PARKINSON DISEASE

GANGGUAN GERAKBERLATAR BELAKANG GANGGUAN SARAFETIOLOGI

PATOLOGI

TOPIS LESI

GAMBARAN KLINIS

DIAGNOSIS NEUROLOGIS:Dx/ KLINIS - TOPIS ETIOLOGISsangat ditunjang oleh penguasaan pengetahuan anatomiGANGGUAN GERAKGANGGUAN SARAFSTROKEPENYAKIT PARKINSON

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

Gangguan gerak abnormal - involunter berlatar belakang gangguan saraf Penyakit Parkinson - tokoh-tokoh terkenal penyandangnya

SUBSTRAT ANATOMIdari sistem saraf yang berkaitan dengan gerak tubuh KOMPONEN FUNGSI MOTORIKSistem piramidal (UPPER MOTONEURON)danSaraf tepi (LOWER MOTONEURON)

Sistem ekstrapiramidalSUBSTRAT 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 KLINISGANGGUAN SISTEM PIRAMIDALIS JARAS KORTIKOBULBARIS: saraf-saraf kranialstrabismus (kero)asimetri otot-otot wajahnasolalia (bindeng)gangguan menelandisartri (pelo)

JARAS KORTIKOSPINALIS (upper motoneuron) kelumpuhan spastik (ciri-ciri?)hemiparesis (lumpuh separuh badan)

akibat stroke: GARENG ?MANIFESTASI KLINISGANGGUAN SARAF TEPI (lower motoneuron)kelumpuhan flaksid (ciri-ciri?)

- poliomyelitis anterior acuta

- Bells palsy .....

- neuropati perifer: sindrom Guillan Barre dll.

SUBSTRAT ANATOMI KOMPONEN FUNGSI MOTORIK:Sistem ekstrapiramidalmemelihara tonus otot, menyiapkan gerakjitu & tangkas

dan

serebelum (otak kecil) integrasi impuls sensibel dan motorik

SUBSTRAT ANATOMISISTEM EKSTRAPIRAMIDAL:

SISTEM EKSTRAPIRAMIDALSUBSTRAT ANATOMI(telah diuraikan di depan)

FUNGSIMeletakkan landasan gerak jitu dan tangkas

Penyampaian impuls difus dan masal keseluruh otot tubuh untuk menjagatonus otot sebelum, selama dansesudah aktifitas sistem piramidal berlangsung

Kelola inhibisi gejala kelepasan (release phenomenon) hiper / hipokinetis

MANIFESTASI KLINISGANGGUAN SISTEM EKSTRAPIRAMIDAL(BURISRAWA atau DURSASANA ? BATARA NARADA ?)(GERAK INVOLUNTER)

TREMORHEMIBALISMUSKHOREAATETOSISDISTONIAMIOKLONIATIKATAKSIA

PERANAN SEREBELUM (otak kecil) INTEGRASI FUNGSI SENSORIMOTORGANGGUAN KOORDINASIMEKANISME REFLEKSLENGKUNG REFLEKSRESEPTOR AFEREN PUSAT EFEREN EFEKTOR

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

REFLEKS FISIOLOGISREFLEKS PATOLOGISPARKINSONS DISEASEPATHOPHYSIOLOGYDIAGNOSISTHERAPY

Amin HusniBagian Anatomi-Neurologi FK UNDIP13DEFINITION AND CLASSIFICATIONPARKINSONISMPARKINSONS DISEASE

IDIOPATHICSECONDARY PARKINSONISMPARKINSON-PLUS SYNDROME

ETIOLOGYIDIOPATHIC

RISK FACTORS(MULTIFACTORIAL)AGINGRACEGENETICENVIRONMENT

PATOPHYSIOLOGYBASAL GANGLIAEXTRAPYRAMIDAL SYSTEM

DOPAMINERGIC VS CHOLINERGIC

DIRECT PATHWAY VS INDIRECT PATHWAY

THE PATOPHYSIOLOGY OF PARKINSONS DISEASE

1.IMBALANCE BETWEEN THE DOPAMINERGIC AND CHOLINERGIC NEURONSKorpus striatum selain menerima persarafan dopaminergik yang datang dari substansia nigra, juga disarafi oleh saraf kolinergik dengan asetilkolin ( AKA ) sebagai neurotransmiternya, pengaruh dari striatum terhadap fungsi motorik korteks ditentukan oleh kegiatan kedua saraf tersebut.Bila mana kegiatan dopaminergik meningkat dan atau kegiatan kolinergik menurun maka pengaruh dopaminergik akan dominan shg timbullah gejala hiperkinesia, sebaliknya jika kegiatan dopaminergik menurun dan atau kolinergik meningkat maka pengaruh kolinergik akan dominan shg timbullah gejala hipokinesia ( sindroma parkinson )

THE PATOPHYSIOLOGY OF PARKINSONS DISEASE2. IMBALANCE BETWEEN THE DIRECT AND INDIRECT PATHWAYS Baik jalur langsung maupun tidak langsung keduanya akan bermuara ke GPi / SNr dan selanjutnya dari sini akan mengeluarkan output menuju talamus dan korteks, bila masukan dari keduanya seimbang maka output-nyapun akan seimbang pula sehingga tidak timbul kelainan gerakan motorik. Akan tetapi manakala terjadi hiperaktif jalur langsung atau hipoaktif jalur tak langsung maka output dari GPi dan SNr ke arah talamo korteks akan menurun maka akan terjadi gerakan hiperkinesia.Sebaliknya jika terjadi hipoaktifitas jalur langsung dan hiperaktifitas jalur tak langsung maka keluaran dari Gpi dan SNr akan meningkat maka terjadi gerakan hipokinesia / sindroma parkinson.

B R A I NGanglia basalisAcetylcholinNormalDopaminAcetylcholinPDPeroksideRadical HTissue damageAnticholinergic(Trihexylphenidyl)MAOMAO I ( selegiline )D2Dopamin ReceptorDopamin AgonistErgot (bromocryptin) Non Ergot (pramipexole)LevodopaLevodopaDopaminDecarboxylaseDecarboxylase Inhibitor(Benzeraside)(carbidopa)3 OMDCOMTCOMT Inhibitor (entacapone)BLOOD BRAIN BARIERPHERIFERDecarboxylase24DIAGNOSISCLINICAL DIAGNOSISBASED ON THE CLINICAL FEATURESGENERAL AND SPECIFICT . R . A . P .

CLINICALLYKOLLERGELB

ETC.DIAGNOSTIC APPROACHCLINICALLY POSSIBLETHE PRESENCE OF ANY ONE OF THE SALIENT FEATURES: TREMOR (RESTING); RIGIDITY; BRADYKINESIA; IMPAIRMENT OF POSTURAL REFLEXESCLINICALLY PROBABLECOMBINATION OF ANY TWO CARDINAL FEATURES (INCLUDING IMPAIRED POSTURAL REFLEXES); ALTERNATIVELY, ANY ONE OF THE FIRST THREE IF ASYMMETRICAL

CLINICALLY DEFINITEANY COMBINATION OF THREE OF THE FOUR FEATURES; ALTERNATIVELY, ANY TWO WITH ONE OF FIRST THREE DISPLAYING ASYMMETRYMODIFIED HOEHN AND YAHR STAGINGSTAGE 0= NO SIGNS OF DISEASESTAGE 1= UNILATERAL DISEASESTAGE 1.5= UNILATERAL PLUS AXIAL INVOLVEMENTSTAGE 2= BILATERAL DISEASE, WITHOUT IMPAIRMENT OF BALANCESTAGE 2.5= MILD BILATERAL DISEASE, WITH RECOVERY ON PULL TESTSTAGE 3= MILD-TO-MODERATE BILATERAL DISEASE; SOME POSTURAL INSTABILITY; PHYSICALLY INDEPENDENTMAJOR CONSEPTUALON PHARMACOLOGIC / SURGICALTREATMENTSYMPTOMATIC

PROTECTIVE

RESTORATIVE28TO IMPROVE SIGNS AND SYMPTOMS OF THE DISEASE

TO INTERFERE WITH THE PATHOPHYSIOLOGIC MECHANISME OF THE DISEASE

TO PROVIDE NEW NEURONS OR TO STIMULATE GROWTH AND FUNCTION OF REMAINING CELLS29GOAL OF THERAPY:TO REVERSE THE FUNCTIONAL DISABILITYABOLITION OF ALL SYMPTOMS AND SIGNS IS NOT CURRENTLY POSSIBLE EVEN WITH HIGH DOSES OF MEDICATION

TREATMENT IS INDIVIDUALIZED

PATIENT AND PHYSICIAN PLAYS A MAJOR ROLE IN THERAPEUTIC DECISIONS30LEVODOPAPRECURSOR OF DOPAMINEREPLACEMENT OF DEPLETED TRANSMITTER

COMPLICATION OF CHRONIC THERAPYTHE ON-OFF REACTION, DYSKINESIAS, AND VISUAL HALLUCINATIONS

31ADDITIONAL AND DISTINCTLY DIFFERENT PHARMACOLOGIC ADVANCESCARBIDOPA

CONTROLLED RELEASE CARBIDOPA/LEVODOPA

DOPAMINE AGONIST

INHIBITOR OF CATECHOL-O- METHYL TRANSFERASE (COMT)

MONOAMINE OXIDASE TYPE B (MAO-B)32CARBIDOPA (INHIBITOR OF DOPA DECARBOXYLASE) COMBINED WITH LEVODOPA, REDUCES PERIPHERAL DECARBOXYLATION OF LEVODOPA TO DOPAMINE

CONTROLLED RELEASETO PROLONGE LEVODOPAS 90-MINUTES HALF-LIFE

DOPAMINE AGONISTUSED AS PHARMACOLOGICALLY SUBSTITUTES FOR CARBIDOPA/LEVODOPA IN EARLY DISEASETO PROVIDE SUPPLEMENTATION IN LATER STAGES33INHIBITORS 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

34THERAPEUTIC ALGORITHMFOR MANAGEMENTOF PARKINSONS DISEASE(SEE TEXT)35

37INITIAL DECISION :WHETHER ANY PHARMACOTHERAPY IS NEEDED

NO CONCLUSIVE EVIDENCETHAT TREATMENT IS HELPFUL BEFORE SYMPTOMS START TO AFFECT THE PATIENTS LIFEEARLY 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 PATIENTS38CHOICE:INTRODUCE LEVODOPAOR ANOTHER ANTIPARKINSONIAN AGENTDEVELOPMENT OF COMPLICATION ASSOCIATED WITH LONG-TERM USE OF LEVODOPA

OTHER ANTIPARKINSONIAN DRUGS SHOULD BE CONSIDERED FIRST TO DELAY THE INTRODUCTION OF LEVODOPA

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

39PATIENTS WITH MILD SYMPTOMSMAY BE TREATED IN OTHER WAYS

CHOICES INCLUDE :

INTRODUCING SELEGILINE FOR ITS POSSIBLE NEUROPROTECTIVE BENEFIT

INITIATING TREATMENT WITH ANTICHOLINERGIC DRUG, AMANTADINE, OR A DOPAMINE AGONIST AGENT40SELEGILINE (L-DEPRENYL)AS AN ADJUNCT TO CARBIDOPA/LEVODOPAFOR PATIENTS WHO EXHIBIT DETERIORATION IN RESPONSE TO LEVODOPASHOWN TO PROLONG THE SYMPTOMATIC BENEFIT OF LEVODOPAIMPROVEMENT OF MOTOR SCORES AFTER THE INITIATION OF THE DRUG AND DETERIORATION OF SCORES ON ITS WITHDRAWL

MAY HAVE SOME NEUROPROTECTIVE EFFECTSTATISTICALLY REDUCED DISABILITY COMPARED TO PLACEBO WAS FOUND EVEN AMONG DEPRENYL PATIENTS WHO INITIALLY HAD NO IMPROVEMENT IN MOTOR SCORES41SELEGILINE MONOTHERAPYSELEGILINES 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)42ANTICHOLINERGICSTO 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 EFFECTS43AMANTADINEFOR PATIENTS WHOSE EARLY SYMPTOMS DO NOT RESPOND TO ANTICHOLINERGICSAN ANTI VIRAL AGENTPRECISE MECHANISM OF ACTION REMAINS TO BE DEFINEDRELEASES 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 EFFECTS44DOPAMINE AGONISTSLONG HALF-LIFE ASSOCIATED WITH LESS RISK OF DEVELOPING DYSKINESIA

USE OF THESE COMPOUNDSPRIOR THE LEVODOPA INITIATION IN EARLY DISEASE TO AVOID OR DELAY THE PRODUCTION OF DYSKINESIA, ESPECIALLY IN PATIENTS WHO ARE YOUNG45DEVELOPMENT OF DYSKINESIADEPEND 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:46NOT ENOUGH DOPAMINE TERMINALS TO REGULATE DOPAMINE RELEASEFLUCTUATION IN STRIATAL LEVODOPATHE 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 PATIENTSWHO ARE MORE PRONE TO THE EARLY DEVELOPMENT OF LEVODOPA-RELATED CLINICAL FLUCTUATIONS47INHIBITORS OFCATECHOL-O-METHYLTRANSFERASEADDITION OF CARBIDOPA TO LEVODOPA INCREASES THE AMMOUNT OF DRUG AVAILABLE TO CROSS THE BLOOD-BRAIN BARRIERLEVODOPA IS METABOLIZED IN THE GUT AND LIVER BY COMTCOMT INHIBITORY AGENTS PREVENT THE BREAKDOWN ; PROLONGING THE HALF-LIFE OF LEVODOPA, INCREASING ITS TRANSPORT INTO THE BRAIN TO RISE DOPAMINE LEVELSCOMT inhibitionLevodopa plus DDCILevodopa plus DDCI plus COMT inhibitorBBB = blood brain barrierDDC = DOPA-decarboxylaseDDC = DOPA-decarboxylase inhibitorCOMT = Catechol-O-methyl transferase 3-OMD = 3-O-methyldopaPeripheralCentralPeripheralCentralDopamineLevodopa3-OMDCOMTBBBDDC3-OMDLevodopaDopamineCOMTDDCDopamineLevodopa3-OMDCOMTBBBDDC3-OMDLevodopaDopamineCOMTDDCKaakkola S, et al. General properties and clinical possibilities of new selective inhibition of cathecol-O-methyl transferase. Gen. Pharmacol 1994a; 25: 813 - 824.49

THANK YOUTHANK YOUTHANK YOUTHANK YOUTHANK YOUTHANK YOUTHANK YOUTHANK YOUTHANK YOU