7 - parkinson’s disease : pathophysiolgy and clincal management Flashcards
1
Q
age of onset in PD?
A
- usually >60
- young onset in 5% - <40
2
Q
what are the core clinical features of PD?
A
- bradykinesia, rigidity
- resting tremor (can also be postural)
3
Q
describe movement in bradykinesia
A
slow and reduced amplitude
4
Q
how is rigidity different from spasticity?
A
not velocity dependent, unlike spasticity
5
Q
what are and what is the main component of Lewy bodies?
A
- occlusion bodies in neurones
- a-synuclein = main component — damages neurones, causes degeneration
6
Q
parkinson’s disease pathology
A
- Lewy bodies — mainly in substantia nigra
- degeneration of SNc — loss of dopamine
- caudo-rostral spread of lewy bodies through brain regions via vagus nerve (starts in brainstem, medulla, olfactory bulb)
7
Q
genetics in PD?
A
- monogenic
- recessive is more common in young onset eg. parkin
- dominant eg. SNCA, LRRK2
- dysfunction in number of cellular pathways
8
Q
environmental factors in PD?
A
- toxins eg. MPTP (neurotoxin which causes DA degeneration), paraquat (pesticide)
- possibility of spread of toxic/infective agents from gut/olfactory system
9
Q
how is PD diagnosed?
A
- bradykinesia + tremor and/or rigidity
- absence of red flags + at least one of:
- clear response to dopaminergic therapy
- levodopa-induced dyskinesia
- rest tremor
- olfactory loss (often occurs early on)
10
Q
what are red flags for idiopathic PD diagnosis?
A
- absent tremor, symmetrical onset (usually asymmetrical in PD)
- early gait abnormality and falls (falls usually happen later on in PD)
- pyramidal tract signs
- poor levodopa response
- supranuclear gaze palsy (problem looking up and down)
- dysautonomia, ataxia stridor (multiple system atrophy)
- apraxia, myoclonus, alien limb
- early dementia
11
Q
what are some non-motor features of PD?
A
- cognitive impairment eg. dementia, behavioural problems
- visual hallucinations
- mood disorders
- olfactory deficit
- pain (brainstem nuclei involved?)
- sleep disorders
- mood disorders
- orthostasis
- constipation, urine and erectile dysfunction
12
Q
what are possible pre-motor features?
A
- REM sleep behaviour disorder (people act out their dreams)
- anosmia
- constipation
- depression
- pain
13
Q
how do symptoms of PD develop throughout the disease?
A
- starts with autonomic and olfactory disturbances
- sleep and motor disturbances
- emotional and cognitive disturbances (spread of Lewy bodies to cortex)
14
Q
what are enkephalin and dynorphin substance P like in PD?
A
- increased ENK due to overactive indirect pathway
- decreased dynorphin due to decrease in direct pathway
15
Q
why is there decreased movement in PD?
A
more inhibiton of thalamus
16
Q
why do you get bradykinesia?
A
- increased inhibitory output to central pattern generators in brainstem
- increased inhibitory output to thalamus and motor cortex
- abnormal B band oscillations (20 Hz) in basal ganglia circuit
17
Q
what happens to oscillations in treatment?
A
‘off’ — more oscillations
on treatment — oscillations normal
18
Q
what does amantadine do?
A
blocks glutamatergic NMDAR in basal ganglia
19
Q
what is and what causes rigidity?
A
- increase in muscle tone
- more obvious during slow movements (unlike spasticity)
- peripheral — reduced inhibiton from type Ib fibres, overactive type II fibres, increased activity due to peripheral stimulation
- central — altered activity in GABA and ACh interneurons, altered inhibition in indirect pathway, increased responsiveness of STN/GPi firing to peripheral stimulation
20
Q
describe tremor in PD
A
- absent in around of 30% patients
- less response to dopaminergic drugs
- not just basal ganglia output
- generated at level of thalamo-cortical-cerebellar loops (modified by basal ganglia activity)
- non-dopaminergic pathways eg. 5-HT?
21
Q
what is the gold standard treatment of PD?
A
L-DOPA
22
Q
name 2 COMT inhibitors
A
entacapone, tolcapone
23
Q
L-DOPA vs DA?
A
- L-DOPA is the precursor to DA — converted to DA once crossed BBB
- DA broken down by dopamine decarboxylase in periphery
- L-DOPA can cross BBB
24
Q
what must levadopa be prescribed with?
A
a DA decarboxylase inhibitor to prevent periphery breakdown
25
levodopa vs dopamine agonists
levodopa
- better motor improvement in short term
- reduced freezing of gait
- more dyskinesia, possibly in long term
dopamine agonists
- less dyskinesia and linger latency to dyskinesia
- more adverse effects such as nausea, postural hypotension, somnolence
- impulse control disorders
- withdrawal problems
26
describe motor complications in PD
- wearing off and motor fluctuations
- L-dopa induced dyskinesia
- occur in 50% after 4-6 years treatment
- related to how long you have had the disease
- young age, disease severity associated
- genetic factors
- decreased duration of action and more dyskinesia as disease progresses
27
pathophysiology of motor complications
- brain less able to handle L-DOPA as disease goes on
- overactive direct pathway
- underactive indirect pathway
- too little inhibition and too much excitation — more involuntary movement
28
what are mechanisms of motor complications?
- pulsatile dopaminergic stimulation
- abnormal handing of dopamine by 5-HT neurones (due to death of DA neurones)
- abnormal synaptic plasticity
29
how can dyskinesias be treated?
- amantadine — NMDA receptor antagonist, blocks glutamate — reduces dyskinesia by around 40%
- continuous dopaminergic stimulation — apomorphine (DA agonist by iv) and duodopa (into intestine)
— fewer fluctuations
30
name some impulse control disorders seen in PD
- pathological gambling
- hypersexuality
- compulsive shopping
- binge eating
31
what are risk factors for impulse control disorders?
- dopamine agonist use > high dose levodopa
- smoking
- male
- young onset PD
- depression
- novelty-seeking behaviour
- family history gambling, alcoholism
32
what can abrupt withdrawal of medications lead to?
neuroleptic malignant syndrome — rigidity, muscle breakdown
33
what % of patients are eligible for DBS?
10%
34
describe SPECT
- single photons registered by rotating gamma camera
- low cost, poor resolution
- long tracer half life
- widely used
35
describe PET
- 2 y-rays emitted at 180 degrees detected by static ring of detectors
- higher cost
- better resolution
- not available in all hospitals
- shorter half life
36
what is 18F-fluorodopa in PET bind to?
vesicles in brain containing DA
37
what is DA loss like in PD?
asymmetric
