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DEPARTEMENT OF NEUROLOGY

CHRISTIAN UNIVERSITY OF INDONESIA


MEDICAL FACULTY

Parkinsons disease (PD) is typically


considered a chronic, progressive
neurodegenerative movement disorder.
However, it is now known to have variety
of nonmotor symptoms as well.

Neurologic disease caused by


degeneration of dopamine neurons

Only neurodegenerative disease whose


symptoms can so readily be treated by
medication

Third most common cause of disability.


In majoriy of cases it is IDIOPATHIC.

English physician
Dr James Parkinson in 1817
An Essay on the shaking palsy
Also called Paralysis agitans

In 1960 pathological and


biochemical changes identified

Annual incidence 0.2/1000 & prevalence of 1.5/1000.

Prevalence rates are similar throughout the world, except


lower rates in China /West Africa.

Affects 1% of those over 55 years, 1.5% of people 70-79


years of age

Generally occurs between 50-80 years


Sex incidence is about equal.

4 major symptoms:
Rigidity muscles are tensed and contracted
Resting tremor trembling which is most obvious
when the patient is at rest or when stressed
Bradykinesia slowness in initiating movement
Loss of postural reflexes or instability poor
balance and coordination

Non-motor symptoms

Anxiety disorders, depression, sleep


disturbances, orthostatic hypotension, olfaction
dysfunction, dysphagia, sialorrhoea, dementia,
psychosis and visual hallucinations

Substantia nigra pars compacta.


Death of neuron.
Symptoms of PD dont appear until 5080% of the neurons in the pars compacta
have died.
Cause of death of neuron is not known.

Unpaired electrons that can easily react


with surrounding molecules and destroy
them.
Metabolism of dopamine by MAO produce
hydrogen peroxide.
Glutathione normally breaks down the
hydrogen peroxide quickly.
Reduced glutathione = loss of protection
against free radicals cell damage

1-methyl-4-phenyl-1,2,3,6tetrahydropyridine (MPTP) neurotoxin.


MPTP crosses the blood-brain barrier and
oxidized to 1-methyl-4-phenylpyridinium
(MPP+) by monoamine oxidase B (MAO)-B
MPP+ selectively enters dopamine
neurons via the dopamine transporter.
MPP+ inhibiting Complex I leads to cell
death via energy deficit.

Mutation of SNCA genes in chromosome 4.


2 types of alterations:
Alanine is replaced with SNCA genes is
threonine.
inappropriately
duplicated or
Cause alpha-synuclein
to misfold.
triplicated.
Extra copies of the
gene lead to an excess
of alpha-synuclein.
Aggregate (Lewy bodies) and attract other protein.
Clog neuron and impair the function of neuron.

Basal Ganglia
Controls movement

Dopamine
Inhibitory neurotransmitter in

the basal ganglia


Acetylcholine
Excitatory neurotransmitter in
the basal ganglia
Without dopamine, inhibitory

influences are lost and excitatory


mechanisms are unopposed
Neurons of basal ganglia are over
stimulated
Excess muscle tone, tremors &
rigidity
13

Normal movement
dependent on dopamine
production in the
substantia nigra that
innervates the striatum
PD is associated with
massive degeneration of
dopamine-producing
neurons in substantia nigra
When 60 to 80% of these
neurons are lost, symptoms
of PD appear

Stages Character of Disability


I

Minimal or absent; unilateral if present.

II

Minimal bilateral or midline involvement.


Balance not impaired

III

Impaired righting reflexes.


Unsteadiness when turning or rising from chair.
Some activities are restricted, but patient can live
independently and continue some forms of
employment.

IV

All symptoms present and severe.


Standing and walking possible only with assistance

Confined to bed or wheelchair

PET Scandecreased dopaminergic


activity in the substantia nigra
Unified Parkinsons Disease Rating Scale
cognitive interview
Normal CT
Normal MRI

The diagnosis is made clinically, as there is no diagnostic test


for Parkinson's disease.
Imaging (CT or MRI) of the head may be needed if there are
any features suggestive of pyramidal, cerebellar or
autonomic involvement, or the diagnosis is otherwise in
doubt (e.g to exclude stroke).
[18F]dopa PET and -CIT
SPECT images. [18F]dopa
PET uptake in the putamen
is reduced in PD.

EARLY STAGE

Onset of
symptoms, treated
with physical
therapy and
medications
(Levodopa,
dopamine
agonists, etc)

LATER STAGE
Usually after having
received 5+ years of
levodopa treatment.
Wearing-off and
On/Off effect
develops, other
medication in
conjunction levodopa
is commenced.
MAO-B and COMT
inhibitors

Neuroprotective therapy
Monoamine Oxidase Inhibitors
Symptomatic Therapy
Levodopa (L-dopa) is the mainstay of
symptomatic treatment for PD.
Dopamine Agonists
Anticholinergic Agents
Nutritional Management
A high-protein diet can block the
effectiveness of L-dopa. Thus the patients
are advised high-calorie, low-protein diet.

Levodopa (L-DOPA)
Preferred medication to control major
symptoms.
Usually administered at the early onset of
disorder.
Drug is well tolerated and side affects are
limited.

Levodopa

Dopamine

L-DOPA is converted to Dopamine by


enzyme DOPA decarboxylase (DDC).

Used with Carbidopa, which blocks the early


conversion of L-DOPA into dopamine.

Carbidopa

Side effects include


Psychiatric

symptoms; linked to depression


Nausea and vomiting

Prolonged use can cause wearing-off


effect.
Leads

to other motor complications, such as


dyskinesia.

Still the preferred treatment for symptoms.


Drug brand name: Sinemet

L-DOPA can cross blood-brain barrier,


when dopamine cannot. This led to the
idea of using L-DOPA as treatment for PD.
First used in the 1960s, with daily
increase dosage program.
L-DOPA used in combination with
Carbidopa in 1967.

Increases potency of L-DOPA up to 4-fold.

Dopamine Agonists
Acts directly on the dopamine receptors.
Initially was used with L-DOPA.
Today, sometimes prescribed before L-DOPA,
to delay wearing-off effect and other motor
complications brought on by prolonged use of
L-DOPA.

Pramipexole

Dopamine

Triggers dopamine receptors in place of


depleted dopamine neurotransmitters.

Adverse side effects


Nausea, dizziness, hallucinations
Sleep attacks, hypotension
Permax (pergolide) pulled after direct link
to fibrosis of cardiac valves that can lead to
death. Unavailable in U.S. since 2007.

Monoamine Oxidase B (MAOB)


Inhibitors
Delays or reduces breakdown of dopamine by
MAO-B.
Used as monotherapy or in conjunction with
L-DOPA, it can reduce the dosage of L-DOPA
by 15%.

Selegeline

MAO-B is an enzyme that metabolizes


dopamine.
From the breakdown of dopamine,
hydrogen peroxide is produced, which
the oxidative stress can damage
dopaminergic neurons in the
substantia nigra. (Possibly
neuroprotective)
MAO-B inhibitor delays or reduces the
metabolism of dopamine.

Side effects of L-DOPA may be enhanced


by selegeline.
Nausea and dizziness.

Catechol O-Methyl Transferase


(COMT) Inhibitors
Inactivates and degrades
neurotransmitters, such as dopamine.
Mainly used in combination with L-DOPA, it
increases the half-life of L-DOPA.
Delays wearing-off effect of L-DOPA and
other motor complications such as
dyskinesia

Tolcapone(Tasmar )

COMT catalyses methylation of L-DOPA.


Addition of COMT inhibitor along with LDOPA and carbidopa prolongs the halflife of L-DOPA and increases the
amount in the CNS.

This increases on time for L-DOPA.

Tasmar are hepatotoxic.


Diarrhea and sleep disturbances

Amantadine
Antiviral agent.
Known to aid in reducing dyskinesia.

Anticholinergics
Improve tremors and stiffness
Cause impairment and constipation

Ablative Surgery
Pallidotomy
Thalamotomy

Deep Brain Stimulation


Neural transplantation

Deep Brain Stimulation


Brain pacemaker, sends electrical impulses
to brain to stimulate the subthalamic
nucleus.
Improves motor functions and reduce motor
complications.
Complications include: brain
hemorrhage, seizures, death.

Slowly progressive
Long sub clinical period of around 5 years
61% die within 10 years and 83% die
within 15 years
Mean survival with L-dopa as increased
by 5 years
Patients with predominantly tremor have
a benign progression and those with PI &
gait disturbances have rapid progression.
Mortality is due to cardiovascular disease
or pneumonia.

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