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Basic Mechanisms Basic Mechanisms Underlying Seizures Underlying Seizures and Epilepsyand Epilepsy
American Epilepsy Society
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Basic Mechanisms UnderlyingBasic Mechanisms UnderlyingSeizures and EpilepsySeizures and Epilepsy
Seizure: the clinical manifestation of an abnormal and excessive excitation and 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
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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.
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Basic Mechanisms Underlying Basic Mechanisms Underlying Seizures and EpilepsySeizures and Epilepsy
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Epilepsy—GlutamateEpilepsy—Glutamate
The brain’s major excitatory neurotransmitter
Two groups of glutamate receptors• Ionotropic—fast synaptic transmission
– NMDA, AMPA, kainate– Gated Ca++ and Gated Na+ channels
• Metabotropic—slow synaptic transmission– Quisqualate– Regulation of second messengers (cAMP and Inositol)– Modulation of synaptic activity
Modulation of glutamate receptors
• Glycine, polyamine sites, Zinc, redox site
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Epilepsy—GlutamateEpilepsy—Glutamate
Diagram of the various glutamate receptor subtypes and locations
From Takumi et al, 1998
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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, mediated by K+ currents
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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
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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
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Neuronal (Intrinsic) Factors Neuronal (Intrinsic) Factors Modifying Neuronal ExcitabilityModifying Neuronal Excitability
Ion channel type, number, and distribution
Biochemical modification of receptors
Activation of second-messenger systems
Modulation of gene expression (e.g., for receptor proteins)
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Extra-Neuronal (Extrinsic) Factors Extra-Neuronal (Extrinsic) Factors Modifying Neuronal ExcitabilityModifying Neuronal Excitability
Changes in extracellular ion concentration
Remodeling of synapse location or configuration by afferent input
Modulation of transmitter metabolism or uptake by glial cells
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Mechanisms of Generating Mechanisms of Generating Hyperexcitable NetworksHyperexcitable Networks
Excitatory axonal “sprouting”
Loss of inhibitory neurons
Loss of excitatory neurons “driving” inhibitory neurons
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Electroencephalogram (EEG)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.
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10/20 System of EEG Electrode 10/20 System of EEG Electrode PlacementPlacement
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Physiological Basis of the EEGPhysiological Basis of the EEG
Extracellular dipole generated
by excitatory post-synaptic potential at apical dendrite of pyramidal cell
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Physiological Basis of the EEG Physiological Basis of the EEG (cont.)(cont.)
Electrical field generated by similarly oriented pyramidal cells in cortex (layer 5) and detected by scalp electrode
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Electroencephalogram (EEG)Electroencephalogram (EEG)
Clinical applications
• Seizures/epilepsy
• Sleep
• Altered consciousness
• Focal and diffuse disturbances in cerebral functioning
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EEG FrequenciesEEG Frequencies
Alpha: 8 to ≤ 13 Hz
Beta: 13 Hz
Theta: 4 to under 8 Hz
Delta: <4 Hz
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EEG FrequenciesEEG Frequencies
EEG FrequenciesA) 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)
Niedermeyer E, Ed. The Epilepsies: Diagnosis and Management. Urban and Schwarzenberg, Baltimore, 1990
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Normal Adult EEGNormal Adult EEG
Normal alpha rhythm
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EEG AbnormalitiesEEG 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
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Sharp WavesSharp Waves
An example of a left temporal lobe sharp wave (arrow)
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The “Interictal Spike and The “Interictal Spike and Paroxysmal Depolarization Shift”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
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Generalize Spike Wave DischargeGeneralize Spike Wave Discharge
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EEG: Absence SeizureEEG: Absence Seizure
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Possible Mechanism of Possible Mechanism of Delayed EpileptogenesisDelayed 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
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Cortical DevelopmentCortical Development
Neural tube
Cerebral vesicles
Germinal matrix
Neuronal migration and differentiation
“Pruning” of neurons and neuronal connections
Myelination
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Behavioral Cycling and EEG Behavioral Cycling and EEG Changes During DevelopmentChanges During Development
EGA = embrionic gestational ageEGA = embrionic gestational age
Kellway P and Crawley JW. A primer of Electroencephalography of Infants, Kellway P and Crawley JW. A primer of Electroencephalography of Infants, Section I and II: Methodology and Criteria of Normality. Baylor University College Section I and II: Methodology and Criteria of Normality. Baylor University College of Medicine, Houston, Texas 1964.of Medicine, Houston, Texas 1964.
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EEG Change During DevelopmentEEG Change During Development
EEG Evolution and Early Cortical Development Estimated Gestational Age, in Weeks
EEG Evolution
8 First appearance of EEG signal across cortex
<24 Discontinuous EEG; no state cycling
24 Some continuous EEG; mostly discontinuous EEG; early state cycling
30-32 Definite state cycling
32-34 Consolidation of behavioral states
Kellway P and Crawley JW. A primer of Electroencephalography of Infants, Kellway P and Crawley JW. A primer of Electroencephalography of Infants, Section I and II: Methodology and Criteria of Normality. Baylor University College Section I and II: Methodology and Criteria of Normality. Baylor University College of Medicine, Houston, Texas 1964.of Medicine, Houston, Texas 1964.
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EEG Change During Development EEG Change During Development (cont.)(cont.)
EEG Evolution and Early Cortical Development
Estimated GestationalAge, in Weeks
EEG Evolution
40 Predictable cycles of “active” and “quiet”sleep
44 - 46 First appearance of sleep spindles duringquiet sleep
4 Months Post-Term Sleep onset quiet sleep and emergence ofmature sleep architecture
Kellway P and Crawley JW. A primer of Electroencephalography of Infants, Kellway P and Crawley JW. A primer of Electroencephalography of Infants, Section I and II: Methodology and Criteria of Normality. Baylor University College Section I and II: Methodology and Criteria of Normality. Baylor University College of Medicine, Houston, Texas 1964.of Medicine, Houston, Texas 1964.