PARKINSON

Definition
 Parkinson’s Disease is the most prevalent type of
Parkinsonism, a clinical syndrome caused by lesions in
the basal ganglia, predominantly in the substantia
nigra, that produce deficits in motor behavior
 Parkinson's disease results from a gradual
degeneration of nerve cells in the portion of the mid-
brain that controls body movements.
 Careful evaluation is necessary to help distinguish
Parkinson's disease from second causes of
parkinsonism.
 Parkinsonism is a clinical rather than an etiologic entity
since it is associated with several pathologic processes
that damage the extrapyramidal system
 Classification Parkinsonism

 Primary or idiopathic (Parkinson’s Disease)

 Secondary Parkinsonism (associated with infectious agent, drug, toxin,
vascular disease, trauma, brain neoplasm)
 Parkinson-plus syndromes
 Heredodegenerative disease
 DIAGNOSIS PD

 There are no blood tests or X-rays that will confirm the diagnosis.
 The diagnosis is made on finding 2 of the 3 cardinal features of the disorder
on neurologic exam and ruling out other possible causes including several
conditions that can mimic Parkinson's Disease but often have additional
features (Parkinsn's "Plus").
 The criteria of the United Kingdom
Parkinson’s Disease Society Brain Bank

 Which identify :
 1) symptoms essential for a diagnosis of Parkinsonian syndrome
 2) the criteria excluding a diagnosis of PD
 3) the criteria supporting a diagnosis of PD
Flow chart for the diagnosis of PD based
on the criteria set by the UK PD Brain
Bank
Exclusion criteria for PD (UK PD Brain
Bank)
 Differential diagnosis of drug-induced
parkinsonism and parkinson’s disease
Drug-induced Parkinson’s
parkinsonism disease
Symptom onset Bilateral and Unilateral or
symmetric asymmetric
course Acute or Insidious, chronic
subacute
Tremor type Bilateral Unilateral or
symmetric asymmetric rest
postural or rest tremor
tremor
Anticholinergic Maybe Usually mild to
drug response pronounced moderate
Withdrawal of Remmitance Symptoms &
suspected within weeks to signs slowly
Miscellaneous drugs associated with
parkinsonism
 Reserpine: tetrabenazine • neuroleptic drug and related agent:
 Calcium chanel bloker: cinnarizine, prochlorperazine, perphenazine,
flunarizine
amitriptiline, promethazine, promazine,
 Amiodarone
trifluoperazine, chlorpromazine, haloperidol,
 Bethanechol droperidol, metocloperamide, loxapine,
 Pyridostigmine clozapine, risperidone
 Lithium
 Diazepam
 Fluoxetine
 Phenelzine
 Procaine
 Meperidine
 Amphotericin B
 Cephaloridine
 5-fluorouracil
 vincristin
 Patophysiology…..1

 The exact cause of the disease remains a mystery.

 In Parkinson's, cells that produce dopamine begin to degenerate.
Insufficient dopamine disturbs the balance between dopamine and other
transmitters, such as acetylcholine.

 Dopamine is a chemical messenger responsible for transmitting signals

between the substantia nigra and the next "relay station" of the brain,
the corpus striatum, to produce smooth, purposeful muscle activity.
 Patophysiology….2

 Loss of dopamine causes the nerve cells of the striatum to fire out of
control, leaving patients unable to direct or control their movements in a
normal manner.
 Studies have shown that Parkinson's patients have a loss of 80 percent or
more of dopamine-producing cells in the substantia nigra.
 Gambar 5
Gambar 6
MAINTAIN THE BALANCE BETWEEN
DOPAMIN AND ACh

Cara mengatasi kekurangan ke-tidak seimbangan antara

dopamin dan asetilkholin ini ada bermacam-2:
1.Dengan menambah persediaan dopamine
2.Dengan mengurangi aktifitas asetilkholin
3.Dengan cara / kombinasi yang lain,terutama sehubungan
dengan perkembangan penyakitnya.
 Pathogenesis PD

 Evidence of oxidative stress and depletion of reduced glutathione

oxidative or oxidant stress occurs when the equilibrium between
antioxidant defense mechanism & factor that promote free radical formation
is disturb.
Oxidation due to free radicals is thought to cause damage to tissues,
including neurons (induce apoptosis). Normally, free radical damage is kept
under control by antioxidant chemicals that protect cells from this damage.
 Pathogenesis PD…….2

 Researchers found that patients with Parkinson's disease have increased

brain levels of iron, especially in the substantia nigra, and decreased levels of
feritin, which serves as a protective mechanism by chelating, or forming a
ring around the iron, and isolating it. This led to the conclusion that oxidative
mechanisms may cause or contribute to Parkinson's disease.
 Pathogenesis PD……3

 Mitochondrial complex I deficiency

MPTP MPP+
MAO-B

MPP+ (neurotoxin’s product), is actively taken up into DA

neurons & concentrated in mitochondrial, inhibits complex I
(NADH CoQ1) reduktase, the 1st enzyme of the respiratory
chain the resulting decrease in ATP synthesis is thought
to account for the death of the DA neuron

MPTP : methylphenyltetrahydropyridine; MPP+: methylphenylpyridinium;

 Pathogenesis……4(Mandel et al, 2003

 Selective oxidative stress

 Excessive iron accumulation
 Inflammatory processes
 Glutamatergic neurotoxicity
 Mitochondrial (complex I deficiency)
 Ubiquitin-proteasome system dysfunction
 Decline in growth factor level
 Etiology of PD…..1

 Parkinson's disease may occur when either an external or an internal toxin

selectively destroys dopaminergic neurons.
 An environmental risk factor such as exposure to pesticides or a toxin in the
food supply is an example of the kind of external trigger that could
hypothetically cause Parkinson's disease. (MPTP model)
 Etiology of PD…….2

 Researchers believe that genetics sometimes plays a role in the

cellular breakdown. 15 to 20% of Parkinson's patients have a
close relative who has experienced parkinsonian symptoms
(such as a tremor).
 Genetic factors predominant cause of Young-Onset PD.
Mutations on several chromosomes have been found (mutation
of α-synuclein gen), also one instance of mutation in
Mitochondrial DNA
 Etiology PD……3

 In some individuals, the normal, age-related wearing away of

dopamine-producing neurons accelerates. The exact cause for
this is not known; but, if this happens, then it can also result in
Parkinson's disease. This theory is supported by the fact that the
loss of antioxidative protective mechanisms is associated with
both Parkinson's disease and increasing age.

 In rare instances, Parkinson's disease may be caused by a viral

infection.
 Etiology PD…….4

 Many researchers believe that a combination of oxidative damage,

environmental toxins, genetic predisposition, and accelerated aging
may ultimately be shown to cause the disease.
 Putative factors reported with increased
risk for PD
 Demographic factors • Environmental exposures
*age – elderly * rural living, farming
*gender – men activities, well-water drinking
neurotoxin(MPTP), pesticide
*race – white
exp- insectiside, herbicide,
 Genetic factors fungicide, rodenticide
*family history of PD or essential • life experience
tremor * head injury, emotional stres,
*onset of PD before 50 years of personality (shyness &
age in twin study depressed mood)
*families with a number of • Dietary factor
kindreds with PD & parkinsonism * animal fat consumption,
 Infection agents or disease metal expos-lead, Mn, Hg,
*HIV,Japanese B encephalitis,
iron, copper &amalgam
coxackie B, influenza A, • Occupational factor
herpessimplek measles, mump, * teacher, oil/gas field
diphteria
Putative factors reported with reduced risk
for PD
 Antioxidant: β caroten, vit A, vit C, Vit E (α-tocopherol)
 Dietary factors: niacin-containing food, coffe, tea
 Life experience: cigarette smoking, alkohol drinking
 Infection disease: measles in chidhood
Neuroprotective actions of smoking in PD
have been suggested:
 Activation of the nicotine calcium channels
 Increases melanin in smokers, which may act as a
neurotoxic sink by binding cell toxic factors & removing
them from the cytosol
 Induction of cytochrome p450, induced by aromatic
hydrocarbons in tobacco smoke, which may promote
detoxification of toxic agent implicated in the development
of the disease
 Presence of Hydrazine in the smoke, suggested to protect
dopaminergic nigrostriatal neurons from MPTP-type
damage
 Regulation of neurotrophic factor genes by nicotine
acetylcholin receptor signalling
Mandel S, et al; 2003
CAUSES OF PARKINSONISM

 An adverse reaction to prescription drugs

 Use of illegal drugs
 Exposure to environmental toxins
 Stroke
 Thyroid and parathyroid disorders
 Repeated head trauma (for example, the trauma
associated with boxing)
 Brain tumor An excess of fluid around the brain (called
hydrocephalus)
 Brain inflammation (encephalitis) resulting from infection
 SYMPTOMS PD

 TREMOR
 Resting tremor (shaking back and forth when the limb is relaxed)
 RIGIDITY
 Rigidity (stiffness, or resistance of the limb to passive movement when
the limb is relaxed)

 AKINESIA
 Bradykinesia (slowness of movement)
 POSTURAL INSTABILITY (poor balance).

back
TREMOR

 Typically, the tremor takes the form of a rhythmic back-and-forth

motion of the thumb and forefinger at three beats per second. This is
sometimes called "pill rolling." Tremor usually begins in a hand,
although sometimes a foot or the jaw is affected first. It is most obvious
when the hand is at rest or when a person is under stress.
 In three out of four patients, the tremor may affect only one part or side
of the body, especially during the early stages of the disease. Later it
may become more general.
 Tremor is rarely disabling and it usually disappears during sleep or
improves with intentional movement.
RIGIDITY

 Rigidity, or a resistance to movement, affects most

parkinsonian patients.
 All of our muscles have an opposing muscle. When we try
to move a muscle, it becomes active, and the opposing
muscle relaxes.
 In Parkinson's disease, this delicate balance of opposing
muscles is disturbed.
 The muscles remain constantly tensed and contracted so
that the person aches or feels stiff or weak.
 The rigidity becomes obvious when another person tries
to move the patient's arm, which will move only in
ratchet-like or short, jerky movements.
 This is known as "cogwheel" rigidity.
AKINESIA/BRADYKINESIA
 Bradykinesia. Bradykinesia is the slowing down and loss of
spontaneous and automatic movement. It is particularly
frustrating because it is unpredictable. One moment the
patient can move easily. The next moment he or she may
need help. This may well be the most disabling and
distressing symptom of the disease because the patient
cannot rapidly perform routine movements. Activities once
performed quickly and easily, such as washing or dressing,
may take several hours.
POSTURAL INSTABILITY

 Postural instability, or impaired balance and coordination,

causes patients to develop a forward or backward lean
and to fall easily.
 Postural instability can cause patients to have a stooped
posture in which the head is bowed and the shoulders are
drooped. As the disease progresses, walking may be
affected. Patients may halt in mid-stride and "freeze" in
place, possibly even toppling over.
THE SYMPTOM OF PARKINSON’S DISEASE INCLUDE :

 Slowness of voluntary movements, especially in the

initiation of such movements as walking or rolling over
in bed.
 Decreased facial expression, monotonous speech and
decreased eye blinking.
 A shuffling gait with poor arm swing and stooped
posture.
 Unsteady balance; difficulty rising from a sitting
position.
 Continuous "pill-rolling" motion of the thumb and
forefinger.
 Abnormal tone or stiffness in the trunk and extremities.
 Swallowing problems in later stages.
Loss of fine motor skills

 Difficulty writing, may be

small and illegible
 Difficulty eating
 Difficulty with any activity that
requires small movements
 Movement, uncontrolled - slow
 Frequent falls
 Decline in intellectual function
(may occur, can be severe)
 A variety of gastrointestinal
symptoms, mainly constipation.
Additional symptoms that may be associated with this
disease:

 Depression
 Confusion
 Dementia
 Seborrhea (skin)
 Muscle function/feeling loss
 Muscle atrophy
 Memory loss
 Drooling
 Anxiety, stress, and tension
 STAGING OF PD
Hoehn and Yahr
 1. Stage One
 Signs and symptoms on one side only Symptoms mild
 Symptoms inconvenient but not disabling
 Usually presents with tremor of one limb
 Friends have noticed changes in posture, locomotion and facial
expression
 STAGING OF PD
Hoehn and Yahr
 2. Stage Two
 Symptoms are bilateral
 Minimal disability
 Posture and gait affected
 STAGING OF PD
Hoehn and Yahr
 3. Stage Three
 Significant slowing of body movements
 Early impairment of equilibrium on walking or standing
 Generalized dysfunction that is moderately severe
 STAGING OF PD
Hoehn and Yahr
 4. Stage Four

 Severe symptoms

 Can still walk to a limited extent

 Rigidity and bradykinesia

 No longer able to live alone

 Tremor may be less than earlier stages

 STAGING OF PD
Hoehn and Yahr

5. Stage Five

Cachectic stage
Invalidism complete
Cannot stand or walk
Requires constant nursing care
 TREATMENT OF PD

 Therapeutic approaches to Parkinson’s disease:

a. symptomatic
b. neuroprotective
c. restorative

Mandel et al, 2003

Pharmacological treatment for Parkinson disease
 Treatment Parkinson’s Diseases

Antagonist Amantadine 100 – 300 mg /day

NMDA
Trihexyphenidyl 3-15 mg/day
Anticholinergic
Dopaminergic Carbidopa/levodopa 25/100 mg, 25/250
Beserazide/levodopa mg
50/100 mg / day
Dopamine Bromocriptine 5-40 mg/day
agonist Pergolide mesylate 0.75-5 mg/day
Premipexole 1.5-4.5 mg/day
Ropinirole 0.75-2.4 mg/day
COMT Entacapone 200 mg / day
MAO-B inhibitor Selegiline 10 mg/ day
 ANTICHOLINERGICS

 Effective mainly for tremor and rigidity

 Start low, go slow
 Side effects:
 Dry mouth, sedation, delirium, confusion, hallucinations,
constipation, urinary retention
 AMANTADINE

 Tremor, bradykinesia, rigidity & dyskinesias

 Exact mechanism unknown; possibly:
 enhancing release of stored dopamine
 inhibiting presynaptic reuptake of catecholamines
 mild anticholinergic effect
 NMDA receptor blockade
 Side effects —autonomic, psychiatric
 200-300 mg/day
 SELEGILINE
 Selective Monoamine oxidase B inhibitor
 Inhibits breakdown of dopamine
 Mild symptomatic effect
 ?Neuroprotection
 ?Increased mortality
– DATATOP study: mild symptomatic effect and delay of l-dopa
treatment
– UKPDRS study: increased mortality (not seen in metanalysis of
other selegiline studies)
 Dopamine Agonists
 Advantages:
 Fewer dyskinesias and fluctuations on monotherapy than on l-dopa
monotherapy
 Improve fluctuations and dyskinesias in advanced disease
 Disadvantages:
 Not as effective as levodopa
 Less well tolerated
 High drop-out rate in early monotherapy (unless dose is gradually
increased to high doses)
Dopamine agonist receptor Effects
D1 D2 D3 D4 D5
Ergot
Bromocriptine - ++ ++ + +
Cabergoline 0 +++ ? ? ?
Lisuride + ++ ? ? ?
Pergolide + +++ ++++ + +

Non-Ergot
Pramipexole 0 ++ ++++ ++ ?
Ropinirole 0 ++ ++++ + 0
 Amelioration of long-term
complications
 Fractionation of l-dopa and dispersible l-
dopa
 Dopamine agonists, incl Apomorphine
 COMT-inhibitors
 Slow release and dispersible levodopa
preparations
 (Amantadine: improvement of dyskinesias?)
 (Selegiline, anticholinergics)
 Stereotactic surgery
 Surgical Therapy

 Resurgence of stereotactic surgery with better imaging and equipment

 Lesioning vs. long-term electrical stimulation with implanted deep brain
electrodes (DBS)
Stereotactic Surgery

 Thalamotomy and thalamic DBS: only improvement of tremor

 Pallidotomy and pallidal stimulation: main effect on
dyskinesias, but mild improvement of parkinsonism
 Subthalamic stimulation (or lesions): all features, but
technically more difficult and greater risk of bleeding
 Transplantation (fetal, genetically engineered cells,
xenografts): still experimental
 Non-medical Intervention in PD

 Physiotherapy
 Speech therapy
 Parkinson’s Disease Society
 Occupational therapy
 Respite care and day centres