Gsbakti Rusip, MD

Professor of Physiology

gusbakti12

Kejang bukan suatu penyakit, tetapi gejala dari

suatu atau beberapa penyakit manifestasi
dari lepasnya muatan listrik yang berlebihan di
sel-sel neuron otak terganggu fungsinya
akibatnya kelainan anatomi-fisiologi, biokimia,
atau gabungankeduanya.

gusbakti12

 Secara pasti terjadi selama kejang

tergantung kepada bagian otak yang
memiliki muatan listrik abnormal
Jika hanya melibatkan daerah yang sempit
penderita hanya merasakan bau atau
rasa yang aneh
jika melibatkan daerah yang luas terjadi
sentakan dan kejang otot di seluruh tubuh,
juga perubahan kesadaran, kehilangan
kesadaran, kehilangan pengendalian otot
atau kandung kemih dan menjadi linglung
gusbakti12

Kejang ggn sistem saraf terjadi

akibat lepas muatan listrik abnormal,
mendadak dan berlebihan
Manifestasi klinis khas berlangsung
secara intermitten dapat berupa gangguan
kesadaran, tingkah laku, emosi, motorik,
sensorik, dan atau otonom yang
disebabkan oleh lepasnya muatan listrik
yang berlebihan di neuron otak
Status epileptikus terjadi lebih dari 30
menit atau kejang berulang lebih dari 30
menit tanpa disertai pemulihan kesadaran.
gusbakti12

Pelepasan muatan neuron-neuron otak

mendadak , tdk terkontrol perubahan
fungsi otak
Terjadi sewaktu neuron-neuron serebelum
dlm keadaan hipereksitasi (mudah
mengalami depolarisas)
Memilki resting potensial lebih rendah
dari normal atau kehilang hubungan
inhibitorik akibatnya kelompok neuron
dekat dgn potensial ambang utk
melepaskan potensial aksi neuron disbt
FOKUS EPILEPTOGRNIK
gusbakti12

Fokus epileptogenik melepaskan

potensial aksi menyebar ke sekitar ke sisi
(kejang parsial) atau kedua sisi otak
(korteks,sukorteks dan btg otak)
KEJANG GENERALISATA
Sewaktu kejang berlanjut neuron2
inhibitorik diotak melepaskan muatan
neuron melambat kmd berhenti
Kejang kedua atau ketiga, kmd sadar
status epileptikus
gusbakti12

Dasar terjadinya peningkatan aktifitas

listrik yang berlebihan pada neuronneuron dan mampu secara berurutan
merangsang sel neuron lain secara
bersama-sama melepaskan muatan
listriknya

gusbakti12

Disebabkan oleh;
kemampuan membran sel sebagai
pacemaker neuron untuk melepaskan
muatan listrik yang berlebihan;
berkurangnya inhibisi oleh
neurotransmitter asam gama amino
butirat [GABA]; atau
Meningkatnya eksitasi sinaptik oleh
transmiter asam glutamat dan aspartat
melalui jalur eksitasi yang berulang
gusbakti12

Disebabkan oleh;
Status epileptikus terjadi oleh karena
proses eksitasi yang berlebihan
berlangsung terus menerus, di samping
akibat ilnhibisi yang tidak sempurna

gusbakti12

Yang tepat belum diketahui

Ada beberapa faktor fisiologik
kejang
Harus ada faktor pencetus
ledakan discharge (sistem hambatan
GABAergik)
Perjalanan discharge kejang
tergantung eksitasi sinap
glutamaterik
gusbakti12

Bukti baru eksitasi

neurotransmiter asam amino
(glutamat, aspartat) berperan
menghslkan eksitasi neuron bekerja
pada reseptor tertentu
Kejang dpt berasal dari kematian
neuron meningkatkan
hiperesksitabel baru dpt
menimbulkan kejang
gusbakti12

Mis: Lesi lobus temporalis ( glioma,

hematoma, malformasi arteriovenos
us) bila jar abnormal scr bedah
kejang berhenti

gusbakti12

Kelainan polarisasi (polarisasi

berlebihan, hipopolarisasi, atau
selang waktu dalamrepolarisasi)
yang disebabkan oleh kelebihan
asetil kolin atau defisiensi asam
gama-aminobutirat (GABA)

gusbakti12

Ketidakseimbang anion mengubah

keseimbangan asam-basa atau
elektrolit mengganggu homeostatis
kimiawi neuron terjadi kelainan
pada depolarisasi neuron
Gangguan keseimbangan
menyebabkan peningkatan berlebihan
neurotransmittereksitatorik atau
deplesi neurotransmitter inhibitorik
gusbakti12

Perubahan metabolic selama dan

setelah kehang meningkatnya
kebutuhan energy akibat hiperaktivitas
neuron
Kebutuhan metabolic lepas muatan
listrik sel-sel saraf motorik dapat
meningkat menjadi 1000 perdetik
Aliran darah otak meningkat, juga
respirasi dan glikolisis jaringan

gusbakti12

Asetilkolin muncul di cairan

serebrospinalis (CSS) selama dan
setelah kejang
Asam glutamate mengalami deplesi
selama aktifitas kejang
Secara umum, tidak dijumpai kelainan
yang nyata pada autopsy
Bukti histopatologikhipotesis bahwa
lesi lebih bersifat neurokimiawi bukan
strukturnya
gusbakti12

Belum ada faktorpatologik yang

secara konsisten ditemukan
Kelainan fokal pada metabolism kalium
dan asetilkolin dijumpai diantara kejang
Focus kejang nampaknya sangat peka
terhadap asetilkolinn
neurotransmitter fasilitatorik focusfokus tersebut lambat mengikat dan
menyingkirkan asetilkolin.
gusbakti12

Tergantung sumber lepas muatan

listrik
Partial (fokal)
Kejang umum (sentrencefalik)

Kejang fokal lepas muatan listrik dari

daerah fokus di otak unilateral temporal
Biasanay akibat Trauma,tumor,lesi
vaskulara atau kel.kongenital
Kelanjutannya GENERALISATA
gusbakti12

Kejang umum primer lepas muatan listrik

dlm struktur grs tengah otak (sep talamus,
btg otak) tdk ada aura (Lesi diotak
tengah,thalamus, dan korteks serebellum dan
batang otak umumnya tidak memicu kejang)
Kejang motorik utama individu normal sekunder
akibat lepas obat atau faktor metabolik (sep
uremia,hipoglikemia)
Kejang fokal atau umum atau reaksi stres bukan
kejang epilepsi

gusbakti12

aura, yang merupakan sensasi yang

tidak biasa dari penciuman,rasa atau
penglihatan atau perasaan yang kuat
bahwa akan terjadi kejang
Sensasimenyenangkan dan tidak
menyenangkan
Sekitar 20% penderita epilepsi mengalami
aura
Kejang berlangsung selama 2-5 menit.
Sesudahnya penderita bisa merasakan
sakitkepala, sakit otot, sensasi yang tidak
biasa, linglung dan kelelahan
Biasanya tidakdapat mengingat apa yang
gusbakti12

Kebutuhan O2 meningkat > 200% tdk

dipenuhi hipoksia kerusakan otak
Kejang dpt terjadi setiap orang yg
mengalami
hipoksemia berat (penurunan O2 drh)
hipoglikemia (penurunan glukosa drh)
Asidemia (peningkatan asam dlm drh)
Alkalemia (penurunan asaam dlm drh)
Dehidrasi, intosikasi air, demam tinggi
Penghentian obat, toksemia pd kehamilan

gusbakti12

Kejang akibat ggn bersifat metabolik

reversibel bila pencetusnya
dihilangkan
Sebgn org memp ambang kejang rendah
rentang mengalami kejang faktor
genetik kejang

gusbakti12

Seizures
Partial Seizures
Simple Partial
Complex Partial

Generalized
Seizures

gusbakti12

Absence
Atypical Absence
Tonic
Clonic
Tonic-Clonic
Atonic
Myoclonic
Mixed Forms

gusbakti12

Basic mechanism of neuronal excitability

is the action potentialnet positive
inward ion flux

gusbakti12

Hyperexcitable state
Increased excitatory neurotransmission
Decreased inhibitory neurotransmission
Alteration in voltage gated ionic channels
Intra/extracellular ionic alterations in favor of
excitation

gusbakti12

Neuronal circuits
Axonal conduction
Synapic transmission

Both of these processes employ ionic

channels
Voltage gated channels
Ligand gated channels

gusbakti12

Depolarizing conductances
Excitatory
Inward sodium and Ca currents

Hyperpolarizing conductances
Inhibitory
Primarily mediated by potassium channels

gusbakti12

Excitatory transmission

Glutamate (NMDA) the principal excitatory

neurotransmitter

Inhibitory transmission

GABA the principal inhibitory neurotransmitter

gusbakti12

The brains major excitatory

neurotransmitter
Two groups of glutamate receptors
Ionotropic: fast synaptic transmission. NMDA,
AMPA, kinate. Gated Ca and Na channels
Metabotropic: slow synaptic transmission.
Modulation of second messengers, e.g.
Inositol, cAMP

gusbakti12

The major inhibitory neurotransmitter in

the CNS
GABA A: presynaptic, mediated by Cl channels
GABA B: postsynaptic, mediated by K currents

gusbakti12

Both Glutamate and GABA require active

reuptake to be cleared from the synaptic
left
Factors that interfere with transporter
function also activate or suppress
epileptiform activity

gusbakti12

Excitation:
Ionic: inward currents of Na, Ca
Neurotransmitter: Glutamate, Aspartate

Inhibition:
Ionic: inward Cl, outward K
Neurotransmitter: GABA

gusbakti12

Ion channel type, number and

distribution
Biochemical modification of receptors
Activation of second messenger systems
Modulation of gene expression

gusbakti12

Changes in extracellular ionic

concentrations
Remodeling of synaptic location
Modulation of transmitter metabolism or
uptake

gusbakti12

Basically inward flux of Na and Ca, and

outward flux of K
Endogenous factors:

Genetic predisposition

Environmental factors:
Trauma or ischemia
convert non-bursting neurons to potentially
epileptogenic populations

gusbakti12

The process by which normal healthy

tissue is transformed into a relatively
permanent epileptic state
1.

2.

Hyperexcitability: The tendency of a neuron

to discharge repetitively to a stimulus that
normally causes a single action potential
Abnormal synchronization: The property of a
population of neurons to discharge together
independently.

gusbakti12

Recurrent excitatory synapses

Electronic coupling by gap junction
Electrical field and ephaptic effects
Changes in extracellular ion
concentrations
Different kinds of seizures are probably
related to different combinations of the
above
gusbakti12

Roles of channels and receptors in normal and epileptic firing

Channel or
receptor

Role in normal neuronal function

Possible role in epilepsy

Voltage-gated
Na+ channel

Sub-threshold EPSP; action potential upstroke

Repetitive action potential firing

Voltage-gated K+
channel

Action potential down-stroke

Abnormal action potential repolarization

Ca2+-dependent
K+ channel

AHP following action potential; sets

refractory period

Limits repetitive firing

Voltage-gated
Ca2+ channel

Transmitter release; carries depolarizing

charge from dendrites to soma

Excess transmitter release; activates

pathophysiological intracellular processes

Non-NMDA
receptor (ie,
AMPA)

Fast EPSP

Initiates PDS

NMDA receptor

Prolonged, slow EPSP

Maintains PDS; Ca2+ activates

pathophysiological intracellular processes

GABAA receptor

IPSP

Limits excitation

GABAB receptor

Prolonged IPSP

Limits excitation

Electrical
synapses

Ultra-fast excitatory transmission

Synchronization of neuronal firing

Na+-K+ pump

Restores ionic balance

Prevents K+-induced depolarization

gusbakti12

Examples of specific pathophysiological defects leading to epilepsy

Level of brain
function

Condition

Pathophysiologic mechanism

Neuronal network

Cerebral dysgenesis, post-traumatic scar,

mesial temporal sclerosis (in TLE)

Altered neuronal circuits: Formation of

aberrant excitatory connections ("sprouting")

Neuron structure

Down syndrome and possibly other

syndromes with mental retardation and
seizures

Abnormal structure of dendrites and dendritic

spines: Altered current flow in neuron

Neurotransmitter
synthesis

Pyridoxine (vitamin B6) dependency

Decreased GABA synthesis: B6, a co-factor for

GAD

Neurotransmitter
receptors:
Inhibitory

Angelman syndrome, juvenile myoclonic

epilepsy

Abnormal GABA receptor subunit(s)

Neurotransmitter
receptors:
Excitatory

Non-ketotic hyperglycinemia

Excess glycine leads to activation of NMDA

receptors

Synapse
development

Neonatal seizures

Many possible mechanisms, including the

depolarizing action of GABA early in
development

Ion channels
channelopathies

Benign familial neonatal convulsions

Potassium channel mutations: Impaired

repolarization

gusbakti12

Major source of input the entorhinal

cortex by way of perforant path to the
dentate gyrus
Dentate gyrus by way of mossy fibers
connects to CA3
CA3 connects to CA1 through Schaffer
collateral pathway

gusbakti12

gusbakti12

In sections from epileptic areas, neurons

from specific regions (CA1) are lost or
damaged
Synaptic reorganization (mossy fiber
sprouting) causes recurrent
hyperexcitability
Variety of brain insults can lead to the
phenomena of mossy fiber sprouting

Trauma, hypoxia, infections, stroke,

gusbakti12

Excitatory axonal sprouting

Loss of inhibitory interneurons
Loss of excitatory interneurons driving
inhibitory neurons

gusbakti12

Graphical depiction of cortical electrical

activity recorded from the scalp
High temporal resolution but poor spatial
resolution
The most important electrophysiological
test for the evaluation of epilepsy

gusbakti12

Physiological Basis of the

EEG

Extracellular dipole generated

by excitatory post-synaptic
potential at apical dendrite of
pyramidal cell

gusbakti12

Brain electrical activity can be recorded

Pyramidal cells all have the same polarity and
orientation
Many cells are synchronously activated

gusbakti12

Physiological Basis of the

EEG (cont.)

gusbakti12

Electrical field
generated by similarly
oriented pyramidal
cells in cortex (layer
5) and detected by
scalp electrode

Seizures/epilepsy
Altered consciousness
Sleep
Focal and diffuse alteration in brain
function

gusbakti12

Recording the electrical activity of the

brain, mostly from the scalp
Frequency of waveforms
Delta 0 to 4 Hz
Theta 4 to 8 Hz
Alpha 8 to 12 Hz
Beta More than 12 Hz

Particularly helpful in the analysis of

seizures and epilepsy

gusbakti12

EEG Frequencies
EEG Frequencies
A) Fast activity
B) Mixed activity
C) Mixed activity
D) Alpha activity (8 to 13 Hz)
E) Theta activity (4 to under 8
Hz)
F) Mixed delta and theta
activity
G) Predominant delta activity
(<4 Hz)
Not shown: Beta activity (>13 Hz)

gusbakti12

Hallmark of focal seizures is the interictal

spike on EEG
Cellular correlate of EEG spike is the
paroxysmal depolarization shift (PDS)
A PDS is an event occurring in a single
neuron

Initial depolarization intitated by AMPA, then

maintained by NMDA receptors

gusbakti12

gusbakti12

Intracellular and
extracellular events
of the paroxysmal
depolarizing shift
underlying the
interictal
epileptiform spike
detected by surface
EEG

Ayala et al., 1973

gusbakti12

gusbakti12

Absence epilepsy
Generalized spike and wave discharges on
EEG reflect phase locked oscillations between
excitation and inhibition in thalamocortical
networks
aberrations of oscillatory rhythms that are
normally generated during sleep by circuits
connecting the cortex and thalamus

Generalized tonic clonic seizures

gusbakti12

GABAergic neurons of the nucleus

reticularis thalami as pacemakersthe
thalamocortical loop
Activation of transient Ca channels (T
channels) and GABA B mediated
hyperpolarization3-4 Hz oscillations
Ethosuximide suppresses the T-current

gusbakti12

gusbakti12

gusbakti12

Mechanisms unclear, buy may include

voltage-, calcium-, or neurotransmitterdependent potassium channels

gusbakti12

Certain forms of epilepsy are caused by

particular events
50% of brain injury patients develop epilepsy
after a silent period
epileptogenic process involves a gradual
transformation of the neural network over
time

gusbakti12

Kindling: repeated administration of

electrical stimulus or convulsant drugs
Initially each stimulus evokes a progressively
longer afterdischarge and a more intense
seizure
Once fully kindled, each successive stimulus
evokes a stimulation-induced clinical seizure,
and in some instances, spontaneous seizures

gusbakti12