Parkinsons Disease

Dept of Medicine for the Elderly

Beaumont Hospital
October 2008

Learning objectives:
Know the differences between Parkinsons
disease and parkinsonism

Describe the features of Parkinsons disease

Principles management of Parkinsons

disease
Outline
Epidemiology

Pathophysiology

Causes

Clinical findings

Treatment
Epidemiology
First described in 1817 by Dr James Parkinson
An Essay on the Shaking Palsy

Majority of cases are idiopathic

Symptoms begin 55-60 years

1% of over 60 year olds

Males:Females 1.5:1
Epidemiology
Chronic, progressive, degenerative disease of CNS

Disturbance of muscle control affects movement

2nd most common neurological disorder

Prevalence varies most studies 120 per 100,000

1 million affected in US greatest prevalence

Pathophysiology
Loss of pigmented dopaminergic neurones in substantia nigra.

Presence of Lewy bodies within pigmented neurons is

characteristic.

60-80% of neurones are lost before the motor signs emerge.

As the disease progresses, components of the autonomic, limbic,

and somatomotor systems become particularly badly damaged.

Braak staging 1-6 correlates with clinical manifestation of the

disease.
Here comes the Science..!
 Basal Ganglia
'basal ganglia' means:
the caudate nucleus,
putamen & globus pallidus.

They are functionally important

for controlling voluntary
movements and establishing
postures.

When they are altered - like in

Parkinsons disease - the
person has unwanted
movements,
 Substantia Nigra
The substantia nigra (in the midbrain) is an important motor
centre.

It projects to the caudate & putamen (2 nuclei of the basal

ganglia that together comprise what is called the Striatum).

These Nigrostriatal cells use the neurotransmitter Dopamine

& cells within the nigra produce dopamine normally.

The substantia nigra is the lesion site in PD - degeneration of

the melanin-containing cells.

Absence of this transmitter produces the crippling features of

PD.

Nigrostriatal pathway
 Motor circuit
This circuit modulates output from the motor
cortex

Loss of Substantia nigra results in

dysfunctional stimuli to basal ganglia.

Imbalance of excitatory and inhibitory

pathways regulating movement.
symptoms seen in PD.

These changes were identified in 1950s.

Nigrostriatal pathway
Parkinsons Disease: A
Neurochemical Imbalance

He a lthy bra in
Normal motor control

Dopamine Acetylcholine

Pa rkins on's dis e a s e

Disrupted motor
control due to
an imbalance of
neurotransmitters
Causes
Idiopathic

Toxins (Mn, Fe, MPTP, pesticides/herbicides)

Head trauma

Drug induced (antipsychotics, antiemetics, antihistamine)

Genetic (Park-1, Park-3 & Park-12) accounts for < 5%

Abnormal proteosome system

Oxygen free radicals

Cardinal Motor Symptoms
Tremor

Bradykinesia

Rigidity

Postural instability
Tremor
pill rolling

unilateral

rapid at rest

increased with stress

frequency of 4- 5 Hertz
Bradykinesia
slowness of movement

difficulty initiating voluntary movement

difficulty with sequential complex movements

decreased amplitude of movement (writing)

rapid fatigability of repetitive movements

Rigidity
Increased resistance of relaxed muscles to passive
stretch

commonly asymmetrical

1. cogwheel (tremor and rigidity)

2. lead pipe
Postural Instability

balance well preserved until later stages

shuffling gait & poor arm swing contribute

high falls risk

Clinical Assessment

On reviewing patients always assess for

Motor and Non-motor symptoms and signs
Motor Symptoms/Signs
Function Gait

Shuffling gait
Poor bed mobility
Difficulty with transfers Flexed axial posture
Poor dexterity/coordination Festination
Micrographia Decreased arm swing
Painful dystonia Turning en bloc
Freezing
Face
Falls
Hypophonia
Dysphagia/Drooling
Hypomimia
Non-Motor Symptoms

Depression Sleep disturbance

prevalence varies (>30%) insomnia

? reactive process daytime somnolence/fatigue
? dopamine effect
vivid dreams
hallucinations

Cognitive decline

executive dysfunction
dementia (~30%) ?DLB
always o/r other causes
Non-Motor Symptoms
Sensation Autonomic

orthostatic hypotension (?meds) seborrhoeic dermatitis

anosmia urinary incontinence
pain constipation
impaired proprioception weight loss
sexual dysfunction
sweating abnormalities
Diagnosis
Medical History & Clinical examination (triad)

Observation

No laboratory tests

CT and MRI brain usually unremarkable

MRI can outrule Multi-infarcts, Hydrocephalus & Wilsons

PET/SPECT useful in atypical cases

Differential Diagnosis

essential tremor

vascular parkinsonism

drug Induced parkinsonism

parkinsonism in parkinson plus syndromes

thyrotoxicosis
Parkinson Plus Syndromes
Multi Systems Atrophy & Progressive Supranuclear
Palsy
Early postural instability & dementia

These progress more quickly than IPD (worsening in first 3-5 yr)

Anti-Parkinsons medications are less effective and patients are very

sensitive to neuroleptic medications/ levodopa

Autonomic features are common.

Axial > limb involvement

Multisystem Atrophy
Postural Instability with falls

Postural Hypotension

Bladder dysfunction

Pyramidal Signs

Cerebellar Signs
Progressive supranuclear
palsy
Parkinsonism (Symmetrical)

Paralysis of upward gaze

Dementia

Personality change

Speech difficulties
Management - Aims

educate & support

preserve function

maintain general health and fitness

treat other medical problems

Management non
pharmacological

PD Support Group

Physiotherapy & Occupational Therapy

SALT & Dietician & MSW

Communication with GP
COMT (Cathecol-O-Methyl-Transferase) Enzyme other
Drug
maintherapy
route for peripheral breakdown of levodopa.

COOH

Tyrosine HO

Tyrosine hydroxylase (TH)

HO
COOH

Dopa (levodopa) HO

Dopa decarboxylase Catechol O-methyltransferase

HO (DDC) (COMT)
CH2O
COOH
HO Dopamine Waste product
3-O-methyldopa (3-OMD) HO

Monoamine oxidase B
(MAO-B) (COMT) CH3O

H
3-methoxytyramine (3-MT) O

Waste products
Dihydroxyphenyl acetic acid (DOPAC)
Homovanillic acid (HVA)
Management - pharmacological

Aims to control signs/symptoms for as long as possible while

minimising adverse effects.

Usually provide good symptomatic control for 4-6 years. After this
disability progresses.

Motor fluctuations and dyskinesias may become troublesome.

No proven neuroprotective therapies exist for PD. ?MAOB Inhibitors

No standard algorithm treat when function is a problem

Management -
pharmacological
1. Replacement of Dopamine deficiency is key to therapy.

2. Aim for stable stimulation of brain dopamine receptors.

3. Prevent breakdown of Dopamine in CNS.

MAOB inhibitors Selgiline, Rasagiline

COMT inhibitor Entacopone
Management -
pharmacological
Levodopa therapy is the mainstay of treatment
in PD but in the long term has troublesome S/E

Its use is therefore often deferred initially due

to long term S/E.

Lower potency drugs are reasonable in patients

with mild symptoms
Management -
pharmacological
MAO-B inhibitor (mild sym effect) Selegiline, Rasagiline
S/E - orthostatic hypotension & insomnia

Anticholinergics for tremor/drooling. Procyclidine,Biperidin

S/E - confusion, memory impairment, blurred vision etc

Dopamine agonists Ropinerole, Pramipexole, Apomorphine

Help delay use of levodopa in young patients & useful as add on therapy
in late disease
S/E OH, hallucinations, nausea, oedema & sleep attacks!
Management Levodopa

Levodopa & DCI (benserazide or carbidopa)

Levodopa is the most potent and effective for initial therapy >70y

Gives greatest benefit with fewest S/E in short term

Aim to restore normal function using minimum dose of levodopa

Management Levodopa

Pre meals on empty stomach gives better absorption

Domperidone for transient nausea when start treatment

Long term S/E as receptor stimulation becomes less effective

motor fluctuations (on-off phenomenon)

dyskinesias (chorea or dystonia)
Disease Monitoring
Usually a slow progression if rapid, reconsider diagnosis.

Check dosage, timing, compliance.

Medication charts are helpful

Check for side effects confusion, sleep, psychiatric symptoms.

Motor complications due to pulsatile stimulation of receptors

Motor fluctuations
Wearing off phenomenon due to decreased response to levodopa

1. at night - use CR nocte

2. frequent wearing off between doses add COMT inhibitor

3. freezing episodes

- increase dose or frequency of levodopa

- add COMT inhibitor, MAO-B inhibitor or dopamine agonist
- use liquid levodopa ( fast onset )
Dyskinesias
Peak dose dyskinesias

1. Add Dopamine Agonist, COMT inhibitor, MAO-B inhibitor

2. Slowly lower the dose of levodopa

Refractory symptoms Apomorphine (Dopamine agonist) is useful.

- Britajet (subcut injections as needed)

- Subcut infusion (usually hospitalised prior to this)
Management - surgery

Since 1960s Thalamotomy & Pallidotomy were common practice

Destruction of brain tissue to control the symptoms

Thalamotomy (thalamus) reduces tremor

Pallidotomy (globus pallidus) reduces tremor, rigidity, bradykinesia &

dyskinesias.

Levodopa subsequently took over but surgery has since re-emerged as

long term complications of levodopa have become apparent.

Has a role where drug therapy is no longer sufficient.

Deep Brain Stimulation
Intracerebral electrode connected to
a pulse generator.

Hand held device activates the

pulse generator

Leads to electrical stimulation of

thalamus/globus pallidus

Resets abnormal firing patterns

Can be reversed & adjusted

Deep Brain Stimulation

It improves symptoms that formerly responded to levodopa.

Extends on time.

Subthalamic stimulation is commonest surgical procedure which

reduces dyskinesias and medication use.

Improvements maintained for up to 5 years post op

Need:
a clear diagnosis of PD
levodopa responsive patients with motor fluctuations or dyskinesias
no psychiatric problems
good insight into risks/benefit of this treatment
Parkinsons Disease - Stages

Ho ne ymo o n Mo to r co mplic a tion

pe rio d pe rio d Late stage
Parkinsons Disease
Progression
Motor Complications

Falls

Autonomic Impairment

Neuropsychiatric

Sleep
Summary
Common but treatable disease where diagnosis is clinical.

Monitoring is important
? Improvement ? Side effects ? fluctuations

Aim to improve function & QOL

Levodopa is mainstay of pharmacological treatment.

Continuous MDT involvement central to care.