Bannon: Movement Disorders

Question 1

Parkinson’s Disease

General:

Answer 1

• Movement disorder

- Age is a prominent risk factor (5-10% of people over the age of 85)

Question 2

Parkinson’s Disease

Clinical Features: (4)

Answer 2

Bradykinesia (slowness of movement and difficulty initiating movement)

Muscular (cogwheel) rigidity

Resting tremor (pill-rolling)

Impairment of postural stability

• Festination (falling forward)
• Retropulsion (falling backward)

Question 3

Parkinson’s Disease

Clinical Presentation: (4)

Answer 3

Early: presentation may be subtle
o	Unilateral weakness or fatigue
o	Weak voice
o	Micrographia (really small writing)
o	Olfactory losses

Question 4

Parkinson’s Disease

Comorbidities:

Answer 4

Comorbidities: depression and dementia are common

Question 5

Parkinson’s Disease
Clinical Course

Mean Duration (Diagnosis to Death):
Postural Instability:
Death:

Answer 5

Mean Duration (Diagnosis to Death): 15 years

• Postural Instability: contributes to falls, immobility, constipation, dependency and depression
• Death: due to general wasting and complications of immobility (pneumonia)

Question 6

Parkinson’s Disease
Pathophysiology

Primarily a loss of:
Presence of:
Impact on other cells:
PNS:

Answer 6

Basics: primarily a loss of midbrain DA-producing neurons (particularly nigrostriatal DA neurons)

Presence of Lewy bodies (inclusions with radiating fibrils)

Many other cell types in other brain regions are impacted in PD (but to a lesser extent)

PNS affected as well

Question 7

DA Pathways

Nigrostriatal DA:
Mesolimbic DA:

Answer 7

Nigrostriatal DA: modulates learning and execution of complex purposeful motor patterns and learned habits; 80% of total DA and particular affected by PD

Mesolimbic DA: modulates motivation, goal-directed thinking, affect and reward

Question 8

DA Pathways

Mesocortical DA:
Hypothalamic DA:
Area Postrema:

Answer 8

Mesocortical DA: modulates cognition
Hypothalamic DA: hormone regulation
Area Postrema: DA receptors outside the BBB that mediate emesis

Question 9

Effects of Loss of DA:

Direct pathway vs. Indirect pathway:

Answer 9

DA modulates EXCITATORY information from the cortex and basal ganglia sends information back to the cortex via excitation from the thalamus

• Direct pathway ENABLES movement
• Indirect pathway INHIBITS movement

Question 10

Effects of Loss of DA

Loss of 70-80% if nigrostriatal DA results in:

Answer 10

Loss of 70-80% if nigrostriatal DA results in PD

• Inhibition of the direct pathway (loss of D1 stimulation)
• Activation of the indirect pathway (release of D2 inhibition)
• Overall result of the above two effects is INHIBITION OF MOVEMENT

Question 11

Effects of Loss of DA

Net Result:

Answer 11

Net Result= decreased excitation of the cortex and decreased drive to move

Question 12

Parkinson’s Disease
Causes

Majority of Cases:
Other Causes:

Answer 12

Majority of Cases: idiopathic (we do not know the cause)

Other Causes:
o Environmental Toxins:
- MPTP (destroys DA terminals)
- Epidemiology (ie. people who drink well water have an increased risk of PD)
o Infection: post-encephalitic
o Oxidative Stress: ongoing generation of ROS may make DA cells more susceptible to damage
o Mitochondrial Defects/Damage: have been implicated
o Genetic Forms: rare but some do exist

Question 13

Levodopa (L-dopa)

MOA:
Absorption:
Metabolism:

Answer 13

MOA: dopa is the precursor of DA (replenish DA)

Pharmacokinetics:
o Absorption: via aromatic amino acid uptake systems (affected by food)
o Metabolism: largely decarboxylated in the periphery; less than 1% reaches the brain
 Solution to this problem: almost exclusively given with carbidopa, an amino acid decarboxylase inhibitor, to all more to reach the brain

Question 14

Levodopa (L-dopa)
Efficacy

Early On:
Over Time:

Answer 14

Early On: very effective, although more so for bradykinesia than for tremor

Over Time: reduced efficacy (wearing off effect after 2-5 years)

Question 15

Levodopa (L-dopa)
Adverse Effects

Major Issues:
Other Effects:

Answer 15

Major Issues:

• On-off phenomenon (follows reduced efficacy)
• Dyskinesias (in up to 80% of patients after 5-8 years of treatment)
• Related to dopa-PD (drug-disease) interaction

Other Effects:

• Early: anorexia, nausea, hypotesion
• Chronic: hallucinations, delusions, agitations, insomnia, pathologic gambling and hypersexuality

Question 16

Levodopa (L-dopa)

Formulations: (3)

Answer 16

Sinemet/Atamet
Parcopa
Lodosyn

Question 17

Sinemet/Atamet:

Answer 17

Sinemet/Atamet: levodopa + carbidopa combination (needs to be dosed 3-6 times per day)
- Sinemet CR (sustained release formulation) now available, but shows erratic absorption

Question 18

Parcopa:

Answer 18

Parcopa: immediate-release levodopa/carbidopa that can be taken w/o water (manage acute events)

Question 19

Lodosyn:

Answer 19

Lodosyn: carbidopa alone that can be added to regimen if needed (not often)

Question 20

Direct Acting DA Receptor Agonists

Ergots:

Answer 20

Ergots: first used DA receptor agonists

Question 21

Direct Acting DA Receptor Agonists
Ergots

Bromocriptine:
Current Use:

Answer 21

Bromocriptine: not typically used for PD anymore (SE profile)

Current Use: rescue from neuroleptic malignant syndrome (due to APDs)

Question 22

Direct Acting DA Receptor Agonists
Ergots

Pergolide:
Current Use:

Answer 22

Pergolide: not FDA approved for PD anymore due to incidence of cardiac valve regurgitation

Current Use: low doses for hyperprolactinemia

Question 23

Direct Acting DA Receptor Agonists
Non-Ergot

Currently Used Agents: (2)

Answer 23

Pramipexole: D3>D2
Ropinirole: D2

Question 24

Direct Acting DA Receptor Agonists
Non-Ergot

Efficacy:
PD:
Other:

Answer 24

Efficacy: probably less effective than dopa, but less side effects make them first line monotherapy

Current Use:

• PD: first used as an adjunct, now first line monotherapy
• Other: Restless Legs Syndrome

Question 25

Direct Acting DA Receptor Agonists Non-Ergot Side Effects: (5)

Answer 25

``` Nausea Edema Hypotension Pathologic gambling and other compulsions Somnolence (drowsiness) ```

Question 26

Direct Acting DA Receptor Agonists Non-Ergot Treatment of Side Effects ``` Daytime Sleepiness (Sleep Attacks): Peripheral DA Effects: ```

Answer 26

Daytime Sleepiness (Sleep Attacks): modafinil (CNS stimulation) Peripheral DA Effects: trimethobenzamide (anti-emetic) or domperidone (antidopaminergic)

Question 27

Direct Acting DA Receptor Agonists Apomorphine Administration: MOA: Use:

Answer 27

Administration: injectable (subQ) MOA: dopamine agonist with some preference for D2 receptors Use: FDA-approved for “off” episodes

Question 28

Direct Acting DA Receptor Agonists Apomorphine Side Effects: Treatment of Side Effects Emesis/Nausea: Ondansetron:

Answer 28

Side Effects: similar to above, plus yawning and hypersexuality Treatment of Side Effects: - Emesis/Nausea: trimethobenzamide (anti-emetic) - Ondansetron: contraindicated because combination with apomorphine results in severe hypotension

Question 29

Direct Acting DA Receptor Agonists Rotigone:

Answer 29

Rotigone: once daily transdermal patch (similar efficacy and adverse effects, but more convenient)

Question 30

Monoamine Oxidase-B Inhibitors: (2)

Answer 30

Selegiline | Rasagiline

Question 31

Selegiline | MOA:

Answer 31

MOA: irreversible inhibitor of MAO-B, resulting in inhibition of DA metabolism - Less peripheral MAO inhibition - Can be used in combination with dopa - Less interaction with tyramine-rich foods than MAO-A inhibitors

Question 32

Selegiline Efficacy:

Answer 32

Efficacy: modest benefits as initial monotherapy OR dopa co-therapy

Question 33

Selegiline Possible Mechanisms of Benefit: (4)

Answer 33

Possible Mechanisms of Benefit: - Increased DA - Metabolism to amphetamine (chemically similar to methamphetamine) - Antidepressant effects - Previously believed it may have neuroprotective qualities (untrue)

Question 34

Rasagiline MOA: Efficacy: Adverse Effects:

Answer 34

Rasagiline: newer MOA: same as above Efficacy: clearly effective for the treatment of early PD or as an adjunct in advanced PD - May have neuroprotective qualities (still an open question) Adverse Effects: - Nausea - Orthostatic hypotension

Question 35

Catechol-O-Methyltransferase (COMT) Inhbitors:

Answer 35

Entacapone

Question 36

Entacapone MOA: Use:

Answer 36

MOA: given with L-dopa to increase its levels by blunting metabolism in periphery and the brain Use: used as an ADJUNCT to Sinemet (levodopa + carbidopa) to reduce fluctuations and “off” time

Question 37

Entacapone Side Effects:

Answer 37

May increase risk of dyskinesia (due to the fact that it increases the action of L-dopa) Does NOT cause hepatotoxicity like earlier COMT inhibitors (Tolcapone)

Question 38

Antivirals:

Answer 38

Amantadine

Question 39

Amantadine MOA: Efficacy:

Answer 39

MOA: relevant MOA to the treatment of PD may be its action as an NMDA antagonist Efficacy: modest transient benefits (may only last a few weeks); better for tremor

Question 40

Amantadine Side Effects: (2)

Answer 40

- Livedo reticularis (skin condition causing lace-like purple discoloration of the lower extremeties) - Psychosis (rare, at high doses)

Question 41

Antimuscarinics | Currently Used: (4)

Answer 41

o Benztropine o Trihexyphenidyl o Procyclidine o Biperiden

Question 42

Antimuscarinics MOA:

Answer 42

MOA: offsets neurochemical imbalance in striatum created by loss of DA (ie. decreases action of ACh)

Question 43

Antimuscarinics Use:

Answer 43

Use: LOW DOSES useful for the following conditions (it is NOT useful for bradykinesia) o Early onset tremor o Rigidity o Drooling

Question 44

Antimuscarinics Side Effects: CNS Effects: PNS Effects:

Answer 44

Side Effects: prominent side effects may contraindicate its use in many patients CNS Effects: impaired memory, drowsiness, confusion, delusions PNS Effects: dry mouth, blurred vision, urinary retention, tachycardia

Question 45

Treatment of Comorbidities Depression: Psychosis:

Answer 45

Depression: SSRIs preferred Psychosis: clozapine or other atypical antipsychotics (less risk for inducing parkinsonism)

Question 46

Treatment of Comorbidities Dementia: Other Therapies:

Answer 46

Dementia: cholinesterase inhibitors that are used in AD/dementia Other Therapies: o Physical therapy and physical/mental exercise recommended

Question 47

Surgical Interventions DA Cell Replacement:

Answer 47

DA Cell Replacement: DA from adrenals, carotid bodies, fetal cells from human, transgenic pigs or stem cells

Question 48

Surgical Interventions Ablations:

Answer 48

Ablations: not done anymore (irreversible and non-adjustable; replaced by deep brain stimulation) o Helped with tremor, bradykinesia and medication response

Question 49

Surgical Interventions Deep Brain Stimulation: Efficacy:

Answer 49

Deep Brain Stimulation: safer, reversible and adjustable Efficacy: more effective than ablations and with fewer complications (can be used bilaterally) - Subthalamic nucleus (improves most Sx) > Globus pallidus > Thalamus - >70% of patients improve (more “on” time per day, decreased meds) - However, little/no improvement in instability AND may actually cause a slight decrease in cognition

Question 50

Surgical Interventions Deep Brain Stimulation Use: (4)

Answer 50

- Patients refractory to medication treatment - Patients with significant dyskinesia - Patients with significant clinical fluctuation on dopa - NEED TO HAVE INTACT COGNITION

Question 51

Surgical Interventions Deep Brain Stimulation Adverse Effects: (4)

Answer 51

Adverse Effects: less of these effects at 6 months post-surgery than 3 months (decrease with time) - May cause a decrease in cognition - Serious effects in ~40% of patients (hemorrhage, surgical site infection) - Increased depression and suicide (possibly unmasked due to decreased dose of DA drugs) - Increased impulsivity (may underlie increase in compulsive gambling and falling)

Question 52

Surgical Interventions Neurorestoration: Unexpected adverse effects:

Answer 52

Infusion of Trophic Factor GDNF into Putamen: had early promise but no efficacy overall Unexpected adverse effects: - Surgical complications - Ataxia - GDNF Abs

Question 53

Surgical Interventions Neurorestoration Local Injections of AAV-GAD: Local Injections of Transgenes:

Answer 53

Local Injections of AAV-GAD: initial findings promising but double-blind results less stellar Local Injections of Transgenes: specificity conferred through receptor-mediated uptake (currently in trials)

Question 54

Current Management of PD Patients:

Answer 54

All current treatments are for SYMPTOMATIC relief only Long-term goal is neuroprotection, or at least, neurorestoration

Question 55

Current Management of PD Patients Basics:

Answer 55

- Basics: o Delay treatment until necessary (try lifestyle adaptations first) o Consider a trial of antimuscarinic agent/MAO-B inhibitor/Amantadine ALONE to start o When it becomes necessary, initiate DA therapy with newer direct acting DA agonist (NOT L-dopa) - Pramipexole or Ropinirole o If necessary, add low-dose Sinemet (levodopa-carbidopa) to the direct acting DA agonist o Adjust Sinemet dosing as necessary

Question 56

Current Management of PD Patients Other Additions:

Answer 56

o For long-term complications of L-dopa, add a COMT inhibitor (thought to prolong/stabilize L-dopa effects, therefore reducing “on/off” phenomena) o SubQ apomorphine for rescue during “off” periods o Addition of anticholinergics to treat tremor or drooling o Consider DBS in patients with treatment failure and intact cognition

Question 57

Essential Tremor | Basics:

Answer 57

Basics: most common neurological disorder among adults (0.4-4% prevalence) Impact is on quality of life NOT life span, and therefore is mistaken as a benign disorder

Question 58

Essential Tremor | Hallmark Feature:

Answer 58

Hallmark Feature: action/kinetic tremor in both upper limbs; less commonly in head, tongue and lower limbs - Often a crescendo tremor (resembling cerebellar intention tremor) - Aggravated by emotions, hunger, fatigue and temperature extremes

Question 59

Essential Tremor Pathophysiology: Causes:

Answer 59

Pathophysiology: uncertain - Possibility: abnormal oscillations within thalamocortical and olivocerebellar loops Causes: - Autosomal dominant pattern of inheritance: gene defects unknown but chromosomal loci identified o Variable penetrance (~50% of cases), but 5-10x increased risk if you have an affected 1st degree relative

Question 60

Essential Tremor | Treatments:

Answer 60

• Treatments: over 50% respond to drug therapy - Beta Blockers: propanolol or others - Anti-Seizure Drugs: low doses of primadone or topiramate - Refractory Patients: ventralis intermedius thalamotomy or DBS (completely effective in >80% of tx resistant patients; DBS preferred)