Parkinson's Disease

Question 1

Diagnosis of Parkinson’s Disease

Answer 1

• Clinical

Question 2

Exclusion criteria for Parkinson’s Disease

Answer 2

Question 3

Red flags suggesting alternative diagnosis to Parkinson’s disease

Answer 3

Question 4

Non-motor symptoms of Parkinson’s

Answer 4

Question 5

Risk factors for Parkinson’s disease

Answer 5

Question 6

Notes on prodromal features of Parkinson’s Disease

Answer 6

2. REM sleep behaviour disorder
3. Hyposmia
4. Anxiety
5. 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

Question 7

Pathophysiology of Parkinson’s disease

Answer 7

• 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

Question 8

Notes on MAOI in Parkinson’s Disease

Answer 8

• 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

Question 9

Notes on amantadine monotherapy in Parkinson’s disease

Answer 9

• 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

Question 10

Role of anticholinergics in Parkinson’s Disease

Answer 10

• 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

Question 11

Options for initial drug therapy in nerly diagnosed Parkinson’s Disase

Answer 11

Question 12

Notes on dopamine agonists vs levodopa

Answer 12

• 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

Question 13

Notes on nonergot dopamine agonists

Answer 13

• 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

Question 14

Notes on ergot dopamine agonists

Answer 14

○ 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

Question 15

Notes on levodopa

Answer 15

• 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

Question 16

Approach to dopaminergic side effects

Nausea

Answer 16

• Common on DA and LD
  
  • If on low doses - additional carbidopa may be adequate. Domperidone. Ondansetron.
  • Avoid metoclopramide, prochlorperazine - dopamine receptor blockers

Question 17

Approach to dopaminergic side effects

Orthostatic hypotension

Answer 17

• May require reduction/discontinuation of antihypertensives
  
  • Lower relative efficacy of amantadine, MAO B inhibitors and DA vs levodopa - usually tapered and withdrawn if necessary prior to lowering levodopa
  • May require symptomatic medications for orthostatic hypotension

Question 18

Approach to dopaminergic side effects

Confusion and hallucinations

Answer 18

• Caused or worsened by dopaminergic therapy - typically develop later in the course of disease rather than on initiation
  Withdraw other agents ahead of levodopa. If symptoms persist - levodopa should be tapered to minimum necessary dose prior to addition of antipsychotics

Question 19

Approach to Dopaminergic Side Effects

Impulse Control Disorders

Answer 19

• Can develop in any patient on dopaminergic therapy.- but most common on DA
  ○ DA should be reduced until ICD resolves
  
  • 5 year cumulative incidence of nearly 50%
  • Risk factors
    ○ DA dose and duration of treatment
    ○ Younger age
    ○ Male
    ○ Comorbid anxiety and depression
  • Untreated PD not associated with ICD. No strong association between levodopa and ICDs

Question 20

Notes on dopamine dysregulation syndrome

Answer 20

• Compulsive use of dopaminergic drugs develops in small number
  
  • Males, early-onset PD
    ○ Patients take increasing quantities of dopaminergic drugs despite increasingly severe drug reactions
    ○ Tolerance to mood elevating effects develops, withdrawal state occurs with dose reduction or withdrawal
    ○ Can be associated with punding - complex, prolonged, purposeless and steriotyped behaviour
    Uncommon, may occur more frequently with DA than LD

Question 21

Notes on levodopa induced dyskinesia

Answer 21

**Peak dose dyskinesia
**30-60 minutes post levodopa - mainly chorea, entire body/upper half, often not aware
Options - reduce levodopa dose, add amantadine, add dopamine agonist and reduce levodopa, stop entacapone

**End of dose dyskinesia
**3-4 hours post levodopa or early morning
Dystonia, often foot and often painful
Options - add entacapone or selegiline, decrease dose interval, increase levodopa dose, add amantadine, add dopamine agonists

Question 22

Notes on COMT inhibitors in Parkinson’s disease

Answer 22

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

Question 23

Treatment of dementia in PD

Answer 23

1. Cholinesterase inhibitors
2. Memantine
3. No convincing evidence (yet) for cognitive training or physical exercise
4. Advice of diet, exercise, hearing aids (no definite evidence yet)

**Psychosis in Parkinson’s disease
**Don’t treat benign hallucinations e.g. something mocing in periphery
Paranoid psychosis - e.g. spousal infedility - treat urgently
Treatment options:
1. Quetiapine nocte
2. Reduce PD drugs one by one starting with least potent
3. Cholinesterase inhibitors if dementia
4. Clozapine if ongoing psychosis - most effective but needs frequent monitoring

Question 24

Notes on Duodopa therapy

Answer 24

• 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

Question 25

Notes on apomorphine subcutaneous infusion

Answer 25

* DA - continuous SC infusion or intermittent as needed * Decreases off time and dyskinesia * Candidates ○ Advanced PD, dyskinesias, intolerance to levodopa * Adverse effects ○ Nausea, hypotension ○ Formation of subcutaneous nodules, pain brusing at needle site ○ Somnolence ○ Autoimmune haemolytic anaemia ○ Sleep attacks which may lead to driving restrictions * Contraindications ○ Hypersensitivity, renal failure, cardiac complications, hepatic impairment, orthostatic hypotension

Question 26

Notes on selection of deep brain stimulation patients

Answer 26

* 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

Question 27

Notes on Multiple System Atrophy

Answer 27

**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

Question 28

Disorders with hot cross bun signs

Answer 28

1. MSA 2. Spinocerebellar atrophy 2 and 3 3. variant Creutzfeldt-Jakob disease

Question 29

Notes on Progressive Supranuclear Palsy

Answer 29

**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

Question 30

Notes on corticobasal syndrome

Answer 30

- Commonest pathology is **corticobasal degeneration (CBD, tauopathy) ** may be due to other pathologies e.g. 1. PSP 2. Pick disease 3. AD 4. DLB 5. CJD Commonest presentation is with a useless rigid jerking arm **Features - **Asymmetric akinetic-rigid syndrome - Apraxia - Frontal lobe dementia - +/-limb pain/cortical sensory loss - +/- supranuclear gaze palsy (not as severe as PSP) - +/- myoclonus - +/- alien limb phenomenon - +/- oculomotor apraxia (delay in launching saccades)

Question 31

Notes on Dementia with Lewy Bodies

Answer 31

**Pathology **Early paralimbic and multiple neocortical Lewy bodies.neurites Most have Alzheimer changes as well **Clinical features **Progressive cognitive decline Deficits on tests of attention, frontal-subcortical skills, visuospatial ability **Core features (need at least two) **1. Fluctuating cognition with pronounced variations in attention and alertness Recurrent visual hallucinations, typically well formed and detailed Parkinsonism Suggestive features: REM SBD, Severe neuroleptic sensitivity

Question 32

Secondary Parkinsonism

Answer 32

* Drugs * Toxins ○ Carbon disulfide, carbon monoxide, cyanide, MPTP, manganese, organic solvents * Head trauma - isolated or repeated * Structural brain lesions that affect striatonigral circuits * Metabolic and micellaneous diroders ○ Wilson's, hypoparathyroidism, chronic liver failure, extrapontine myelinolysis * Infections e.g. encephalitis lethargica, HIV/AIDs, neurosyphilis, prion disease, progressive multifocal leukoencephalopathy * Cerebrovascular disease

Question 33

Drugs that cause drug-induced Parkinsonism

Answer 33

* Typically bilateral rather than unilateral * First generation antipsychotics ○ High potency D2R antagonism - Droperidol, flupenthixol, haloperidol ○ Low potency D2R antagonism - chlorpromazine, levomepromazine * Second generation antisychotics ○ D2R antagonism - clozapine, olanzapine, quetiapine, risperidone § Partial - aripiprazole * Antiemetics ○ D2R antagonism - metoclopramide, prochlorperazine, promethazine

Question 34

Distinguishing between MSA and PSP on MRI

Answer 34

- MSA = Pons, PSP = midbrain - MSA = hot cross bun sign - PSP = king penguin/hummingbird sign