Park in Son

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GANGGUAN GERAKBERLATAR BELAKANG GANGGUAN SARAF

ETIOLOGI

PATOLOGI

TOPIS LESI

GAMBARAN KLINIS

DIAGNOSIS NEUROLOGIS:

Dx/ KLINIS - TOPIS – ETIOLOGIS

sangat ditunjang oleh penguasaan pengetahuan anatomi



GANGGUAN GERAK

GANGGUAN SARAF

• STROKE

• PENYAKIT PARKINSON

•

Gangguan Gerak Hipokinetis(kelumpuhan = paresis/paralisis plegi)

• Gangguan Gerak Hiperkinetis

(gangguan gerak abnormal - involunter)

http://images.google.com/imgres?imgurl=http://www.opengroup.com/sports/images/(SC)Muhammad_Ali_Photo.jpg&imgrefurl=http://www.opengroup.com/sports/Muhammad_Ali.shtml&h=373&w=474&sz=29&tbnid=kufvv1B4gskJ:&tbnh=99&tbnw=126&prev=/images?q=muhammad+ali&hl=en&lr=&oi=imagesr&start=1



Gangguan gerak abnormal - involunter

berlatar belakang gangguan saraf

Penyakit Parkinson - tokoh-tokoh terkenal penyandangnya

http://images.google.com/imgres?imgurl=http://www.resistere.it/foto/leader/papa.gif&imgrefurl=http://www.centomovimenti.com/2005/aprile/01_tg3.htm&h=236&w=222&sz=25&tbnid=sp5kZXK5L4kJ:&tbnh=104&tbnw=97&hl=en&prev=/images?q=pope+john+paul&hl=en&lr=&oi=imagesr&start=1

http://images.google.com/imgres?imgurl=http://hem.passagen.se/danielho/FamilyTies/michael.jpg&imgrefurl=http://hem.passagen.se/danielho/FamilyTies/bios.htm&h=263&w=220&sz=10&tbnid=Er1V5Z9OIRwJ:&tbnh=107&tbnw=89&hl=en&prev=/images?q=michael+j+fox&hl=en&lr=&oi=imagesr&start=3



Diagnosa Neurologis:

- Diagnosa Klinis Gambaran Klinik yang muncul

Simptom, Sign, Sindrom- Topis Dimana letak lesi

- Etiologi Penyebabnya

Problem Klinis:

- Tingkat individu: Manifestasi Klinis Sistem apa yang

terkena

Organ

Jaringan

sel

Biomolekuler- Tingkatan Sistem/ subsistem

- Tingkatan Organ

- Tingkatan Sel dengan sub selnya



Gangguan Gerak - Gangguan Gerak Hipokinetis(kelumpuhan = paresis/paralisis plegi)- Gangguan Gerak Hiperkinetis(gangguan gerak abnormal - involunter)

Gangguan Saraf - STROKE- PENYAKIT PARKINSON

Gangguan gerak abnormal - involunterberlatar belakang gangguan saraf Penyakit

Parkinson dan Stroke



SUBSTRAT ANATOMIdari sistem saraf yang berkaitan dengan gerak tubuh

KOMPONEN FUNGSI MOTORIK

Sistem piramidal (UPPER MOTONEURON )dan

Saraf tepi (LOWER MOTONEURON )

Sistem ekstrapiramidal



SUBSTRAT ANATOMI

KOMPONEN FUNGSI MOTORIK:

• sistem piramidal *melanjut sebagai serabut-serabut

saraf tepi **

gerakan “jitu” dan“tangkas”

... jari-jari lentik

gadis kecil memetik bunga …

(* upper motoneuron …...... penyilangan

dan ** lower motoneuron)



MANIFESTASI KLINIS

• GANGGUANSISTEM PIRAMIDALIS – JARAS KORTIKOBULBARIS:

saraf-saraf kranial

• strabismus (kero)• asimetri otot-otot wajah• nasolalia (bindeng)• gangguan menelan• disartri (pelo)

– JARAS KORTIKOSPINALIS

(upper motoneuron) kelumpuhan spastik (ciri-ciri?)• hemiparesis (lumpuh separuh badan) akibat stroke:

GARENG ?



MANIFESTASI KLINIS

• GANGGUAN SARAF TEPI (lower

motoneuron)

kelumpuhan flaksid (ciri-ciri?)

- poliomyelitis anterior acuta

- Bell’s palsy …………….....

- neuropati perifer:

sindrom Guillan Barre dll.

Bell Palsy Gangguan saraf VII perifer (LMN) otot dahi, wajah,mata lumpuh

Gangguan n.VII central dahi masih bisa berkerut

Gangguan Supranuklear PusatInfranuklear Tepi

Polio Kerusakan badan sel motorik Cornu anterior medulla spinalis tapikerusakan yang kenanya adalah LMN menifestasi gangguan saraf tepi.Ciri: Flacid, Uniparesis, monoparesis, (tungkai saja)



SUBSTRAT ANATOMI

KOMPONEN FUNGSI MOTORIK:

• Sistem ekstrapiramidal memelihara tonus otot,

“menyiapkan” gerak“jitu” &“tangkas”

dan

• serebelum

(otak kecil) integrasi impuls sensibel dan motorik

Sistem Piramidal lintasan spesifik Sistem Extrapiramidal:

- Kumpulan badan sel dengan sirkuit memberikan impuls masalkeseluruh otot tanpa disadari untuk pelihara tonus otot gerakan jitu dan tangkas

- Melibatkan cerebellum



SUBSTRAT ANATOMI

SISTEM EKSTRAPIRAMIDAL:



SISTEM EKSTRAPIRAMIDAL

SUBSTRAT ANATOMI(telah diuraikan di depan)

FUNGSI

Meletakkan landasan gerak “jitu” dan“tangkas”

Penyampaian impuls difus dan masal keseluruh otot tubuh untuk menjaga

tonus otot sebelum, selama dansesudah aktifitas sistem piramidalberlangsung

Kelola inhibisi gejala kelepasan (release phenomenon)

hiper / hipokinetis

Inhibisi – Eksitasi Proses yang kontinyuInhibisi yang berlebihan terjadi eksitasi.Eksitasi yang berlebihan terjadi inhibisi



MANIFESTASI KLINIS• GANGGUAN SISTEM EKSTRAPIRAMIDAL

(BURISRAWA atau DURSASANA ? BATARA NARADA ?)

(GERAK INVOLUNTER)

TREMOR

HEMIBALISMUS KHOREA

ATETOSIS

DISTONIA

MIOKLONIA TIK

ATAKSIA



PERANAN SEREBELUM (otak kecil)

INTEGRASI FUNGSI SENSORIMOTOR

GANGGUAN KOORDINASI

MEKANISME REFLEKS‘LENGKUNG REFLEKS’

RESEPTOR – AFEREN – PUSAT – EFEREN – EFEKTOR

REFLEKS PADA INDIVIDU DEWASA:GERAK OTOT SKELETAL YANG BANGKITSEBAGAI JAWABAN ATAS SUATU RANGSANGAN

• REFLEKS FISIOLOGIS• REFLEKS PATOLOGIS

- Ataxia Kecenderungan untuk jatuh pada 1 sisi ~ lesi.Tergantung topisnya : Nistagmus, Trunk ataxia, Lumataxia

- Tremor Intensional Tremor yang muncul waktu akan memulaigerakan. Bedakan dengan Tremor pada Parkinson ( Tremor atrest/waktu istirahat)



Refleks pada individu dewasa:Gerak otot skeletal yang bangkit Sebagai jawaban atassuatu rangsangan

Refleks fisiologis:- Reflek Monosinaptic Reflek yang serabut

afferen dan eferennya pake saraf yang sama.

Ex: Refleks Patela, Reflek TendoReflek patela Monosinaptic dan Polisinaptic(karena adanya relaksasi otot antagonisnya)

- Refleks Polisinaptic Ex: Refleks cornea

Refleks patologis Tidak bisa deskripsikan dengan

baik arcusnya dimana. Ex: Refleks Balbinski



PARKINSON’S DISEASE

PATHOPHYSIOLOGYDIAGNOSIS

THERAPY

Amin Husni

Bagian Anatomi-Neurologi FK UNDIP



DEFINITION

AND CLASSIFICATION

• PARKINSONISM

•

PARKINSON’S DISEASE

IDIOPATHIC

SECONDARY PARKINSONISM

PARKINSON-PLUS SYNDROME



ETIOLOGY

IDIOPATHIC

RISK FACTORS(MULTIFACTORIAL)

• AGING

• RACE

• GENETIC

• ENVIRONMENT



PATOPHYSIOLOGY

BASAL GANGLIAEXTRAPYRAMIDAL SYSTEM

DOPAMINERGIC VS CHOLINERGIC

DIRECT PATHWAY

VS

INDIRECT PATHWAYParkinson dissease kerusakan pada substansia nigra pars compacta yang didalamnyaterdapat sel yang mensekresi dopamin karena rusak maka kadar dopamin <<

Substansia nigra Inhibisi Globus palidus kurang Galak

Kolinergik ↑ Hipokinesia ( Sindroma Parkinson)

Dopamin ↑, Kolinergik ↓ Hiperkinesia



THE PATOPHYSIOLOGY OF PARKINSON’S DISEASE

1. IMBALANCE BETWEEN THE DOPAMINERGIC AND

CHOLINERGIC NEURONS

Korpus striatum selain menerima persarafandopaminergik yang datang dari substansia nigra, jugadisarafi oleh saraf kolinergik dengan asetilkolin ( AKA )

sebagai neurotransmiternya, pengaruh dari striatumterhadap fungsi motorik korteks ditentukan olehkegiatan kedua saraf tersebut.

Bila mana kegiatan dopaminergik meningkat dan atau

kegiatan kolinergik menurun maka pengaruhdopaminergik akan dominan shg timbullah gejalahiperkinesia, sebaliknya jika kegiatan dopaminergikmenurun dan atau kolinergik meningkat maka pengaruhkolinergik akan dominan shg timbullah gejala hipokinesia

( sindroma parkinson )



THE PATOPHYSIOLOGY OF PARKINSON’S DISEASE

2. IMBALANCE BETWEEN THE DIRECT AND INDIRECT

PATHWAYS

Baik jalur langsung maupun tidak langsung keduanyaakan bermuara ke GPi / SNr dan selanjutnya dari siniakan mengeluarkan output menuju talamus dan korteks,bila masukan dari keduanya seimbang maka output -

nyapun akan seimbang pula sehingga tidak timbulkelainan gerakan motorik.

Akan tetapi manakala terjadi hiperaktif jalur langsungatau hipoaktif jalur tak langsung maka output dari GPi

dan SNr ke arah talamo korteks akan menurun makaakan terjadi gerakan hiperkinesia.

Sebaliknya jika terjadi hipoaktifitas jalur langsung danhiperaktifitas jalur tak langsung maka keluaran dari Gpidan SNr akan meningkat maka terjadi gerakan

hipokinesia / sindroma parkinson.



B R A I N



B R A I N

Ganglia basalis

Acetylcholin Normal

Dopamin

Acetylcholin PD

Perokside Radical HTissue

damage

Anticholinergic

(Trihexylphenidyl)

MAO MAO I ( selegiline )

D2

Dopamin

Receptor

Dopamin Agonist

Ergot

(bromocryptin) Non Ergot

(pramipexole)

Levodopa

Levodopa

Dopamin

Decarboxylase

Decarboxylase Inhibitor

(Benzeraside)

(carbidopa)

3 OMD

COMT

COMT Inhibitor

(entacapone)

BLOOD BRAIN BARIER

PHERIFER

Decarboxylase



• Neurotransmiter:

Produksi Transport (mikrotubuler) Penyimpanan (Vesicle) Pelepasan (pembukaan vesikle) Synaptic clef ditangkapreseptor neuron binding, dihancurkan, atau ditangkap kembali(autoreseptor)

• Produksi dopamin ↓: - Dopamin yang diberikan dari luar tidak bisa menembus sawar

darah otak yang diberikan Rivodopa (prekursor dopamin)

Agonis Dopamin membuat seolah-olah dopamin meningkat

bisa ditangkap- penghancuran dopamin oleh : Enzim monoamin Inhibitor,

COMT inhibitor, radikal bebas



DIAGNOSIS

CLINICAL DIAGNOSISBASED ON THE CLINICAL FEATURES

GENERAL AND SPECIFIC

T . R . A . P .• CLINICALLY

• KOLLER

• GELB• ETC.



DIAGNOSTIC APPROACH

• CLINICALLY POSSIBLETHE PRESENCE OF ANY ONE OF THE SALIENT FEATURES: TREMOR(RESTING); RIGIDITY; BRADYKINESIA; IMPAIRMENT OF POSTURALREFLEXES

• CLINICALLY PROBABLECOMBINATION OF ANY TWO CARDINAL FEATURES (INCLUDINGIMPAIRED POSTURAL REFLEXES); ALTERNATIVELY, ANY ONE OFTHE FIRST THREE IF ASYMMETRICAL

• CLINICALLY DEFINITEANY COMBINATION OF THREE OF THE FOUR FEATURES;ALTERNATIVELY, ANY TWO WITH ONE OF FIRST THREEDISPLAYING ASYMMETRY



MODIFIED HOEHN AND YAHR

STAGING

• STAGE 0 = NO SIGNS OF DISEASE

• STAGE 1 = UNILATERAL DISEASE

• STAGE 1.5 = UNILATERAL PLUS AXIAL

INVOLVEMENT

• STAGE 2 = BILATERAL DISEASE,

WITHOUT IMPAIRMENT OF BALANCE

• STAGE 2.5 = MILD BILATERAL DISEASE,

WITH RECOVERY ON PULL TEST

•

STAGE 3 = MILD-TO-MODERATE BILATERAL DISEASE;SOME POSTURAL INSTABILITY;

PHYSICALLY INDEPENDENT



MAJOR CONSEPTUAL

ON PHARMACOLOGIC / SURGICALTREATMENT

»SYMPTOMATIC

»PROTECTIVE

»RESTORATIVE



• TO IMPROVE SIGNS AND SYMPTOMS

OF THE DISEASE

• TO INTERFERE WITH THE

PATHOPHYSIOLOGIC MECHANISMEOF THE DISEASE

•

TO PROVIDE NEW NEURONS ORTO STIMULATE GROWTH AND

FUNCTION OF REMAINING CELLS



GOAL OF THERAPY: TO REVERSE

THE FUNCTIONAL DISABILITY

• ABOLITION OF ALL SYMPTOMS AND SIGNS

IS NOT CURRENTLY POSSIBLE EVEN WITHHIGH DOSES OF MEDICATION

• TREATMENT IS INDIVIDUALIZED

• PATIENT AND PHYSICIAN PLAYS A MAJOR

ROLE IN THERAPEUTIC DECISIONS



LEVODOPAPRECURSOR OF DOPAMINE

• REPLACEMENT OF DEPLETED

TRANSMITTER

• COMPLICATION OF CHRONIC

THERAPYTHE “ON-OFF” REACTION, DYSKINESIAS,

AND VISUAL HALLUCINATIONS



ADDITIONAL AND DISTINCTLY

DIFFERENT PHARMACOLOGIC

ADVANCES

• CARBIDOPA

• CONTROLLED RELEASECARBIDOPA/LEVODOPA

• DOPAMINE AGONIST

•

INHIBITOR OF CATECHOL-O- METHYLTRANSFERASE (COMT)

• MONOAMINE OXIDASE TYPE B (MAO-B)



• CARBIDOPA

(INHIBITOR OF DOPA DECARBOXYLASE)

COMBINED WITH LEVODOPA, REDUCESPERIPHERAL DECARBOXYLATION OFLEVODOPA TO DOPAMINE

• CONTROLLED RELEASE

TO PROLONGE LEVODOPA’S 90-MINUTESHALF-LIFE

• DOPAMINE AGONIST

USED AS PHARMACOLOGICALLY SUBSTITUTES

FOR CARBIDOPA/LEVODOPA IN EARLY DISEASETO PROVIDE SUPPLEMENTATION IN LATERSTAGES



• INHIBITORS OF CATECHOL-O-METHYL

TRANSFERASE (COMT)

INCREASE THE AMMOUNT OF LEVODOPACROSSING THE BLOOD BRAIN BARRIER

• MONOAMINE OXIDASE TYPE B (MAO-B)

INHIBITORS

TO SLOW DOPAMINE’S METABOLIC

BREAKDOWN



THERAPEUTIC ALGORITHM

FOR MANAGEMENTOF PARKINSON’S DISEASE

(SEE TEXT)



• INITIAL DECISION :WHETHER ANY PHARMACOTHERAPY IS

NEEDED

• NO CONCLUSIVE EVIDENCETHAT TREATMENT IS HELPFUL BEFORE

SYMPTOMS START TO AFFECT THEPATIENT’S LIFE

EARLY STAGE : MAY BE BETTER LEFTUNTREATED IF IT DOES NOT LIMIT MOTORFUNCTION

• DECISION IS MADE ON THE BASIS OF HOWSYMPTOMS ARE AFFECTING INDIVIDUALPATIENTS



CHOICE:INTRODUCE LEVODOPA

OR ANOTHER ANTIPARKINSONIAN AGENT

• DEVELOPMENT OF COMPLICATIONASSOCIATED WITH LONG-TERM USE OFLEVODOPA

• OTHER ANTIPARKINSONIAN DRUGS SHOULD BE CONSIDERED FIRST TO DELAYTHE INTRODUCTION OF LEVODOPA

• LEVODOPA IS APPROPRIATE IF THE

PATIENT’S SYMPTOMS ARE STARTING TOINTERFERE WITH HIS OR HER ACTIVITIES



PATIENTS WITH MILD SYMPTOMS

MAY BE TREATED IN OTHER WAYS

CHOICES INCLUDE :

INTRODUCING SELEGILINE FOR

ITS POSSIBLENEUROPROTECTIVE BENEFIT

INITIATING TREATMENT WITH

ANTICHOLINERGIC DRUG,AMANTADINE,

OR A DOPAMINE AGONIST AGENT



SELEGILINE (L-DEPRENYL) AS AN ADJUNCT TO CARBIDOPA/LEVODOPA

FOR PATIENTS WHO EXHIBIT DETERIORATION IN

RESPONSE TO LEVODOPA

•

SHOWN TO PROLONG THE SYMPTOMATICBENEFIT OF LEVODOPA

• IMPROVEMENT OF MOTOR SCORES AFTER THE INITIATION OFTHE DRUG AND DETERIORATION OF SCORES ON ITS WITHDRAWL

•

MAY HAVE SOME NEUROPROTECTIVEEFFECT• STATISTICALLY REDUCED DISABILITY COMPARED TO PLACEBO

WAS FOUND EVEN AMONG DEPRENYL PATIENTS WHO INITIALLYHAD NO IMPROVEMENT IN MOTOR SCORES



SELEGILINE MONOTHERAPY

• SELEGILINE’S NEUROPROTECTIVE EFFECTS

• LEVODOPA TREATMENT TOXICITY WILL BE REDUCED BY

SELEGILINE INHIBITION OF MAO-B OXIDATION OF

DOPAMINE

• APPROPRIATE CANDIDATES FOR SELEGILINE

MONOTHERAPY:

- EARLY-STAGE PATIENTS

WITHOUT DISABLING SYMPTOMS

- YOUNG PATIENTS (< 65 YEARS OF AGE)



ANTICHOLINERGICS

• TO BE EFFECTIVE FOR THE SYMPTOMS OF

TREMOR, ALTHOUGH RIGIDITY AND

BRADYKINESIA ARE NOT MUCH ALTERED

• SHOULD BE USED WITH CAUTION IF AT ALL

IN THE ELDERLY SINCE THEY HAVE A POOR

THERAPEUTIC INDEX AND HIGH TOXICITY

• NUMBER OF SIDE EFFECTS



AMANTADINEFOR PATIENTS WHOSE EARLY SYMPTOMS DO NOT RESPOND

TO ANTICHOLINERGICS

• AN ANTI VIRAL AGENTPRECISE MECHANISM OF ACTION REMAINS TO BEDEFINED

RELEASES DOPAMINE FROM PERIPHERAL NEURAL STOAGE SITES;

SIMILAR ACTION ON THE RESIDUAL, INTACT DOPAMINERGIC

TERMINALS IN THE STRIATUM OF PARKINSONIAN PATIENTS

• REPORTED ACTIONS :

- RELEASE OF DOPAMINE FROM CENTRAL NEURON

- DELAY OF DOPAMINE UPTAKE BY NEURAL CELLS

- BLOCKADE F NMDA RECEPTORS- ANTICHOLINERGIC EFFECTS



DOPAMINE AGONISTS

• LONG HALF-LIFE

ASSOCIATED WITH LESS RISK OFDEVELOPING DYSKINESIA

• USE OF THESE COMPOUNDSPRIOR THE LEVODOPA INITIATION IN EARLYDISEASE TO AVOID OR DELAY THEPRODUCTION OF DYSKINESIA, ESPECIALLY

IN PATIENTS WHO ARE YOUNG



DEVELOPMENT OF DYSKINESIA

• DEPEND ON DISEASE SEVERITY AND THE

HALF-LIFE OF THE DOPAMINERGIC AGENT

• ENOUGH DOPAMINE TERMINALS TO

REGULATE DOPAMINE RELEASE AND

PROVIDE POSTSYNAPTIC DOPAMINE

RECEPTOR WITH RELATIVELY PHYSIOLOGIC

DOPAMINE STIMULATION

• MORE ADVANCED DISEASE:



NOT ENOUGH DOPAMINE TERMINALS TO

REGULATE DOPAMINE RELEASE

FLUCTUATION IN STRIATAL LEVODOPA

THE RESULTING EXPOSURE OF STRIATAL RECEPTORSTO ALTERNATING HIGH AND LOW CONCENTRATIONSOF DOPAMINE ----

INDUCE THE POSTSYNAPTIC CHANGES THAT LEAD TO

THE DEVELOPMENT OF DYSKINESIA & MOTORCOMPLICATIONS

INITIAL MONOTHERAPY: USEFUL IN YOUNGERPATIENTS

WHO ARE MORE PRONE TO THE EARLY DEVELOPMENTOF LEVODOPA-RELATED CLINICAL FLUCTUATIONS



INHIBITORS OFCATECHOL-O-METHYLTRANSFERASE

ADDITION OF CARBIDOPA TO LEVODOPAINCREASES THE AMMOUNT OF DRUGAVAILABLE TO CROSS THE BLOOD-BRAIN

BARRIER LEVODOPA IS METABOLIZED IN THE GUT

AND LIVER BY COMT

COMT INHIBITORY AGENTS PREVENT THE

BREAKDOWN ; PROLONGING THE HALF-LIFE OF LEVODOPA, INCREASING ITS

TRANSPORT INTO THE BRAIN TO RISE

DOPAMINE LEVELS



COMT inhibitionLevodopa plus DDCI Levodopa plus DDCI plus COMT inhibitor

BBB = blood brain barrierDDC = DOPA-decarboxylaseDDC = DOPA-decarboxylase inhibitorCOMT = Catechol-O-methyl transferase3-OMD = 3-O-methyldopa

Peripheral CentralPeripheralCentral

Dopamine

Levodopa

3-OMD

COMT

BBB

DDC

3-OMD

Levodopa

Dopamine

COMT

DDC

Dopamine

Levodopa

3-OMD

COMT

BBB

DDC

3-OMD

Levodopa

Dopamine

COMT

DDC

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



• Pengobatan dengan Levodopa tunda sedini mungkin komplikasi motorik.

Levodopa Toksik pemberian jangka panjang akan merusak

reseptor secara struktural dan fungsional• Penyakit dengan stage ringan jangan pake levodopa tapi pake

Agonis Dopamin

• Pasien Muda pake Agonis Dopamin

• Levodopa Pasien tua dengan stage berat

• Komplikasi muncul pada tahun kelima

• Antikolinergik muncul tremor

Park in Son

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