Clinical Movement Disorders 2: Parkinsonian Disorders

Question 1

What are the chief motor signs of Parkinson’s disease?

Answer 1

TRAP
Tremor - resting tremor
Rigidity - Cogwheel
Akinesia / bradykinesia
Postural instability

Question 2

Define cogwheel rigidity and resting tremor?

Answer 2

Cogwheel rigidity - inconsistent resistance, patient resists hard and then lets you then resists hard again

Resting tremor - 4-6 Hz slow pill-rolling tremor better with movement

Question 3

What is bradykinesia vs hypokinesia? When else could these occur?

Answer 3

Bradykinesia - Slowness of movement, also caused by psychomotor retardation or deliberate slowing if you’re ataxic

Hypokinesia - Reduction in number of movements and AMPLITUDE of movement - can also occur in lethargy or frontal akinesis

Question 4

What are the features of postural instability in Parkinsonism?

Answer 4

1. Flexed posture - shoulders bent over
2. Festination - shuffling gait, walking forward quickly to catch weight
3. Retropulsion - difficulty balancing oneself when pulled backward, need to take a few steps back (walking backward)

Question 5

How does the onset of Parkinsonian tremor differ from essential tremor?

Answer 5

Parkinsonian tremor begins unilaterally and remains asymmetric

Question 6

Other than the motor features, what are some other broad functional deficits which occur in Parkinson’s? When do these occur in relation to motor symptoms?

Answer 6

1. Cognitive disturbances - depression and dementia
2. Autonomic dysfunction
3. Altered senses
4. Sleep disorders

These can occur before motor symptoms

Question 7

What autonomic dysregulation occurs in Parkinsonism?

Answer 7

Constipation (super common)
Nocturia
Orthostatic hypotension
Problems with temperature regulation

Question 8

What senses are altered in Parkinsonism?

Answer 8

1. Anosmia - loss of smell is very common

2. Pain - lowered pain threshold, and muscles often ache from rigidity

Question 9

What sleep problems does Parkinsonism cause?

Answer 9

Insomnia, sleep apnea

REM sleep behavior syndrome - disinhibited movements related to dream activity which can be violent

Question 10

What does the pathology of Parkinson’s look like? Is it just substantia nigra pars compacta that is affected?

Answer 10

Neural degeneration with gliosis and Lewy body formation

-> no, other nuclei in the ventral mesencephalic tegmentum are also affected

Question 11

What is the pattern of spread of neuronal loss in Parkinson’s? What symptoms does this explain?

Answer 11

“Braak Stages” - Starts in medulla and moves its way up to eventually involve the cortex.

Parkinson’s development exists on a spectrum, and at least 50% of dopaminergic neurons need to be lost in order to have disease

Explains early symptoms

• > anosmia - anterior olfactory nucleus involved early
• > constipation - dorsal motor nucleus of X affected early in medulla

Question 12

In what ways is Parkinsonism like CJD?

Answer 12

Spread of synuclein is via protein misfolding, forming neurotoxic fibrils, which can spread from cell to cell in a prion-like manner causing more misfolding and neural degeneration

Question 13

What compound is known to induce Parkinson’s and how?

Answer 13

MPTP - a contaminant in the production of the opiate drug MPPP

MPTP is converted by MAO-B to MPP+ in dopaminergic neurons, which is toxic and causes their death.

Question 14

What other information suggests Parkinson’s might have an environmental cause?

Answer 14

There is an ALS/Parkinson’s syndrome occurring only in Guam, probably due to diet

Also, rural life increases change of Parkinson’s (probably due to agricultural chemicals)

Question 15

What was the first discovered cause of Familial Parkinson’s disease? What is the function of the malfunctioning protein?

Answer 15

Autosomal dominant mutations in synuclein on chromosome 4

• synucleins are abundant in neurons at presynaptic terminals
• bind lipid vesicles and integrate signalling and membrane trafficking
• important in dopamine vesicle organization, and plays are role in other neurodegenerative diseases

Question 16

What gene is mutated in autosomal recessive Parkinson’s inheritance and what is the clinical picture?

Answer 16

Parkin gene - functions as an E3 ubiquitin ligase and proteasome regulator

• Early Parkinson’s (20s) but slow progression
• Patients do NOT have Lewy bodies

Question 17

What is the most common cause of inherited PD? Clinical progression?

Answer 17

LRRK-2 mutations - Lysine-Rich Repeat Kinase -> has GTPase and Kinase domains

• > Patients present clinically exactly the same as idiopathic Parkinson, with low penetrance
• > can be viewed as a “super risk factor”

Question 18

Why is the proteasome thought to be involved in even sporadic cases of Parkinsonism? And what is the function of E3?

Answer 18

Involved because ubiquinated alpha-synuclein can be seen in Lewy Bodies

E1 - activates ubiquitin (via ATP)
E2 - Carries ubiquitin, will do the conjugation
E3 - Brings substrate in proximity of E2 carrying ubiquitin so ubiquitin can be attached (ligating enzyme)

Question 19

Do twin studies show a major role of genetics in the development of Parkinson’s disease?

Answer 19

No - after age 50 there is no correlation

Early onset forms yes

Question 20

What are the non-pharmacologic interventions which can be used for Parkinson’s disease?

Answer 20

Deep brain stimulation -> stimulate subthalamic nucleus (to release pallidum control of thalamus) or GPi

Stem cell replacement may have some efficacy

Question 21

How can Huntington’s cause Parkinsonism?

Answer 21

If you have severe Juvenile Huntington’s, you can develop Parkinson’s late in the disease because it progresses so quickly, the direct pathway also degrades

Question 22

What Parkinson plus syndrome is characterized by more severe autonomic dysfunction and what is this dysfunction? What are its subclassifications?

Answer 22

Severe orthostatic hypotension and urinary incontinence, preceding movement disorder

1. Multiple System Atrophy with predominant parkinsonian features (MSA-P)
2. Multiple System Atrophy with predominant cerebellar features (MSA-C)

Question 23

What are the clinical features of the Parkinsonism of MSA? Other motor signs?

Answer 23

No resting tremor, early gait disorder, may or may not response to levadopa.

Often associated with hyperreflexia, cervical dystonia and limb dystonia, etc

Question 24

What are the cerebellar signs of MSA? What one does it occur in?

Answer 24

Gait disorder with limb ataxia

Mostly in MSA-C, but can happen in MSA-P as well

Question 25

What are the hallmark features of progressive supranuclear palsy (PSP)?

Answer 25

1. Parkinsonism
2. Impaired eye movements
3. Cervical dystonia with bulbar dysfunction
4. Frontal dementia

Question 26

How are the Parkinsonian features of PSP unique?

Answer 26

Very early gait / balance problems (falls within the first year), and the Parkinsonism is symmetric (usually asymmetric)

Question 27

What are ocular features of PSP?

Answer 27

1. Supranuclear palsy - elimination of vertical gaze, but preserved vestibulo-ocular reflex (oculocephalic, subcortical reflex)
2. Square wave jerks - sacchadic eye movements with no smooth phase
3. Absent optokinetic reflex - no tracking of train as it goes by (cortical reflex)

Question 28

What are the characteristic features of corticobasal degeneration (CBD)?

Answer 28

1. Parkinsonism (parkinson+ syndrome)
2. Alien hand syndrome
3. Pyramidal tract weakness - usually unilateral
   - > patients will have been told that must have had a stroke with no actual stroke history
4. Apraxia - inability to repeat or mimic movement
5. Sensory dysfunction

Question 29

What is alien limb syndrome?

Answer 29

Patient is unable to control the movements of their hand, as it response to external stimuli. This makes the patient feel that their hand is “foreign” or “alien”