08. Parkinson 2014 Dr. an an, M.sc., Sp.S

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Curiculum vitae

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

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



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PARKINSON’S DISEASE

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



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What Is Parkinson's Disease?

Parkinson's Disease is aclinical syndrome caused bylesion in the basal ganglia

,predominantly in thesubstantia nigra ,thatproduce deficits in motorbehavior.





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HistoryIn 1817 James Parkinson published a study on the"shaking palsy," which he also referred to asparalysis agitans,In 1957 Carlsson observed similarities betweenparkinsonian symptoms and the side effects of

chronic treatment with reserpine, a knownmonoamine depleting drug (Yurek and Sladek1990).In 1960 Ehringer and Hornykiewicz observed thatconcentrations of striatal dopamine were depletedin parkinsonian patients.

Yurek and Sladek (1990) is "severe reduction ofdopamine in all compartments of the basalganglia."



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The disease is chronic, (it persistsover a long period of time) andprogressive (its symptoms growworse over time). It is notcontagious nor is it usuallyinherited-that is, it does not pass

directly from one family member orgeneration to the next.



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Parkinson's Disease affects about 1 in every 250people over 40 years old and about 1 in every100 people over 65 years old.It is slightly more common in men than in

women.Medication can treat its symptoms, and thedisorder 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 ofthe disease.



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CAUSES (1)

The exact cause of the diseaseremains a mystery.In Parkinson's, cells that producedopamine begin to degenerate.Insufficient dopamine disturbs thebalance between dopamine andother transmitters, such asacetylcholine.Dopamine is a chemicalmessenger responsible fortransmitting signals between thesubstantia nigra and the next"relay station" of the brain, thecorpus striatum, to producesmooth, purposeful muscleactivity.



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CAUSES (2)

Loss of dopamine causes thenerve cells of the striatum tofire out of control, leavingpatients unable to direct orcontrol their movements in anormal manner.Studies have shown thatParkinson's patients have aloss of 80 percent or more ofdopamine-producing cells inthe substantia nigra.



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Oxidation due to free radicals is thought tocause damage to tissues, including neurons.Normally, free radical damage is kept undercontrol by antioxidant chemicals that protect cells

from this damage.Researchers found that patients with Parkinson'sdisease have increased brain levels of iron,especially in the substantia nigra, and decreasedlevels of feritin, which serves as a protective mechanism by chelating, or forming a ring aroundthe iron, and isolating it. This led to theconclusion that oxidative mechanisms may causeor contribute to Parkinson's disease.



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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 pesticidesor a toxin in the food supply is

an example of the kind of

external trigger that could

hypothetically cause

Parkinson's disease.



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Researchers believe that genetics sometimes plays a role in thecellular breakdown. Fifteen totwenty percent of Parkinson'spatients have a close relative whohas experienced parkinsonian

symptoms (such as a tremor).



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Genetic factors predominantcause of Young-Onset PDMutations on several

chromosomes have beenfoundAlso one instance of mutationin Mitochondrial DNA



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In some individuals, the normal, age-related wearing away of dopamine-producing neurons accelerates. The exact

cause for this is not known; but, if thishappens, then it can also result inParkinson's disease. This theory issupported by the fact that the loss of

antioxidative protective mechanisms isassociated with both Parkinson's diseaseand increasing age.



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In rare instances, Parkinson'sdisease may be caused by a viralinfection .Many researchers believe that acombination of oxidative damage,environmental toxins, genetic

predisposition, and acceleratedaging may ultimately be shown tocause the disease.



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PARKINSONISM

Parkinsonism is a clinical ratherthan an etiologic entity since it isassociated with several pathologicprocesses that damage theextrapyramidal system.



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CAUSES OF PARKINSONISM

An adverse reaction to prescription drugsUse of illegal drugsExposure to environmental toxinsStrokeThyroid and parathyroid disordersRepeated head trauma (for example, the traumaassociated with boxing)Brain tumor

An excess of fluid around the brain (calledhydrocephalus)Brain inflammation (encephalitis) resulting frominfection



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SYMPTOMS

TREMORResting tremor (shaking back and forth whenthe limb is relaxed)

RIGIDITYRigidity (stiffness, or resistance of the limb topassive movement when the limb is relaxed)

AKINESIABradykinesia (slowness of movement)

POSTURAL INSTABILITY (poor balance).



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TREMOR

Typically, the tremor takes the form of arhythmic back-and-forth motion of thethumb and forefinger at three beats persecond. This is sometimes called "pill

rolling." Tremor usually begins in a hand,although sometimes a foot or the jaw isaffected first. It is most obvious when thehand is at rest or when a person is understress.

In three out of four patients, the tremor mayaffect only one part or side of the body,especially during the early stages of thedisease. Later it may become more general.

Tremor is rarely disabling and it usuallydisappears during sleep or improves with

intentional movement.



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RIGIDITY

Rigidity, or a resistance tomovement, affects mostparkinsonian patients.All of our muscles have anopposing muscle. When we try tomove a muscle, it becomes

active, and the opposing musclerelaxes.In Parkinson's disease, thisdelicate balance of opposingmuscles is disturbed.The muscles remain constantlytensed and contracted so that theperson aches or feels stiff orweak.The rigidity becomes obviouswhen another person tries tomove the patient's arm, which willmove only in ratchet-like or short,

jerky movements.This is known as "cogwheel"rigidity.



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AKINESIA/BRADYKINESIABradykinesia. Bradykinesiais the slowing down and lossof spontaneous and automaticmovement. It is particularlyfrustrating because it is

unpredictable. One momentthe patient can move easily.The next moment he or shemay need help. This may wellbe the most disabling anddistressing symptom of thedisease because the patientcannot rapidly perform routinemovements. Activities onceperformed quickly and easily,such as washing or dressing,

may take several hours.



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POSTURAL INSTABILITY

Postural instability, or impaired balanceand coordination, causes patients todevelop a forward or backward lean and

to fall easily. Postural instability can cause patientsto have a stooped posture in which thehead is bowed and the shoulders are

drooped. As the disease progresses,walking may be affected. Patients mayhalt in mid-stride and "freeze" in place,possibly even toppling over.



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Muscle rigidity

StiffnessDifficulty bending arms or legs

Loss of balance Gait (walkingpattern) changes Shuffling walk



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THE SYMPTOM OF PARKINSON’S

DISEASE INCLUDE :

Slowness of voluntary movements, especially inthe initiation of such movements as walking orrolling over in bed.Decreased facial expression, monotonous speechand decreased eye blinking. A shuffling gait with poor arm swing and stoopedposture. Unsteady balance; difficulty rising from a sittingposition.Continuous "pill-rolling" motion of the thumb and

forefinger.Abnormal tone or stiffness in the trunk andextremities.Swallowing problems in later stages.



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SLOW MOVEMENTS

Difficulty beginning to walkDifficulty initiating any voluntary movement Smallsteps followed by the need to run to maintainbalance

Freezing of movement when the movement isstopped, inability to resume - movementMuscle aches and pains (myalgia)Shaking, tremors (varying degrees, may not bepresent) Characteristically occur at rest, mayoccur at any time

May become severe enough to interfere withactivities May be worse when tired, excited, orstressed Finger-thumb rubbing (pill-rollingtremor) may be present



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Changes in facial expression

Reduced ability toshow facialexpressions"mask"appearance to faceStaring May be unable toclose mouth Reduced rate ofblinking



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Voice/speech changes

Slow speech

Low-volume voiceMonotoneDifficulty speaking



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Loss of fine motor skills

Difficulty writing, may besmall and illegibleDifficulty eatingDifficulty with any activity

that requires smallmovementsMovement, uncontrolled -slowFrequent fallsDecline in intellectualfunction (may occur, canbe severe)A variety ofgastrointestinalsymptoms, mainlyconstipation.



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Additional symptoms that may beassociated with this disease:

DepressionConfusionDementia

Seborrhea (skin)Muscle function/feeling lossMuscle atrophyMemory lossDroolingAnxiety, stress, and tension



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STAGING OF PDHoehn and Yahr

1. Stage One Signs and symptoms on one side only Symptoms mild

Symptoms inconvenient but notdisablingUsually presents with tremor of onelimb

Friends have noticed changes inposture, locomotion and facialexpression



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2. Stage Two Symptoms are bilateralMinimal disabilityPosture and gait affected



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3. Stage Three Significant slowing of body movementsEarly impairment of equilibrium onwalking or standingGeneralized dysfunction that ismoderately severe



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4. Stage FourSevere symptoms

Can still walk to a limited extentRigidity and bradykinesia

No longer able to live alone

Tremor may be less than earlier stages



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5. Stage FiveCachectic stage

Invalidism complete

Cannot stand or walk

Requires constant nursing care



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DIAGNOSIS

There are no blood tests or X-rays thatwill confirm the diagnosis.The diagnosis is made on finding 2 of the3 cardinal features of the disorder onneurologic exam and ruling out otherpossible causes includung severalconditions that can mimic Parkinson's

Disease but often have additional features(Parkinsn's "Plus").



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PATHOPHYSIOLOGY



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DOPAMIN PRODUCING NERVE CELL



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Gambar3

DOPAMIN RELEASE TO THE SYNAPS



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Gambar4



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Gambar5



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Gambar 6



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MAINTAIN THE BALANCE BETWEENDOPAMIN AND ACh

Cara mengatasi kekurangan ke-tidak seimbangan antaradopamin dan asetilkholin iniada bermacam-2:

1.Dengan menambah persediaandopamine

2.Dengan mengurangi aktifitasasetilkholin

3.Dengan cara / kombinasi yanglain,terutama sehubungandengan perkembanganpenyakitnya .



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Gambar 8

1 . Replacing the Missing Dopamine

Sinemet(LEVIDOPA/CARBIDOPA)

berangkali merupakan pengobatan tunggal yang palingefektif untuk mengontrol gejalaPD.Sinemet ditranport (dibawa )ke otak dan ditangkap (picked

up)oleh sel-2 yangmemproddusir dopamin.Setelah itu sinemet dikonversimenjadi dopamin dan dipakaisebagai neurotransmitter,



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Sebagian besar pasien dapat teratasi gejala PD-nyadengan menggunakan sinemet yang sebagai penggantidopamin yang hilang sampai beberapa tahun.Tetapikarena hilangnya /rusaknya sel-2 yang penghasildopamin berlanjut terus, maka gejalaPD akan makinmemburuk sehingga dosis sinemet akan makinmeningkat.Umumnya akan diberikan dosis sinemet dosis rendahselama mungkin.Hal ini dimaksudkan untukmenghindari side efek dari Sinemet.Dikemudian haripenambahan dosis Sinemet ini akan mengakibatkantimbulnya efek samping sehingga tidak mungkin lagi

menambah dosis Sinemet lebih tinggi lagi.Pada saat ituopsi pengobatan menjadi terbatas .Karena itu hal inidiatasi dengan penambahan Eldepryl®2 Capsules, 5mg(selegiline hydrochloride)untuk menjaga agar dosisSinemet dapat teap rendah dan memperpanjangpengguanaan V



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2. Substituting a DifferentSubstance That "Mimics" Dopamine



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Parlodel®3 (bromocriptine mesylate) and Permax®4(pergolide mesylate) adalah obat yang mempunyai aksimenyerupai dopamin dengan cara mengepas /mencocokkan diri kedalam kantong dopamin padapermukaan sel saraf yang menerima dopamin (NTdopamin).Salah satu keuntungan dari pendekatan darisubstitusi ini kurang tampaknya gejala diskinese(dyskinesias* are less likely to occur).Hal ini terjadi karena jumlah dopamin yang ada tidakbenar-2 ditambah sebagaimana kerja sinemet .Dalamhal ini, Parlodel atau Permax sebagai penggantidopamin tadi

Hal ini mengakibatkan kurang munculnya dyskinesakarena dyskinesa timbul akibat terlau banyaknyadopamin dalam otak



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3. Helping Nerve Cells Release StoredDopamine



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Symmetrel®5 (amantadinehydrochloride) memperlihatkan keadaandimana sel-2 saraf penghasil dopamin(dopamine-producing nerve cells ) lebih

mudah untuk membuka jendela danmelepaskan kandungan dopamin masukkedalam sinaps.Pendekatan seperti ini berguna untukkasus-2 ringan PD dimana Symmetrel

bekerja untuk mengurangi gejala PD



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4. Adjusting the Activity of Acetylcholine to Restore the Dopamine/Acetylcholine Balance

Artane®6 (trihexyphenidyl HCl)andCogentin®7 (benztropinemesylate)



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Artane®6 (trihexyphenidyl HCl) dan Cogentin®7(benztropine mesylate) dapat digunakan untukmempertahakan keseimbangan dopamin / asetilkholin dengan cara mengurangi aktifitas

asetilkholin di otak..cara ini sangat berhasil untukmengurangi tremor dan kekakuan otot yangdiakibatkan oleh banyaknya asetil kholindibanding dengan dopamin Namun pengobatan /obat ini tidak mengoreksi problem dasar akibatpenurunan dopamin .Umumnya obat ini

digunakan untuk kasus-kasus awal PD dandikombinasikan dengan obat-obat lain.



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5. Conserving the Dopamine Already inthe Brain



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Eldepryl bekerja beda sekali dengan obat lain yangmemperlambat hilangnya dopamin dan mengembalikankeseimbangan Dopamin / asetilkholin,Eldepryl bekerja dengan memblokir zat kimia yang terdapatdalam sinaps yang mempunyai aksi memecah dopamin(MAO-B).Dengan demikian meskipun secara alamiah hanya

sedikit saja produksi dopamin atau lebih besar jumlahnyadengan replacement therapy dengan sinemet --Eldeprylmenjaga sejumlah itu dengan agar tidak dihancurkan,sehingga dopamindapat lebih lama berada di synaps.dan nakin lama berada disinaps, makim lama partikel itu mencapai dopamin recieverpada sel-sel penerima untuk selanjutnya mengirimkanmessage.Dengan demikian Eldepryl membantu secaranatural/alamiah mengkonservasi dopamin dan me-maksimalkan jumlah dopamin pengganti (dopaminereplacement ) yang diberikan oleh sinemet teap dalam dosisrendah sepenjang waktu

Pharmacological Treatments for Parkinson’s



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Pharmacological Treatments for Parkinson sDiseaseThe table summarizes these pharmacological

approaches.PharmacologicalApproach

Example ofdrug used

Rationale Drawbacks (side effects)

Increase thedopamine

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 loosesensitivity to the drug, may develop episodesof immobility, alternating with episodes ofnormal or involiuntary movements

Give drugs that actlike dopamine(dopamineagonists)

Bromocriptine(Parlodel)

Since there is a loss of dopaminergic neurons,replace with drugs that act like dopamine

These drugs are expensive, may causeconfusion, diziness on standing, involuntarymotion

Decreaseacetylcholine bygivinganticholinergic

grugs

Artane,Cogentin

Parkinsonism is caused by excess stimulation ofextrapyramidal motor system due to imbalnce

between dopamine and acetycholine (lessdopamine, greater effect of acetycholine which is

excitatory). Therefore, restore balance by ecreasingacetycholine to levels that match the decreaseddopamine

Side effects can be blurred vision, memoryimpairment

Increase the effectof remainingdopamine by

blocking its breakdown

Selegiline(deprenyl)

Dopamine is normally broken down by the enzymemonamime oxidase B. If you inhibit this enzyme,then dopamine is not broken down as quickly, itreamins longer in the tissue exerting its effect. In asense, this is physiologically equivalent to

increasing the amount of dopamine

Side effects are onsomnia



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ANTICHOLINERGICS

Effective mainly for tremor andrigidityStart low, go slowSide effects:

Dry mouth, sedation, delirium,confusion, hallucinations, constipation,

urinary retention



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AMANTADINE

Tremor, bradykinesia, rigidity &dyskinesiasExact mechanism unknown; possibly:

enhancing release of stored dopamineinhibiting presynaptic reuptake ofcatecholaminesmild anticholinergic effect

NMDA receptor blockadeSide effects —autonomic, psychiatric200-300 mg/day



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SELEGILINE

Selective Monoamine oxidase BinhibitorInhibits breakdown of dopamine

Mild symptomatic effect?Neuroprotection?Increased mortality

– DATATOP study: mild symptomatic effect

and delay of l-dopa treatment – UKPDRS study: increased mortality (notseen in metanalysis of other selegilinestudies)



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LEVODOPA

Mainstay in the treatment of earlyand advanced diseaseBut:

1. Response declining after severalyears?

2. Long-term motor complications3. ?Neurotoxicity

Delay of l-dopa treatment?



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LEVODOPA/PDI Formulations

Onset Duration

Immediate Release 20-40 min 2-4 hr

12.5/50, 10/100,25/100, 25/250

Controlled Release 30-60 min 3-6 hr

25/100, 50/200

Dispersible 10-20 min 2-3.5 hr

12.5/50, 25/100



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Surgical Therapy

Resurgence of stereotactic surgerywith better imaging and equipmentLesioning vs. long-term electricalstimulation with implanted deepbrain electrodes (DBS)



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Stereotactic Surgery

Thalamotomy and thalamic DBS: onlyimprovement of tremorPallidotomy and pallidal stimulation: main

effect on dyskinesias, but mildimprovement of parkinsonismSubthalamic stimulation (or lesions): allfeatures, but technically more difficult and

greater risk of bleedingTransplantation (fetal, geneticallyengineered cells, xenografts): stillexperimental



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Non-medical Intervention in PD

PhysiotherapySpeech therapy

Parkinson’s Disease Society Occupational therapyRespite care and day centres



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08. Parkinson 2014 Dr. an an, M.sc., Sp.S

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