Movement Disorders B&B Flashcards by casey kozak

which components of the basal ganglia are affected by the following movement disorders?
a. Parkinson’s
b. Huntington’s
c. Wilson’s
d. hemiballism

a. Parkinson’s: substantia nigra (pars compacta)

b. Huntington’s: striatum

c. Wilson’s: striatum + globus pallidus (externus/internus)

d. hemiballism: subthalamic nucleus

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_____ is a compound that destroys dopamine neurons, causing Parkinson’s disease (may be contaminant of opioid drugs —> drug-induced Parkinson’s)

MPTP: methyl-phenyl-tetrahydropyridine

[now used in lab animals to study Parkinson’s]

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describe the clinical symptoms of Parkinson’s Disease (6)

rest tremor
bradykinesia (can’t initiate)
shuffling gate
stooped posture
cogwheel rigidity of joints
movement gets BETTER with exercise

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how do each of the following drugs treat Parkinson’s?
a. carbidopa
b. entacarpone, tolcapone
c. selegiline
d. bromocriptine
e. pramipexole, ropinirole
f. benztropine, trihexyphenidyl
g. amantadine

a. carbidopa: converted to dopamine in CNS

b. entacarpone, tolcapone: COMT inhibitors (prevent L-dopa breakdown)

c. selegiline: prevent dopamine breakdown

d. bromocriptine: dopamine agonist (ergot)

e. pramipexole, ropinirole: dopamine agonist (non-ergot)

f. benztropine, trihexyphenidyl: antimuscarinic

g. amantadine: dopamine agonist + anticholinergic (also antiviral)

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what is the MOA and clinical use of Sinemet?

sinemet = L-dopa/carbidopa

L-dopa crosses BBB and is converted to dopamine in CNS by dopa decarboxylase —> treats Parkinson’s

note, peripheral decarboxylase limits benefits and causes cardiac side effects (tachycardia) + N/V (vomiting center outside of BBB)…

… carbidopa inhibits peripheral decarboxylase to prevent this (still get CNS side effects - anxiety, agitation, insomnia)

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describe how L-dopa + carbidopa (= Sinemet) are used together to treat Parkinson’s

L-dopa crosses BBB, converted to dopamine by dopa decarboxylase

carbidopa prevents peripheral decarboxylase to enhance benefits and decrease peripheral side effects (tachycardia, N/V)

note, CNS side effects still occur - anxiety, agitation, insomnia… therefore, given lowest dose possible

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describe the peripheral vs central adverse effects of L-dopa

peripheral: cardiac effects (tachycardia), N/V (vomiting center outside BBB)… these are prevented by combining L-dopa with carbidopa (= Sinemet)

central: anxiety, agitation, insomnia… can’t be prevented, so use lowest dose possible

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which vitamin should be avoided in large quantities by patients taking Sinemet?

Sinemet = L-dopa + carbidopa, treats Parkinson’s

vitamin B6 promotes conversion of L-dopa to dopamine in periphery —> side effects (tachycardia, N/V)

this isn’t really as much of a problem anymore since we started combing L-dopa with carbidopa (Sinemet) because carbidopa inhibits peripheral dopa decarboxylase

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describe the consequences of long-term use of Sinemet (L-dopa + carbidopa)

long term —> motor side effects because of reduced natural L-dopa production in the CNS

creates “on/off” phenomenon - patients are dependent on drug and dyskinesia or even akinesia (frozen, no movement) can occur between doses

because of this, use lowest dose possible, but unavoidable eventually and patients can only tolerate for several years before serious side effects

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what is the MOA and clinical use of entacapone and tolcapone?

treat Parkinson’s by inhibiting COMT (catechol-O-methyltransferase), which breaks down L-dopa

only work in combo with L-dopa!!

entacapone works peripherally only; tolcapone works centrally and peripherally but is very hepatotoxic

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what is different between entacapone and tolcapone? which one is prescribed more often and why?

both treat Parkinson’s by inhibiting COMT (catechol-O-methyltransferase)

entacapone works peripherally only; tolcapone works centrally and peripherally but is very hepatotoxic

therefore, entacapone is used more because LFT must be monitored closely with tolcapone

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name a drug that treats Parkinson’s by inhibiting COMT, but has serious hepatotoxic side effects.

now name a drug that works by the same mechanism but is used more often to avoid this adverse effect.

tolcapone: inhibits COMT peripherally + centrally, but very hepatotoxic [that is the TOLL you pay]

entacapone: inhibits COMT only peripherally, but safer

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what is the effect of MAO-a vs MAO-b? how is this clinically significant?

MAO-a breaks down serotonin - inhibiting this can treat depression

MAO-b breaks down dopamine - inhibiting this can treat Parkinson’s (ex, selegiline)

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what is the MOA and clinical use of selegiline?

treats Parkinson’s by inhibiting MAO-b, which breaks down dopamine in CNS (and 5HT a little - see side effects)

used to boost treatment with L-dopa/carbidopa (Sinemet)

side effects: N/V, hypotension, daytime sleepiness, serotonin syndrome, ”cheese effect”

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name a drug that treats Parkinson’s by inhibiting MAO-b

selegiline: treats Parkinson’s by inhibiting MAO-b, which breaks down dopamine in CNS (and 5HT a little - see side effects)

used to boost treatment with L-dopa/carbidopa (Sinemet)

side effects: N/V, hypotension, daytime sleepiness, serotonin syndrome, ”cheese effect”

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what are the side effects of selegiline? (5)

treats Parkinson’s by inhibiting MAO-b, (and 5HT a little - see side effects)

N/V
hypotension
somnolence
serotonin syndrome
”Cheese effect”: HTN crisis due to eating food with tyramine (red wine, aged cheese, aged meat)

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what is the “Cheese effect”?

hypertensive crisis caused by eating foods containing tyramine (red wine, aged cheese, aged meat) while taking drug that inhibits MAO

MAO breaks down NT, but also tyramine - therefore, MAO inhibitors block breakdown of tyramine —> HTN

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Pt is 74yo M presenting to the ED due to a hypertensive crisis. PMH includes Parkinson’s, for which the patient takes Sinemet and selegiline, and CHF, for which the patient takes a thiazide diuretic. The patient was at dinner at a nice steak restaurant celebrating their spouse’s birthday when they began to feel chest pain. Their heart exam appears normal. What might be going on?

”Cheese effect” due to selegiline

selegiline: treats Parkinson’s by inhibiting MAO-b, which breaks down dopamine in CNS, used to boost treatment with L-dopa/carbidopa (Sinemet)

MAO inhibitors prevent breakdown of tyramine (red wine, aged cheese, aged meat) —> HTN

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how is trihexyphenidyl used to treat Parkinson’s? given what kind of drug this is, what are the expected side effects?

anti-muscarinic that is helpful for treating tremor

tremor is often the first presenting symptom

side effects: sedation, dry mouth

Tremor often is the first presenting sign of Parkinson’s. How is this typically treated?

trihexyphenidyl: anti-muscarinic that treats tremor

side effects: sedation, dry mouth

how are ropinirole and pramipexole used to treat Parkinson’s?

dopamine agonists used to treat bradykinesia, rigidity

name 2 dopamine agonists used to treat bradykinesia and rigidity caused by Parkinson’s

ropinirole
pramipexole

Patients with Parkinson’s often present first with tremor. This can be treated with ________. Once patients develop bradykinesia and rigidity, they are often treated with _______. If these become ineffective, patients are then usually treated with a combination of levodopa and carbidopa called _____.

Patients with Parkinson’s often present first with tremor. This can be treated with trihexyphenidyl (anti-muscarinic). Once patients develop bradykinesia and rigidity, they are often treated with ropinirole or pramipexole (dopamine agonists) If these become ineffective, patients are then usually treated with a combination of levodopa and carbidopa called Sinemet

what surgical intervention is used to treat Parkinson’s?

deep brain stimulation: high frequency energy suppresses neural activation of basal ganglia

this is used more often in young patients because of toxicity risk from long-term use of L-dopa/carbidopa

stimulation of globus pallidus internus or subthalamic nucleus for bradykinesia or rigidity; stimulation of VL for tremors

which part of the basal ganglia degenerates in Huntington’s disease, and how does this appear on brain imaging?

*striatum = caudate + putamen* degeneration due to loss of GABA neurons (also ACh) brain imaging shows *large lateral ventricles* due to atrophy of caudate nucleus (right next to ventricles) also shows atrophy of frontal and temporal lobes

what specifically causes death of GABA neurons in the striatum (caudate + putamen) in Huntington’s disease?

*glutamate toxicity* —> binds NMDA receptor and causes excessive calcium influx, causing cell death

young patient (30s-40s) who was adopted with dementia and abnormal movements = [most likely, on a board exam]

Huntington’s Disease why adopted? because Huntington’s is AD and runs in families, so most people are tested early and know they have it already. Patients who were adopted might not know their genetic risk. note, this could be mistaken for substance abuse!

how are tetrabenazine and reserpine used to treat Huntington’s?

chorea is associated with excessive dopamine signaling these drugs inhibit *VMAT* —> limit dopamine vesicle packaging/release [note tetrabenzine has increased risk of suicidality]

name 2 drugs that treat Huntington’s by inhibiting VMAT

1. *tetrabenazine* 2. *reserpine* chorea is associated with excessive dopamine signaling, these drugs inhibit VMAT —> limit dopamine vesicle packaging/release

how is haloperidol used to treat Huntington’s disease?

chorea is associated with excessive dopamine signaling haloperidol is a *dopamine receptor antagonist*

hemiballism, seen in rare subtypes of lacunar strokes, is due to damage of _______

subthalamic nucleus

which part of the brain is affected by Wilson’s Disease?

Wilson’s Disease: accumulation of copper in tissues can cause lesions in *lentiform nucleus* of basal ganglia = putamen + globus pallidus —> parkinsonian symptoms, *”wing-beating tremor”*, *dysarthria*

describe the neurological symptoms of Wilson’s Disease

Wilson’s Disease: accumulation of copper in tissues, can cause lesions in *lentiform nucleus* (putamen + globus pallidus) —> parkinsonian symptoms (chorea, UE>LE tremor), *”wing-beating tremor”* (elbows flap when hands are clasped out in front), *dysarthria* (most common symptom)

“wing-beating tremor” =

*Wilson’s Disease*: accumulation of copper in tissues, can cause lesions in *lentiform nucleus* (putamen + globus pallidus) —> parkinsonian symptoms, *”wing-beating tremor”* (elbows flap when hands are clasped out in front), *dysarthria* (most common symptom)

chorea vs athetosis vs myoclonus vs dystonia

chorea = random, purposeless movements due to basal ganglia damage athetosis = slow, writhing movements of fingers due to basal ganglia damage myoclonus = sudden muscle contraction/ jerk/ twitch, can occur with renal or liver failure dystonia = sudden contractions/ twitching, can be due to writer’s cramp or blepharospasm (eye twitching)

what is on your differential for chorea (2)? how can the patient history be used to differentiate?

1. *Huntington’s*: history describes patient in 20s/30s with aggressive behavior and dementia 2. *acute rheumatic fever*: history describes child with recent sore throat

what is indicated by resting tremor vs intention tremor vs wing-beating tremor?

resting tremor: at rest, usually hands, improves with movements, “pill-rolling” —> indicates Parkinson’s intention tremor: zig-zag motion when trying to reach target —> indicates cerebellar dysfunction (“finger to nose” test) wing-beating tremor: elbows flap when hands are clasped out in front —> indicates Wilson’s disease (copper accumulation in lentiform nucleus)

how does essential tremor present? How can it be treated (3)?

aka “benign familial tremor”: genetic predisposition, occurs with intentional movement tx: 1. *EtOH* helps - patients often self-medicate 2. *propranolol* (beta blocker) 3. *primidone* (converted to phenobarbital) don’t ask why, they just work.

how does Huntington’s cause neurodegeneration of the basal ganglia in early vs late stage disease? how does this present clinically?

early: *indirect pathway* (inhibits movement) affected —> *hyperkinesia* late: *direct pathway* (initiates movement) affected —> *akinesia* also note, early disease is unilateral, later disease is bilateral

what is the mutation that causes Wilson’s Disease?

AR mutation of ATP7B gene which encodes *copper-transporting ATPase* —> impaired biliary copper excretion —> copper accumulation in liver, brain, eyes (Kayser-Fleischer rings!), etc

rapid eye movement sleep behavior disorder

parasomnia characterized by dream-enactment behaviors (hand gestures, violent thrashing, punching/kicking) that emerge during loss of REM sleep prodromal syndrome of alpha-synuclein pathology (Parkinson’s, Lewy body dementia)

atypical Parkinson’s syndromes are characterized by: (4)

1. lack of resting tremor 2. symmetrical symptoms 3. early postural instability 4. lack of response to dopamine “atypical Parkinsonism” = other primary neurodegenerative syndromes that share characteristics of PD

what features of Multiple System Atrophy distinguish it from Parkinson’s? (3)

1. tremor unlikely 2. symmetrical presentation 3. limited response to dopamine cause unknown, Lewy bodies with alpha-synuclein inclusions in neurons and glial cells

what are the features of the following variants of Multiple System Atrophy? a. nigrostriatal degeneration MSA-P b. “Shy-Drager” c. olivopontocerebellar atrophy MSA-C

a. *nigrostriatal degeneration MSA-P*: loss of neuron in substantia nigra pars compact (SNpc), globus pallidus (GP), striatum —> akinesia and bradykinesia but *little tremor* b. *“Shy-Drager”*: loss of neurons in SNpc, GP, and intermediolateral cell columns —> Parkinsonism with *autonomic signs* - severe variability in BP/HR, orthostatic hypotension, bowel/bladder, dry eyes, pupils c. *olivopontocerebellar atrophy MSA-C*: loss of neurons in SNpc, GP, cerebellar Purkinje cells, basis pontis —> Parkinsonism with *ataxia*

what is the most common form of atypical Parkinsonism, and how does it present?

*Progressive Supranuclear Palsy*: affects rostral midbrain —> supranuclear gaze palsy (decreased range of vertical eye motion), early postural instability, symmetrical presentation, dysphagia, dementia characteristic “mouse-ears” appearance of midbrain on imaging due to cell loss

tauopathy that presents as atypical Parkinsonism, characterized by vertical gaze palsy and early postural instability

*Progressive Supranuclear Palsy*: most common form of atypical Parkinsonism, but has neurofibrillary tangles a like in AD (tau protein) affects rostral midbrain (“mouse-ears” appearance of midbrain on imaging due to atrophy)