Basic

Mechanisms Underlying
Seizures and Epilepsy

Basic Mechanisms Underlying

Seizures
and Epilepsy

Basic Mechanisms Underlying

Seizures and Epilepsy

s Seizure: the clinical manifesta<on of an abnormal and

s Feedback and
feed-forward
inhibi<on, illustrated
via cartoon and
schema<c of simplied
hippocampal circuit

excessive excita<on and synchroniza<on of a popula<on

of cor<cal neurons

s Epilepsy: a tendency toward recurrent seizures

unprovoked by any systemic or acute neurologic insults

s Epileptogenesis: sequence of events that converts a

normal neuronal network into a hyperexcitable network

American Epilepsy Society

B-Slide 1

Basic Mechanisms Underlying

Seizures and Epilepsy

B-Slide 2

EpilepsyGlutamate

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.

B-Slide 3

EpilepsyGlutamate

s The brains major excitatory neurotransmiKer

s Two groups of glutamate receptors

s Diagram of the

Ionotropicfast synap<c transmission

various glutamate
receptor subtypes
and loca<ons

NMDA, AMPA, kainate

Gated Ca++ and Gated Na+ channels

Metabotropicslow synap<c transmission

Quisqualate
Regula<on of second messengers (cAMP and Inositol)
Modula<on of synap<c ac<vity

From Takumi et al, 1998

s Modula<on of glutamate receptors

Glycine, polyamine sites, Zinc, redox site

B-Slide 6

B-Slide 4

EpilepsyGABA

B-Slide 5

Cellular Mechanisms of
Seizure Genera<on

EpilepsyGABA
GABA site

s Major inhibitory neurotransmiKer in the

CNS
s Two types of receptors

Barbiturate site

Benzodiazepine
site

GABAApost-synap<c, specic recogni<on sites,

linked to CI- channel
GABAB presynap<c autoreceptors, mediated by
K+ currents

Steroid site
Picrotoxin site

s Excita<on (too much)

Ionicinward Na+, Ca++ currents
NeurotransmiKerglutamate, aspartate

s Inhibi<on (too liKle)

Ionicinward CI-, outward K+ currents
NeurotransmiKerGABA

Diagram of the GABAA receptor

From Olsen and Sapp, 1995
B-Slide 7

B-Slide 8
B-Slide 9

Neuronal (Intrinsic) Factors Modifying

Neuronal Excitability
s Ion channel type, number, and distribu<on
s Biochemical modica<on of receptors

Extra-Neuronal (Extrinsic) Factors

Modifying Neuronal Excitability
s Changes in extracellular ion concentra<on

s Ac<va<on of second-messenger systems

s Remodeling of synapse loca<on or

congura<on by aerent input

s Modula<on of gene expression

(e.g., for receptor proteins)

s Modula<on of transmiKer metabolism or

uptake by glial cells
B-Slide 10

Electroencephalogram (EEG)

Mechanisms of Generating
Hyperexcitable Networks
s Excitatory axonal sprouting
s Loss of inhibitory neurons
s Loss of excitatory neurons driving
inhibitory neurons

B-Slide 11

10/20 System of EEG Electrode Placement

B-Slide 12

Physiological Basis of the EEG

s

s Graphical depic<on of cor<cal electrical ac<vity, usually recorded from the scalp.
s Advantage of high temporal resolu<on but poor spa<al resolu<on of cor<cal disorders.
s EEG is the most important neurophysiological study for the diagnosis, prognosis, and
treatment of epilepsy.

Extracellular dipole generated

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

B-Slide 15
B-Slide 13

Physiological Basis of the EEG

(cont.)
s

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

B-Slide 14

Electroencephalogram (EEG)
s Clinical applica<ons

EEG Frequencies
s Alpha: 8 to 13 Hz

Seizures/epilepsy

s Beta: >13 Hz

Sleep
Altered consciousness

s Theta: 4 to under 8 Hz

Focal and diuse disturbances in

cerebral func<oning

s Delta: <4 Hz

B-Slide 16
B-Slide 17

B-Slide 18

EEG Abnormali<es

Normal Adult EEG

EEG Frequencies
EEG Frequencies
A) Fast ac<vity

s Normal alpha rhythm

s Background ac<vity abnormali<es

Slowing not consistent with behavioral state

May be focal, lateralized, or generalized

B) Mixed ac<vity
C) Mixed ac<vity
D) Alpha ac<vity (8 to 13 Hz)
E) Theta ac<vity (4 to under 8 Hz)
F) Mixed delta and theta ac<vity
G) Predominant delta ac<vity
(<4 Hz)
Not shown: Beta ac<vity (>13 Hz)

Niedermeyer E, Ed. The Epilepsies: Diagnosis and Management. Urban

and Schwarzenberg, Baltimore, 1990

Signicant asymmetry
s Transient abnormali<es / Discharges

Spikes
Sharp waves
Spike and slow wave complexes
May be focal, lateralized, or generalized
B-Slide 19

B-Slide 20
B-Slide 21

The Interictal Spike and

Paroxysmal Depolariza<on Shie

Sharp Waves
s An example of a

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

lee temporal lobe

sharp wave
(arrow)

B-Slide 22

Ayala et al., 1973

B-Slide 23
B-Slide 24

Possible Mechanism of
Delayed Epileptogenesis

EEG: Absence Seizure

Generalize Spike Wave Discharge

Cor<cal Development
s Neural tube

s Kindling model: repeated subconvulsive

s<muli resul<ng in electrical aeerdischarges

s Cerebral vesicles

Eventually lead to s<mula<on-induced clinical seizures

s Germinal matrix

In some cases, lead to spontaneous seizures (epilepsy)

s Neuronal migra<on and dieren<a<on

Applicability to human epilepsy uncertain

s Pruning of neurons and neuronal

connec<ons
s Myelina<on

B-Slide 25

B-Slide 26

B-Slide 27

Behavioral Cycling and EEG Changes

During Development

EEG Change During Development

EEG Evolution and Early Cortical Development

EEG Evolution and Early Cortical Development

EGA = embrionic gestational age

Kellway P and Crawley JW. A primer of Electroencephalography of Infants,
Section I and II: Methodology and Criteria of Normality. Baylor University College
of Medicine, Houston, Texas 1964.

Estimated Gestational
Age, in Weeks
8

EEG Evolution

<24

Discontinuous EEG; no state cycling

24

Estimated Gestational
Age, in Weeks

EEG Evolution

40

Predictable cycles of active and quiet

sleep

Some continuous EEG; mostly

discontinuous EEG;
early state cycling

44 - 46

First appearance of sleep spindles during

quiet sleep

30-32

Definite state cycling

4 Months Post-Term

Sleep onset quiet sleep and emergence of

mature sleep architecture

32-34

Consolidation of behavioral states

First appearance of EEG signal across

cortex

Kellway P and Crawley JW. A primer of Electroencephalography of Infants,

Section I and II: Methodology and Criteria of Normality. Baylor University College
of Medicine, Houston, Texas 1964.

Kellway P and Crawley JW. A primer of Electroencephalography of Infants,

Section I and II: Methodology and Criteria of Normality. Baylor University College
of Medicine, Houston, Texas 1964.
B-Slide 28

EEG Change During Development (cont.)

B-Slide 29

B-Slide 30