Parkinsons Flashcards
pathology in parkinsons
loss of pigmente dopaminergic cells of the zona compacta of the substantia nigra. in the remaining neurones there are cytoplasmic inclusions - Lewy bodies.
what are Lewy bodies?
lewy bodies are spherical eosinophilic cytoplasmic inclusions, primary composed of alpha-synuclein. two morphological types: classical (brainstem) and the cortical LEwy body
the 4 main classical features of Parkinsons
and generally early features
resting tremor
rigidity (lead pip + cogwheeling)
bradykinesia
Postural instability
Stiffness, difficulty with fine movement - writing, buttoning, fatigue.
what is the typical onset of parkinsons?
typically features begin asymmetrically and generally upper limbs are first.
daily fluctuation in severity
Non-motor features of PD
- Sense of smell reduced
- Constipation
- Visual hallucinations
- Frequency/urgency
- Dribbling of saliva
- Depression & dementia
- Insomnia
- Postural Hypotension
epidemiology
Typical age at onset: 65yrs. Prevalence: 0.6% at 60–64yrs; 3.5% at 85–89yrs (Europe).
neurological findings of PD
Hypertonia, rigidity, bradykinesia (test: tap fingers, tap foot, clap rotating hand) soft and monotonous speech, reduced blinking frequency, dysarthria, lack of sweating, micrographia.
Features are worse with concurrent activity: eg waving the right arm when assessing for hypertonia in the left
hOW to exagerate PD features on examination?
With concurrent activity eg arm waving whilst examining the other arm
gait in PD
Narrow base slow initiation shortened stride length slow turns lack of arm swing
daignostic features suggesting idiopathic parkinsons disease
asymmetrical onset
good therapeutic response to L-dopa
DDx for parkinsonism
- Parkinson’s disease
- Cerebellar dysfunction
- Dementia with Lewy bodies
- Drug-induced (antipsychotics)
- Normal-pressure hydrocephalus
- CVA or space occupying lesion affecting basal ganglia
- Post-encephalitis
- Wilson’s disease
- Parkinsons-plus syndromes:
a. progressive supranuclear palsy,
b. multisystem atrophy: Shy-Drager syndrome,
c. corticobasal degeneration
what is shy-drager syndrome?
Multiple-system atrophy (MSA) is a degenerative neurological disorder.
Aka olivopontocerebellar atrophy and striatonigral degeneration
Features: varying degrees of parkinsonism autonomic failure, cerebellar dysfunction and pyramidal signs
This cell degeneration causes problems with movement, balance, and other autonomic functions of the body such as bladder control or blood-pressure regulation.
The cause of MSA is unknown and no specific risk factors have been identified.
Around 55% of cases occur in men, with typical age of onset in the late 50s to early 60s.
MSA often presents with some of the same symptoms as Parkinson’s disease. However MSA patients generally show minimal if any response to the dopamine medications used for Parkinsons.
What are Parkinson-plusconditions?
Parkinson-plus conditions are neurodegenerative conditions with parkinsonian characteristics but with additional features that help distinguish from the idiopathic PD. progressive supranuclear palsy, multisystem atrophy (shy-drager), Lewy body dementia. cortico-basal degeneration vascular parkinsonism
progressive supranuclear palsy features
Most common Parkinson-plus syndrome
Involves multiple neurotransmitter pathways.
what are parkinson’s plus signs?
Poor response to levodopa
Marked symmetry of sings in the early stages
Early onset of dementia
Early onset of postural instability and falls
Early onset of hallucinations
Early onset of Sx of autonomic dysfunction, ie postural hypotension
Pyramidal signs
Cerebellar signs
Oscular signs – gaze palsies, nuystagmus
TX for Parkinsons
Management: MDT – neurologist, physiotherapist, OT, specialist nurse, SALT
Levodopa
Other meds:
dopamine agonists – eg ropinirole
anticholinergics – eg trihexyphenidyl useful for tremor
MAO-B inhibitor - eg selegiline
COMT inhibitors – eg entacapone, help decrease immobility by shortening the off time associated with L-dopa
Apomorphine – parenteral dopamine agonist.
Surgery: deep brain stimulation when meds fail
Anticholinergic drugs examples
benzhexol, benzatropine
rationale for anticholinergics
Rationale:
loss of DA dis‐inhibits striatal cholinergic interneurones →
□↑ striatal ACh levels →
□Activation of muscarinic ACh receptors in striatum □Further ↑ overactivity of indirect pathway
→□ Contributes to symptoms of tremor
SE of anticholinergic
central:confusion, mood changes Peripheral: constipation, blurred vision, dry mouth
effectiveness of anticholinergics
Muscarinic antagonists are v effective against tremor (~30% patients) ◊ useful if sialorrhoea is a problem
Minimal effect against bradykinesia and rigidity
Dopaminergic drugs mechanisms to increase availability and reduce destruction
□Levo DOPA or L –DOPA: Natural DA precursor which, unlike DA, can cross BBB
●BUT L‐DOPA is ~90% converted by DDC in intestinal wall →
□Co‐administered with peripherally‐acting DDC inhibitors
Carbidopa ( as Sinemet) or benserazide (as Madopar)
● L‐DOPA is ~5% metabolised by plasma Catechol O‐Methyl Transferase
COMT inhibitor, entacapone, may be used as adjunct
● Ensure majority of L‐DOPA enters brain unchanged
● Conversion by DDC (inside DA (and 5‐HT?) neurones) produces DA
can Dopamine cross BBB?
Dopamine canNOT cross BBB, but L-DOpa, which is its natural precursor) can
what converts L-dopa into DA?
dopa decarboxylase DDC
where is DDC present and what is the implicayion + ways around it
in intestinal wall, 90% of L-dopa is converted there into DA. L-dopa coadministered with peripherally acting DDC inhibitors (carbidopa, benserazide)
The effects (and fate) of L Dopa administration on the brain:
L DOPA with benserazide/ carbidopa raises striates DA levels ○Activity normalised in direct (D1) and indirect (D2) circuits;
○ Improves rigidity, bradykinesia, facial expression, speech and handwriting in ~80% patients
Acute SE of LDOP
□Nausea – due to remaining peripheral DA-R activation → □Peripheral DA receptor antagonist domperidone given as adjunct
□ Postural hypotension (esp. in patients on antihypertensive drugs)
□Psychological – hallucinations, confusion, insomnia, nightmares
peripheral DA receptor antagonis NAME and function
domperidone, to prevent nausea from remaining dopaine receptor activation peripherally
chronic SE of LDOPA`
within 2 years of starting the drug 1/3 patients develop
1)motor fluctuations (‘on-off’ effect and wearing off)
○Rapid fluctuations in clinical state. Freezing may last min or hours.
□Related to plasma fluctuations in L-DOPA? (entacapone help?)
□Related to ltd. storage of dopamine as degeneration progresses?
2) Levodopa-induced dyskinesia (LID)
○Excess, hyperkinetic involuntary movements (choreic or dystonic).
□ Face and limbs mostly affected. □Occur at peak dose or at beginning and end of dose. □Mechanism uncertain. Related to dose and disease severity. □ Thalamocortical feedback is increased above normal.
□Amantadine (NMDA-type glutamate receptor blocker) only drug offering relief
dopamine agonists examples
bromocriptine, lysuride, ropinirole, pramipexole
dopamine agonists effects
○Produce effects mainly through activation of striatal D2 receptors ○Not affected by progressive neurodegeneration
○Longer half‐life so, less plasma fluctuation, less “on‐off” effect & reduced incidence of dyskinesia
side effects of dopamine agonists
▼ Acute SE – as for L‐DOPA ▼Chronic SE lessened
dopamine agonist use indicati
○ Often as first line treatment in the younger BUT less effective than L‐DOPA in relieving symptoms, so L‐dopa needed eventually
□ Used as adjuncts to lower L‐DOPA dose when L‐DOPA required
○Alternative routes of drug administration
to circumvent dyskinesia: Rotigotine (dopamine agonist) patch effective in early PD;
Duo-Dopa: intraduodenal infusion of L-DOPA (no sc formulation)
MAO-B inhibitors
example and reason for indication o
selegiline
● Monoamine oxidase B (MAO‐B) is principal route of DA metabolism in DA rich brain regions
● MAO‐B inhibitors block DA metabolism ● Often used as an adjunct to lower L‐DOPA dose required
● May be used as monotherapy in early stage PD
MAOB inhibitor side effects
SE: Unlike non‐selective MAO inhibitors, selegiline does not inhibit peripheral tyramine metabolism so NO cheese reaction.
Surgical g Approaches to treating PD
Neuroablative Surgery (“otomy”) Deep Brain Stimulation (DBS)
Neuroablative Surgery (“otomy”) mechanism and types
● Very popular prior to L‐DOPA ● Now used in medically‐refractory patients only
● A stereotaxic thermolytic lesion (uni‐ or bi‐lateral) is made in part of basal ganglia motor loop to restore normal thalamocortical feedback.
Thalamotomy (tremor‐dominant cases)
Pallidotomy (improves rigidity & bradykinesia)
Subthalamotomy (improves rigidity, bradykinesia and LIDs)
disadvantages of ablative therapy
• Irreversible • Risk of visual impairment (if optic tract damaged); intracerebral haemorrhage; mild speech & cognitive impairment
DBS mechanism and advantages
● High frequency stimulation to ‘switch off’ or normalise firing of motor loop nuclei
● Mechanism likely involves depolarising block of nerve conduction
● Subthalamic nucleus (STN) – preferred region
● Advantage over lesioning as procedure is REVERSIBLE & graded
● Improved imaging technology now means surgery can be performed confidently with patient under anaesthesia.
●Patient controls stimulation using a pacemaker attached via wires implanted under skin to the indwelling electrode
Failings of current treat
- Only treat some of the symptoms ₋ Postural imbalance left unaffected
- Side effects ₋Very disabling in some cases ; dyskinesia
- Do not address the progressive degeneration
