Parkinsons Disease

• Progressive neurological disorder due to substantia nigra degeneration and midbrain dopamine deficiency
• Lewy bodies are also found in the nigra: significance of this is uncertain.
• 10-15% of  patients have a genetic component (ask about family history).
• Prevalence – 1-2 per 1000 in Australia, male = female
• Traps in missing diagnosis – 10-15% before age 50, absence of resting tremor in 50% of people at onset

SIGNS and SYMPTOMS

• Tremor / Rigidity / Bradykinesia/ Postural Instability

Tremor

• 4-5Hz resting tremor that improves with movement. Disappears during sleep.
• Often involves the thumb and the 2^nd finger: ‘pill-rolling
• Usually asymmetric / unilateral.

Rigidity

• Rigidity is increase resistance on passive movement of a joint.
• The rigidity may be of the same intensity (‘lead pipe’) or fluctuating (‘cogwheel’).

Bradykinesia

• Bradykinesia means slowed movement. Can also get hypokinesia (reduced movement) and akinesia (no movement).
• Examples include:
  • Patient often complains about difficulties in doing dextrous tasks.
  • Reduction in arm swinging when walking.
  • Drooling due to decreased swallowing.
• Testing: get patient to do a repetitive movement: eg fist opening and closing; foot tapping. There is a progressive decrease in amplitude and speed of the movements over the next 10-20 seconds.

Postural Instability

• Due to loss of postural reflexes. Emerges in later disease progress.
• Test by retropulsion: stand behind the patient and give him/her quick pull on the shoulder. Rather than just taking 1 step back, the PD sufferer will need to take multiple shuffling steps backwards in order to maintain balance.
• Loss of postural reflexes causes festination where the patient appears to be ‘hurrying along’ in an attempt to stop falling.
• Postural instability occurs late in the disease process. If falls are an early feature, consider another diagnosis.

Freezing

• Freezing is a transient akinesia, which often occurs when patient is turning, or initiating movement.
• Can manifest in other ways such as palilalia and ‘apraxia of eyelid opening’.

Other Manifestations

• Motor:
  • Reduced arm swing
  • Slow, shuffling gait
  • Parkinson facies:  Hypomimia (reduced facial expression – giving ‘mask’ facies).
  • Postural disturbances
  • Voice changes – often soft but harsh sounding voice
• Non motor features – often seen prodromally – often stronger impact on quality of life
  • Depression and anxiety
  • autonomic symptoms
  • daytime somnolence
  • fatigue
  • constipation
  • urinary urgency
  • erectile dysfunction
  • anosmia(doesn’t occur in the Parkinson-plus syndromes progressive supranuclear palsy).
  • abnormal color perception
• Mild autonomic disturbances
  • orthostatic hypotension
  • constipation
  • bladder dysfunction e
• Cognitive changes
  • Attention
  • executive function
  • language 
• Dementia occurs in late disease – 50% will develop dementia
• Consider Lewy body if hallucinations, fluctuating attention, nocturnal confusion, visual spatial impairment 

DIFFERENTIAL DIAGNOSES OF PARKINSON’S DISEASE

• Essential tremor
  • most common cause of tremor in the elderly
  • Tremor in both hands, Intention, may involve head, Shaky voice
  • classically occurs with action or posture (as opposed to resting tremor in Parkinson’s disease).
    • Note: the two can co-exist. 
  • Clues to the diagnosis include
    • family history
    • bilateral onset
    • absence of bradykinesia or rigidity
    • improvement with propanolol or alcohol.
  • essential tremor may involve the head or the Jaw
    • causing head nodding/titubation
    • staggering gait with head/trunk nodding)
    • Begins in early adult life
    • Relieved by alcohol
    • Exclude drug or toxin induced, or systemic illness
    • Rx – propranolol, intermittent benzos before stress, modest alcohol
• Drug-induced Parkinsonism
  • Antipsychotics, such as haloperidol
  • Prochlorperazine
  • metoclopramide
• Vascular Parkinsonism
  • Lacunar infarcts in basal ganglia or multiple infarcts in frontal and parietal motor areas
  • pseudobulbar features with the characteristic gait disorder, marche à petit pas (tiny, stuttering steps).
  • Clues to the diagnosis include history of progression associated with strokes and lack of response to L-dopa
• Dementia with Lewy Bodies
  • early dementia, prominent hallucinations, fluctuating cognition, and rigidity being more prominent than bradykinesia.
  • Antipsychotics (especially the older class) are best avoided due to increased sensitivity, such as excessive extrapyramidal side effects or life-threatening neuroleptic malignant syndrome.
  • Motor aspects may respond to L-dopa, but often at a cost of worsening neuropsychiatric symptoms.
• Progressive supranuclear palsy
  • cognitive and personality changes involving frontal impulsiveness
    • classic eye signs of loss of downward gaze initially, followed by
    • loss of upward and horizontal gaze.
  • There is axial (vertebral column) rather than limb, rigidity and bulbar dysarthria. 
  • Falling is common, due to loss of downward gaze. 
  • There is poor, or no, response to L-dopa.
• Multisystem atrophy
  • striatonigral degeneration, sporadic olivopontocerebellar atrophy and Shy-Drager syndrome.
  • characterised by
    • autonomic dysfunction (including orthostatic hypotension and sexual impotence)
    • bladder dysfunction.
  • do not respond to L-dopa, although about 20% have good response to it, at least initially.
  • L-dopa is less effective in this group than when used for patients with Parkinson’s disease, and may induce increased drug sensitivity (causing postural hypotension or neuropsychiatric symptoms)
• Others
  • Advanced Alzheimer’s disease
    • A mild degree of Parkinsonism can occur
    • dementia occurs early and is the dominant feature.
    • When dementia occurs after the onset of Parkinson’s disease, around 30% of cases may have co-existing Alzheimer’s disease.

following features are not usually part of Parkinson’s disease:

• Poor or no response to L-dopa
• Hypersensitivity to L-dopa (neuropsychiatric or postural hypotension)
• Early onset of dementia or hallucinations
• Early onset of postural instability or postural hypotension.

Parkinson Disease Examination

Rigidity, Bradykinesia and Tremor

• General Inspection
  • Lack of facial expression (mask-like facies), drooling
  • Flexed posture
  • Soft, monotonous, dysprosodic voice
  • Tremor
  • Poverty of spontaneous movement
  • Stooped posture
• Gait
  • Hesitancy
  • Small steps
  • shuffling
  • festinating (catching up to centre of gravity), knees bent, flexed neck, hurried feet
  • loss of arm swing, turning in clockwise fashion, able to walk over obstacles (e.g. examiners foot)
  • Propulsion and retropulsion
  • Kinesia paradoxica
• Hands
  • Resting tremor – pill rolling – finger nose testing to elucidate presence of other tremors – can be facilitated by serial 7s or moving the contralateral hand/neck
  • Bradykinesia – rapid movements (touch thumb with each finger)
  • Tone – Test at wrists and elbows (lead-pipe/cogwheel rigidity) – facilitated by movements of contralateral limb or neck – independent of velocity or position
• Face
  • Titubation (tremor) of head
  • Absence of blinking
  • Dribbling of saliva
  • Lack of facial expression
  • Glabellar tap – not 100% specific
  • Speech
  • Ocular movements – Primary weakness of upward gaze in idiopathic Parkinson disease; PSP – subgroup of patients with truncal rigidity, especially neck, early failure of downward gaze, then upward then horizontal – falls a prominent feature 
• Autonomic Instability (Multisystem Atrophy – Shy Drager)
  • Greasy/sweaty brow (seborrhoea)
  • Othrostatic hypotension (also due to L-dopa)
• Function
  • Micrographia
  • Cognition – MMSE
  • Dementia – test higher centres if appropriate
  • Mood, behaviour 
  • General statement about overall function
• Medication Side-Effects
  • Dyskinesias
  • Dystonias
  • Visual Hallucinations
• Neurological Exam
  • Power, reflexes and sensation usually normal
  • frontal lobe signs may be present with glabellar and grasp tap reflexes being present
• Mental State
  • Depression

Investigations:

• It is a clinical diagnosis
• Levodopa and apomorphine challenge test: should get clinical improvements.
• Olfaction testing: anosmia supports the diagnosis

Consider Parkinsons plus syndromes 

1. progressive supranuclear palsy – PSP
2. corticobasal degeneration – CBD
3. multiple system atrophy – MSA)

Red flags for these include: (table in murtaghs pg 298)

1. Bilateral onset/dystonia(PSP)
2. poor response to L-dopa, early onset dementia (LewyBD)
3. Myoclonus (CBD, mad cow)

Hoehn and Yahr Scale of disability in PD:

Stage 1:  unilateral, minimal functional impairment

Stage 2: bilateral without impairment of balance

Stage 3: bilateral, positive instability , physically dependent

Stage 4: severe disability, but can walk and stand without assistance

Stage 5: wheelchair bounded, bedridden 

FUNCTIONAL IMPAIRMENT

1. Motor disability:  gait freezing, shuffling gait, tremor bradykinesia, rigidity, postural instability

2. Non-Motor disabling features : dementia, psychosis, fatigue, depression, anxiety , sleep disturbance, constipation, bladder, sexual dysfunction

MANAGEMENT

Goals

1. Symptom control   
2. Optimize function

Multi-Disciplinary Team

– specialist neurologist, physio, OT , dietician, mental health

Optimise Function

1. Motor function rehabilitation

1. cued exercise training
2. balance training
3. treadmill walking

2. Orthostatic hypotension
   • avoid heat, fluids, slow to stand, fludrocortisone
3. Dementia, Psychosis
   • regular activities, music therapy, review meds, clozapine, quetiapine
4. Depression, Anxiety
   • CBT, psychotherapy, antidepressants
5. Constipation
   • dietary measures, exercise, laxatives
6. Bladder, sexual dysfunction
   • bladder training, ED and uro meds

Pharmacological treatment

• start medication at minimal possible amount only when there is functional impairment
• individualize to patient age, occupation, lifestyle, preferences
• common side effect is nausea, treat with Domperidone. 
• Avoid Metoclopramide and Prochlorperazine.
• Levodopa 
  • A/E
    • Dyskinesias
    • motor fluctuations during day
    • nausea and vomiting
    • orthostatic hypotension
  • As PD progression advances 🡪 develop
    • on–off phenomenon – rapid fluctuations in their motor function
    • results in drug-induced involuntary movements, anxiety and hallucinations
    • effect of the drug usually wears off after shorter durations
    • increased frequency of dosing is often required
    • Options include more reduced L-dopa dose but with more frequent dosings
    • switching over to a D-agonist; and adding adjunct agents. 
    • Specialist advise is necessary

Levodopa

• replace the dopamine in the depleted striatum.
• dopamine itself is unable to cross the BBB and cannot be used to treat PD
• the dopamine precursor levodopa is able to cross the BBB and can be administered as a therapy. 
• After absorption and transit across the BBB, it is converted into the neurotransmitter dopamine by DOPA decarboxylase
• commenced on a low dose of levodopa, with the dose being titrated up based on the patient’s response to treatment, balanced against the adverse effects – range of 150–1000 mg daily, divided into multiple doses
• Clinical effect of levodopa is noticed quickly, and may last for several hours, particularly in the early stages of disease
• Carbidopa
  • is often combined with levodopa in Parkinson’s disease medications.
  • is a peripheral dopa decarboxylase inhibitor
  • inhibits the breakdown of levodopa before it reaches the brain. 
  • Carbidopa does not cross the blood-brain barrier
  • so it does not interfere with the conversion of levodopa to dopamine in the brain. 

• The combination of levodopa and carbidopa allows for lower doses of levodopa to be used, reducing the risk of side effects such as nausea and vomiting.
• It also helps to increase the efficiency of levodopa in managing the symptoms of Parkinson’s disease, providing better control over motor symptoms like tremors, rigidity, and bradykinesia.
  • Fludrocortisone
    • For postural hypotension with levodopa
    •  0.1 mg in the morning, increasing if necessary up to 0.5 mg in the morning
  • neuroleptic drugs = clozapine, olanzapine, quetiapine and risperidone
    • to manage Psychotic symptoms such as visual hallucinations and persecutory delusions

Dopamine agonist

• oral dopamine agonists directly stimulate striatal neurons. 
• They have a longer plasma half-life than levodopa, and thus provide a more continuous dopaminergic stimulation. 
• In the doses tolerated by most patients, they usually do not provide the same degree of motor improvement as levodopa
  • Pramipexole
  • cabergoline (A/E compulsive behaviours e.g. gambling, punding)

MAOI-B inhibitors

•  selegiline

Anti-Cholinergics

• when tremor is prominent and poorly responsive to dopaminergic therapy 
• Amantaine: Where symptoms are largely tremor

Drug	Usual dose range	Adverse effects
Levodopa
levodopa+benserazide	50+12.5 mg to 250+62.5 mg orally, 3 times daily	nausea and vomiting (initially), orthostatic hypotension, involuntary movements, neuropsychiatric
levodopa+carbidopa	50+12.5 mg to 250+62.5 mg orally, 3 times daily
Non-ergot-derived dopamine agonists
apomorphine	dosing is complex, may be given by intermittent SC injection or by SC infusion; see product information	nausea (requires pre-treatment with domperidone), neuropsychiatric, injection site reaction
pramipexole	immediate-release: 0.125 to 1.5 mg orally, 3 times dailyextended-release: 0.375 to 4.5 mg orally, once daily	nausea, neuropsychiatric, somnolence, fatigue, orthostatic hypotension, behavioural (eg pathological gambling, hypersexuality), application site reaction (rotigotine)
ropinirole	0.25 to 8 mg orally, 3 times daily
rotigotine	2 to 8 mg transdermally, daily
Ergot-derived dopamine agonists
bromocriptine	ergot-derived dopamine agonists are no longer recommended for treatment of Parkinson’s disease due to the risk of adverse effects. For the management of patients on these medications, seek specialist advice	fibrosis (pleuro, pulmonary, retroperitoneal), cardiac valvular incompetence (cabergoline and pergolide), nausea, neuropsychiatric, orthostatic hypotension, erythromelalgia, behavioural (eg pathological gambling, hypersexuality)
cabergoline
pergolide
Catechol-O-methyltransferase (COMT) inhibitors
entacapone	200 mg orally, with each dose of levodopa	potentiation of levodopa adverse effects, diarrhoea, discolouration of urine
Monoamine oxidase type B (MAO-B) inhibitors
selegiline	2.5 to 5 mg orally, once or twice daily (morning and noon)	insomnia, neuropsychiatric
Anticholinergic drugs
benzhexol	2 mg orally, 2 to 3 times daily	neuropsychiatric, dry mouth, urinary retention, constipation, blurred vision, orthostatic hypotension
benztropine	1 to 2 mg orally, twice daily
biperiden	1 to 2 mg orally, 1 to 4 times daily
Other
amantadine	100 mg orally, twice daily	neuropsychiatric, nightmares, insomnia, livedo reticularis, ankle oedema

Non-Pharmacological Management

1. Goals:
   • Symptom control and optimization of function through a multidisciplinary approach.
2. Multidisciplinary Team:
   • Involvement of specialists including neurologists, physiotherapists, occupational therapists, dietitians, and mental health professionals.
3. Motor Function Rehabilitation:
   • Exercise:
     • Regular physical activity tailored to the patient’s abilities.
     • Cued exercise training, such as using visual or auditory cues to improve movement.
     • Balance training and treadmill walking to enhance mobility and reduce fall risk.
4. Orthostatic Hypotension Management:
   • Avoiding rapid changes in posture, ensuring adequate hydration, and considering the use of compression stockings.
5. Cognitive and Psychological Support:
   • Engagement in regular cognitive activities and social interactions.
   • Cognitive-behavioral therapy (CBT) and psychotherapy for managing depression and anxiety.
6. Dementia and Psychosis:
   • Structured daily routines and involvement in meaningful activities.
   • Music therapy and regular review of medications to manage symptoms.
7. Lifestyle and Dietary Modifications:
   • High-fiber diet to manage constipation, increased fluid intake.
   • Bladder training exercises for urinary symptoms.
   • Sexual health counseling and appropriate medical management for erectile dysfunction.
8. Speech and Swallowing Therapy:
   • Speech therapy to improve voice quality and address dysarthria.
   • Swallowing exercises and dietary modifications to prevent aspiration and manage drooling.
9. Environmental Adjustments:
   • Home modifications to reduce fall risk, such as removing loose rugs and ensuring adequate lighting.
   • Use of assistive devices like canes or walkers for stability.
10. Patient and Caregiver Education:
    • Educating patients and caregivers about the disease process, symptom management, and available resources.
    • Support groups and counseling to provide emotional support and share coping strategies.

Patient Advice

• Stay Active: Engage in regular, tailored exercise to maintain mobility and balance.
• Healthy Diet: Follow a high-fiber diet, stay hydrated, and manage constipation.
• Cognitive Engagement: Participate in cognitive activities and social interactions to maintain mental function.
• Safety Measures: Make home safety modifications to prevent falls and use assistive devices if needed.
• Seek Support: Join support groups and seek counseling for emotional and psychological support.
• Regular Check-ups: Maintain regular follow-ups with the healthcare team to monitor and adjust the management plan as needed.