Parkinson's Disease Flashcards
Diagnosis of Parkinson’s Disease
- Clinical
Exclusion criteria for Parkinson’s Disease
Red flags suggesting alternative diagnosis to Parkinson’s disease
Non-motor symptoms of Parkinson’s
Risk factors for Parkinson’s disease
Notes on prodromal features of Parkinson’s Disease
- REM sleep behaviour disorder
- Hyposmia
- Anxiety
- Constipation
**REM Sleep Behaviour Disorder
**Movements of the body/limbs associated eith dreaming plus at least one of:
- Potentially harmful sleep behaviour
- Dreams that appear to be acted out
- Sleep behaviour that disrupts sleep continuity
50-75% isolated RBD develop Parkinson’s disease
Can predate Parkinson’s disease by up to 20 years
**Treatment of RBD
**Clonazepam - nocte, modulates dreaming/complex behaviours
Melatonin - increases REM sleep atonia levels, useful in those with comorbid OSA or dementia
Mirtazepine, B blockers, tramadol may worsen RBD
Pathophysiology of Parkinson’s disease
- Lewy bodies (intracytoplasmic inclusions) and Lewy neurites are the pathological hallmark
- Lewy bodies contain ubuquitin, alpha-synuclein and other proteins
- Starts in medulla and olfactory bulb, then spreads upwards to SN, then finally to cortex
**Genetics
**25% PD risk due to genetic variation
GBA mutations present in 10% with variable penetrance
LRRK2 mutations in 1-2 % with variable penetrance
Genetic cause more likely if early onset (<50 years) or 1st degree relative has PD
Notes on MAOI in Parkinson’s Disease
- Low potency in terms of dopaminergic effects - may not produce functionally significant benefit but generally well tolerated
- Selegiline, rasagiline, safinamide
- Moderately effective as early symptomatic treatment of PD
- Adverse effects:
○ Nausea, headaches most common
○ Confusion and hallucinations - selegiline causes confusion more so than the others (limits use in late-onset disease)
○ Falls, insomnia, dyskinesia - may just be manifestations of advanced Parkinson’s
Recommend avoid use with TCAs and SSRIs
In high doses -> non selective MAO inhibition -> risk of hypertensive crisis due to dietary interactions with tyramine containing foods
Notes on amantadine monotherapy in Parkinson’s disease
- Weak dopamine agonist
- Alternative to MAO-B inhibitor for younger patients with PD (<70 years) and mild symptoms, particularly if tremor prominent
○ Benefit can be transient - in some limited to 1-2 years - ER and IR preparations
- Excreted in urine unchanged - dose adjust in renal failure
- Adverse effects:
○ Livedo reticularis
○ Ankle oedema
○ Confusion, hallucinations, nightmares - more common in older patients - switch to morning dosing if nightmares an issue
Can also be useful for managing levodopa-induced dyskinesias and off time in advanced PD
- Alternative to MAO-B inhibitor for younger patients with PD (<70 years) and mild symptoms, particularly if tremor prominent
Role of anticholinergics in Parkinson’s Disease
- Useful monotherapy if < 65 years, with disturbing tremor but no significant bradykinesia or gait disturbance
○ Also useful in more advanced disease with persistent tremor despite levodopa or DAs- Avoid in older patients with cognitive impairment - monitor side effects - cognitive impairment, constipation, urinary retention
- Examples:
○ Orphenadrine, procyclidine, biperiden - Adverse effects:
○ Older adults and cognitively impaired patients particularly susceptible to side effects such as memory impairment, confusion, hallucinations
○ Dry mouth, blurred vision, constipation, nausea, urinary retention, impaired sweating, tachycardia
○ Caution in known BPH or angle closure glaucoma
○ Discontinuation - gradual to avoid withdrawal
Options for initial drug therapy in nerly diagnosed Parkinson’s Disase
Notes on dopamine agonists vs levodopa
- Levodopa more effective than DAs for reduction of motor symptoms but more frequently produces dyskinesias than DA - particularly in younger patients
○ DA - dyskinesia rare, also available in once daily preparation
§ More nonmotor side effects - somnolence, peripheral oedema, nausea, dizziness, impulse control disorders
§ Hallucinations and confusion also more frequent - though these less common in younger patients generally
§ Ineffective in patients who have shown no therapeutic response to levodopa - do have a role in advanced PD as a treatment for motor complications of levodopa- Individualised decision
Notes on nonergot dopamine agonists
- Pramipexole, ropinirole, transdermal rotigotine
- Pramipexole, ropinirole - oral - IR and ER formulations
○ Pramipexole - dose adjust in renal insufficiency - Apomorphine - rescue parenteral DA
- Should not be stopped abruptly - sudden withdrawal DA rarely associated with syndrome resembling neuroleptic malignant syndrome
- Adverse effects:
○ Nausea, vomiting, sleepiness, orthostatic hypotension, confusion, hallucinations - similar to levodopa
○ Peripheral oedema (unlike levodopa)
○ Low and slow
○ Older patients and patients with dementia - more susceptible to hallucinations and confusion
○ Pathologic gambling, compulsive sexual behaviour, compulsive buying
○ DAs - decrease prolactin, potential for decreased milk production in postpartum women - Dopamine agonist withdrawal syndrome
○ Abruptly stop taking DA - can develop anxiety, panic attacks, depression, sweating, nausea, pain and drug craving - similar to that of any drug withdrawal
- Pramipexole, ropinirole - oral - IR and ER formulations
Notes on ergot dopamine agonists
○ Bromocriptine, cabergoline - no longer used due to potentially severe complications of therapy
§ Bromocriptine -> potential risk of valve fibrosis/valvular heart disease
§ Pergolide and cabergoline - risk of cardiac, pulmonary, peritoneal fibrosis and valvular heart disease
Notes on levodopa
- Preferred therapy at any age with moderate to severe symptoms
- Superior effects on motor function, activites of daily life, and quality of life compared to other drug classes including dopamine agonists
○ Higher risk of dyskinesias compared to DA - Formulation
○ Combined with peripheral decarboxylase inhibitor (carbidopa in Sinemet, benserazide in Madopar) to block conversion to dopamine in systemic circulation and liver (before crossing blood brain barrier) to prevent nausea, vomiting, and orthostatic hypotension - Dosing
○ Small doses IR release BD/TDS with meals and uptitrated over weeks - titrate to lowest levodopa dose that produces a useful clinical response
○ Absence of response or requiring large doses early on (1000-1500mg/day - max dose)- original diagnosis of Parkinson’s may be wrong - need to consider MSA, PSP, vascular Parkinsonism
§ Exception is tremor predominant PD - large amplitude tremors may be resistant to levodopa - Should not be stopped abruptly (syndrome similar to NMS)
- CR preparations not recommended as initial therapy
○ Less completely absorbed - require 30% increase in dose to achieve equivalent effect
○ Difficulty in assessing response as peak clinical effect is less than that of IR preparations
○ Usually switch to CR if BD dosing preferred by patient
○ CR tablets do not give long term advantage in terms of motor fluctuations - but sometimes better tolerated in terms of nausea and confusion - Should be taken with meals early on to prevent nausea (but advanced Parkinson’s may benefit from taking 30min before meal - less competition for absorption)
- Adverse effects
○ Nausea, somnolence, dizziness, headaches
○ Confusion, hallucinations, delusions, agitation, psychosis, orthostatic hypotension
○ Mild to moderate elevation in serum homocysteine - may be A/W increased risk of hip fractures
○ May be A/W low B12, raised methylmalonic acid, sensorimotor peripheral neuropathy
○ Unclear if ICDs occur with levodopa monotherapy alone - No benefit of early COMT inhibitor
○ No advantage for using levodopa combined with a COMT inhibitor as initial therapy for PD, compared with LD alone
- Superior effects on motor function, activites of daily life, and quality of life compared to other drug classes including dopamine agonists
Notes on COMT inhibitors in Parkinson’s disease
Prolong half life of levodopa, no increase in peak plasma level
- Tolcapone - small risk liver toxicity - need to monitor LFTs
- Entacapone - diarrhoea can develop after a month of treatment but no LFT monitoring required
Notes on Duodopa therapy
- Continuous levodopa-carbidop intestinal gel infusion via percutaneous gastrojejunostomy tube
- Decrease in off time and increased on times and without dyskinesias
- Requires daily attachment of tubes and morning bolus dose, daily flushing of tubes required
- Candidates
○ Advanced PD, dyskinesias, motor fluctuations, dysphagia, unpredictable response to oral medications - Complications
○ Neuropathy and procedure related adverse effects - abdo pain, peritonitis, displacement of tube into stomach
○ Melanoma should be ruled out prior to considering - Conrtaindications
- Uncommonly associated with neuropathy (B12 related) - check B12, methymelonic acid, homocysteiene, B6
Notes on selection of deep brain stimulation patients
- Surgical procedure - placing of probes into subthalamic nucleus or internal globus pallidus - electrical impulses to specific nuclei
- Should have PD for 5 years before consideration
○ Require thorough assessment including neuropsychiatric - Candidates
○ Response to dopaminergic therapy
○ Presence of on-off fluctuations
○ <70 years (can be considered in higher age groups)
○ Severe dyskinesias impacting quality of life
○ Tremor that cannot be controlled with medications
○ Reasonable cognitive function - Contraindications
○ Dementia, active psychiatric disorders, dominant levo-dopa resistant motor symptoms, structural abnormalities on MRI
- Should have PD for 5 years before consideration
Notes on Multiple System Atrophy
**MSA-C - Cerebellera predominant form
**Nystagmus, dysarthria, ataxia
**MSA-= Parkinsonian predominant form
**Mainly akinetic rigid (symmetric rigidity), little tremor, poor postural reflexes - early instability
Erectile failure, urinary incontinence
Pyramidal/cerebellar signs
Poor response to levodopa
More rapid progression
**Shy Drager
**Rare, autonomic form
Alphasynucleinopathy
Many patients develop features of all three
Pyramidal features usually mild (e.g. upgoing plantars, decreased reflexes, no spasticity)
Additional features may include: dystonia, stridor, myoclonus
Men - impotence, women - incontinence
Survival 10 years
If any response to levodopa not marked or sustained
**Imaging
**Hot cross bun sign
Putaminal rim sign
Notes on Progressive Supranuclear Palsy
**Richardson’s syndrome
**53% cases
Classic features of PSP:
1. Early onset falls
2. Supranuclear down gaze palsy (or slow vertical saccades)
3. Postural instability
4. Frontal dementia
**PSP-P (Parkinsonisn)
**32% cases
Characterised by:
1. Assymetric onset
2. Tremor
3. Response to levodopa
4. Better prognosis
**MRI Findings
**Hummingbird or Kind Penguin sign
**Tauopathy
