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    Basic Mechanism of Epilepsy N Seizures

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    This document provides definitions and discusses basic mechanisms underlying seizures and epilepsy. It defines a seizure as abnormal neuronal synchronization, epilepsy as recurrent seizures, and epileptogenesis as the process converting normal neurons into hyperexcitable networks. Mechanisms include changes in ion channels, neurotransmitters like glutamate and GABA, synaptic remodeling, and channelopathies. The electroencephalogram is described as detecting abnormal electrical activity through electrodes on the scalp, and can help diagnose and classify seizure types and epilepsies.

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    Basic Mechanism of Epilepsy N Seizures

    Uploaded by

    tania
    86 views44 pages
    This document provides definitions and discusses basic mechanisms underlying seizures and epilepsy. It defines a seizure as abnormal neuronal synchronization, epilepsy as recurrent seizures, and epileptogenesis as the process converting normal neurons into hyperexcitable networks. Mechanisms include changes in ion channels, neurotransmitters like glutamate and GABA, synaptic remodeling, and channelopathies. The electroencephalogram is described as detecting abnormal electrical activity through electrodes on the scalp, and can help diagnose and classify seizure types and epilepsies.

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    Basic Mechanism of Epilepsy n Seizures

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    This document provides definitions and discusses basic mechanisms underlying seizures and epilepsy. It defines a seizure as abnormal neuronal synchronization, epilepsy as recurrent seizures, and epileptogenesis as the process converting normal neurons into hyperexcitable networks. Mechanisms include changes in ion channels, neurotransmitters like glutamate and GABA, synaptic remodeling, and channelopathies. The electroencephalogram is described as detecting abnormal electrical activity through electrodes on the scalp, and can help diagnose and classify seizure types and epilepsies.

    Copyright:

    © All Rights Reserved
    Download as PPT, PDF, TXT or read online from Scribd
    Download as ppt, pdf, or txt
    86 views44 pages

    Basic Mechanism of Epilepsy N Seizures

    Uploaded by

    tania
    This document provides definitions and discusses basic mechanisms underlying seizures and epilepsy. It defines a seizure as abnormal neuronal synchronization, epilepsy as recurrent seizures, and epileptogenesis as the process converting normal neurons into hyperexcitable networks. Mechanisms include changes in ion channels, neurotransmitters like glutamate and GABA, synaptic remodeling, and channelopathies. The electroencephalogram is described as detecting abnormal electrical activity through electrodes on the scalp, and can help diagnose and classify seizure types and epilepsies.

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    © All Rights Reserved
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    of 44

    Basic Mechanisms

    Underlying Seizures
    and Epilepsy
    American Epilepsy Society

    B-Slide 1

    Definitions
    Seizure: the clinical manifestation of an
    abnormal and excessive synchronization of
    a population of cortical neurons

    Epilepsy: a tendency toward recurrent


    seizures unprovoked by any systemic or
    acute neurologic insults

    Epileptogenesis: sequence of events that


    converts a normal neuronal network into a
    hyperexcitable network
    Revised per Ruteckie 7/06

    B-Slide 2

    Hippocampal Anatomy

    B-Slide 3

    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 4
    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.

    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

    B-Slide 5

    EpilepsyBasic Neurophysiology
    Major Neurotransmitters in the brain:
    Glutamate
    GABA
    Acetylcholine
    Dopamine
    Serotonin
    Histamine
    Other modulators: neuropeptides, hormones
    B-Slide 6

    EpilepsyGlutamate

    The brains major excitatory neurotransmitter


    Two groups of glutamate receptors
    Ionotropicfast synaptic transmission
    Three subtypes AMPA, kainate, NMDA
    Glutamate-gated cation channels
    Metabotropicslow synaptic transmission
    G-protein coupled, regulation of second messengers
    (cAMP and phospholipase C)
    Modulation of synaptic activity

    Modulation of glutamate receptors


    Glycine, polyamine sites, Zinc, redox site
    B-Slide 7

    EpilepsyGlutamate
    Diagram of the
    various glutamate
    receptor
    subtypes and
    locations
    From Takumi et al, 1998

    B-Slide 8

    EpilepsyGABA
    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 9

    EpilepsyGABA
    GABA site
    Barbiturate site

    Benzodiazepine
    site
    Steroid site
    Picrotoxin site

    Diagram of the GABAA receptor


    From Olsen and Sapp, 1995

    B-Slide 10

    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 11

    Normal CNS Function

    Excitation

    Inhibition

    glutamate,
    aspartate

    GABA
    Modified from White, 2001
    B-Slide 12

    Hyperexcitability reflects both increased


    excitation and decreased inhibition

    Inhibition

    glutamate,
    aspartate

    GABA

    Excitation
    Modified from White, 2001

    B-Slide 13

    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 14

    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 15

    Ion Channel & Neurotransmitter


    Receptors Mutated in Epilepsy - I
    Voltage-gated Sodium Channel Gene Mutations

    SCN1A
    Generalized Epilepsy & Febrile Seizures Plus
    (GEFS+) type 2
    Severe Myoclonic Epilepsy of Infancy (SMEI)

    SCN1B
    GEFS+ type 1

    SCN2A1
    GEFS+
    Benign Familial Neonatal-Infantile Seizures (BFNIS)
    B-Slide 16

    Ion Channel & Neurotransmitter


    Receptors Mutated in Epilepsy - II
    Voltage-gated Chloride Channel Gene Mutations

    CLCN2A
    Juvenile Absence Epilepsy (JAE)
    Juvenile Myoclonic Epilepsy (JME)
    Epilepsy with Grand Mal upon Awakening (EGMA)

    B-Slide 17

    Ion Channel & Neurotransmitter


    Receptors Mutated in Epilepsy - III
    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 18

    Ion Channel & Neurotransmitter


    Receptors Mutated in Epilepsy - IV
    Neurotransmitter Receptor Mutations

    GABRG2 (GABA-receptor gamma-2 subunit)


    GEFS+ type 3

    GABRA1 (GABA-receptor alpha-1 subunit)

    JME
    CHRNA4 (nicotinic acetylcholine receptor alpha-4 subunit)
    Autosomal Dominant Nocturnal Frontal Lobe Epilepsy
    (ADNFLE) type 1

    CHRNB2 (nicotinic acetylcholine receptor beta-2 subunit)


    ADNFLE type 3
    B-Slide 19

    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 20

    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 21

    Mechanisms of Generating
    Hyperexcitable Networks
    Excitatory axonal sprouting
    Loss of inhibitory neurons

    Loss of excitatory neurons driving


    inhibitory neurons

    Change in neuronal firing properties


    (channelopathies)
    B-Slide 22

    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 23

    Hippocampal Circuit Changes With


    Hippocampal Sclerosis

    Chang and Lowenstein, 2003


    B-Slide 24

    Epileptogenesis

    B-Slide 25

    Cavazos and Cross, 2006

    Electroencephalogram (EEG)
    Graphical depiction of cortical electrical activity, usually recorded from the scalp.
    Advantage of high temporal resolution but poor spatial resolution of cortical
    disorders.
    EEG is the most important neurophysiological study for the diagnosis,
    prognosis, and treatment of epilepsy.

    B-Slide 26

    10/20 System of EEG Electrode


    Placement

    B-Slide 27

    Physiological Basis of the EEG

    Extracellular dipole generated


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

    B-Slide 28

    Physiological Basis of the EEG


    (cont.)

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

    B-Slide 29

    Electroencephalogram (EEG)
    Clinical applications
    Seizures/epilepsy
    Sleep
    Altered consciousness
    Focal and diffuse disturbances in
    cerebral functioning

    B-Slide 30

    EEG Frequencies

    Gamma: 30-60 Hz

    Beta: 13-30 Hz

    Alpha: 8 to 13 Hz

    Theta: 4 to under 8 Hz

    Delta: < 4 Hz
    B-Slide 31

    EEG Frequencies

    Radtke, in Ebersole and Pedley, 2003

    B-Slide 32

    EEG Frequencies

    Radtke, in Ebersole and Pedley, 2003

    B-Slide 33

    EEG Abnormalities
    Background activity abnormalities
    Slowing not consistent with behavioral state
    May be focal, lateralized, or generalized
    Significant asymmetry

    Transient abnormalities / Discharges

    Spikes
    Sharp waves
    Spike and slow wave complexes
    May be focal, lateralized, or generalized

    B-Slide 34

    Focal seizure generation

    Seizure initiation
    burst of action potentials, i.e. paroxysmal
    depolarizing shift
    hypersynchronization of neighboring cells

    Propagation
    activation of nearby neurons
    loss of surrounding inhibition
    B-Slide 35

    Sharp Waves
    An example of a
    left temporal
    lobe sharp wave
    (arrow)

    B-Slide 36

    The Interictal Spike and


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

    Ayala et al., 1973

    B-Slide 37

    Generalized Spike Wave Discharge

    B-Slide 38

    EEG: Absence Seizure

    B-Slide 39

    Circuitry Underlying Generalized


    Epilepsies

    McCormick and Contreras, 2001


    B-Slide 40

    Causes of Acquired Epilepsy

    Severe head injury

    Cerebral hemorrhage

    Brain tumor

    CNS infection

    ? Early life febrile seizures


    B-Slide 41

    Development of acquired epilepsy

    B-Slide 42

    Development of acquired epilepsy

    B-Slide 43

    Possible Mechanism of
    Delayed Epileptogenesis
    Kindling model: repeated subconvulsive
    stimuli resulting in electrical
    afterdischarges
    Eventually lead to stimulation-induced clinical
    seizures
    In some cases, lead to spontaneous seizures
    (epilepsy)
    Applicability to human epilepsy uncertain
    B-Slide 44

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