Curiculum vitae

Dr. An An, M. Sc., Sp.S

Lulus dokter FK UGM th 2001

Lulus Spesialis Saraf FK UGM th 2013
Lulus S2 Ilmu Kedokteran Klinik FK UGM th 2013
Staf Pengajar Neurologi FK UNTAN
Dokter Sp.S di SMF Saraf RSUD Dr.Soedarso & RS UNTAN
Dokter Sp.S di RS Promedika
Dokter Sp.S visiting di RS Mitra Medika
Praktek di Apotik Abadi Jl. Diponegoro no.27 Pontianak

PARKINSONS DISEASE

Dr. An An, M.Sc., Sp.S

What Is Parkinson's Disease?

Parkinson's Disease is a
clinical syndrome caused by
lesion in the basal ganglia
,predominantly in the
substantia nigra ,that
produce deficits in motor
behavior.

Who is Affected by
Parkinsons Disease
Moh.Ali

Pop John Paul II

Michael Fox
Artis
4

History

In 1817 James Parkinson published a study on the

"shaking palsy," which he also referred to as
paralysis agitans,
In 1957 Carlsson observed similarities between
parkinsonian symptoms and the side effects of
chronic treatment with reserpine, a known
monoamine depleting drug (Yurek and Sladek
1990).
In 1960 Ehringer and Hornykiewicz observed that
concentrations of striatal dopamine were depleted
in parkinsonian patients.
Yurek and Sladek (1990) is "severe reduction of
dopamine in all compartments of the basal
ganglia."

The disease is chronic, (it persists

over a long period of time) and
progressive (its symptoms grow
worse over time). It is not
contagious nor is it usually
inherited-that is, it does not pass
directly from one family member or
generation to the next.

Parkinson's Disease affects about 1 in every 250

people over 40 years old and about 1 in every
100 people over 65 years old.
It is slightly more common in men than in
women.
Medication can treat its symptoms, and the
disorder is not directly life-threatening.
Mostly it is a quality of life issue.
About half of all patients treated with drugs have
no major disabilities 10 years after the onset of
the disease.

CAUSES (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.
8

CAUSES (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.

Oxidation due to free radicals is thought to

cause damage to tissues, including neurons.
Normally, free radical damage is kept under
control by antioxidant chemicals that protect cells
from this damage.
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.

10

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.

11

Researchers believe that genetics

sometimes plays a role in the
cellular breakdown. Fifteen to
twenty percent of Parkinson's
patients have a close relative who
has experienced parkinsonian
symptoms (such as a tremor).

12

Genetic factors predominant

cause of Young-Onset PD
Mutations on several
chromosomes have been
found
Also one instance of mutation
in Mitochondrial DNA

13

In some individuals, the normal, agerelated wearing away of dopamineproducing 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.
14

In rare instances, Parkinson's

disease may be caused by a viral
infection.
Many researchers believe that a
combination of oxidative damage,
environmental toxins, genetic
predisposition, and accelerated
aging may ultimately be shown to
cause the disease.

15

PARKINSONISM

Parkinsonism is a clinical rather

than an etiologic entity since it is
associated with several pathologic
processes that damage the
extrapyramidal system.

16

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

17

SYMPTOMS

TREMOR

RIGIDITY

Rigidity (stiffness, or resistance of the limb to

passive movement when the limb is relaxed)

AKINESIA

Resting tremor (shaking back and forth when

the limb is relaxed)

Bradykinesia (slowness of movement)

POSTURAL INSTABILITY (poor balance).

18

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.

19

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.
20

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.

21

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.
22

Muscle rigidity

Stiffness
Difficulty bending arms or legs
Loss of balance Gait (walking
pattern) changes Shuffling walk

23

THE SYMPTOM OF PARKINSONS

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.
24

SLOW MOVEMENTS

Difficulty beginning to walk

Difficulty initiating any voluntary movement Small
steps followed by the need to run to maintain
balance
Freezing of movement when the movement is
stopped, inability to resume - movement
Muscle aches and pains (myalgia)
Shaking, tremors (varying degrees, may not be
present) Characteristically occur at rest, may
occur at any time
May become severe enough to interfere with
activities May be worse when tired, excited, or
stressed Finger-thumb rubbing (pill-rolling
tremor) may be present

25

Changes in facial expression

Reduced ability to
show facial
expressions
"mask"
appearance to face
Staring
May be unable to
close mouth
Reduced rate of
blinking

26

Voice/speech changes

Slow speech
Low-volume voice
Monotone
Difficulty speaking

27

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.
28

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

29

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

30

STAGING OF PD
Hoehn and Yahr

2. Stage Two

Symptoms are bilateral

Minimal disability
Posture and gait affected

31

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

32

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

33

STAGING OF PD
Hoehn and Yahr
5.

Stage Five
Cachectic

stage

Invalidism

Cannot

complete

stand or walk

Requires

constant nursing care

34

DIAGNOSIS

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 includung several
conditions that can mimic Parkinson's
Disease but often have additional features
(Parkinsn's "Plus").

35

36

PATHOPHYSIOLOGY

37

DOPAMIN PRODUCING NERVE CELL

38

DOPAMIN RELEASE TO THE SYNAPS

Gambar
3
39

Gambar
4
40

Gambar
5

41

Gamba
r6
42

MAINTAIN THE BALANCE BETWEEN

DOPAMIN AND ACh
Cara mengatasi kekurangan ketidak 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.

43

1. Replacing the Missing Dopamine

Gambar 8
Sinemet
(LEVIDOPA/CARBIDOPA)
berangkali merupakan
pengobatan tunggal yang paling
efektif untuk mengontrol gejala
PD.
Sinemet ditranport (dibawa )
ke otak dan ditangkap (picked
up)oleh sel-2 yang
memproddusir dopamin.
Setelah itu sinemet dikonversi
menjadi dopamin dan dipakai
sebagai neurotransmitter,
44

Sebagian besar pasien dapat teratasi gejala PD-nya

dengan menggunakan sinemet yang sebagai pengganti
dopamin yang hilang sampai beberapa tahun.Tetapi
karena hilangnya /rusaknya sel-2 yang penghasil
dopamin berlanjut terus, maka gejalaPD akan makin
memburuk sehingga dosis sinemet akan makin
meningkat.
Umumnya akan diberikan dosis sinemet dosis rendah
selama mungkin.Hal ini dimaksudkan untuk
menghindari side efek dari Sinemet.Dikemudian hari
penambahan dosis Sinemet ini akan mengakibatkan
timbulnya efek samping sehingga tidak mungkin lagi
menambah dosis Sinemet lebih tinggi lagi.Pada saat itu
opsi pengobatan menjadi terbatas .Karena itu hal ini
diatasi dengan penambahan Eldepryl2 Capsules, 5mg
(selegiline hydrochloride)untuk menjaga agar dosis
Sinemet dapat teap rendah dan memperpanjang
pengguanaan V
45

2. Substituting a Different
Substance That "Mimics" Dopamine

46

Parlodel3 (bromocriptine mesylate) and Permax4

(pergolide mesylate) adalah obat yang mempunyai aksi
menyerupai dopamin dengan cara mengepas /
mencocokkan diri kedalam kantong dopamin pada
permukaan sel saraf yang menerima dopamin (NT
dopamin).Salah satu keuntungan dari pendekatan dari
substitusi ini kurang tampaknya gejala diskinese
(dyskinesias* are less likely to occur).
Hal ini terjadi karena jumlah dopamin yang ada tidak
benar-2 ditambah sebagaimana kerja sinemet .Dalam
hal ini, Parlodel atau Permax sebagai pengganti
dopamin tadi
Hal ini mengakibatkan kurang munculnya dyskinesa
karena dyskinesa timbul akibat terlau banyaknya
dopamin dalam otak

47

3. Helping Nerve Cells Release Stored

Dopamine

48

Symmetrel5 (amantadine
hydrochloride) memperlihatkan keadaan
dimana sel-2 saraf penghasil dopamin
(dopamine-producing nerve cells ) lebih
mudah untuk membuka jendela dan
melepaskan kandungan dopamin masuk
kedalam sinaps.
Pendekatan seperti ini berguna untuk
kasus-2 ringan PD dimana Symmetrel
bekerja untuk mengurangi gejala PD

49

4. Adjusting the Activity of

Acetylcholine to Restore the

Dopamine/Acetylcholine Balance

Artane6 (trihexyphenidyl HCl)

and
Cogentin7 (benztropine
mesylate)

50

Artane6 (trihexyphenidyl HCl) dan Cogentin7

(benztropine mesylate) dapat digunakan untuk
mempertahakan keseimbangan dopamin / asetil
kholin dengan cara mengurangi aktifitas
asetilkholin di otak..cara ini sangat berhasil untuk
mengurangi tremor dan kekakuan otot yang
diakibatkan oleh banyaknya asetil kholin
dibanding dengan dopamin Namun pengobatan /
obat ini tidak mengoreksi problem dasar akibat
penurunan dopamin .Umumnya obat ini
digunakan untuk kasus-kasus awal PD dan
dikombinasikan dengan obat-obat lain.

51

5. Conserving the Dopamine Already in

the Brain

52

Eldepryl bekerja beda sekali dengan obat lain yang

memperlambat hilangnya dopamin dan mengembalikan
keseimbangan Dopamin / asetilkholin,
Eldepryl bekerja dengan memblokir zat kimia yang terdapat
dalam sinaps yang mempunyai aksi memecah dopamin
(MAO-B).Dengan demikian meskipun secara alamiah hanya
sedikit saja produksi dopamin atau lebih besar jumlahnya
dengan replacement therapy dengan sinemet --Eldepryl
menjaga sejumlah itu dengan agar tidak dihancurkan
,sehingga dopamin
dapat lebih lama berada di synaps.dan nakin lama berada di
sinaps, makim lama partikel itu mencapai dopamin reciever
pada sel-sel penerima untuk selanjutnya mengirimkan
message.Dengan demikian Eldepryl membantu secara
natural/alamiah mengkonservasi dopamin dan memaksimalkan jumlah dopamin pengganti (dopamine
replacement ) yang diberikan oleh sinemet teap dalam dosis
rendah sepenjang waktu

53

Pharmacological Treatments for Parkinsons

DiseaseThe table summarizes these pharmacological
approaches.
Pharmacological
Approach

Example of
drug used

Rationale

Drawbacks (side effects)

Increase the
dopamine

L- dopa
(Levodopa)

Since there is a loss of dopaminergic neurons,

replace the dopamine

After about 4 yrs most pts experience a

"wearing Off" phenomenon, they loose
sensitivity to the drug, may develop episodes
of immobility, alternating with episodes of
normal or involiuntary movements

Give drugs that act

like dopamine
(dopamine
agonists)

Bromocriptine
(Parlodel)

Since there is a loss of dopaminergic neurons,

replace with drugs that act like dopamine

These drugs are expensive, may cause

confusion, diziness on standing, involuntary
motion

Decrease
acetylcholine by
giving
anticholinergic
grugs

Artane,
Cogentin

Parkinsonism is caused by excess stimulation of

extrapyramidal motor system due to imbalnce
between dopamine and acetycholine (less
dopamine, greater effect of acetycholine which is
excitatory). Therefore, restore balance by ecreasing
acetycholine to levels that match the decreased
dopamine

Side effects can be blurred vision, memory

impairment

Increase the effect

of remaining
dopamine by
blocking its
breakdown

Selegiline
(deprenyl)

Dopamine is normally broken down by the enzyme

monamime oxidase B. If you inhibit this enzyme,
then dopamine is not broken down as quickly, it
reamins longer in the tissue exerting its effect. In a
sense, this is physiologically equivalent to
increasing the amount of dopamine

Side effects are onsomnia

54

ANTICHOLINERGICS

Effective mainly for tremor and

rigidity
Start low, go slow
Side effects:

Dry mouth, sedation, delirium,

confusion, hallucinations, constipation,
urinary retention

55

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
56

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)
57

LEVODOPA

Mainstay in the treatment of early

and advanced disease
But:
1. Response declining after several
years?

2. Long-term motor complications

3. ?Neurotoxicity
Delay of l-dopa treatment?

58

LEVODOPA/PDI Formulations

Immediate Release

Onset

Duration

20-40 min

2-4 hr

30-60 min

3-6 hr

10-20 min

2-3.5 hr

12.5/50, 10/100,

25/100, 25/250

Controlled Release
25/100, 50/200

Dispersible
12.5/50, 25/100

59

Surgical Therapy

Resurgence of stereotactic surgery

with better imaging and equipment
Lesioning vs. long-term electrical
stimulation with implanted deep
brain electrodes (DBS)

75

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
76

Non-medical Intervention in PD

Physiotherapy
Speech therapy
Parkinsons Disease Society
Occupational therapy
Respite care and day centres

78

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