Rockroth: Movement Disorders

Question 1

PD is a progressive neurodegenerative disorder associated with the loss of (blank) neurons contributing to the nigrostriatal tract. Degeneration of neurons within the (blank) leads to a shortage of dopamine in this extrapyramidal motor circuit

Answer 1

dopaminergic; substantia nigra

Question 2

Which neurons are the primary victims of PD-related degeneration?

Answer 2

the dopaminergic neurons in the PARS COMPACTA of the substantia nigra

Question 3

Mean age of onset of Parkinsons?

Who gets it, males or females?

Answer 3

55 years; 3:2 male:female

Question 4

About what percentage of dopaminergic neurons are lost before motor signs of the disease emerge?

Answer 4

60-80%

**you have to lose lots of your motor neurons before you reach this threshold level

Question 5

What causes Parkinson’s disease?

Answer 5

We don’t know!!
genetics, epigenetics, environmental toxins, diet, multiple causes??
lewy bodies of alpha-synuclein

Question 6

In PD, the loss of dopamine results in a relative excess of (blank) activity via mACh receptors

Answer 6

cholinergic

Question 7

Clinical manifestations of Parkinson’s disease?

Answer 7

TRAP!

Tremor (course resting tremor, “pill rolling”)

Rigidity (increase in muscle tone, “cogwheeling”)

Akinesia (inability to initiate movement) or bradykinesia (slowness of movement), masked facies (reptilian stare), short, shuffling steps

Postural changes (imbalance, loss of righting reflexes), stooped posture

Other: drool, trouble writing, low melody of speech

Question 8

Parkinson’s is a disease characterized by asymmetry of (blank).

Answer 8

motor signs

dopamine vs ACh

Question 9

What are some drugs that increase dopamine levels?

Answer 9

Drugs that increase dopamine:

levodopa combined with carbidopa (prevents peripheral breakdown of L-DOPA)
amantadine
MAO-B inhibitors
COMT inhibitors

dopamine agonists: ropinirole

anti-cholinergics

Question 10

Why do you combine levodopa with carbidopa?

Answer 10

carbidopa is a DOPA decarboxylase inhibitor that doesn’t cross the BBB - it increases the effective concentration of levodopa getting to the brain by preventing its breakdown

Question 11

How is levodopa different from dopamine?

Answer 11

it can cross the BBB via an L-amino acid transporter

Question 12

What is one downside to the use of L-dopa?

Answer 12

it’s short-acting, so it wears off and causes an end-of-dose effect

**works for 2-3 hours, and then the pt returns to previous state of bradykinesia, etc

Question 13

What is the on-off effect that can occur with patients treated with levodopa?

Answer 13

terrible parkinsonism which fluctuates with periods of hyperkinesia

**causes a roller-coaster effect, may be corrected with more continuous dopamine receptor stimulation

Question 14

Side effects of levodopa?

Answer 14

nausea and vomiting
orthostatic hypotension
hallucinations and distorted thinking
dyskinesias (involuntary movements)

Question 15

What is amantadine? How is it believed to work?

Answer 15

used to treat Parkinson’s disease; believed to promote release of dopamine from substantia nigra

Question 16

One downside to amantadine? Side effects of amantadine?

Answer 16

tachyphylaxis: its benefit wears off easily;
restlessness, insomnia, agitation
hallucinations and confusion
livedo reticularis (discoloration of extremities)

Question 17

How do MAO-B inhibitors increase dopamine levels?

Answer 17

inhibit dopamine metabolism to keep more around

Question 18

When are MAO-B inhibitors used?

Answer 18

often used mono-therapeutically for early/mild PD;

in combo with levodopa/carbidopa for advanced PD

Question 19

Give an example of an MAO-B inhibitor

Answer 19

rasagiline (Azilect)

Question 20

Side effects of MAO-B inhibitors?

Answer 20

confusion, hallucinations
can enhance dopaminergic side effects when taken with levodopa
5HT syndrome

Question 21

When are COMT inhibitors used? How do they work?

Answer 21

only in combo with levodopa/carbidopa;
these are catechol-o-methyltransferase inhibitors, they convert levodopa to 3-O-methyldopa which competes w levodopa to access the brain

Question 22

Give an example of a COMT inhibitor?

Answer 22

entacapone

**acts at peripheral sites

Question 23

Side effects of COMT inhibitors?

Answer 23

nausea/diarrhea
urine discoloration (bright red/orange)
sleep disturbances

Question 24

If you have too much ACh around relative to dopamine, what do you get?

Answer 24

parkinsonism

**not to be confused w Parkinson’s disease; Parkinson’s is a cause of parkinsonism

Question 25

If you have too much dopamine around relative to ACh, what do you get?

Answer 25

choreoathetosis

Question 26

What things can cause parkinsonism?

Answer 26

dopamine inhibitors (antipsychotics)

Question 27

provide more smooth and continuous DM receptor activation than levodopa and rarely cause dyskinesias do not require functional DM neurons to produce their effects and are therefore sometimes helpful as adjuncts in advanced cases of PD in which few DM neurons remain used as monotherapy in the early stages of PD

Answer 27

dopamine agonists

Question 28

What is one dopamine receptor agonist we should know about?

Answer 28

Pramipexole (Mirapex) **also indicated for treatment of restless leg syndrome

Question 29

Side effects of D2 agonists like Pramipexole?

Answer 29

``` dizziness and hallucinations impulse control disorders hypotension insomnia nausea ```

Question 30

Another D2 agonist that is an ergot alkaloid; rarely used for PD, but used for neuroleptic malignant syndrome

Answer 30

bromocriptine

Question 31

What is this? rigidity, tremulousness, fever, autonomic instability (BP), agitation>delirium>coma plasma CPK markedly elevated due to rhabdomyolysis rapidly progressive/manage aggressively usually caused by “typical” antipsychotic drug

Answer 31

neuroleptic malignant syndrome **use dopamine agonist like bromocriptine

Question 32

may improve tremor in early PD but have little effect on rigidity and bradykinesis (thus most useful when TREMOR is the major clinical feature) typically used as adjunctive Rx in combination with levodopa and other drugs that augment DM activity; also frequently used in

Answer 32

anticholinergics

Question 33

What are some anticholinergics used in PD?

Answer 33

trihexyphenidyl | benztropine mesylate

Question 34

How will your treatment strategy change for younger vs older patients with parkinsonism?

Answer 34

in younger pts (less than 65yo), more emphasis on long-term considerations bc they have more life to live! start with a dopamine agonist +/ MAOI, only add levodopa when motor symptoms are no longer in control in older pts with cognitive impairment, emphasis on decreasing symptoms! start with levodopa/carbidopa

Question 35

What to use for pts who have a disability due only to mild tremor?

Answer 35

anticholinergic monotherapy

Question 36

Targeting the subthalamic nucleus (STN) and globus pallidus internus (GPi) Complimentary to pharmacologic management

Answer 36

deep brain stimulation **this is done in addition to medication, not used alone

Question 37

What type of parkinson's patient makes a good candidate for deep brain stimulation?

Answer 37

tremor is the main symptom, less likely to help balance/gait excessive "off time" dopamine-responsive significant dyskinesia w current med regimen

Question 38

Dopamine agonists and MAO-B inhibitors may be preferable as initial Rx, particularly in (blank) patients.

Answer 38

younger

Question 39

COMT inhibitors are complimentary to l-dopa and are not useful as (blank) agents.

Answer 39

monotherapy

Question 40

In more advanced patients who are reaching their limit with meds, consider whether they may be good candidates for (blank)

Answer 40

deep brain stimulation

Question 41

This is a variant of Parkinson's that looks a lot like it! It's Parkinson's disease "in extension," because they have extension posture. They have impaired eye movements esp vertical gaze, axial rigidity, dysphagia, and typically don't respond to PD meds

Answer 41

Progressive supranuclear palsy

Question 42

Different types of action tremors?

Answer 42

physiologic tremor ***symmetric, high freq/low ampl; may involve speech; worse w/ fatigue, caffeine, exposure to cold; better w/ alcohol essential tremor **may involve head, central tremor, autosomal dominant pattern benign familial tremor **family history of essential tremor cerebellar intention tremor **as you get toward the target of the action, the tremor increases!

Question 43

Type of resting tremor

Answer 43

parkinsonian **asymmetric, low freq/high amplitude; tends to spare speech and head