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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
04/11/23 Fitri Octaviana
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 rendah Na tinggiCa tinggiCl 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)
Pathophysiology of Seizure
B-Slide B-Slide 1010
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 1111
Epilepsy—Basic Neurophysiology Major Neurotransmitters in the brain:
Glutamate– GABA
– Acetylcholine
– Dopamine
– Serotonin
– Histamine
– Other modulators: neuropeptides, hormones
B-Slide B-Slide 1212
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 13
Vezzani A,2005
annamaritagelgelsinardja-epilepsipalembang08 14
Abbas K,2007
B-Slide B-Slide 1616
EpilepsyEpilepsy——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
B-Slide B-Slide 1818
Epilepsy—GlutamateEpilepsy—Glutamate
Diagram of the various glutamate receptor subtypes and locationsFrom Takumi et al, 1998
B-Slide B-Slide 1919
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
B-Slide B-Slide 2121
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
Pathophysiology of Seizure
Synaptic level Glutamate
(excitatory) GABA
(inhibitory)
Pathophysiology of Seizure
B-Slide B-Slide 2525
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
B-Slide B-Slide 2828
Hippocampal AnatomyHippocampal Anatomy
From Chang and Lowenstein, 2003From Chang and Lowenstein, 2003
B-Slide B-Slide 2929
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.
B-Slide B-Slide 3030
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
B-Slide B-Slide 3131
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
B-Slide B-Slide 3232
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)
B-Slide B-Slide 3333
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
B-Slide B-Slide 3434
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
B-Slide B-Slide 3535
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