GANGGUAN GERAK DAN PENYAKIT PARKINSON Tinjauan Umum

SISTEM MOTORIK
1. Sistem piramidal 2. Sistem ekstrapiramidal 3. Serebelum Interaksi ketiganya menghasilkan gerak

Types of Movements
Automatic movement Learned motor behaviors performed without conscious effort (walk, speak) Voluntary movement Intentional planned or self initiated, or externally triggered Involuntary movement Not suppressible (tremor, myoclonus) Semi-voluntary (un-voluntary) movement induced by inner sensory stimulus, move to suppress unpleasant sensation, suppressible for short time (tic, akathisia, RLS)

GANGGUAN SISTEM MOTORIK

Lumpuh 1. Sistem piramidal Kejang 2. Sistem ekstrapiramidal Gangguan gerak 3. Serebelum Gangguan koordinasi (ataksia)

Extrapyramidal System
Facilitation Physiology: function by

Suppression
Facilitate

Pathophysiology: failure to
Suppress

Extrapyramidal dysfunction

MOVEMENT DISORDER

MOVEMENT DISORDER
Definition Movement disorder Is a neurological syndrome in which there is either an excess of movement, or a paucity of voluntary and Automatic movement. Unrelated to weakness or spasticity It is a term for: 1. A physical sign 2. Describing a specific syndrome / condition

The Origin of Movement Disorders

1. Basal ganglia - Cerebral Globus pallidus, Caudate nucleus, Putamen - Diencephalon Subthalamic nucleus - Mesencephalon Substantia nigra 2. Non-basal ganglia a. Cerebellum b. Cerebral cortex c. Brainstem 3. Peripheral ? (Hemifacial spasm)

Specific Site for Specific MD

1. Basal Ganglia - Substantia nigra Bradykinesia, rest tremor - Subthalamic nucleus Ballism - Caudate nucleus Chorea - Putamen Dystonia

2. Non-ganglia basal - Cerebellum ataxia, dysmetria, intention tremor, progressive myoclonic ataxia - Brainstem reticular reflex myoclonus, hyperekplexia, palatal myoclonus, ocular myoclonus - Cerebral cortex cortical reflex myoclonus - Limbic structure + basal ganglia (?) tics

Classification of Movement disorders

Extrapyramial Dysfunction

Failure to Facilitate

Failure to Suppress

HYPOKINESIA
- Akinesia/Bradykinesia - Rigidity - Diminished postural response - Freezing

HYPERKINESIA (Involuntary movement)

- Dyskinesia - Tremor - Chorea - Athetose - Dystonia Myoclonus - Tics - Akathesia - Hyperekplexia - Stereotypy

No Weakness

!!

Pattern and Type of Movement

HYPERKINESIA
Tremor rhythmic, alternating agonist and antagonist , sinusoidal, regular Type: essential, rest, action trremor Chorea (dance) rapid, forceful, semipurposeful Ballism large amplitude choreic movements of proximal parts of limbs Athetosis slow, writhing, mostly distally Dystonia involuntary, sustained muscle contraction, causing repetitive twisting movement and abnormal posture - focal, segmental, generalized Myoclonus sudden brief shock-like involuntary movement from: muscle contraction (positive myoclonus) or muscle inhibition (negative myoclonus)

Pattern and Type of Movement

HYPERKINESIA (contd) Tics -abnormal movement (motor tics) or abnormal sounds (phonic tics), or both (Tourettes syndrome) - abrupy, brief moments - preceded by urge Akathesia feeling of inner restlesness leading to complex stereotyped movements, which may reduce the sensation Stereotypy - coordinated movements that repeat themselves continually and identically - not preceded by urge - In tardive dyskinesia Restless leg syndrome - urge to move the limb with uncomfortable sensations

Pattern and Type of Movement

HYPOKINESIA Rigidity - increased tone throughout all directions of movement. - Flexor > extensor - lead pipe/plastic, cogwheel phenomenon Bradykinesia slowness of movement Freezing - motor act halted transiently (several seconds) - Includes: start hesitation, turning hesitation, destination hesitation Apraxia - inability to perform complex learned voluntary movement - not due to weakness, spasticity, rigidity, sensory loss

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 BANGKIT SEBAGAI JAWABAN ATAS SUATU RANGSANGAN

REFLEKS FISIOLOGIS REFLEKS PATOLOGIS

PARKINSONS DISEASE

ETIOLOGY
IDIOPATHIC
RISK FACTORS
(MULTIFACTORIAL)

AGING RACE GENETIC ENVIRONMENT

PATOPHYSIOLOGY
BASAL GANGLIA
EXTRAPYRAMIDAL SYSTEM

DOPAMINERGIC VS CHOLINERGIC
DIRECT PATHWAY VS INDIRECT PATHWAY

Substrat anatomi utama pada PD

DIAGNOSTIC APPROACH
CLINICALLY POSSIBLE
THE PRESENCE OF ANY ONE OF THE SALIENT FEATURES: TREMOR (RESTING); RIGIDITY; BRADYKINESIA; IMPAIRMENT OF POSTURAL REFLEXES

CLINICALLY PROBABLE
COMBINATION OF ANY TWO CARDINAL FEATURES (INCLUDING IMPAIRED POSTURAL REFLEXES); ALTERNATIVELY, ANY ONE OF THE FIRST THREE IF ASYMMETRICAL

CLINICALLY DEFINITE
ANY COMBINATION OF THREE OF THE FOUR FEATURES; ALTERNATIVELY, ANY TWO WITH ONE OF FIRST THREE DISPLAYING ASYMMETRY

DIAGNOSIS

Vascular PD

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

PROGNOSTIC FACTORS

TO REVERSE THE FUNCTIONAL DISABILITY

ABOLITION OF ALL SYMPTOMS AND SIGNS IS NOT CURRENTLY POSSIBLE EVEN WITH HIGH DOSES OF MEDICATION TREATMENT IS INDIVIDUALIZED

GOAL OF THERAPY:

PATIENT AND PHYSICIAN PLAYS A MAJOR ROLE IN THERAPEUTIC DECISIONS

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BRAIN
Ganglia basalis
Dopamin
MAO MAO I ( selegiline )

Acetylcholin

Normal
Anticholinergic

Receptor

D2

Dopamin
Decarboxylase

Perokside

Radical H

Tissue damage

(Trihexylphenidyl)

Levodopa

Acetylcholin

PD

BLOOD BRAIN BARIER

Levodopa
3 OMD COMT Inhibitor COMT

Dopamin Agonist

(entacapone)

Decarboxylase Dopamin Decarboxylase Inhibitor

(Benzeraside) (carbidopa)

Ergot (bromocryptin)

Non Ergot (pramipexole)

PHERIFER

PRECURSOR OF DOPAMINE

LEVODOPA

REPLACEMENT OF DEPLETED TRANSMITTER COMPLICATION OF CHRONIC THERAPY

THE ON-OFF REACTION, DYSKINESIAS, AND VISUAL HALLUCINATIONS
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ADDITIONAL AND DISTINCTLY DIFFERENT PHARMACOLOGIC ADVANCES

CARBIDOPA CONTROLLED RELEASE CARBIDOPA/LEVODOPA DOPAMINE AGONIST INHIBITOR OF CATECHOL-O- METHYL TRANSFERASE (COMT) MONOAMINE OXIDASE TYPE B (MAO-B)
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 CARBIDOPA
(INHIBITOR OF DOPA DECARBOXYLASE)

COMBINED WITH LEVODOPA, REDUCES PERIPHERAL DECARBOXYLATION OF LEVODOPA TO DOPAMINE CONTROLLED RELEASE TO PROLONGE LEVODOPAS 90-MINUTES HALF-LIFE DOPAMINE AGONIST
USED AS PHARMACOLOGICALLY SUBSTITUTES FOR CARBIDOPA/LEVODOPA IN EARLY DISEASE

TO PROVIDE SUPPLEMENTATION IN LATER STAGES

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 INHIBITORS OF CATECHOL-O-METHYL TRANSFERASE (COMT) INCREASE THE AMMOUNT OF LEVODOPA CROSSING THE BLOOD BRAIN BARRIER
MONOAMINE OXIDASE TYPE B (MAO-B) INHIBITORS TO SLOW DOPAMINES METABOLIC BREAKDOWN

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THERAPEUTIC ALGORITHM
FOR MANAGEMENT OF PARKINSONS DISEASE

(SEE TEXT)

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 INITIAL DECISION :
WHETHER ANY PHARMACOTHERAPY IS NEEDED

NO CONCLUSIVE EVIDENCE
THAT TREATMENT IS HELPFUL BEFORE SYMPTOMS START TO AFFECT THE PATIENTS LIFE EARLY STAGE : MAY BE BETTER LEFT UNTREATED IF IT DOES NOT LIMIT MOTOR FUNCTION

DECISION IS MADE ON THE BASIS OF HOW SYMPTOMS ARE AFFECTING INDIVIDUAL PATIENTS
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INTRODUCE LEVODOPA OR ANOTHER ANTIPARKINSONIAN AGENT

CHOICE:

DEVELOPMENT OF COMPLICATION
ASSOCIATED WITH LONG-TERM USE OF LEVODOPA

OTHER ANTIPARKINSONIAN DRUGS

LEVODOPA IS APPROPRIATE IF THE PATIENTS SYMPTOMS ARE STARTING TO INTERFERE WITH HIS OR HER ACTIVITIES

SHOULD BE CONSIDERED FIRST TO DELAY THE INTRODUCTION OF LEVODOPA

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PATIENTS WITH MILD SYMPTOMS MAY BE TREATED IN OTHER WAYS

CHOICES INCLUDE :
INTRODUCING SELEGILINE FOR ITS POSSIBLE NEUROPROTECTIVE BENEFIT INITIATING TREATMENT WITH ANTICHOLINERGIC DRUG, AMANTADINE, OR A DOPAMINE AGONIST AGENT
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AS AN ADJUNCT TO CARBIDOPA/LEVODOPA FOR PATIENTS WHO EXHIBIT DETERIORATION IN RESPONSE TO LEVODOPA SHOWN TO PROLONG THE SYMPTOMATIC BENEFIT OF LEVODOPA
IMPROVEMENT OF MOTOR SCORES AFTER THE INITIATION OF THE DRUG AND DETERIORATION OF SCORES ON ITS WITHDRAWL

SELEGILINE (L-DEPRENYL)

MAY HAVE SOME NEUROPROTECTIVE EFFECT

STATISTICALLY REDUCED DISABILITY COMPARED TO PLACEBO WAS FOUND EVEN AMONG DEPRENYL PATIENTS WHO INITIALLY HAD NO IMPROVEMENT IN MOTOR SCORES
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SELEGILINE MONOTHERAPY
SELEGILINES 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)
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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
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FOR PATIENTS WHOSE EARLY SYMPTOMS DO NOT RESPOND TO ANTICHOLINERGICS

AMANTADINE

AN ANTI VIRAL AGENT

PRECISE MECHANISM OF ACTION REMAINS TO BE DEFINED
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
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DOPAMINE AGONISTS
LONG HALF-LIFE
ASSOCIATED WITH LESS RISK OF DEVELOPING DYSKINESIA

USE OF THESE COMPOUNDS

PRIOR THE LEVODOPA INITIATION IN EARLY DISEASE TO AVOID OR DELAY THE PRODUCTION OF DYSKINESIA, ESPECIALLY IN PATIENTS WHO ARE YOUNG
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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:
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NOT ENOUGH DOPAMINE TERMINALS TO REGULATE DOPAMINE RELEASE

FLUCTUATION IN STRIATAL LEVODOPA THE RESULTING EXPOSURE OF STRIATAL RECEPTORS TO ALTERNATING HIGH AND LOW CONCENTRATIONS OF DOPAMINE --- INDUCE THE POSTSYNAPTIC CHANGES THAT LEAD TO THE DEVELOPMENT OF DYSKINESIA & MOTOR COMPLICATIONS
INITIAL MONOTHERAPY: USEFUL IN YOUNGER PATIENTS WHO ARE MORE PRONE TO THE EARLY DEVELOPMENT OF LEVODOPA-RELATED CLINICAL FLUCTUATIONS
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CATECHOL-O-METHYLTRANSFERASE
ADDITION OF CARBIDOPA TO LEVODOPA INCREASES THE AMMOUNT OF DRUG AVAILABLE TO CROSS THE BLOOD-BRAIN BARRIER LEVODOPA IS METABOLIZED IN THE GUT AND LIVER BY COMT
COMT INHIBITORY AGENTS PREVENT THE BREAKDOWN ; PROLONGING THE HALFLIFE OF LEVODOPA, INCREASING ITS TRANSPORT INTO THE BRAIN TO RISE DOPAMINE LEVELS
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INHIBITORS OF

COMT inhibition
Levodopa plus DDCI
3-OMD 3-OMD COMT Levodopa DDC Dopamine Peripheral COMT Levodopa DDC Dopamine COMT Levodopa DDC Dopamine Central Peripheral

Levodopa plus DDCI plus COMT inhibitor

3-OMD 3-OMD COMT Levodopa DDC Dopamine

BBB

BBB
Central

BBB DDC DDC COMT 3-OMD

= = = = =

blood brain barrier DOPA-decarboxylase DOPA-decarboxylase inhibitor Catechol-O-methyl transferase 3-O-methyldopa

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

Akinesia
The absence of movement Facial characteristics: decreased blinking, a reptillian 'stare,' or an immobile or mask-like face (hypomimia) Gradual softening of the voice (hypophonia).

Bradykinesia
the slowness of movement : micrographia Impaired movements result : difficulty turning in bed, standing up from sitting in a chair getting out of a car. Festinating increasing in velocity

Postural Imbalance
A symptom that manifest itself in the inability of a patient to balance or remain steady

Clinical Tests of Balance Used by Physical Therapists

Standing Feet apart Feet together Stride stance Tandem stance Single-limb stance Romberg Test

 Perturbation of standing balance by self-initiated movements Response to externally generated perturbations

Arm raises Step test Functional reached Sternal push Postural stress Pastor, Marsden, and Day Test

 Ability to maintain balance during functional tasks

Berg Balance Scale "Get up and go" test Gait Tinetti MobilityIndex Subcomponents of functional assessment scales such as Barthel index, Functional Independence Measure, and Webster Scale

 Ability to integrate sensory

Sensory organization information to maintain

Tersebut di bawah ini adalah instrumen / perasat yang berkaitan dengan diagnostik Penyakit Parkinson
Hoehn and Yahr Staging of Parkinsons Disease Kriteria Hughes Unified Parkinsons Disease Rating Scale MMSE

Tersebut di bawah ini adalah instrumen / perasat yang berkaitan dengan pemilihan medikamentosa pada pengobatan awal Penyakit Parkinson
Hoehn and Yahr Staging of Parkinsons Disease Kriteria Hughes Unified Parkinsons Disease Rating Scale MMSE

Tersebut di bawah ini adalah hal-hal yang merupakan pertimbangan pemilihan medikamentosa pada pengobatan awal Penyakit Parkinson
Usia Berat-ringannya gambaran klinis Lamanya menderita

Kemungkinan komplikasi obat jangka panjang

Komplikasi penggunaan jangka panjang levodopa terjadi berkaitan dengan:

Stadium penyakit Tingginya penggunaan dosis pengobatan Pulsatilitas kadar levodopa dalam plasma Waktu paruh levodopa yang pendek Peranan Mono Amine Oxidase -B Peranan Catechol-O-Methyl Transferase Kerusakan struktur dan fungsi reseptor dopamin

Pertimbangan untuk digunakannya Dopamine Agonists

Stimulasi langsung pada reseptor dopamin Tidak memerlukan konversi presinaptik Tidak ada kompetisi di usus maupun sawar darah otak

Dimungkinkan aktivasi terhadap reseptor selektif

Dimungkinkan adanya sejumlah jalur pemberian