Basic Mechanism of Epilepsy n Seizures

8/19/2019 Basic Mechanism of Epilepsy n Seizures

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Basic Mechanisms Basic Mechanisms

Underlying SeizuresUnderlying Seizuresand Epilepsyand Epilepsy

American Epilepsy Society


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Definitions 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 thatconverts a normal neuronal network into a

hyperexcitable network

Revised per Ruteckie 7/06Revised per Ruteckie 7/06


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Hippocampal Anatomy Hippocampal Anatomy

From Chang and Lowenstein, 2003From Chang and Lowenstein, 2003


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Basic Mechanisms Underlying Basic Mechanisms Underlying

Seizures and Epilepsy Seizures and Epilepsy

Feedback and

feed-forward

inhibition illustrated

via cartoon andschematic 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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Epilepsy—Basic Neurophysiology Epilepsy—Basic Neurophysiology

!auses of "yperexcitability:

# excitatory post synaptic potentials $E%S%s&

# inhibitory post synaptic potentials $'%S%s&

# changes in voltage gated ion channels

# alteration of local ion concentrations


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Epilepsy—Basic Neurophysiology Epilepsy—Basic Neurophysiology

(a)or *eurotransmitters in the brain:

# +lutamate

# +,,

# ,cetylcholine

# .opamine

# Serotonin

# "istamine

# /ther modulators: neuropeptides hormones


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Epilepsy—Glutamate Epilepsy—Glutamate

0he brain1s ma)or excitatory neurotransmitter

0wo groups of glutamate receptors

# 'onotropic2fast synaptic transmission

3 0hree subtypes 3 ,(%, kainate *(., 3 +lutamate-gated cation channels

# (etabotropic2slow synaptic transmission

3 +-protein coupled regulation of second messengers

$c,(% and phospholipase !&

3 (odulation of synaptic activity

(odulation of glutamate receptors

# +lycine polyamine sites 4inc redox site


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Epilepsy—Glutamate Epilepsy—Glutamate

Diagram of the

various glutamatereceptorsubtypes andlocationsFrom Takumi et al, 1998


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Epilepsy—GABA Epilepsy—GABA

(a)or inhibitory neurotransmitter in the

!*S

0wo types of receptors

# +,, ,2post-synaptic specific recognition

sites linked to !'- channel

# +,, 2presynaptic autoreceptors that

reduce transmitter release by decreasingcalcium influx postsynaptic coupled to +-

proteins to increase 56 current


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Epilepsy—GABA Epilepsy—GABA

.iagram of the +,, , receptor

From Olsen and Sapp, 1995

GABA siteGABA site

Barbiturate siteBarbiturate site

BenzodiazepineBenzodiazepine

sitesite

Steroid siteSteroid site

Picrotoxin sitePicrotoxin site


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ellular Mechanisms ofellular Mechanisms of

Seizure Generation Seizure Generation Excitation $too much&

# 'onic2inward *a6 !a66 currents

# *eurotransmitter2glutamate aspartate

'nhibition $too little&

# 'onic2inward !'- outward 56 currents# *eurotransmitter2+,,


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Normal NS !unction Normal NS !unction

Excitation 'nhibition

glutamate

aspartate +,,

(odified from 7hite 899


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Hypere"cita#ility reflects #oth increased Hypere"cita#ility reflects #oth increased

e"citation and decreased inhi#itione"citation and decreased inhi#ition

Excitation

'nhibition

+,,

glutamateaspartate

(odified from 7hite 899


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Neuronal $%ntrinsic& !actors Neuronal $%ntrinsic& !actors

Modifying Neuronal E"cita#ility Modifying Neuronal E"cita#ility 'on channel type number and distribution

%ost-translational modification of channels

$phosphorylation etc&;

,ctivation of second-messenger systems that

affect channel function $e;g; + proteins&

(odulation of gene expression of ion channels


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Epilepsy and hannelopathies Epilepsy and hannelopathies

'nherited

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

,cquired

Auto-immune (anti-potassium channel antibodies)

Changes in channel epression after seizures


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%on hannel ' Neurotransmitter %on hannel ' Neurotransmitter

(eceptors Mutated in Epilepsy ) % (eceptors Mutated in Epilepsy ) %

Voltage-gated Sodium Channel !ene "utations

# SCN1A

# !eneralized Epilepsy # $ebrile Seizures %lus

(!E$S&) type '

# Seere "yoclonic Epilepsy of nfancy (S"E)

# SCN1B

# !E$S& type *

# SCN2A1 # !E$S&

# +enign $amilial ,eonatal-nfantile Seizures (+$,S)


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(eceptors Mutated in Epilepsy ) %% (eceptors Mutated in Epilepsy ) %%

Voltage-gated Chloride Channel !ene "utations

# CLCN2A

# uenile Absence Epilepsy (AE)

# uenile "yoclonic Epilepsy ("E)

# Epilepsy .ith !rand "al upon A.a/ening (E!"A)


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(eceptors Mutated in Epilepsy ) %* (eceptors Mutated in Epilepsy ) %*

N eurotransmitter 1eceptor "utations

# GABRG2 (!A+A-receptor gamma-' subunit)

# !E$S& type 2

# GABRA1 (!A+A-receptor alpha-* subunit)

# "E

# CHRNA4 (nicotinic acetylcholine receptor alpha-3 subunit)

# Autosomal Dominant ,octurnal $rontal Lobe Epilepsy

(AD,$LE) type *# CHRNB2 (nicotinic acetylcholine receptor beta-' subunit)

# AD,$LE type 2


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Synaptic !actors Modifying Synaptic !actors Modifying

Neuronal E"cita#ility Neuronal E"cita#ility

,lterations in expression of transmitter gated

ionotropic channels

%ost-translational changes in neurotransmitter

channels


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Non)synaptic $E"trinsic& !actors Non)synaptic $E"trinsic& !actors

Modifying Neuronal E"cita#ility Modifying Neuronal E"cita#ility

!hanges in extracellular ion concentration

!hanges in extracellular space

(odulation of transmitter metabolism or

uptake by glial cells


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Mechanisms of Generating Mechanisms of Generating

Hypere"cita#le Net+or,s Hypere"cita#le Net+or,s Excitatory axonal =sprouting>

?oss of inhibitory neurons

?oss of excitatory neurons =driving>

inhibitory neurons

!hange in neuronal firing properties

$channelopathies&


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*ormal


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!hang and ?owenstein 899A

Hippocampal ircuit hanges .ith Hippocampal ircuit hanges .ith

Hippocampal Sclerosis Hippocampal Sclerosis


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!avazos and !ross 899@

Epileptogenesis Epileptogenesis


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Electroencephalogram $EEG& Electroencephalogram $EEG&

+raphical depiction of cortical electrical activity usually recorded from the scalp;

,dvantage of high temporal resolution but poor spatial resolution of cortical

disorders;

EE+ is the most important neurophysiological study for the diagnosisprognosis and treatment of epilepsy;


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/0120 System of EEG Electrode/0120 System of EEG Electrode

3lacement 3lacement


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3hysiological Basis of the EEG 3hysiological Basis of the EEG

Extracellular dipole generated

by excitatory post-synaptic

potential at apical dendrite of

pyramidal cell


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3hysiological Basis of the EEG 3hysiological Basis of the EEG

$cont4&$cont4& Electrical field

generated by similarly

oriented pyramidal

cells in cortex $layer

B& and detected by

scalp electrode


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Electroencephalogram $EEG& Electroencephalogram $EEG&

!linical applications

# SeizuresCepilepsy

# Sleep

# ,ltered consciousness

# Focal and diffuse disturbances in

cerebral functioning


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EEG !re5uencies EEG !re5uencies

+amma: A9-@9 "z

eta: A-A9 "z

,lpha: D to A "z

0heta: to under D "z

.elta: G "z


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EEG A#normalities EEG A#normalities

ackground activity abnormalities# Slowing not consistent with behavioral state

3 (ay be focal lateralized or generalized

# Significant asymmetry 0ransient abnormalities C .ischarges

# Spikes

# Sharp waves

# Spike and slow wave complexes

# (ay be focal lateralized or generalized


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!ocal seizure generation!ocal seizure generation

# Seizure initiation

# burst of action potentials i;e; paroxysmaldepolarizing shift

# hypersynchronization of neighboring cells

# %ropagation

# activation of nearby neurons

# loss of surrounding inhibition


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Sharp .a6es Sharp .a6es

,n example of aleft temporal

lobe sharp wave

$arrow&


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-he 7%nterictal Spi,e and-he 7%nterictal Spi,e and

3aro"ysmal Depolarization Shift8 3aro"ysmal Depolarization Shift8 'ntracellular and

extracellular events

of the paroxysmal

depolarizing shift

underlying the

interictal

epileptiform spike

detected by surface

EE+

,yala et al; HIA


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Generalized Spi,e .a6e DischargeGeneralized Spi,e .a6e Discharge


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EEG9 A#sence Seizure EEG9 A#sence Seizure


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ircuitry Underlying Generalizedircuitry Underlying Generalized

Epilepsies Epilepsies

(c!ormick and !ontreras 899


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auses of Ac5uired Epilepsyauses of Ac5uired Epilepsy

# Seere head in4ury

# Cerebral hemorrhage

# +rain tumor

#

C,S infection

# 5 Early life febrile seizures

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De6elopment of ac5uired epilepsy De6elopment of ac5uired epilepsy



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De6elopment of ac5uired epilepsy De6elopment of ac5uired epilepsy

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3ossi#le Mechanism of 3ossi#le Mechanism of

Delayed Epileptogenesis Delayed Epileptogenesis 5indling model: repeated subconvulsive

stimuli resulting in electrical

afterdischarges# Eventually lead to stimulation-induced clinical

seizures

# 'n some cases lead to spontaneous seizures

$epilepsy&

# ,pplicability to human epilepsy uncertain

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Basic Mechanism of Epilepsy n Seizures

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