Bannon: Movement Disorders Flashcards
Parkinson’s Disease
General:
- Movement disorder
- Age is a prominent risk factor (5-10% of people over the age of 85)
Parkinson’s Disease
Clinical Features: (4)
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)
Parkinson’s Disease
Clinical Presentation: (4)
Early: presentation may be subtle o Unilateral weakness or fatigue o Weak voice o Micrographia (really small writing) o Olfactory losses
Parkinson’s Disease
Comorbidities:
Comorbidities: depression and dementia are common
Parkinson’s Disease
Clinical Course
Mean Duration (Diagnosis to Death):
Postural Instability:
Death:
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)
Parkinson’s Disease
Pathophysiology
Primarily a loss of:
Presence of:
Impact on other cells:
PNS:
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
DA Pathways
Nigrostriatal DA:
Mesolimbic DA:
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
DA Pathways
Mesocortical DA:
Hypothalamic DA:
Area Postrema:
Mesocortical DA: modulates cognition
Hypothalamic DA: hormone regulation
Area Postrema: DA receptors outside the BBB that mediate emesis
Effects of Loss of DA:
Direct pathway vs. Indirect pathway:
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
Effects of Loss of DA
Loss of 70-80% if nigrostriatal DA results in:
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
Effects of Loss of DA
Net Result:
Net Result= decreased excitation of the cortex and decreased drive to move
Parkinson’s Disease
Causes
Majority of Cases:
Other Causes:
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
Levodopa (L-dopa)
MOA:
Absorption:
Metabolism:
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
Levodopa (L-dopa)
Efficacy
Early On:
Over Time:
Early On: very effective, although more so for bradykinesia than for tremor
Over Time: reduced efficacy (wearing off effect after 2-5 years)
Levodopa (L-dopa)
Adverse Effects
Major Issues:
Other Effects:
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
Levodopa (L-dopa)
Formulations: (3)
Sinemet/Atamet
Parcopa
Lodosyn
Sinemet/Atamet:
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
Parcopa:
Parcopa: immediate-release levodopa/carbidopa that can be taken w/o water (manage acute events)
Lodosyn:
Lodosyn: carbidopa alone that can be added to regimen if needed (not often)
Direct Acting DA Receptor Agonists
Ergots:
Ergots: first used DA receptor agonists
Direct Acting DA Receptor Agonists
Ergots
Bromocriptine:
Current Use:
Bromocriptine: not typically used for PD anymore (SE profile)
Current Use: rescue from neuroleptic malignant syndrome (due to APDs)
Direct Acting DA Receptor Agonists
Ergots
Pergolide:
Current Use:
Pergolide: not FDA approved for PD anymore due to incidence of cardiac valve regurgitation
Current Use: low doses for hyperprolactinemia
Direct Acting DA Receptor Agonists
Non-Ergot
Currently Used Agents: (2)
Pramipexole: D3>D2
Ropinirole: D2
Direct Acting DA Receptor Agonists
Non-Ergot
Efficacy:
PD:
Other:
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
Direct Acting DA Receptor Agonists
Non-Ergot
Side Effects: (5)
Nausea Edema Hypotension Pathologic gambling and other compulsions Somnolence (drowsiness)
Direct Acting DA Receptor Agonists
Non-Ergot
Treatment of Side Effects
Daytime Sleepiness (Sleep Attacks): Peripheral DA Effects:
Daytime Sleepiness (Sleep Attacks): modafinil (CNS stimulation)
Peripheral DA Effects: trimethobenzamide (anti-emetic) or domperidone (antidopaminergic)
Direct Acting DA Receptor Agonists
Apomorphine
Administration:
MOA:
Use:
Administration: injectable (subQ)
MOA: dopamine agonist with some preference for D2 receptors
Use: FDA-approved for “off” episodes
Direct Acting DA Receptor Agonists
Apomorphine
Side Effects:
Treatment of Side Effects
Emesis/Nausea:
Ondansetron:
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
Direct Acting DA Receptor Agonists
Rotigone:
Rotigone: once daily transdermal patch (similar efficacy and adverse effects, but more convenient)
Monoamine Oxidase-B Inhibitors: (2)
Selegiline
Rasagiline
Selegiline
MOA:
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
Selegiline
Efficacy:
Efficacy: modest benefits as initial monotherapy OR dopa co-therapy
Selegiline
Possible Mechanisms of Benefit: (4)
Possible Mechanisms of Benefit:
- Increased DA
- Metabolism to amphetamine (chemically similar to methamphetamine)
- Antidepressant effects
- Previously believed it may have neuroprotective qualities (untrue)
Rasagiline
MOA:
Efficacy:
Adverse Effects:
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
Catechol-O-Methyltransferase (COMT) Inhbitors:
Entacapone
Entacapone
MOA:
Use:
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
Entacapone
Side Effects:
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)
Antivirals:
Amantadine
Amantadine
MOA:
Efficacy:
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
Amantadine
Side Effects: (2)
- Livedo reticularis (skin condition causing lace-like purple discoloration of the lower extremeties)
- Psychosis (rare, at high doses)
Antimuscarinics
Currently Used: (4)
o Benztropine
o Trihexyphenidyl
o Procyclidine
o Biperiden
Antimuscarinics
MOA:
MOA: offsets neurochemical imbalance in striatum created by loss of DA (ie. decreases action of ACh)
Antimuscarinics
Use:
Use: LOW DOSES useful for the following conditions (it is NOT useful for bradykinesia)
o Early onset tremor
o Rigidity
o Drooling
Antimuscarinics
Side Effects:
CNS Effects:
PNS Effects:
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
Treatment of Comorbidities
Depression:
Psychosis:
Depression: SSRIs preferred
Psychosis: clozapine or other atypical antipsychotics (less risk for inducing parkinsonism)
Treatment of Comorbidities
Dementia:
Other Therapies:
Dementia: cholinesterase inhibitors that are used in AD/dementia
Other Therapies:
o Physical therapy and physical/mental exercise recommended
Surgical Interventions
DA Cell Replacement:
DA Cell Replacement: DA from adrenals, carotid bodies, fetal cells from human, transgenic pigs or stem cells
Surgical Interventions
Ablations:
Ablations: not done anymore (irreversible and non-adjustable; replaced by deep brain stimulation)
o Helped with tremor, bradykinesia and medication response
Surgical Interventions
Deep Brain Stimulation:
Efficacy:
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
Surgical Interventions
Deep Brain Stimulation
Use: (4)
- Patients refractory to medication treatment
- Patients with significant dyskinesia
- Patients with significant clinical fluctuation on dopa
- NEED TO HAVE INTACT COGNITION
Surgical Interventions
Deep Brain Stimulation
Adverse Effects: (4)
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)
Surgical Interventions
Neurorestoration:
Unexpected adverse effects:
Infusion of Trophic Factor GDNF into Putamen: had early promise but no efficacy overall
Unexpected adverse effects:
- Surgical complications
- Ataxia
- GDNF Abs
Surgical Interventions
Neurorestoration
Local Injections of AAV-GAD:
Local Injections of Transgenes:
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)
Current Management of PD Patients:
All current treatments are for SYMPTOMATIC relief only
Long-term goal is neuroprotection, or at least, neurorestoration
Current Management of PD Patients
Basics:
- 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
Current Management of PD Patients
Other Additions:
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
Essential Tremor
Basics:
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
Essential Tremor
Hallmark Feature:
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
Essential Tremor
Pathophysiology:
Causes:
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
Essential Tremor
Treatments:
• 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)
