7 - parkinson’s disease : pathophysiolgy and clincal management Flashcards
age of onset in PD?
- usually >60
- young onset in 5% - <40
what are the core clinical features of PD?
- bradykinesia, rigidity
- resting tremor (can also be postural)
describe movement in bradykinesia
slow and reduced amplitude
how is rigidity different from spasticity?
not velocity dependent, unlike spasticity
what are and what is the main component of Lewy bodies?
- occlusion bodies in neurones
- a-synuclein = main component — damages neurones, causes degeneration
parkinson’s disease pathology
- 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)
genetics in PD?
- monogenic
- recessive is more common in young onset eg. parkin
- dominant eg. SNCA, LRRK2
- dysfunction in number of cellular pathways
environmental factors in PD?
- toxins eg. MPTP (neurotoxin which causes DA degeneration), paraquat (pesticide)
- possibility of spread of toxic/infective agents from gut/olfactory system
how is PD diagnosed?
- 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)
what are red flags for idiopathic PD diagnosis?
- 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
what are some non-motor features of PD?
- 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
what are possible pre-motor features?
- REM sleep behaviour disorder (people act out their dreams)
- anosmia
- constipation
- depression
- pain
how do symptoms of PD develop throughout the disease?
- starts with autonomic and olfactory disturbances
- sleep and motor disturbances
- emotional and cognitive disturbances (spread of Lewy bodies to cortex)
what are enkephalin and dynorphin substance P like in PD?
- increased ENK due to overactive indirect pathway
- decreased dynorphin due to decrease in direct pathway
why is there decreased movement in PD?
more inhibiton of thalamus
why do you get bradykinesia?
- 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
what happens to oscillations in treatment?
‘off’ — more oscillations
on treatment — oscillations normal
what does amantadine do?
blocks glutamatergic NMDAR in basal ganglia
what is and what causes rigidity?
- 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
describe tremor in PD
- 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?
what is the gold standard treatment of PD?
L-DOPA
name 2 COMT inhibitors
entacapone, tolcapone
L-DOPA vs DA?
- 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
what must levadopa be prescribed with?
a DA decarboxylase inhibitor to prevent periphery breakdown
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
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
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
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
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
name some impulse control disorders seen in PD
- pathological gambling
- hypersexuality
- compulsive shopping
- binge eating
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
what can abrupt withdrawal of medications lead to?
neuroleptic malignant syndrome — rigidity, muscle breakdown
what % of patients are eligible for DBS?
10%
describe SPECT
- single photons registered by rotating gamma camera
- low cost, poor resolution
- long tracer half life
- widely used
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
what is 18F-fluorodopa in PET bind to?
vesicles in brain containing DA
what is DA loss like in PD?
asymmetric
