Parkinson's Disease

Aka: Parkinson's Disease, Parkinsonism

1. Epidemiology
   1. Onset after age 50 years
   2. Prevalence: 0.3% in U.S. (4-5% over age 85 years)
   3. Associated with positive Family History in >25% cases
   4. More common in men
2. Pathophysiology
   1. Slow degeneration of substantia nigra in Midbrain
   2. Dopaminergic neurons degenerate
      1. Effects Extrapyramidal systems
         1. Start in substantia nigra pars compacta
         2. Continue via Striatum to Globus pallidus
         3. Basal ganglia project to cortex
      2. System regulates movement initiation and control
   3. Lewy bodies accumulate in residual Dopamine neurons
   4. Ascending process (Lower Brainstem affected first)
      1. Step 1: Medulla and later, Pons affected
         1. REM Sleep disorder
         2. Depression
         3. Dysautonomia
         4. Olfactory deficits
      2. Step 2: Midbrain and later basal forebrain affected
         1. Parkinsonian motor symptoms
      3. Step 3: Prefrontal cortex and ultimately neocortex affected diffusely
         1. Dementia
3. Signs
   1. Bradykinesia (PPV >4 when combined with rigidity)
      1. Smaller handwriting (micrographia) (PPV 2.8)
      2. Masklike stare
      3. Infrequent blink
      4. Slowed walking and dressing
      5. Soft Voice trails off
      6. Difficulty opening jars (PPV 6.1)
      7. Difficulty rolling over in bed (PPV 13)
   2. Impaired gait and Mobility
      1. Change in stride
      2. Poor Heel to toe gait (tandem walking) (PPV 2.9)
      3. Short, shuffling steps (PPV 3.3)
   3. Postural Instability
      1. Imbalance while walking or standing
      2. Frequent falls
      3. Stooping forward to maintain center of gravity
   4. Resting Tremor (primarily, although also displays Action Tremor as well)
      1. Hands and feet considerably affected
         1. Begins as low frequency, pill-rolling finger motion
         2. Progresses to involve Forearm pronation and supination
         3. Then involves elbow flexion and extension
      2. Also affects head, face, lips, Tongue, jaw and neck
      3. Presenting Symptom in 50-75% of Parkinson's patients
      4. Regular Rhythm (3-6 beats/sec)
      5. Tremor absent in up to 20% of Parkinson's Disease
   5. Rigidity (PPV >4 with Bradykinesia)
      1. Affects breathing, eating, swallowing, and speech
      2. Cogwheel rigidity or lead-pipe rigidity
   6. Secondary Effects
      1. Akathisia
      2. Cognitive Impairment
      3. Depression
      4. Fatigue
      5. Freezing of movement (motor blocks)
      6. Impotence
      7. Increased Salivation
      8. Orthostatic Hypotension,
      9. Paroxysmal drenching sweats
      10. Seborrheic Dermatitis
      11. Urinary frequency
      12. Decreased olfaction
      13. Micrographia
   7. Abbreviations
      1. PPV: Positive Predictive Value
   8. References
      1. Rao (2003) JAMA 289:347-53
4. Presentations: Atypical (often refractory to treatment)
   1. Rapidly progressive or early Dementia
   2. Rapidly progressive course
   3. Supranuclear gaze palsy
      1. Difficulty reading
      2. Loss of Down gaze
   4. Upper motor neuron signs
   5. Cerebellar signs (dysmetria, ataxia)
   6. Urinary Incontinence
   7. Early symptomatic Postural Hypotension
5. Diagnosis: Criteria
   1. Response to Levodopa or Dopamine agonist challenge and
   2. Classic symptoms and signs
      1. Distal resting Tremor at 3-6 beats per second (Hz)
      2. Rigidity
      3. Bradykinesia
      4. Asymmetric onset
         1. Parkinsonism usually presents with one limb affected more than others
         2. Common pitfall in missed diagnosis is ruling-out Parkinsonism based on asymmetry
6. Diagnosis: Findings that suggest alternative diagnosis
   1. Hallucinations
   2. Prominent and early Dementia
   3. Early postural instability
   4. Severe and early Autonomic Dysfunction
   5. Upward gaze paralysis
   6. Involuntary movements beyond Tremor
7. Differential Diagnosis: Secondary Parkinsonism
   1. Dementia with Lewy Bodies
      1. Resting Tremor often absent in Lewy Body Dementia
   2. Drug Induced Parkinsonism: Dopamine blocking drugs
      1. Metoclopramide (Reglan)
      2. Reserpine
      3. Antipsychotic (e.g. Haloperidol, Risperidone)
   3. Toxin-Induced Parkinsonism
      1. Manganese Poisoning
      2. Wilson's Disease
   4. Structural lesions
      1. Vascular Parkinsonism (CVA or TIA related)
      2. Cortical degeneration
      3. Brainstem infarction
      4. Multiple system atrophy (e.g. Shy-Drager syndrome)
   5. Hydrocephalus
      1. Normal Pressure Hydrocephalus
   6. CNS Infection
   7. Other Tremor
      1. Rest Tremor
      2. Essential Tremor (Subtype of Postural Tremor)
      3. Progressive Supranuclear palsy
         1. Vertical gaze paralysis and postural instability
         2. Olfaction is normal
8. Differential Diagnosis: Based on specific findings
   1. Stiff and slow without Tremor (seen in >20% of Parkinsonism)
      1. Progressive supranuclear palsy
   2. Isolated Tremor
      1. Essential Tremor
      2. Drug-Induced Tremor (e.g. Wellbutrin, Valproic Acid)
   3. Bradykinesia and gait change
      1. Advanced age
      2. Vascular Parkinsonism
   4. Dementia
      1. With mild Bradykinesia: Alzheimer's Disease
      2. With hallucinations: Lewy Body Dementia
      3. With Incontinence: Normal Pressure Hydrocephalus
   5. Prominent autonomic symptoms
      1. Shy-Drager Syndrome
9. Imaging
   1. SPECT Imaging
      1. Consider in unclear cases of Parkinsonism to differentiate from other causes
      2. Visualizes integrity of CNS Dopaminergic pathways
      3. Vlaar (2007) BMC Neurol 7:27
   2. MRI Head or CT Head
      1. Not routinely indicated
      2. Order if atypical presentation (see above)
      3. Evaluates for alternative diagnosis
10. Management: General Measures
    1. Consult neurology for all patients under age 60 years
    2. Adjunctive services
       1. Group support
       2. Disease specific education
       3. Nutrition guidance (Healthy Diet)
    3. Exercise guidance
       1. Stretching
       2. Strengthening
       3. Balance training
       4. Voice training
11. Management: Treatment Algorithm
    1. Precautions
       1. Levodopa is the most effective agent, but has serious Extrapyramidal Side Effects
       2. Longterm Levodopa causes Dyskinesias that may be permanent
       3. Delay starting Levodopa until it is indicated (see protocol below)
          1. However, start when there is any impact on activity
    2. No functional deficit (normal ADLs, quality of life)
       1. No medications needed
       2. See General Measures below
    3. Cognitive Changes and Functional Disability
       1. Conservative use of Sinemet
    4. No Cognitive changes
       1. No functional Disability
          1. Consider Selegiline (Eldepryl)
       2. Mild Functional Disability with Tremor predominant
          1. Consider Amantadine
          2. Consider Anticholinergics
             1. Trihexyphenidyl HCl (Artane)
             2. Benztropine mesylate (Cogentin)
       3. Moderate to severe functional Disability
          1. Sinemet SR
          2. Consider Dopamine agonists (see below)
    5. Late Stage Parkinson's Disease
       1. Characteristics
          1. Dyskinesia (involuntary Choreiform movements)
          2. Early wearing-off effect of levodopa
          3. On-Off fluctuations in motor activity
       2. Medication Adjuncts (used in consult with Neurology)
          1. Apomorphine (Apokyn): Dopamine agonist
          2. COMT Inhibitors: e.g. Entacapone (Comtan)
          3. MAO-B Inhibitors
          4. Amantadine
       3. Surgery
          1. Unilateral Pallidotomy
          2. Deep brain stimulation
12. Management: Dopa decarboxylase inhibitor/Dopamine precursors
    1. General pointers
       1. Sinemet (regular release) is by far the single most effective agent
          1. This agent should be the first line and main agent used for Parkinsonism
          2. All other agents are adjuncts only
       2. Dosing Threshold
          1. Identify the individual patient's optimal dose and use this dose at each dosing interval
          2. Using a lower dose below threshold will be inadequate
       3. Food Interactions
          1. Take at least one hour before a meal or 2 hours after a meal
       4. Wearing off of effect
          1. See frequency of dosing of Sinemet below
          2. Most common cause of Insomnia
          3. May cause anxiety, nocturnal cramps
       5. Dyskinesia (e.g. Choreiform movements)
          1. Dyskinesia is more age related than that of duration of levodopa use
          2. Reducing each levodopa dose decreases this adverse effect
          3. Amantadine decreases Dyskinesia
       6. Adverse Effects: Educate patients about serious effects (most are reduced by tapering dose)
          1. Drowsiness
          2. Pathologic Gambling, Hypersexuality, Excessive shopping/spending
          3. Hallucinations or Delusions
          4. Swelling
    2. Carbidopa/Levodopa (Sinemet)
       1. Preferred option over sustained release
          1. Lower cost
          2. Better pharmacokinetics
          3. Less drug interactions
       2. Start at 25/100 orally three times daily
       3. Increase by one tablet every 1-2 days as needed
       4. Maximum : 3 tablets per dose
       5. Frequency of dose
          1. Initially give dose three times daily
          2. Long term, dose may wear off early
             1. Frequency may need to be increased to every 6 hours (at same number of tablets at each dose)
    3. Carbidopa/Levodopa Sustained release (Sinemet CR)
       1. Start at 50/200 PO bid
       2. Increase by one tablet every 3 days as needed
       3. Maximum : 8 tablets daily
       4. No benefit over immediate release in motor function
    4. Carbidopa/Levodopa/Entacapone (Stalevo)
       1. Start at 12.5/50/200 PO bid
       2. Increase slowly
       3. Maximum : 8 tablets daily
    5. Rotigotine Transdermal
       1. Dopamine agonist transdermal patch
       2. Dosing
          1. One patch applied daily to a new site
          2. Do not repeat the same site for 14 days
          3. Start at 2 mg/24 hours
          4. May increase weekly to a maximum of 6 mg/24 h
13. Management: Other Medications
    1. Dopamine Agonist
       1. Bromocriptine mesylate (Parlodel)
          1. Start at 1.25 mg PO bid
          2. Increase every 2 weeks to 5-20 mg PO bid
          3. Half life: 3-8 hours
          4. Hepatic metabolism
       2. Ropinirole (Requip)
          1. Start at 0.25 mg PO tid
          2. Increase every week to 1 mg PO tid
          3. Half life: 6 hours
          4. Hepatic metabolism
       3. Pramipexole (Mirapex)
          1. Start at 0.125 mg PO tid
          2. Increase every week to 1.5 mg PO tid
          3. Half life: 7-17 hours
          4. Minimal metabolism
       4. Pergolide mesylate (Permax): Not recommended
          1. Half life: 27 hours
          2. Hepatic metabolism
          3. Risk of valvular disease and Pulmonary Hypertension
             1. Van Camp (2004) Lancet 363:1179-83
    2. Monoamine oxidase Type B inhibitor
       1. Selegiline HCL (Eldepryl) 5 mg at breakfast and lunch
       2. Rasagiline (Azilect)
    3. Anticholinergic Medications
       1. Preparations
          1. Trihexyphenidyl HCl (Artane)
             1. Artane 4-10 mg/day divided tid
          2. Benztropine mesylate (Cogentin)
             1. Cogentin 1-4 mg/day divided qd-bid
       2. Adverse effects (limit use to under age 70)
          1. Memory Impairment
          2. Hallucinations
          3. Dry Mouth
          4. Urinary difficulty
          5. Blurred vision
    4. Adjunctive Agents (Vitamin supplementation)
       1. Amantadine HCL (Symadine, Symmetrel)
          1. Decreases levodopa induced motor disorder
          2. Continue long-term
          3. Metman (1999) Arch Neurol 56:1383-6
       2. Conenzyme Q10 360-1200 mg PO daily
          1. Shults (2002) Arch Neurol 59:1541-50
    5. COMT Inhibitors
       1. Indications
          1. Late-stage Parkinson's Disease
       2. Mechanism
          1. Extends Levodopa half-life
       3. Agents
          1. Entacapone (Comtan)
          2. Tolcapone (Tasmar)
       4. Adverse effects
          1. Rare lethal hepatotoxicity (closely watch Liver Function Tests)
14. Associated Conditions
    1. Constipation
       1. Increase fluids and fiber
       2. Wean anticholinergics
       3. Consider Lactulose, enemas
    2. Major Depression
    3. Cognitive Impairment
       1. Wean any anticholinergics
       2. Consider cholinesterase inhibitors
    4. Dysphagia
       1. Swallowing evaluation
       2. Use adjuncts to extend medication active time
       3. Eat during "on" time and stick to soft foods
    5. Urine urgency
       1. Consider Oxybutynin (Ditropan)
    6. Psychosis or hallucinations
       1. Wean anticholinergics, Dopamine agonists, Amantadine
       2. Decrease Levodopa dosing
       3. Consider low dose Antipsychotics
          1. Clozapine (Clozaril)
          2. Quetiapine (Seroquel)
    7. Sleep disturbance
       1. Daytime somniolence: Stop Dopamine agonists
       2. Awakens from Bradykinesia
          1. Dose Sinemet before bed or
          2. Use COMT Inhibitor or
          3. Dopamine agonist
       3. REM Sleep problem
          1. Decrease nighttime anti-parkinson drug dose and
          2. Consider Clonazepam (Klonopin)
15. References
    1. Ahlskog (2011) Mayo Internal Medicine Review Lecture
    2. Schim (2001) CMEA Medicine Lecture, San Diego
    3. Clarke (2003) Clin Evid 10:1582-98
    4. Clarke (2004) Lancet Neurol 3:466-74
    5. Nutt (2005) N Engl J Med 353:1021-7
    6. Olanow (2001) Neurology 56:S1-88
    7. Rao (2006) Am Fam Physician 74:2046-56
    8. Young (1999) Am Fam Physician 59(8):2155-67