Epilepsi Dan Penanganannya

EPILEPSIBerasal dari kata Epilambanein = serangan

1. Primer ( idiopatic ) = # penyebabnya- Ggn imbangan cairan / zat kimia dlm sel saraf

2. Sekunder ( ada kel struktur jar otak )- dpt sejak lahir, kerusakan saat/setelah lahir

1. saat dlm kandung (obatan,infeksi, alkohol,radiasi)2. Saat kelahiran ( hipoksia,Forcep,facum )3. Cedera kepala 4. Tumor ( tidak umum )5. Penyumbatan pembuluh darah otak )6. Radang / infeksi ( mengitis,encfalitis )7. Peny.turunan

( FKU,Tuberosklerosis,neurofibromatois )8. Diturunkan dari orang tua

Etiologi

Penyebab spesifik epilepsi

Faktor pencetus

Kurang tidur ( Mgg sel otak )Sres emosionalInfeksi ( demam )Obat-obatan (TAD,Setadin,fenotiasin ) Alkohol ( menghilangkan GABA )Perubahan hormonal (Estrogen )Terlalu lelah ( Co2 )Foto sensitif ( flas ligh,TV, Bising )

Mekanisme dasar serangan epilepsi

“Lepas muatan listrik neuron otak yg berlebihan”

1. Ggn fs neuron dan transmisi sinaps

2. Potensial membran sel

Keadaan Polarisasi ( normal ) diatur olehSodium pump

Ion ( Na,K,Cl,Ca ) bekerja di membran.

Ion Ektra sel Intra sel

K rendah tinggi

Na,Ca,Cl Tinggi Rendah

Depolarisasi

KNaCaCl

PolarisasiNa

Ca

K tinggi Na rendahCa rendahCl rendah

Na

Ca

Cl

Klasifikasi serangan epilepsiI. Serangan parsial ( fokal,lokal ) kesadaran tdk berubahA. Serangan parsial sederhana ( kesadaran tetap baik1. dgn gej motorik2. dgn gej somatosensorik atau sensorik khusus3. dgn gej. Autonom4. dgn gej psikis.B. Serangan parsial kompleks( kesadaran menurun )1. Awalnya parsial sederhana berkemb jadi penrn kesadaran

a. tanpa gambaran lainnyab. dgn gambaran seperti A 1-4c. dgn automatismus

2. dengan penurunan kesadaran sejak awitana. tanpa gambaran lainnyab. dgn gambaran seperti A 1-4c. dgn automatismus

II. Serangan umum ( konvulsi atau non konvulsi )A. Absence C Absence tak khasB. Mioklonik D. Klonik E. Tonik F. Tonik-klonik G. Atonik

III. Serangan epilepsi tak terklasifikasikan ( rith mata,mengunyah, gerk berenang

Cellular level– Sodium channels– Calcium channels– Potassium channels

Pathophysiology of Seizure

Synaptic level Glutamate

(excitatory) GABA

(inhibitory)


B-Slide B-Slide 88

Epilepsy—Basic Neurophysiology Causes of Hyperexcitability:

– excitatory post synaptic potentials (EPSPs)

– inhibitory post synaptic potentials (IPSPs)

– changes in voltage gated ion channels

– alteration of local ion concentrations

B-Slide B-Slide 99

Epilepsy—Basic Neurophysiology Major Neurotransmitters in the brain:

Glutamate– GABA

– Acetylcholine

– Dopamine

– Serotonin

– Histamine

– Other modulators: neuropeptides, hormones

B-Slide B-Slide 1010

Cellular Mechanisms of Cellular Mechanisms of Seizure GenerationSeizure Generation

Excitation (too much) – Ionic—inward Na+, Ca++ currents– Neurotransmitter—glutamate, aspartate

Inhibition (too little)– Ionic—inward CI-, outward K+ currents– Neurotransmitter—GABA

annamaritagelgelsinardja-epilepsipalembang08 11

Vezzani A,2005

annamaritagelgelsinardja-epilepsipalembang08 12

Abbas K,2007


Epilepsy—Epilepsy—GlutamateGlutamate The brain’s major excitatory neurotransmitter

Two groups of glutamate receptors– Ionotropic—fast synaptic transmission

• Three subtypes – AMPA, kainate, NMDA• Glutamate-gated cation channels

– Metabotropic—slow synaptic transmission• G-protein coupled, regulation of second

messengers (cAMP and phospholipase C)• Modulation of synaptic activity

Epilepsy—GlutamateEpilepsy—Glutamate

Modulation of glutamate receptors– Glycine, polyamine sites, Zinc, redox site


Epilepsy—GlutamateEpilepsy—Glutamate

Diagram of the various glutamate receptor subtypes and locationsFrom Takumi et al, 1998


Epilepsy—GABAEpilepsy—GABA Major inhibitory neurotransmitter in the

CNS Two types of receptors

– GABAA—post-synaptic, specific recognition sites, linked to CI- channel

– GABAB —presynaptic autoreceptors that reduce transmitter release by decreasing calcium influx, postsynaptic coupled to G-proteins to increase K+ current

CORTICAL STRUCTURE OF PARTICULAR IMPORTANCE IN GENERATION OF EPILEPTIC SYNDROMES

• HUMAN CEREBRAL CORTEX HAS 3-6 CELL LAYERS• HIPPOCAMPUS PART OF ARCHIPALLIUM 3 CELL LAYERS:

DENTATE GYRUS, SUBICULUM ,AMMON HORN• PRINCIPAL NEURON—EXCITATORY ON POST SYNAPTIC,

PROJECTION TO DISTANT AREAS• INTERNEURON :INHIBITORY, LOCAL CIRCUITRY TO

PRINCIPAL OR OTHER INTERNEURON


Epilepsy—GABAEpilepsy—GABA

Diagram of the GABAA receptor

From Olsen and Sapp, 1995

GABA siteGABA site

Barbiturate siteBarbiturate site

BenzodiazepineBenzodiazepine sitesite

Steroid siteSteroid site

Picrotoxin sitePicrotoxin site

Cellular level– Sodium channels– Calcium channels– Potassium channels


Synaptic level Glutamate

(excitatory) GABA

(inhibitory)



Normal CNS FunctionNormal CNS Function

Excitation Inhibition

glutamate,aspartate

GABA

Modified from White, 2001

Classification of AEDsClassification of AEDs MECHANISMS OF ACTIONMECHANISMS OF ACTION

Pharmacology & Therapeutics 113 (2007) 165–183

1. Na+ channel blockers

2. GABAergics

3. Ca++ channel blockers

4. EAA inhibition


Hippocampal AnatomyHippocampal Anatomy

From Chang and Lowenstein, 2003From Chang and Lowenstein, 2003


Basic Mechanisms Underlying Basic Mechanisms Underlying Seizures and EpilepsySeizures and Epilepsy

Feedback and feed-forward inhibition, illustrated via cartoon and schematic of simplified hippocampal circuit

Babb TL, Brown WJ. Pathological Findings in Epilepsy. In: Engel J. Jr. Ed. Babb TL, Brown WJ. Pathological Findings in Epilepsy. In: Engel J. Jr. Ed. Surgical Treatment of the Epilepsies. New York: Raven Press 1987: 511-540.Surgical Treatment of the Epilepsies. New York: Raven Press 1987: 511-540.


Neuronal (Intrinsic) Factors Modifying Neuronal (Intrinsic) Factors Modifying Neuronal ExcitabilityNeuronal Excitability

Ion channel type, number, and distribution

Post-translational modification of channels (phosphorylation, etc).

Activation of second-messenger systems that affect channel function (e.g. G proteins)

Modulation of gene expression of ion channels


Epilepsy and ChannelopathiesEpilepsy and Channelopathies Inherited

Voltage-gated ion channel mutations Ligand-gated ion channel (neurotransmitter receptor)

mutations Different mutations in the same gene can result in

radically different types of seizures and epilepsy Acquired

Auto-immune (anti-potassium channel antibodies) Changes in channel expression after seizures


Ion Channel & Neurotransmitter Ion Channel & Neurotransmitter Receptors Mutated in Epilepsy -Receptors Mutated in Epilepsy -

Voltage-gated Potassium Channel Mutations• KCNQ2, KCNQ3

– Benign Familial Neonatal Convulsions (BFNC)• KCND2

– Temporal Lobe Epilepsy (TLE)• KCNMA1

– Generalized Epilepsy with Paroxysmal Dyskinesia (GEPD)


Synaptic Factors Modifying Synaptic Factors Modifying Neuronal ExcitabilityNeuronal Excitability

Alterations in expression of transmitter gated ionotropic channels

Post-translational changes in neurotransmitter channels

Remodeling of synapse location or configuration (deafferentation, sprouting)

Changes in gap-junction synaptic function


Non-synaptic (Extrinsic) Factors Non-synaptic (Extrinsic) Factors Modifying Neuronal ExcitabilityModifying Neuronal Excitability

Changes in extracellular ion concentration

Changes in extracellular space

Modulation of transmitter metabolism or uptake by glial cells


Normal Rat Dentate Gyrus Epileptic Rat Dentate Gyrus

Epileptic Human Dentate Gyrus

Cavazos and Cross, 2006

Timm Stain Showing Mossy Fiber Timm Stain Showing Mossy Fiber SproutingSprouting

Timm stain Timm stain (black) for (black) for mossy fiber mossy fiber terminals terminals containing zinccontaining zinc

SIMPULAN PENGGUNAAN OBAT ANTI EPILEPSI Epileptic seizures

General Partial

Absences Myoclonic Bilateral tonic-clonic

Infn spasm Lennox juv. myoclonic gastaut

Sod valproat ACTH Sod valproat Sod valproat Carbamazepin Clonazepam Vigabatrin lamotrigin luminal dilantin Ethosuksimid clonazepam Sod Valproat luminal

VigabatrinLamotriginGabapentin

Epilepsi jenis umum

1. Infantile spasme- 6 -12 bulan- obat yang sangat efektif ACTH 20 – 50 IU Im sekali sehari- hasil terlihat sesudah 2-3 minggu kemudian- Jika ACTH gagal Coba Prednisolon 1 - 2 mg / kg / hari oral

( 4 minggu)- Jika masih gagal ( clonazepam,Nitrazepam,Sod Valproat, vigabatrine)

2. Lennox Gastaut ( Myoclonic epilepsi )- 1,5 – 3 tahun- Asam Valproat, Clonazepam,Lamotrigin- Biasanya umur 5 – 15 tahun- Ethosuximide, clonazepam, sodium valproate

3. Absensi epilepsi anak dan bayi- Biasanya umur 5 – 15 tahun- Ethosuximide, clonazepam, sodium valproate

4. Epilepsi myoclonic juvenilis.- Remaja dan dewasa muda- kejang otot pagi hari hari, serangan 2 jam setelahjalan - sangat responsif dengan carbamsepin- Vodium valproat, Clonazepam, Luminal, Primidon

5. Tonic clonic ( epilepsi umum )- Ditemukan pada semua umur umumya18 tahun- obat efektif :Carbamasepin, phenitoin, Asam valproat

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Epilepsi Dan Penanganannya