GANGGUAN GERAK

(GERAKAN INVOLUNTAR)
Gangguan Gerak
(Movement Disorders)

1. Gerakan Involuntar
2. Penyakit Parkinson
Gerakan Involuntar
Definisi :
Gerakan yg timbul akibat gangguan
system ekstrapiramidal

Ciri :
• Diluar kehendak
• Tidak bertujuan
• Tidak terkordinasi
• Tidak dikendalikan
Komponen
Sistem Motorik :
1. Sistem Piramidal
a. Traktus kortikospinal
b. Traktus kortikobulbo-spinal
2. Inti-inti basal
* Nucleus Cauditus, putamen, globus palidus
Substansia nigra
3. Serebellum
Gerakan involuntar merupakan tanda
klinik gangguan pada :
Sistem ekstrapiramidal :
a. Hiperkinesia
- Tics, tremor & mioklonus
- Khorea, atetosis, balismus & distonia
- Gangguan gerakan karena obat-obatan.
b. Hipokinesia
- Sindrom Parkinson
- Paralisis subranuklear progresif
- Gangguan serebellum & hubungan spinoserebellar
disertai perubahan tonus otot & sikap tubuh.
Beda dengan serebellum :

Kelainan

• Kecepatan
• rentang gerakan

• Daya gerakan

• Kekuatan tidak terganggu

Klasifikasi lain (Marsden
1992)
• Hipokinesia / Akinesia + rigiditas
Misalnya : P.Parkinson
Parkinsonisme
P. Wilson
• Diskinesia (gerakan involunter abnormal &
berlebihan)
Neurotransmitter yang terlibat :
A. Dopamin  jalur nigrostriatal, system
mesolimbik dan mesokortikal
B. GABA  jalur striatonigral
C. Glutamat  jalur kortikostriatal
D. Neurotransmitter kolinergik  talamostriatal
E. Substansi – P dan Metenkefalin  jalur
striopalidal dan strionigral peptidergik
F. Kolesistokinin
Jenis-jenis gerakan involunter :
1. Tics
2. Tremor
3. Mioklonus
4. Khorea Sydenham
5. Khorea Huntinton
6. Atetosis Dobel
7. Hemibalismus
8. Distonia
9. Sindrom ekstrapiramidal terinduksi obat
TICS
• Gerakan involuntar dengan ciri :
a. Berulang
b. Cepat
c. Singkat
d. Stereotipik
e. Kompulsif
f. Tidak berirama

ps : Bisa bagian kepribadian normal

Jenis – jenis TICS
a. Sederhana
- Kedipan mata
- Tics facialis
PS : Pada anak yg cemas
Dpt hilang spontan

b. Konvulsif (Sindr. Gilles de la tourette)

= tics herediter multipleks
Gejala Sindr.Gilles de la
tourette
1. Gerakan involuntar kompleks
a. Tics respiratorik & vokal
b. Ekholalia / suka meniru
c. Suara menggonggong / bersiul
d. Menggerutu / batuk-batuk
2. Perubahan kepribadian
3. Koprolalia
Terapi TICS :

a. Sederhana  benzodiazepin

b. Multipleks
- Haloperidol (DOC)
- Klonidin
- Pimozide
- Lorazepam
TREMOR
1. Fisiologik
2. Patologik
a. Resting / static tremor
b. Ataxic / intention tremor
c. Postural / action tremor
MIOKLONUS

Definisi : Kontraksi suatu/ sekelompok otot

- tidak disadari
- bersifat mendadak
- ada gerakan terlihat pada sendi ybs
Gerakan abnormal pada mioklonus
 oleh karena lesi/ kel. pada SSP
Bisa akibat :
* gangguan metabolic
* lesi fokal
* gangguan struktur SSP
* familial
Jenis-jenis mioklonus
1. Berdasarkan penyebab
a. Mioklonus idiopatik (kausa tidak diketahui)
b. Mioklonus esensial herediter
c. Mioklonus nocturnal
2. Berdasarkan gambaran klinik
a. Mioklonus epileptic
b. Ramsay Hunt
c. Mioklonus palatal
d. Mioklonus pasca hipoksia (sindr. Lance-Adam)
Mioklonus esensial herediter
– = paramioklonus multipleks
– timbul dalam suatu keluarga
– diwariskan secara autosomal dominant
– tidak progresif jika tidak ada kelainan
neurologik lain
Mioklonus nocturnal
• timbul pada malam hari
• tidak progresif
• benigna
• tidak dijumpai kelainan neurologik
• bersifat familiar
Mioklonus simptomatik
* Dilatar-belakangi kelainan otak / serebelum
yang difus
- ensefalofati metabolic
- hipoksia
- toksik
- infeksi virus
* Atau kelainan otak / serebelum yang fokal
- GPDO
- demielinisasi
- tumor
Mioklonus Ramsay Hunt = mioklonus
serebellaris disinergi

• progresif
• lambat
• akhirnya disertai mioklonus intensional
• terjadi secara sporadic
• familiar autosomal dominant maupun
resesif
Mioklonus palatal
• contoh klasik mioklonus fokal
• disebabkan lesi di batang otak
• muncul pada waktu tidur
• didasari factor :
- gangguan vaskuler
- tumor
- demielinisasi pada segitiga Guillain dan
mollaret
Terapi Mioklonus

• Karbidopa
• 5-hidroksi triptofan
Khorea sydenham
- Gangguan imunologik
* Infeksi streptokokus
* demam rematik)
- Ditemukan vaskulitis selurh jar. Otak
- 5-15- tahun
- wanita > laki-laki
- Pemeriksaan darah
* LED meninggi
* Kadar antistreptolisin O meninggi
- EKG  karditis reumatik
- Terapi haloperidol, klorpromazina atau valproat.
Khorea Huntington
• autosomal dominant
• neuron-neuron menghilang
• gliosis di globus palidus dan thalamus
• serebellum atrofi
• aktivitas system dopaminergik berlebih
• pembentukan asetilkolin dan GABA berkurang
• ada demensia dan hipotoni
• DD :  keracunan merkuri, tirotoksikosis dan
khorea senilis
• Terapi :  haloperidol, klorpromazina,
propranolol, dantrolen
Atetosis dobel

• Anoksia pada waktu lahir

• Demielinisasi putamen dan globus palidus
(kdg-kdg)
• Terapi haloperidol atau diazepam
Hemibalismus
• gangguan vaskuler
• infeksi
• trauma
• tumor
• destruksi nucleus subthalamik
• gerakan spontan melempar bola
• terapi  haloperidol dan diazepam
Distonia
• Tipe umum
– Idiopatik  distonia muskulorum
deformans
– Simtomatik  akibat kerusakan otak/
pengaruh obat-obatan
• Tipe segmental
– Tortikolis
– Retrokolis
– Blefarospasmus
– Distonia fasial (Meige’s dystonia)
– Writer’s cramp
Distonia muskulorum deformans
• = distonia torsi
• neuron menghilang di nukc. kaudatus, putamen,
nuc. Dentatus, subs. Nigra dan thalamus.
• Gejala pertama timbul umur 5-15 tahun
• Obat-obat yang dapat digunakan :
– Levodopa pada stadium awal
– Antikolinergik  triheksifinidil
– Antikonvulsan  karbamazepin
– Agonis dopamine  bromokriptin, klonazepam
– Penekan dopamine  haloperidol dan reserpin
– Penghambat reseptor dopamine  tetrabenazin
– Obat-obat lian : baklofen, amantadin antidepresan,
lithium
Tortikolis spasmodic
Defenisi : Kontraksi otot-otot kuduk bersifat
involuntar & intermitten, yg menyebabkan
laterokolis.
• patogenesis  belum jelas
• pada semua umur
• lebih sering pada pria
• muskulus sternokleidomastoideus paling sering
terkena
• emosi dan rangsang luar dapat memperberat
• DD :
– fibrosis/ hematom pada m.
sternokleidomastoideus
– miositis local
– limfadenitis servikal
– kelainan tulang belakang servikal
– tortikolis histerik
Sindrom ekstrapiramidal terinduksi obat

• obat-obat anti psikosis : fenotiasin,

butirofenon
• obat-obat anti muntah : prokhlorperazine,
metoklopramide
• obat-obat katekolamin : metildopa,
tetrabenazin, reserpin
• pengobatan lama dengan l-dopa
Gerakan abnormal pada Sindrom
ekstrapiramidal

• diskinesia idiosinkratik akut

• distonia
• parkinsonisme
• akatisia
• diskinesia Tardif
PARKINSON
 PENYAKIT PARKINSON
• SUATU PENYAKIT NEURODEGENERATIF
• TERDAPAT DEGENERASI GANGLIA BASALIS
TERUTAMA SUBSTANTIA NIGRA PARS COMPACTA
• LEWY BODIES POSITIF
• KLINIS DIKETAHUI DARI TANDA TANDA TRAP:
• TREMOR
• RIGIDITAS
• AKINESIA
• POSTURAL INSTABILITAS
PENYAKIT PARKINSON

BEBERAPA FAKTA TENTANG

LEVODOPA (1)
 DIPAKAI LEBIH
DARI 30 TAHUN
 MEMPUNYA
KOMPLIKASI
DISKINESIA DAN
FLUKTUASI
PENYAKIT PARKINSON

BEBERAPA FAKTA TENTANG

LEVODOPA (2)
 MENUNDA
LEVODOPA
SELAMA MUNGKIN
 AGONIS LEBIH
BAIK DAN
BERSIFAT
NEUROPROTEKTIF
PENYAKIT PARKINSON

BEBERAPA FAKTA TENTANG

LEVODOPA (3)

APAKAH INI SEMUA

BENAR??
GANGLIA BASALIS (1)
Tersusun dari kelompok inti :
1. Striatum ( neo & limbic striatum )
Neostriatum : - Putamen (Put) &
- Nucleus Caudatus
2. Globus Palidus (GP)
3. Substansia Nigra (SN) :
- SNc : Pars Compacta
- SNr : Pars Reticular
4. Subthalamic Nucleus (STN)
GANGLIA BASALIS (2)
 KERUSAKAN SUBSTANTIA NIGRA
PROGRESIF :

- 50% SEL HILANG

- KADAR DOPAMINE SEPER
LIMA DARI NORMAL
NEURONAL DENSITY
The dopaminergic diffuse modulatory
systems arising from the substantia nigra and
the ventral tegmental area
CORTICAL MOTOR
AREAS

THALAMUS BASAL
GANGLIA

CEREBELLUM

BRAINSTEM

SPINAL
CORD
Peran GB dalam
Menciptakan Gerakan :
 GB
GB memberi
memberi stimulasi
stimulasi korteks
korteks motorik
motorik
 Pintu
Pintu masuknya
masuknya putamen
putamen (Striatum)
(Striatum)
 Pintu
Pintu keluarnya
keluarnya globus
globus palidus
palidus internus
internus
 Jalur
Jalur direk
direk dan
dan indirek.
indirek.
 BASAL GANGLIA -
THALAMOCORTICAL CIRCUITRY
(glu) (glu)
CEREBRAL CORTEX
(glu) (glu)

STRIATUM (glu)
D2 D1
Indirect Pathways Direct Pathway
(GABA enk) (GABA Sb.P)

GPe (DA) THALAMUS

(GABA)
(glu)
SNc
STN
(glu)

(GABA)
GPI/SNr

BRAINSTEM (glu) Inhibitory

(glu)
& PPN Excitatory
NEUROTRANSMITTER DI
GB

 Glutamat Korteks
 Dopamin (D1/D2) Substantia nigra
 Asetilkholin Pedunkulopontis
 GABA Striatum
Direk/Indirek
(Gabaergik/Glutamatergik)
PERANAN DOPAMINE
 Hubungan Sistem DOPAMIN dengan
sistem ASETILKHOLIN :
• Reciprocal Inhibition  Reseptor
muskarinik AsetilKholin
• Reseptor Nikotinik Asetilkholin.
 Hubungan jalur direk dengan indirek.
Reciprocal Inhibition
ACh DA
Keterangan :
- Ach : Acethyl Choline
- DA : Dopamine
DA

ACh

ACh
DA
Patofisiologi GB
Ketidak seimbangan fungsi jalur direk
dengan jalur indirek.

PENGOBATAN
PENYAKIT PARKINSON
STIMULASI RESEPTOR D1 DAN D2
DIPERLUKAN
 Excitatory
Hubungan Jalur Direct-Indirect Inhibitoatory

Normal
Normal Parkinson
Parkinson Dystonia
Dystonia
CORTEX CORTEX CORTEX

PUTAMEN
PUTAMEN PUTAMEN
PUTAMEN PUTAMEN
PUTAMEN
D
D22 D
D11 D
D22 D
D11 D
D22 D
D11

SNc
SNc SNc
SNc SNc
SNc

GPe
GPe GPe
GPe GPe
GPe
VL
VL VL
VL VL
VL

STN
STN STN
STN STN
STN

GPi/SNr
GPi/SNr GPi/SNr
GPi/SNr GPi/SNr
GPi/SNr
Brain
Brain stem
stem Brain
Brain stem
stem Brain
Brain stem
stem Inhibitor
Spinal
Spinal cord
cord Spinal
Spinal cord
cord Spinal
Spinal cord
cord y
Patogenesa PP Excitatory

Inhibitoatory

Normal
CORTEX

PUTAMEN
D22 D
D11

SNc
GPe
VL
STN

GPi/SNr
Brain stem
Spinal cord
 Excitatory

Inhibitoatory
Parkinsonism

CORTEX

PUTAMEN D
D22 D
D11

SNc
GPe
VL
STN

GPi/SNr
Brain stem
Spinal cord
MANAJEMEN PENYAKIT
PARKINSON
• KENDALA DALAM PENGOBATAN PP

DIANGGAP BUKAN PENYAKIT

PENDERITA MUDAH
MENGABAIKAN KONTROL
PENGOBATAN
TIDAK PERNAH OLAHRAGA
OBAT ANTIPARKINSON KURANG
DIKENAL
MASALAH DALAM
PENGOBATAN (1)

• KAPAN PENDERITA HARUS MENJALANI

PENGOBATAN (TREMOR) ?
• PENGOBATAN PERTAMA APA YANG
HARUS DIBERIKAN?
• APAKAH LEVODOPA MASIH TERUS DAPAT
DIBERIKAN?
• APAKAH LEVODOPA TIDAK
MEMBAHAYAKAN NEURON?
MASALAH DALAM • SEBERAPA JAUH
PENGOBATAN (2) DOPAMINE AGONIS
DAPAT DIBERIKAN?
• SEBERAPA LAMA
PENDERITA DAPAT
MENJALANI
PENGOBATAN?
• BAGAIMANA
MENGATASI
PROBLEMA ON-OFF?
• APAKAH CONTINUOUS
DOPAMINERGIC
STIMULATION (CDS)
BERMANFAAT?
Usually treatment is highly individualized, since the therapy of
Parkinson's disease is based on its pathophysiology.
The therapy of Parkinson's disease can be grouped to main
categories of drugs:

NMDA antagonis
Anticholinergic drugs
Dopamine agonist
Dopaminergic and decarboxilase
COMT-inhibitor
MAO-B inhibitor
NMDA ANTAGONIST
 
There is a good evidence that glutamate can induce neuronal
degeneration. Systemic administration of glutamate to neonatal rats
results in retinal degeneration and excitotoxicity has been implicated
in the pathogenesis of a variety of neurodegenerative disorders
including Parkinson's disease.Since then an NMDA antagonists has
been considered to be an effective drug in treating Parkinson's
disease (Rodriguez, 1998).
Patients who early symptoms do not respond to anticholinergics may
benefit from substitution or by addition of an NMDA antagonist such
as amantadine.
Dosage and administration

Amantadine
 The therapeutic antiparkinsonian effect of amantadine was
discovered empirically, as the drug was originally developed as an
antiviral agent. Its mechanism of action is probably enhancement of
the presynaptic synthesis and release of dopamine by blocking the
NMDA receptor of the cell membrane, but it also has some
anticholinergic properties. Although it can benefit 60 to 70% of
patients to a mild degree, its effect seldom persists for more than a
few months when used alone. It has a synergistic action with
levodopa but its role in therapy appears to be limited to mild or early
disease (Waters, 1999). Usual dose is 100 – 300 mg a day in divided
dose.
Side effects:
Depression, heart failure, leg oedema, dry mouth, blurred vision,
hallucinations, insomnia, confusion, urine retention, cognitive
impairment, and nausea.
 

Contra indications:
Renal failure
 
DOPAMINERGIC + DECARBOXYLASE INHIBITOR

LEVODOPA: precursor of dopamine

>95% is rapidly decarboxylated to dopamine (periphery)
little unchanged drug reaches the cerebral circulation
<1 % actually crosses the blood-brain barrier (achieve
therapeutic levels) in the striatal tissue.
THEREFORE LEVODOPA is always administered in
COMBINATION with CARBIDOPA, a peripheral INHIBITOR
of decarboxylase enzyme
Dosage and administration:

• Carbidopa + Levodopa
10/100, 25/100, 25/250 mg per hari 
• Benserazid + Levodopa
50/100 mg per hari
DOPAMINE AGONIST

1. can bypass the failing nigrostriatal pathway

2. directly stimulate receptors in the normal striatum
3. do not require conversion and storage
4. the most effective class of drugs for Parkinson's disease after
levodopa.
Four dopamine agonist are:
• Bromocriptine
• Pergolide
• Pramipexole
• Ropinirole.
DOPAMINE AGONIST
long half-life are associated with less risk of developing dyskinesia
than levodopa.
bromocriptin ergot alkaloid with potent D2 agonists effects

approved as adjunctive therapy to carbidopa/levodopa for patients

who develop tolerance to levodopa and end-of dose failure.

Side effects :
Nausea, dyskinesia, hallucinations, confusions, postural hypotension
Dosage and administration
Bromocriptin mesylate 5 – 40 mg per day
Pergolide mesylate 0.75 – 5 mg per day
Cabergoline 0.5 – 5 mg per day
Pramipexole 1.5 – 4.5 mg per day
Ropinirole 0.75 – 2.4 mg per day
Apomorphine 10-80 mg per day

Side effects of Apomorphine are:

Yawning, besides nausea, vomiting, sedation and postural hypotension.
Depression of the central nervous systems, psychiatric symnptoms,
dementia, and sensitivity to apomorphine are contraindicated for the
administration of this drug.
 COMT (Catechol-O-Methyl Transferase) Inhibitors

Side effects:
Anorexia, nausea, vomiting, dyskinesia, hypotension, sedation,
headache, constipation and diarhhoea.
Entacapone 200 - 1600 mg per hari
Side effects:
Anorexia, nausea, vomiting, dyskinesia, hypotension, sedation,
headache, constipation and diarhhoea.
Tolcapone 300 – 600 mg per hari
Efek Samping:
Diskinesia, diare lebih berat, mual, muntah, hipotensi, meningkatkan tes
faal hati
 COMT (Catechol-O-Methyl Transferase) Inhibitors

Side effects:
Anorexia, nausea, vomiting, dyskinesia, hypotension, sedation,
headache, constipation and diarhhoea.
Entacapone 200 - 1600 mg per hari
Side effects:
Anorexia, nausea, vomiting, dyskinesia, hypotension, sedation,
headache, constipation and diarhhoea.
Tolcapone 300 – 600 mg per hari
Side effects:
Dyskinesia, severe diarhhoea, mual, muntah, hypotension, meningkatkan
tes faal hati
MAO-B (Mono Amine Oxidase – B) Inhibitor

During MAO-B-mediated oxidation of dopamine, toxic oxygen free

radicals are likely to be produced (Cohen 1983) with the potential for
nigral degeneration.
 
Hydrogen peroxide (H2O2) is a by product of dopamine oxidation,
and in the presence of iron and superoxide radicals it can form
hydroxyl ions and highly reactive hydroxyl radicals (Halliwell 1989)
which can ultimately lead to cell death.
Since then inhibition of MAO-B activity can reduce the
production of free radicals.
 
Side effect :
Dyskinesia, postural hypotension, anorexia, nausea,
vomiting, dizziness, anxiety, dry mouth, liver dysfunction,
confusion.
Selegiline (1)
1. Recommended oral dosage of selegiline is 10 mg daily
2. Single dose in the morning or
3. Two divided dose of 5 mg taken at breakfast and midday
4. Monotherapy in early disease
5. Combination with levodopa or levodopa plus a peripheral
decarboxylase inhibitor.
6. A reduction in levodopa dosage of about 10 to 30% can be
achieved without compromising symptom control and may be
necessary to avoid peak concentration dyskinesias, etc.

Side effect:
Dyskinesia, postural hypotension, anorexia, nausea, vomiting,
dizziness, anxiety, dry mouth, liver dysfunction, confusion.
ANTIOXIDANT
Askorbic acid (vitamine C) 500 – 1000 mg per hari
Betacarotene (pro vitamine A) 4000 IU/day

BETABLOCKER
Propranolol 10 – 30 mg/day
Hypotension, bradycardi
 L-dopa Metabolisme 56
3-OMD
3-OMD

COMT
COMT
Levodopa
Levodopa DDC
Dopamine
DDC

Dopamine
BBB

Peripheral Central

BBB = Blood Brain Barrier

DDC = DOPA-decarboxylase
COMT = Catechol-O-methyl transferase
3-OMD = 3-O-methyldopa

3.4
Kaakkola S, et al. General properties and clinical possibilities of new selective inhibition of
cathecol-O-methyl transferase. Gen. Pharmacol 1994a; 25: 813 - 824.
 57
L-dopa Pharmacokinetic
Levodopa
Stomach

DDC in intestine wall

DDC in periphery
90%
9%
10%
COMT
Blood and peripheral tissues
Blood–brain barrier

<1%
Circulatio
n Brain

Handbook of Parkinson’s Disease: second edition, revised and expanded, edited by William C. Koller
 58

Parkinson’s disease course

Cognitive
Honeymoon Motor complication
period decline
period
period

0 5 12 15 years

Onset Death
 60
Progression of Parkinson disease

Early PD Moderate PD Advanced PD

Dyskinesia Dyskinesia
Dyskinesia
Clinical Effect

Threshold Threshold

Clinical Effect

Clinical Effect
Threshold
Response
Response Threshold Response
Threshold Threshold

2 4 6 2 4 6 2 4 6
Levodopa Levodopa Levodopa
Time (h) Time (h) Time (h)

Target Response

Adapted with permission from Obeso JA et al. In: Olanow CW, Obeso JA, eds. Beyond the Decade of the Brain. Vol 2.
Dopamine agonists in early Parkinson’s disease. Tunbridge Wells, UK: Wells Medical Ltd; 1997: 11-35.
 62
DOPA decarboxylase (DDC)
inhibition
Levodopa Levodopa plus DDCI

3-OMD 3-OMD
3-OMD 3-OMD

COMT COMT COMT COMT

Levodopa Levodopa
Levodopa DDC Levodopa DDC
Dopamine Dopamine
DDC DDC

Dopamine Dopamine
BBB BBB

Peripheral Central Peripheral Central

BBB = Blood Brain Barrier

DDC = DOPA-decarboxylase
DDCI = DOPA-decarboxylase inhibitor
COMT = Catechol-O-methyl transferase
3-OMD = 3-O-methyldopa
3.4
Kaakkola S, et al. General properties and clinical possibilities of new selective inhibition of
cathecol-O-methyl transferase. Gen. Pharmacol 1994a; 25: 813 - 824.
 64
COMT inhibition
Levodopa plus DDCI Levodopa plus DDCI plus COMT inhibitor

3-OMD 3-OMD
3-OMD 3-OMD

COMT COMT COMT COMT

Levodopa Levodopa
Levodopa DDC Levodopa DDC
Dopamine Dopamine
DDC DDC

Dopamine Dopamine
BBB BBB

Peripheral Central Peripheral Central

BBB = blood brain barrier

DDC = DOPA-decarboxylase
DDC = DOPA-decarboxylase inhibitor
COMT = Catechol-O-methyl transferase
3-OMD = 3-O-methyldopa
3.5
Kaakkola S, et al. General properties and clinical possibilities of new selective inhibition of
cathecol-O-methyl transferase. Gen. Pharmacol 1994a; 25: 813 - 824.
TERIMA KASIH