Gsbakti Rusip, MDProfessor of Physiology

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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.

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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

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.

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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

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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

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Dasar terjadinya peningkatan aktifitas listrik yang berlebihan pada neuron-neuron dan mampu secara berurutan merangsang sel neuron lain secara bersama-sama melepaskan muatan listriknya

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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

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Disebabkan oleh; Status epileptikus terjadi oleh karena

proses eksitasi yang berlebihan berlangsung terus menerus, di samping akibat ilnhibisi yang tidak sempurna

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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

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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

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Mis: Lesi lobus temporalis ( glioma, hematoma, malformasi arteriovenos us) bila jar abnormal scr bedah kejang berhenti

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

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Ketidakseimbang anion mengubah keseimbangan asam-basa atau elektrolit mengganggu homeostatis kimiawi neuron terjadi kelainan pada depolarisasi neuron

Gangguan keseimbangan menyebabkan peningkatan berlebihan neurotransmitter eksitatorik atau deplesi neurotransmitter inhibitorik

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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

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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 histopatologik hipotesis bahwa lesi lebih bersifat neurokimiawi bukan strukturnya

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Belum ada faktor  patologik yang secara konsisten ditemukan

Kelainan fokal pada metabolism kalium dan asetilkolin dijumpai diantara kejang

Focus kejang nampaknya sangat peka terhadap asetilkolinn neurotransmitter fasilitatorik focus-fokus tersebut lambat mengikat dan menyingkirkan asetilkolin.

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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 GENERALISATAgusbakti12

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

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aura, yang merupakan sensasi yang tidak biasa dari penciuman,rasa atau penglihatan atau perasaan yang kuat bahwa akan terjadi kejang

Sensasimenyenangkan dan tidak menyenangkanSekitar 20% penderita epilepsi mengalami auraKejang berlangsung selama 2-5 menit. Sesudahnya penderita bisa merasakan sakitkepala, sakit otot, sensasi yang tidak biasa, linglung dan kelelahan Biasanya tidak dapat mengingat apa yang terjadi selama dia mengalami kejang.

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

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Kejang akibat ggn bersifat metabolik reversibel bila pencetusnya dihilangkan

Sebgn org memp ambang kejang rendah rentang mengalami kejang faktor genetik kejang

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Seizures

• Partial Seizures– Simple Partial– Complex Partial

• Generalized Seizures– Absence– Atypical Absence– Tonic– Clonic– Tonic-Clonic– Atonic– Myoclonic– Mixed Forms

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Basic mechanism of neuronal excitability is the action potential…net positive inward ion flux

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

excitation

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Neuronal circuits Axonal conduction Synapic transmission

Both of these processes employ ionic channels Voltage gated channels Ligand gated channels

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Depolarizing conductances Excitatory Inward sodium and Ca currents

Hyperpolarizing conductances Inhibitory Primarily mediated by potassium channels

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Excitatory transmission Glutamate (NMDA) the principal excitatory

neurotransmitter Inhibitory transmission

GABA the principal inhibitory neurotransmitter

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The brain’s 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

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The major inhibitory neurotransmitter in the CNS GABA A: presynaptic, mediated by Cl channels GABA B: postsynaptic, mediated by K currents

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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

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

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

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Ion channel type, number and distribution

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

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Changes in extracellular ionic concentrations

Remodeling of synaptic location Modulation of transmitter metabolism or

uptake

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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

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• The process by which normal healthy tissue is transformed into a relatively permanent epileptic state

1. Hyperexcitability: The tendency of a neuron to discharge repetitively to a stimulus that normally causes a single action potential

2. Abnormal synchronization: The property of a population of neurons to discharge together independently.

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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

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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 up-stroke

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 EPSPMaintains 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 depolarizationgusbakti12

Examples of specific pathophysiological defects leading to epilepsy

Level of brain function

Condition Pathophysiologic mechanism

Neuronal networkCerebral dysgenesis, post-traumatic scar, mesial temporal sclerosis (in TLE)

Altered neuronal circuits: Formation of aberrant excitatory connections ("sprouting")

Neuron structureDown 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) dependencyDecreased 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 hyperglycinemiaExcess glycine leads to activation of NMDA receptors

Synapse development

Neonatal seizuresMany possible mechanisms, including the depolarizing action of GABA early in development

Ion channels channelopathies

Benign familial neonatal convulsionsPotassium channel mutations: Impaired repolarization

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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

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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, …

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Excitatory axonal sprouting Loss of inhibitory interneurons Loss of excitatory interneurons “driving”

inhibitory neurons

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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

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Physiological Basis of the EEG

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Extracellular dipole generated

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

Brain electrical activity can be recorded Pyramidal cells all have the same polarity and

orientation Many cells are synchronously activated

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Physiological Basis of the EEG (cont.)

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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

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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

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EEG Frequencies

EEG FrequenciesA) Fast activity

B) Mixed activityC) Mixed activityD) Alpha activity (8 to ≤ 13 Hz)

E) Theta activity (4 to under 8 Hz)F) Mixed delta and theta activityG) Predominant delta activity

(<4 Hz)Not shown: Beta activity (>13 Hz)

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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

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

Ayala et al., 1973gusbakti12

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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

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GABAergic neurons of the nucleus reticularis thalami as pacemakers…the thalamocortical loop

Activation of transient Ca channels (T channels) and GABA B mediated hyperpolarization…3-4 Hz oscillations

Ethosuximide suppresses the T-current

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Mechanisms unclear, buy may include voltage-, calcium-, or neurotransmitter-dependent potassium channels

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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

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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

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