Parkinson's Disease

Question 1

Helpful historical features for diagnosing Parkinson’s

Answer 1

• Presence of parasomnias/REM sleep behavior disorders
• Micrographia
• Mask fascies / flat affect
• Shuffling gait and difficulty turning
• Hyposmia (80 - 100% of patients over the course of the disease)

Question 2

Families of drugs used to treat Parkinson’s

Answer 2

• Dopaminergic agonists (levodopa/carbidopa)
• MAO type B inhibitors
• Catechol-O-methyltransferase (COMT) inhibitors

Question 3

Main four Parkinson’s Plus syndromes

Answer 3

• Dementia with Lewy Bodies
• Multiple systems atrophy
• Corticobasal degeneration
• Progressive supranuclear palsy

Question 4

Parkinsonism

Answer 4

Clinical triad of bradykinesia, rigidity, and resting tremor

Sometimes also includes postural instability, which develops later in the disease progression.

Gets its name from Parkinson’s disease, but appears in many clinical scenarios. The most common cause is idiopathic Parkinson’s disease

Question 5

Causes of secondary parkinsonism

Answer 5

• Drug exposure
• Stroke
• Parkinson’s Plus syndrome

Question 6

Lewy bodies

Answer 6

Inclusion bodies of alpha synuclein that develop in neurons in both Parkinson’s Disease and Lewy Body dementia

Appear as an eosinophilic cytoplasmic inclusion consisting of a dense core surrounded by a halo of 10-nm-wide radiating fibrils

Question 7

Vascular parkinsonism

Answer 7

Results from subcortical infarcts affecting the extrapyramidal motor system

Should be considered in a patient with a history of stroke, CAD, or PAD who presents with new onset parkinsonism

More commonly associated with “negative” Parkinsonian symptoms (bradykinesia, rigidity). Tremor is often absent.

Question 8

Drug-induced parkinsonism

Answer 8

Caused by dopamine blocking agents: antipsychotics, antiemetics (specifically metoclopramide)

Question 9

Multiple Systems Atrophy

Answer 9

• Associated with parkinsonism or cerebellar features with prominent autonomic insufficiency
  
  • Orthostatic hypotension, constipation, urinary frequency, impotence
• Two forms:
  
  • MSA-P: MSA with parkinsonism
  • MSA-C: MSA with cerebellar dysfunction

Question 10

Diffuse Lewy Body disease (aka Lewy Body Dementia)

Answer 10

• Dementia syndrome frequently associated with Parkinsonism
• Key features:
  
  • Parkinsonism
  • Clinical fluctuation
  • Visual hallucinations
  • Marked sensitivity to neuroleptics
• Pathology:
  
  • Diffuse Lewy bodies
  • Loss of cholinergic neurons
• Treatment:
  
  • Cholinesterase inhibitors (stigmines)
  • Quetiapine and clozapine (the atypical antipsychotics) are preferred as they are less likely to worsen parkinsonian symptoms
  • Parkinsonian symptoms generally less responsive to carbidopa/levodopa than primary PD

Question 11

Corticobasal degeneration

Answer 11

• Neurodegenerative disorder with Parkinsonism and prominent ataxia
• Alien limb phenomenon is often observed and is considered a hallmark finding
  
  • Feeling that the limb has a mind of its own and is controlling its own movements
• Predominantly unilateral, much like primary Parkinson’s Disease

Question 12

Progressive supranuclear palsy

Answer 12

• Neurodegenerative condition which presents with parkinsonism and impaired voluntary vertical gaze​
• Impaired downward gaze is the most specific historical finding
  
  • Often presents as gaze limitations leading to frequent falls
• Doll’s eyes testing remains intact (unlike vistibular lesions), as brainstem pathways are unaffected

Question 13

How much of PD is familial vs sporadic?

Answer 13

10% familial

90% sporadic

Question 14

Levodopa

Answer 14

Crosses the blood-brain barrier (unlike dopamine) and is converted to dopamine on the other side.

Peripheral breakdown in the gut is inhibited by adding carbidopa to block the activity of aromatic amino acid decarboxylase. Levodopa is also broken down by the enzyme COMT, so COMT inhibitors (entacapone, tolcapone) are also useful adjunct therapies.

Treatment paradigms generally favor levodopa sparing therapies initially unless symptoms are severe at the time of diagnosis (as levodopa will inevitably lead to levodopa-induced dyskinesia over time). Over time, response to levodopa may become fluctuant.

Question 15

COMT inhibitors

Answer 15

Entacapone, tolcapone

Question 16

Dopamine agonists for PD

Answer 16

Cross the blood brain barrier and act predominantly at D2 receptors without requiring conversion.

Include pramipexole, ropinirole, and rotigotine.

More likely to cause problems with impulsivity, including dopamine-induced gambling syndrome, excessive shopping, and hypersexual tendencies.

Question 17

MAO-B inhibitors for PD

Answer 17

Selegiline, rasagiline

Improve symptoms in patients with mild disease as a monotherapy, and can also be used as an adjunct to levodopa.

Many clinicians prefer MAO-B inbitiors for patients younger than 75 and/or with mild PD.

These drugs should be used cautiously with other drugs that may induce serotonin syndrome.

Question 18

Amantadine for PD

Answer 18

Acts by blocking glutamate NMDA receptors

Has mild attenuation of the cardinal parkinsonian symptoms of resting tremor and dystonia.

Similar to MAO-B inbitiors, amantadine may be used for early and/or mild PD.

Also shown to help alleviate levodopa-induced dyskinesias.

Question 19

Deep brain stimulation for PD

Answer 19

For cases refractory to medical therapy

Dementia is an exclusion criterion, as worsening of dementia has been reported following DBS.

Involves placement of stimulating electrodes into the subthalamic nucleus or globus pallidus interna bilaterally.

Question 20

Dopaminergic antagonist antiemetics

Answer 20

Prochlorperazine (aka compazine)

and metoclopramide (aka reglan)

Question 21

Dopaminergic depleting medications

Answer 21

Reserpine, tetrabenazine

Both are centrally acting vesicular monoamine transporter blockers which reduce outflow of all monoamines (dopamine, serotonin, norepinephrine, and histamine)

Reserpine is usually used as an antihypertensive, while tetrabenazine is used to treat choreiform movement disorders like Huntington’s. Both may cause drug-induced parkinsonism, similar to antipsychotics and dopamine-blocking antiemetics.

Question 22

Best “test” for true Parkinson’s disease

Answer 22

Therapeutic trial of levodopa

If they don’t respond well, it is more likely to be something else (or maybe a Parkinson’s Plus syndrome like LBD)

Question 23

Hot-Cross Bun sign in the brainstem on MRI

Answer 23

Present in multiple systems atrophy

Question 24

Two components of “bradykinesia”

Answer 24

1. Slower movements
2. Lower amplitude movements

Question 25

Anticholinergics in Parkinson’s disease

Answer 25

• Can be used in younger patients who (1) will have relatively unaffected cognition and (2) will likely need levodopa later in life, but will live for more than ~15 years and experience its side effects
• Some of the anticholinergis used for this purpose are:
  
  • Trihexyphenidyl
  • Benztropine
  • Biperiden

Question 26

Main side effect of amantadine

Answer 26

~5% of patients may develop livedo reticularis and peripheral edema

Question 27

Parkinson’s drugs and where they work

Answer 27