Movement Disorders

Question 1

What are the 4 cardinal features of Parkinsons?

a progressive, neurodegenerative disorder

Answer 1

1) resting tremor
2) bradykinesia
3) rigidity
4) gait instability

*all due to nigrostriatal dopamine neruons

Question 2

Parkinsons Pathology

Answer 2

degeneration of pigmented brainstem neurons (in substantia nigra etc)

Lewy bodies = accumulation of alpha-synuclein (thus anti-synuclein Abs can be used in histology)

Reduced dopamine in striatum (aka caudate + putamen)

Question 3

What is the biochemical pathway to make endogenous dopamine?

Answer 3

tyrosine —> L-DOPA (via tyrosine hydroxylase **rate-limiting step)

L-DOPA —> Dopamine (via dopamine de-carboxylase)

Dopamine into vesicle (via vesicular monoamine transporter) into synapse

Question 4

what are the non-motor features of PD?

Answer 4

1) olfactory dysfunction
2) constipation
3) autonomic dysfunction
4) REM sleep behavior disorder

-these all occur well before the motor problems present

Question 5

Some important Parkinsons epidemiology facts

Answer 5

• 2nd most common neuroDegen disorders
• cumulative risk = 2.7%
• slightly more common in men
• 90-95% are sporadic (aka not inherited)

risk factors include:

• severe head trauma (comatose for at least a day)
• pesticides, well water, rural living
• Low Uric acid

Question 6

Carbidopa-Levodopa

Answer 6

Carbidopa = de-carboxylase inihibitor that prevents L-DOPA being converted to dopamine (with cannot cross the BBB as well as L-DOPA)

Levodopa = given to skip the rate-limiting tyrosine hydroxylase step

ALWAYS give together

Levodopa is an Amino Acid, thus it will compete with dietary amino acids for absorption if taken with food resulting in much LESS absorption… thus NEVER take with food/milk

Question 7

entacapone

Answer 7

Catechol-O-methyltransferase Inhibitor (COMT inhibitor)

prevents the breakdown of Dopamine in the synapse also prevents breakdown of dopa in periphery

Question 8

Name 2 dopamine agonists used to treat parkinsons and what dopamine receptor is targeted?

Answer 8

1) Parmipexole
2) ropinirole

D2 receptors are most targeted

Question 9

Name 2 monoamine oxidase inhibitors to treat parkinsons

Answer 9

1) selegiline (irreversible)

2) rasagiline

Question 10

Pros and Cons of dopamine agonists

Answer 10

pros: reduce long-term risk of motor complications, have a longer duration of action than levodopa
cons: hallucinations, dyskinesias, nausea, sleepiness, leg edema ***compulsive disorders in 15% like gambling, sex etc. probably due to binding of D3/D4 receptors

Question 11

what is the biggest myth in treating parkinsons?

Answer 11

Levodopa does NOT accelerate parkinsons progression (its a myth)

there is NO benefit to delaying treatment

Question 12

What is the biggest challenge to treating parkinsons with medication?

Answer 12

There is a response threshold, and then a dyskinesia threshold sometimes with a small therapeutic window in between

dyskinesias don’t always bother the patient (may not need to treat)… if they do want it treated, amantidine can help (NMDA antagonist with some D2 agonism)

Question 13

What are some red flags that tell you it is NOT parkinsons?

Answer 13

1) supranuclear gaze
2) dementia, hallucinations (early dementia)
3) prominent dysautonomia
4) acute changes
5) very early onset (less than 40)
6) poor response to L-DOPA

Question 14

Differential diagnosis of Parkinsons

Answer 14

• secondary parkinsonism (normal pressure hydrocephalus aka wet wobbly wacky)
• progressive supranuclear palsy
• multiple system atrophy
• corticobasal degeneration
• wilsons disease
• huntingtons

Question 15

Progressive supranuclear palsy

Answer 15

early falls

down-gaze paresis

axial rigidity

wide-eyed unblinking face

Path = accumulation of hyper-phosphorylated “tau” protein in neurons

Question 16

Multiple systems atrophy

Answer 16

prominent early disautonomia

nocturnal stridor (crazy-ass yell during bedtime)

Path = alpha-synuclein inclusions in glial cells

Question 17

3 types of multiple systems atrophy and there cardinal sign

Answer 17

1) Striatonigral Degeneration (SND) - levodopa unresponsive parkinsonism
2) Olivopontocerebellar atrophy - cerebellar features predominate
3) Shy-Drager Syndrome - severe dysautonomia and prominent early orthostatic hypotension

Question 18

Corticobasal Degeneration

Answer 18

Progressive asymmetric rigidity

levodopa unresponsive

alien limb fixed extensor/flexor muscles in one hand… asymmetry is important feature as well

Question 19

Parkinsonism in dementia

Answer 19

30% with alzheimers have signs of Parkinsonism

vascular parkinsonism and dementia

normal pressure hydrocephalus (wet wobbly wacky) AKA urinary incontinence, gait ataxia, and dementia

Question 20

Wilsons Disease

Answer 20

auto recessive deficient copper excretion

copper deposits in basal ganglia result in akinetic-rigid, wing-beating tremor, dystoria, and chorea

kayser-fleischer ring copper deposits in eye

VERY rare disease but actually curable!

Question 21

name the 6 hyperkinetic movement disorders and one important hypokinetic one

Answer 21

1) tremor
2) chorea
3) myoclonus
4) dystonia
5) tics
6) hemiballismus

*Parkinsons is hypokinetic

Question 22

Tremor

Answer 22

repititive, rhythmic, alternating contractions of agonist and antagonist muscle

Question 23

Rest tremor

Answer 23

parkinsonism, associated with rigidity and bradykinesia

Question 24

terminal tremor

Answer 24

cerebellar disease associated with dysmetria, dysarthria, nystagmus

seen as hand moves distally

Question 25

essential tremor

Answer 25

bilateral action tremor of hands/forearms
may have isolated head tremor
NO rest tremor

Long duration (3years or more)
beneficial response to alcohol
Non-selective Beta-antagonists as Tx

Question 26

Dystonia

Answer 26

sustained and/or phasic contraction of muscle causing abnormal posture or repetitive movements

*Co-contraction! so coming on and off can look like a tremor

usually people have some sensory “trick” (geste antagoniste) to make it better***

Question 27

Name 2 childhood onset dystonias

Answer 27

1) generalized torsion dystonia - dyt-1 gene mutation

2) dopa-responsive dystonia (GTP cyclohydrolase mutation)

Question 28

Idiopathic adult-onsets dystonia

Answer 28

most common one you’ll see

focal = cervical dystonia
segmental=truncal dystonia
task-specific dystonia = writers cramp, musician

*tx = botulinum toxin injections

Question 29

symptomatic dystonia

Answer 29

as a result of:

• focal basal ganglia lesion
• drugs
• trauma
• NeuroD disorders (corticobasal degeneration, progressive supranuclear palsy) wilsons, Iron accumulation, Fahrs (ca2+)

Question 30

Myoclonus

Answer 30

rapid, “lightning-like” muscle contraction producing irregular jerking

Question 31

asterixis

Answer 31

hepatic and renal failure causing toxic metabolite encephalopathy resulting in myoclonus

Question 32

Chorea

Answer 32

brief, irregular jerking movements flowing from one body part to the next

Question 33

5 subtypes of chorea

Answer 33

1) degenerative - huntingtons
2) auto-immune - lupus
3) metabolic - pregnancy, hyperthyroidism
4) drugs
5) vascular

Question 34

huntingtons disease

Answer 34

• Chorea, dementia, and psychiatric probs
• prominent atrophy of caudate nuclei! (box-car ventricles)
• trinucleotide CAG repeats with anticipation (40 or more repeats almost guarantee development of HD)
• AutoDOM

Question 35

hemiballismus

Answer 35

• rapid, large amplitude, unilateral, proximal flinging movements
• think subthalamic nucleus!

Question 36

tics

Answer 36

repetitive, stereotypic, brief semi-involuntary movements

“urge” to perform movement, and releif after

Question 37

amyotrophic lateral sclerosis

Answer 37

degeneration of BOTH upper and lower motor neurons

usually presents at age 50 or older

about 10% are autodom inherited with a mutation in superoxide dismutase (SOD1)