis is essential to maintain the
  causes motor and nonmotor dysfunction                                                               highest quality of life.
   – Characterized by loss of dopaminergic neurons                                                  • Wide range of treatment options must be
     in substantia nigra pars compacta                                                                individualized to each patient.
   – Can affect other areas of the nervous system
     including the autonomic and enteric nervous
• Second most common neurodegenerative
  disorder after Alzheimer’s disease

           Epidemiology (PD)                                                                                          Epidemiology

 • Affects 1 to 1.5 million people in the                                                           • Incidence rate
   United States alone                                                                                 – 11/100,000 in the general population
 • 30,000 new diagnoses/year.                                                                          – 50 per 100,000 in those over 50.
 • Direct and indirect costs associated with                                                        • Median onset age 62.
   PD exceed $20 billion annually in United                                                         • Rare <30yrs of age (4-10% of cases by 40
                                                                                                    • Men > women
 • Number of PD cases in individuals ≥50
   years predicted to reach 8.7 million
   worldwide in next 25 years2
                                        1. Weintraub et al. Am J Manag Care. 2008;14(2):S49-S58.
                                                  2. Dorsey et al. Neurology. 2007;68(5):384-386.


                                                                                                                                                                                   Models of Causation of Parkinson’s Disease
                                        Age-Specific Prevalence of PD
                                                                                                                                                                                                              Normal Aging
                                                                                                                                                                                                                                  Environmental Toxins

                                                                                                                                                          % Striatal Dopamine
                                                2005 estimate                                                                                                                                                                     Free radicals
                                                2030 estimate
                             5.0                                                                                                                                                                                                  Genetics
                                                                                                                                                                                              Decreased                           Brain trauma
Prevalence of PD, millions

                             4.0                                                                                                                                                 50            at birth
                             3.0                                                                                                                                                                                                                                 Aging

                                                                                                                                                                                                    Parkinsonian Symptom Threshold
                             1.0                                                                                                                                                  0

                             0.0                                                                                                                                                      0                               60                                                             120
                                                                                                                                                                                                             Age (Years)
















                                                                                       PD, Parkinson’s disease; UK, United Kingdom; US, United States.
                                                                                                           Dorsey et al. Neurology. 2007;68(5):384-386.

                             Risk Factors and Protective Factors                                                                                                                                               Genes
                        • Most cases = genetic? + environmental risk factors ?                                                                                        • 13 genes in familial PD
                        • Risk factors:                                                                                                                                            – LRRK2 - the autosomal dominant gene, encodes a
                                   – Greatest single risk factor is advancing age.
                                                                                                                                                                                     protein of unknown function
                                   – Family history = 1st-degree Relatives = 3X risk
                                   – Exposure to pesticides, rural living, well water.                                                                                             – Glucocerebrosidase - the autosomal recessive
                        • Protective factors:                                                                                                                                        gene responsible for Gaucher disease is found in
                                   – Tobacco smoking                                                                                                                                 3% in PD cases
                                   – Caffeine                                                                                                                                      – Parkin - autosomal recessive gene found in 15%
                                        • Decreased risk in men                                                                                                                      of early-onset and familial PD < 40 years
                                        • HRT + low caffeine = decreased risk
                                        • HRT + high caffeine = increase risk

                                                                Diagnosis                                                                                                                       Motor Features of PD
                        •     By clinical observation and excluding other dx.
                                                                                                                                                                                                          • 75% of patients
                        •     No lab test available to confirm PD                                                                                                               Resting tremor1,2         • “Pill-rolling” tremor in hands
                        •     Many complaints attributed to “old age”.                                                                                                                                    • Can involve lips, chin, jaw, legs
                                                                                                                                                                                                          • 80% to 90% of patients
                        •     Nonmotor symptoms may have a greater impact                                                                                                       Bradykinesia1,3,4
                                                                                                                                                                                                          • Most disabling symptom of PD
                              on quality of life than motor symptoms.                                                                                                                                     • >90% of patients
                                   – When prominent early neither patient nor physician                                                                                         Rigidity1,4               • “Cogwheel” (fluctuating) or “lead pipe”
                                     may associate them with PD
                                                                                                                                                                                                          • Indicative of advanced-stage PD
                                   – Depression, anxiety, shoulder bursitis, and muscle                                                                                         Postural instability1
                                                                                                                                                                                                          • Frequent cause of falls
                                                                                                                                                                                                                        1. Jankovic. J Neurol Neurosurg Psychiatry. 2008;79(4):368-376.
                                                                                                                                                                                                                        2. Bhidayasiri. Postgrad Med J. 2005;81(962):756-762.
                                                                                                                                                                                                                        3. Berardelli et al. Brain. 2001;124(pt 111):2131-2146.
                                                                                                                                                                                                                        4. Weintraub et al. Am J Manag Care. 2008;14(2 suppl):S40-S48.


                                                                                                                                           Clues of PD from the History
                      Evolution of Parkinson’s Disease                                                           Motor                  Sensory                Cognitive               Autonomic
                                                                                                                 Slowness               Pain                   Mood changes            Hot/cold sensation
                                                                                                                 Tremor                 Aching                 Depression              Bladder problems
                          Non-motor           Motor                Treatment
                                                                                                                 Stiffness              Restlessness           Anxiety                 Sweating
                          Phase               Phase                Phase
                                                                                                                 Postural instability   Paresthesia            Panic attacks           Abdominal
                                                                                                                 Stooped, shuffling    Chest discomfort        Tiredness               Constipation
Progression                                                                                                      gait
                                                                                                                 Decreased arm swing Anosmia                   Confusion               Sialorrhea
                                                                                                                 when walking
                                                                                                                 Lower extremity                               Slowed thinking         Urinary
                                                                                                                 cramps                                                                frequency/urgency
                                                                                                                 Weakness                                                              Erectile dysfunction
                                                                                                                 Swallowing difficulty
                                                                                                                 Reduced dexterity
                                                      Diagnosis                                                  Masked facies

                                                                                                                       Potential Premotor Biomarkers for
                 Nonmotor Features of PD
                                                                                                                           Parkinson’s Disease (PD)
                                      • Depression in up to 40% of patients
     Psychiatric disorders1
                                      • Anxiety in ~30% of patients                                                               Strong link to PD                          Weak link to PD

                                      • Mild cognitive impairment                                                       • Olfactory dysfunction                  • Excessive daytime sleepiness
     Cognitive disorders1,2
                                      • Dementia in 15% to 40% of patients                                              • REM Sleep Behavioral Disorder          • Adiposity
                                      • >70% of patients                                                                • Autonomic dysfunction (eg,             • Apathy
     Sleep    abnormalities1,3
                                      • REM sleep behavior disorder                                                       constipation, MIBG uptake
                                                                                                                                                                 • Fatigue
                                                                                                                          on heart scan)
                                      • Constipation
     Autonomic dysfunction1-3                                                                                                                                    • Anxiety
                                      • Orthostatic hypotension                                                         • Depression
                                                                                                                                                                 • RLS
     Sensory3                         • Olfactory dysfunction

     Miscellaneous1,2                 • Fatigue and weight loss

                                                                                                                                                                  MIBG = metaiodobenzylguanidine
                                               1. Thanvi et al. Postgrad Med J. 2003;79(936):561-565.                                                             RLS = restless legs syndrome.
                                               2. Fahn and Sulzer. NeuroRx. 2004;1(1):139-154.
                                               3. Jankovic. J Neurol Neurosurg Psychiatry. 2008;79(4):368-376.

                                      Tremor                                                                                   Differential Diagnosis of Parkinsonism
                                      PD vs ET
                                                                                                                                                       1 Degenerative                Secondary
                       PD                                                 ET                                                                            Parkinsonism                Parkinsonism

         Tremor plus other signs                                Tremor only
                                                                                                                                         PSP               MSA               CGBD              •Stroke
       Rest tremor predominates                 Postural and action tremor                                                                                                                     •Tumor
                                                      predominates                                                                                       Striatonigral                         •CO
                                                                                                                                                         Degeneration                          •Manganese
          Response to levodopa                     Response to alcohol                                                                                     (MSA-P)                             •Medications

                                                                                                                                                          Shy Drager
         *Both PD and ET can have kinetic and rest components of
         tremor, but ET is consistently postural and kinetic, usually                                                                                       OPCA
         lessening at rest.


Progressive Supranuclear Palsy (PSP)                                                                                                 Supranuclear
                      Steele-Richardson-Olszewski syndrome                                                                           Palsy
 •   Most Common of the PD+ syndromes
 •   Onset around 60 years of age
                                                                                                                                    Facial appearance
 •   Men > Women
                                                                                                                                    “Poker face”
 •   Insidious - symmetrical
      – Postural instability – retropulsion
      – Bradykinesia
      – Axial rigidity – not limbs
 • Later – vertical gaze palsy (downward)
      – Awkward when eating
      – “Poker-faced”
      – Cervical dystonia - retrocollis
 • Higher incidence of dementia
 • CAT – atrophy of midbrain

                                                                                                Vertical Gaze Paresis
                                                               Supranuclear                                                         Paresis downward gaze

                                                           “Cervical dystonia”                                                           Upward gaze
                                                            (neck extension)
                                                                                                                                     Relatively preserved

                                                                                                                                     Right horizontal gaze intact

                                                                                                                                      Left horizontal gaze intact

             Multiple System Atrophy                                                     Corticobasal Degeneration
• Shy Drager Syndrome (men > women)                                              •   Insidious onset in the 60s
     – Autonomic dysfunction                                                     •   Men > Women
        • Early - bowel & bladder dysfunction – in their 50s                     •   Asymmetrical clumsiness of an upper limb
        • Later - orthostatic hypotension                                        •   Associated with an action tremor
     – Parkinsonism                                                              •   Early
• Striatonigral degeneration                                                         – prominent postural instability
                                                                                     – Sensory signs (paresthesia and hypothesia)
     – Tremor is usually lacking
                                                                                 • Classic feature “alien limb phenomenon”
     – Akinetic-rigid parkinsonism                                               • Cognitive
• Sporadic Olivopontocerebellar atrophy                                              – Apraxia of eyelid opening
     – Cerebellar signs                                                              – Impairment of visuospatial and constructive functions
        • Lower limbs earlier than upper                                         • MRI –Asymmetrical fronto-temporal atrophy contralateral to
                                                                                   the affected limb
        • Dysarthria
     – Parkinsonism


                      Characteristics                                           Secondary Causes of Parkinsonism
           Atypical parkinsonian syndromes
•   Rapid progression                                                         • Drug exposure (dopamine-blocking or dopamine-
•   Early onset of dementia or hallucinations                                   depleting drugs)
                                                                                 – Antipsychotics
•   Early onset of loss of balance with falls                                    – Antidepressants
•   Early and prominent autonomic signs                                          – Antiemetics (Reglan)
    – Urinary incontinence                                                    • Toxins (manganese and carbon monoxide)
    – Orthostatic hypotension                                                 • Thyroid disorders
•   Upper motor neuron signs                                                  • Vascular or structural lesions/Normal pressure
•   Ataxia, dysmetria, or other cerebellar signs                                hydrocephalus
•   Diplopia, any abnormal eye movements                                      • Cervical stenosis (urinary frequency, peripheral
                                                                                hyperreflexia with normal jaw jerk)
•   Lack of response to levodopa

     Drugs That May Cause Secondary
Antipsychotics and tranquilizers       Thioridazine (Mellaril)
Acetophenazine (Tindal)                Thiothixene (Navane)
Chlorpromazine (Thorazine)             Trifluoperazine (Stelazine)
Fluphenazine (Permitil, Prolixin)      Triflupromazine (Vesprin)
Haloperidol (Haldol)                   Antiemetics
Loxapine (Loxitane, Daxolin)           Metoclopramide (Reglan)
Mesoridazine (Serentil)                Thiethylperazine (Torecan)
Molindone (Lindone, Moban)             Antidepressants/bipolar treatments
Olanzapine (Zyprexa)                   Amoxapine (Asendin)
Perphenazine (Trilafon or Triavil)     Olanzapine plus fluoxetine (Symbyax)
Piperacetazine (Quide)                 Perphenazine plus amitriptyline
Prochlorperazine (Compazine, Combid)   (Etrafon, Triavil)
Promazine (Sparine)                    Antihistamines
Risperidone (Risperdal)                Trimeprazine (Temaril)

                  Dopamine Projection Systems                                                        Braak Model
                                                                                            Staging of a-synuclein pathology
                                                                                    thought to be associated with the evolution of PD

                                                                                Braak Stages 1 & 2     Braak Stages 3 & 4    Braak Stages 5 & 6
                                                                                    Preclinical           Clinical PD       Cognitive impairment


Braak Model for Pathologic Staging of                              Imaging Biomarkers for Parkinson’s
        Parkinson’s Disease                                                   Disease (PD)
• Based on Lewy body localization                             Method               Tracer                        Assessment                            Expected results with PD

• Suggests that Lewy body pathology does not
                                                              fMRI1                   NA          Indirect marker of neuronal activity             ↓ activation in specific brain areas

                                                              SPECT1,2           [123I]b-CIT      DA transporter levels                            ↓ levels

  begin in substantia nigra                                                   [99mTc]TRODAT
                                                              PET1,2               [18F]DOPA      Estimate number of DA terminals and nigral       ↓ levels
    – Begins in dorsal motor nucleus of                                                           neurons
                                                              PET1,2               [11C]DTBZ      VMAT2 as estimate of number of DA terminals      ↓ levels
      glossopharyngeal and vagus nerves, anterior                                                 and nigral neurons

      olfactory nucleus, and enteric nerve cell plexus        PET1,3               [11C]RAC       • Striatal DA receptor availability
                                                                                                  • Estimate synaptic DA concentration
                                                                                                                                                   • Early PD: ↑ in putamen
                                                                                                                                                   • Advanced PD or after chronic DRT: ↓
                                                                                                                                                     in caudate
    – Proceeds in rostral direction toward neocortex          PET1,2,4               FDG          Metabolic activity of basal ganglia network      ↑PDRP and PDCP

• Progression of Parkinson’s Disease may not always comply
  with this model                                            11C = carbon 11;18F = fluoride 18;99mTc= technetium 99 metastable nuclear isomer;  123I
                                                                                                                                                  = iodine 123; β-CIT = 2β-carbomethoxy-
                                                             3-β (4-iodophenyl) tropane; DA = dopamine; DTBZ = dihydrotetrabenazine; FDG = fluorodeoxyglucose; fMRI = functional
                                                             magnetic resonance imaging; MP = d-threo-methylphenidate; NA = not applicable; PDCP = PD-related cognitive pattern; PDRP
                                                             = PD-related motor pattern; PET = positron emission tomography; RAC = raclopride; SPECT = single-photon emission
                                                             computerized tomography; VMAT2 = vesicular monoamine transporter type 2.

                                                               Fluorodeoxyglucose PET imaging
                                                                             PD-related motor pattern                                     PD-related cognitive pattern

[18F]dopa PET


                                                                    Current Therapies for Parkinson’s
         Symptomatic Treatment
1. Reasons to Begin Symptomatic Treatment
   – Improve quality of life
   – Maintain ability to work
   – Reduce disability
2. Regular aerobic exercise
3. Early treatment > delayed treatment in                                                                                   1%

   maintaining quality of life


   Current Therapies for Parkinson’s                                         PD Medications
               Disease                                  Class                   Drug

                                                        Anticholinergic         Trihexyphenidyl, Artane.

                                                        COMT inhibitor          Entacapone, Comtan; Stalevo (with levodopa).

                                                        Dopamine agonist        Pramipexole, Mirapex; ropinirole; Requip,
                                                                                bromocriptine, Parlodel; cabergoline, Dostinex;
                                                                                rotigotine, Neupro (transdermal patch), apomorphine,
                                                                                Apokyn (subcutaneous injectable solution).
                                                        Dopamine precursor      Levodopa (with carbidopa), Sinemet; Stalevo, (with
                                                                                entacapone); Parcopa, (orally disintegrating tablet).
                   10%         70%
                                                        MAO-B inhibitors        Rasagiline, Azilect; selegiline, Eldepryl and Zelepar,
                                                                                (orally disintegrating tablet).
                                                        Other                   Amantadine, Symmetrel.

Considerations in Treatment of PD                                                Levodopa
                                                                             Symptomatic Treatment

• The age and overall health of the patient             Initial Treatment Considerations
• Concern for development of motor                      1.      No definitive neuroprotective therapy
  complications                                         2.      Younger patients: minimize long-term
• Comorbidities                                                 dyskinesia risk => DA
   – Dementia                                           3.      Older patients: minimize cognitive effects =>
   – Orthostatic hypotension                                    levodopa
   – Sleep disorders                                    4.      Mild symptoms => nondopaminergic
   – Polypharmacy                                               medication
• Cost of medications                                   5.      Warn patients about sudden onset of sleep on
                                                                a DA or levodopa

                   Levodopa                                                  Neupro Crystals
• Levodopa/carbidopa (Sinemet)
  Start at ½ tablet 3× daily, then raise to 1 tablet,
  3× daily
  Evaluate at 1 month, adjust upward if necessary
  Take 1 hour before meals
  AE: nausea, postural hypotension, drowsiness
• Dosing levodopa near a protein meal may
  significantly reduce uptake from the GI tract in
  some patients


                                  Dopamine Agonists                                            COMT Inhibitors
• Pramipexole (Mirapex)                                                     • Entacapone (Comtan)
  Start at 0.125 mg 3× daily
  Titrate over 6 weeks to 3.0 mg/day                                          200 mg with each levodopa dose
  AE: nausea, postural hypotension, psychosis,                                AE: diarrhea, dopaminergic effects
  ankle edema, drowsiness
• Ropinirole (Requip)                                                           Tolcapone (Tasmar)
  Start at 0.25 mg 3× daily
  Titrate over 6-8 weeks to 8 mg/day; Requip XL                                 100 mg 3× daily; can raise to 200 mg 3× daily
  1x daily                                                                      AE: diarrhea, dopaminergic effects
  AE: nausea, postural hypotension, psychosis,                                  Liver monitoring
  ankle edema, drowsiness

                                      MAO-B Inhibitors                               Putative Neuroprotection

                                                                                Selegiline (Eldepryl)
       Selegiline (Eldepryl)                                                    DOSING 5 mg 1×/day, up to 5 mg 2×/day
       DOSING 5 mg 1×/day, up to 5 mg 2×/day                                    AE: insomnia, hallucinations
       AE: insomnia, hallucinations
                                                                                Rasagiline (Azilect)
       Rasagiline (Azilect)                                                     DOSING 0.5 mg 1×/day, up to 1 mg 1×/day
       DOSING 0.5 mg 1×/day, up to 1 mg 1×/day                                  AE: uncommon with monotherapy
       AE: uncommon with monotherapy
                                                                                Coenzyme Q10 (Nutritional supplement)
       .                                                                        DOSING: 1200 mg/day
                                                                                AE: unknown (relative bioavailability differs by brand) .

     Delayed-Start Rasagiline Results in Smaller UPDRS
                      Score Changes                                               Rasagiline Contraindications
                                                                            • Meperidine, Tramadol, methadone, propoxyphene
                                                                            • Dextromethorphan
                                                                            • St. Johns wort, mirtazapine, cyclobenzaprine
                                                                            • Pseudoephedrine, phenylephrine, phenylpropanolamine,
                                                                            • MAO inhibitors
                                                                            • Elective surgery requiring:
                                                                                – General anesthesia
                                                                                – Cocaine or local anesthesia with vasoconstrictors
                                                                            • If surgery is necessary: Benzodiazepines, mivacurium,
                                                                              rapacuronium, fentany, morphine, and codeine may be used
UPDRS = Unified Parkinson’s Disease Rating Scale.
The Parkinson Study Group. Arch Neurol. 2004;61:561-566. With permission.


                       Anticholinergics                                                    Amantadine
    • Trihexyphenidyl (Artane) 2-6mg/d                            • Dosage:100 mg 1-2 × daily;
    • Limited benefit for tremor
                                                                  • AE: confusion, dry mouth, hallucinations,
    • Significant antimuscarinic adverse effects in the
      elderly                                                       livedo reticularis
        –   Confusion
        –   Dry mouth
        –   Urinary retention
        –   Blurred vision
        –   Constipation
    • Rarely used in elderly, limited utility in young patients

                  Motor Complications
                                                                          Prevalence of Off Episodes
    •   Wearing off = 5 years of treatment
    •   Delay to turning on = may take 30-45 minutes                       Up to            Approximately                More than
    •   On-off periods = unpredictable                                     50%                    70%                        90%
    •   Dyskinesias = during peak effect of medication
                                                                  of PD patients treated   of PD patients treated   of young-onset patients
    •   Dystonia = painful (foot or leg) early A.M.               with levodopa for        with levodopa for 9      (who develop PD
                                                                  5 years or more          years or more            symptoms before the
    •   Freezing = occurs late in disease                         experienced off          experienced off          age of 40 years) treated
                                                                  episodes.                episodes.                with levodopa for 5
    •   Falling = due to worsening postural instability                                                             years developed off

                                                                           Treatment of Wearing Off
                                                                  •   Add a DA
                                                                  •   Add a COMT inhibitor
                                                                  •   Increase dose of dopaminergic therapy
                                                                  •   Substitute sustained-release levodopa
                                                                  •   Adjust diet - protein
                                                                  •   Adjust timing of drug
                                Typical Day
                                                                  •   Increase gastric motility


       Treatment of Dyskinesias                                          Surgical Options
• Reduce levodopa dose                                     • Deep brain stimulation (DBS) of the globus
• Increase frequency of levodopa dosing                      pallidus or of the subthalamic nucleus is
                                                             recognized to be potentially beneficial.
• Add adjunct medications                                  • The best candidates for surgery are patients
   – Dopamine agonist                                         – who have little or no cognitive impairment
   – COMT Inhibitor                                           – who have no significant medical problems
• Switch to controlled-released levodopa                      – who remain responsive to levodopa.
• Add amantadine                                           • Stem cell therapy offers hope but is unproven
                                                             at this time.

        Key Points: Summary                                          Key Points: Summary
                                                           • Treatment should be individualized depending on
  • Global burden of PD will increase over next              the patient's lifestyle and symptoms.
    25 years
                                                           • Levodopa-carbidopa is generally the first-choice
  • Diagnosing PD is challenging                             medication, especially for elderly patients, and
     – Recognition of subtle, nonmotor signs crucial for     complications may limit its long-term use.
       early diagnosis
                                                           • Dopamine agonists are often introduced with
  • Parkinson's disease is characterized by
    tremor at rest, rigidity, bradykinesia,                  levodopa-carbidopa early after disease onset, and
    stooped posture, loss of postural reflexes,              may be the first choice in younger patients.
    and beneficial response to levodopa-

          Key Points: Summary                                      Key Points: Summary
• Early use of a monoamine oxidase type-B inhibitor        • Because PD is a progressive disorder, early diagnosis
  in patients with mild impairment may be effective          and treatment intervention with neuroprotective
  at reducing symptoms and for potential                     therapies to slow or prevent further degeneration
  neuroprotection.                                           and to promote neuronal repair are current goals in
                                                             the management of PD
• Deep Brain Stimulation may be considered for             • The development and validation of diagnostic
  patients with disabling symptoms refractory to             markers in symptom recognition and neuroimaging
  medications, especially in relatively young patients        – will aid in early diagnosis of PD
  with intact cognition.
                                                              – will also improve evaluation of potential
                                                                neuroprotective therapies


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