EPILEPSI

Berasal dari kata Epilambanein = serangan

Etiologi
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
Penyebab spesifik epilepsi 1. 2. 3. 5. 6. 7. 8. saat dlm kandung (obatan,infeksi, alkohol,radiasi) Saat kelahiran ( hipoksia,Forcep,facum ) Cedera kepala 4. Tumor ( tidak umum ) Penyumbatan pembuluh darah otak ) Radang / infeksi ( mengitis,encfalitis ) Peny.turunan ( FKU,Tuberosklerosis,neurofibromatois ) Diturunkan dari orang tua

Faktor pencetus
Kurang tidur ( Mgg sel otak ) Sres emosional Infeksi ( 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
Ion Ektra sel Intra sel K rendah tinggi Na,Ca,Cl Tinggi Rendah

Keadaan Polarisasi ( normal ) diatur oleh Sodium pump Ion ( Na,K,Cl,Ca ) bekerja di membran.

Depolarisasi
K K Na Ca Cl tinggi rendah rendah rendah

Na Ca Cl

Polarisasi
Na Ca Na Ca Cl

Klasifikasi serangan epilepsi

I. Serangan parsial ( fokal,lokal ) kesadaran tdk berubah A. Serangan parsial sederhana ( kesadaran tetap baik 1. dgn gej motorik 2. dgn gej somatosensorik atau sensorik khusus 3. dgn gej. Autonom 4. dgn gej psikis. B. Serangan parsial kompleks( kesadaran menurun ) 1. Awalnya parsial sederhana berkemb jadi penrn kesadaran a. tanpa gambaran lainnya b. dgn gambaran seperti A 1-4 c. dgn automatismus 2. dengan penurunan kesadaran sejak awitan a. tanpa gambaran lainnya b. dgn gambaran seperti A 1-4 c. dgn automatismus II. Serangan umum ( konvulsi atau non konvulsi ) A. Absence C Absence tak khas B. Mioklonik D. Klonik E. Tonik F. Tonik-klonik G. Atonik III. Serangan epilepsi tak terklasifikasikan ( rith mata,mengunyah, gerk berenang

Pathophysiology of Seizure
Cellular level
Sodium channels Calcium channels Potassium channels
Synaptic level Glutamate (excitatory) GABA (inhibitory)

Pathophysiology of Seizure

EpilepsyBasic 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 8 B-Slide

EpilepsyBasic Neurophysiology
Major Neurotransmitters in the brain: Glutamate
GABA

Acetylcholine
Dopamine Serotonin Histamine Other modulators: neuropeptides, hormones
B-Slide 9

Cellular Mechanisms of Seizure Generation

Excitation (too much) Ionicinward Na+, Ca++ currents Neurotransmitterglutamate, aspartate Inhibition (too little) Ionicinward CI-, outward K+ currents NeurotransmitterGABA
B-Slide 10

Vezzani A,2005
annamaritagelgelsinardjaepilepsipalembang08 11

Abbas K,2007
annamaritagelgelsinardjaepilepsipalembang08 12

 The brains major excitatory neurotransmitter Two groups of glutamate receptors

Ionotropicfast synaptic transmission
Three subtypes AMPA, kainate, NMDA Glutamate-gated cation channels

EpilepsyGlutamate

Metabotropicslow synaptic transmission

G-protein coupled, regulation of second messengers (cAMP and phospholipase C) Modulation of synaptic activity

B-Slide 14

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

EpilepsyGlutamate

Diagram of the various glutamate receptor subtypes and locations

From Takumi et al, 1998

B-Slide 16

 Major inhibitory neurotransmitter in the CNS Two types of receptors

GABAApost-synaptic, specific recognition sites, linked to CI- channel GABAB presynaptic autoreceptors that reduce transmitter release by decreasing calcium influx, postsynaptic coupled to Gproteins to increase K+ current
B-Slide 17

EpilepsyGABA

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 NEURONEXCITATORY ON POST SYNAPTIC, PROJECTION TO DISTANT AREAS INTERNEURON :INHIBITORY, LOCAL CIRCUITRY TO PRINCIPAL OR OTHER INTERNEURON

EpilepsyGABA
GABA site Barbiturate site

Benzodiazepine site Steroid site Picrotoxin site

Diagram of the GABAA receptor

From Olsen and Sapp, 1995
B-Slide 19

Pathophysiology of Seizure
Cellular level
Sodium channels Calcium channels Potassium channels
Synaptic level Glutamate (excitatory) GABA (inhibitory)

Pathophysiology of Seizure

Normal CNS Function

Excitation glutamate, aspartate

Inhibition
GABA
Modified from White, 2001
B-Slide 23

Classification of AEDs
1. 2. 3. 4. Na+ channel blockers GABAergics Ca++ channel blockers EAA inhibition
MECHANISMS OF ACTION

Pharmacology & Therapeutics 113 (2007) 165183

Hippocampal Anatomy

B-Slide 26

From Chang and Lowenstein, 2003

Basic Mechanisms Underlying Seizures and Epilepsy

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

B-Slide 27 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.

Neuronal (Intrinsic) Factors Modifying Neuronal 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
B-Slide 28

Epilepsy 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
B-Slide 29

Ion Channel & Neurotransmitter 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)

B-Slide 30

Synaptic Factors Modifying Neuronal 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

B-Slide 31

Non-synaptic (Extrinsic) Factors Modifying Neuronal Excitability

Changes in extracellular ion concentration

Changes in extracellular space

Modulation of transmitter metabolism or uptake by glial cells
B-Slide 32

Timm Stain Showing Mossy Fiber Sprouting

Timm stain (black) for mossy fiber terminals containing zinc

Normal Rat Dentate Gyrus

Epileptic Rat Dentate Gyrus Epileptic Human Dentate Gyrus

Cavazos and Cross, 2006

B-Slide 33

SIMPULAN PENGGUNAAN OBAT ANTI EPILEPSI

Epileptic seizures General Absences Myoclonic Bilateral tonic-clonic Partial

Infn spasm Lennox gastaut

Sod valproat Clonazepam Ethosuksimid ACTH Sod valproat Vigabatrin lamotrigin

juv. myoclonic

Sod valproat luminal clonazepam

Carbamazepin dilantin Sod Valproat luminal Vigabatrin Lamotrigin Gabapentin

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

2.

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