Demensia Parkinson

Skenario B Blok 20 Tahun 2013

Ny. L umur 69 tahun, dibawa ke dokter karena sering tidak bias pulang (lupa jalan pulang)  dan sering ketinggalan belanjaan di pasar. Kejadian ini sudah berlangsung 1  tahun dan semakin berat. Sejak 1,5 tahun yang lalu penderita sudah sukar berjalan karena badannya kaku,  tangannya mengalami tremor kasar dan mudah jatuh.

Pemeriksaan Fisik

GCS 15,TD 170/100, nadi 82x/menit regular, RR 20x/menit, temperature 37,2⁰C

Status neurologis                 :gerakan dan kekuatan ekstremitas menurun, tremor kasar di kedua lengan, lain-lain dalam batas normal

Pemeriksaan laboratorium    : GDS 140 mg/dl, kolesterol total 260 mg%, TG 120 mg%

Pemeriksaan penunjang       : MRI kepala dalam batas normal dengan atropi ringan di lobus anterior

Pemeriksaan kognitif            : MMSE 17/30

Hipotesis : Nyonya L berusia 69 tahun menderita demensia parkinson.

Parkinson

Proses degeneratif progresif sehubungan dengan proses menua di substansia nigra pars compacta (SNc). penyebab penyakit ini kebanyakan idiopatik.

1) Keturunan (Genetik)

Ditemukan 3 gen yang menjadi penyebab gangguan degradasi protein dan mengakibatkan protein beracun tak dapat didegradasi di ubiquitin proteasomal pathway. Kegagalan degradasi ini menyebabkan peningkatan apoptosis di sel-sel SNc sehingga meningkatkan kematian sel neuron SNc. Hal ini mendasari penyakit Parkinson bersifat familial.

2) Lingkungan

Baha beracun seperti carbon disulfide, manganese, dan pelarut hidrokarbon yang menyebabkan sindroma Parkinson. Saat ini yang paling diterima adalah adanya stress oksidatif pada ganglia basalis, apapun penyebabnya. Berbagaipenelitian telah dilakukan antara lain peran xenobiotik, pestisida, herbisida, terpapar pekerjaan terutama zat kimia seperti bahan-bahan cat dan logam, kafein, alcohol, diet tinggi protein, dan merokok.

3) Umur (proses menua) 

Didasarkan pada evidence based pada usia 50 thn kejadian 10-12 per 100.000 penduduk. meningkat pada usia 80 thn dengan kejadian 200-250 per 100.000 penduduk.

4) Cedera kraniocerebral

Prosesnya belum jelas.

5) Stress emosional

6) Efek samping dari obat-obatan yang dikonsumsi dalam jangka yang lama seperti obat hipertensi, jantung dan stroke.

Sirkuit ganglia basalis dan kortikospinal

berawal dari area asosiasi premotor dan suplemental serta somatosensorik (sekresi Ach) --> melintasi nukleus kaudatus (meneruskan Ach) --> menuju putamen --> ke globus palidus menuju 3 area (1) langsung ke nuklei ventroanterior dan ventrolateral pada talamus (2) menuju subtalamus terlebih dahulu atau (3) menuju substansia nigra dahulu (sekresi dopamin) --> dari talamus akan kembali ke korteks motorik primer serebri dan area asosiasi premotor dan suplemental --> ke formasio retikularis --> ke otot

Mekanisme:

adanya lesi pada substansia nigra yang berfungsi menghasilkan dopamin yang akan menuju puitamen dan nukleus kaudatus, membuat dopamin ini menjadi menurun. dopamin ini berfungsi dalam proses inbitor dari putamen dan nukleus kaudatus. sehingga proses eksitatorik akan melebihi inhibitorik sehingga terjadilah gejala-gejala pada manifestasi klinis.

Versi 1

LGP = Lateral globus pallidus

MGP = Medial globus pallidus

SNpc  = Substantia nigra pars compacta

SNpr = Substantia nigra pars reticulate

STN = Sub thalamic nucleus 

STR = Neostriatum

VA/VL = Ventro anterior and Ventro lateral nuclei of thalamus

The primary deficit in PD is a loss of the neurons in the substantia nigra pars compacta that provide dopaminergic innervation to the striatum. The basal ganglia can be viewed as a modulatory side loop that regulates the flow of information from the cerebral cortex to the motor neuron of spinal cord. The neostriatum is the principle input structure of the basal ganglia and receives excitatory glutamatergic input from the many areas of the cortex. The majority of neurons within the striatum are projection neuron that innervates other basal ganglia structure. A small but important subgroup of striatal neurons is interneurons that interconnect neurons within striatum but do not project beyond its border. Ach as well as neuropeptides are used as transmitter by the striatal interneurons. The outflow of the striatum proceeds along with 2 distinct routes, identified as direct and indirect pathways. The direct pathway is formed as neurons in the stratum that project directly to the output stages of the basal ganglia, substantia nigra pas reticulata (SNpr) and the medial globus pallidus (MGP); this in turn relay to the ventro-anterior and ventro-lateral thalamus, which provides excitatory input to the cortex. The neurotransmitter of both links of the direct pathway of GABA, which is inhibitory, so that net effect of stimulation of direct pathway at the level of striatum is to increase the excitatory outflow from the thalamus to the cortex. The indirect pathway is composed of the strital neurons that project to the lateral globus pallidus (LGP). This structure in turn innervates the subthalamic nucleus (STN), which provides outflow to the SNpr and MGP output stage. As in the direct pathway, 1st two links – projection from the striatum to the LGP and LGP to STN – use the inhibitory transmitter GABA; however the final link – the projection from to SNpr and MGP- is excitatory glutametrgic pathway. Thus the net effect of stimulating the indirect pathway at the level of striatum is to reduce the excitatory outflow from the thalamus to the cerebral pathway.

The key feature of this model of basal ganglia function, which accounts for the symptoms observed in PD as results of loss of dopaminergic neurons, is the differtial effect of dopamine on direct and indirect pathway. The dopaminergic neuron of the SNpc innervates all the parts of striatum; however the target striatal neurons express distinct types of dopamine receptors. The striatal neurons giving rise to the direct pathway express primarily the excitatory D1 dopamine receptor protein, while the striatal neurons forming the indirect pathway express primarily the inhibitory D2 type.

Thus dopaminergic in the striatum tends to increase the activity of the direct pathway and reduce the activity of indirect pathway, where as the depletion that occurs in PD has the opposite effect. The net effect of reduced dopaminergic input in PD is to increase markedly the inhibitory outflow from the SNpr and MGP to the thalamus and reduce excitation of the motor cortex.

This model of the basal ganglia function has important implication for the rational design and the use of the pharmacological agents in PD. First, it suggest that, to restore the balance of the system through stimulation of dopamine receptors, as well as he possibility of adverse effect that may be mediated by the STR is the principal input structure of the basal ganglia and receives excitatory, glutametrgic input from the many areas of cerebral cortex. Outflow from the STR proceeds along two routes. The direct pathway, from the STR to SNpr and MGP, uses the inhibitory transmitter GABA. The indirect pathway, from the STR through the LGP and the STN to the SNpr and MGP consists two inhibitory, GABAnergic links and one excitatory, glutametrgic. The SNpc provides the dopaminergic innervation to the strital neurons giving rise to both direct and indirect pathway, and regulates the relative activity of these two paths. The SNpr and MGP are the output structure of basal ganglia, and provide feedback to the cerebral cortex through the VA/VL.

The primary defect is the destruction of the dopaminergic neurons of the SNpc. The striatal neurons that form the direct pathway from the STR to the SNpr and MGP express primarily the excitatory D1 dopamine receptor, while the strital neurons that project to the LGP and form the indirect pathway express the inhibitory D2 dopamine receptor. Thus, loss of dopaminergic input to the stritam has a differtial effect on the two outflow pathways; the direct pathway to the SNpr and MGP is less active, while the activity in the indirect pathway is increased. The net effect is that neurons in the SNpr and MGP become more active. This leads to increased inhibition of the VA/VL thalamus and reduced excitatory input to the cortex. This line, normal pathway activity; thick line, increased pathway activity in PD; dashed lines, reduced pathway activity in PD.

Versi 2

The thick arrows mean and excessive stimulus and lighter arrows mean a deficient stimulus.

In Parkinson Disease neurons in Substantia Nigra Compacta (SNc) are lost. They cannot excitate certain neurons of the Putamen and cannot inhibit others. This results in an excessive inhibition by Putamen of Globus Pallidus Externus (GPe) which cannot inhibit Sub-Talamic-Nucleus (STN) which therefore activates Globus Pallidus Internus (GPi) and Substantia Nigra Reticulata (SNr) too strongly. GPi and SNr inhibit Thalamus which activates the cortex to start a movement. Therefore the cortex does not receive a strong signal to start the movement and this is the main cause of slowness of movement, postural instability and rigidity. The causes of tremor are not well understood and are subject of intense research.

Manifestasi klinis

1. Rigidity, Adanya kekakuan pada banyak otot tubuh termasuk otot wajah sehingga disebut wajah topeng (mask face)

2. Tremor involunter pada area yang istirahat.
3. Akinesia , kesulitan memulai gerakan.inesia , kesulitan memulai gerakan.