Upload
tania
View
219
Download
0
Embed Size (px)
Citation preview
8/19/2019 Basic Mechanism of Epilepsy n Seizures
1/44
B-SlideB-Slide 11
Basic Mechanisms Basic Mechanisms
Underlying SeizuresUnderlying Seizuresand Epilepsyand Epilepsy
American Epilepsy Society
8/19/2019 Basic Mechanism of Epilepsy n Seizures
2/44
B-SlideB-Slide 2 2
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
8/19/2019 Basic Mechanism of Epilepsy n Seizures
3/44
B-SlideB-Slide 33
Hippocampal Anatomy Hippocampal Anatomy
From Chang and Lowenstein, 2003From Chang and Lowenstein, 2003
8/19/2019 Basic Mechanism of Epilepsy n Seizures
4/44
B-SlideB-Slide 44
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.
8/19/2019 Basic Mechanism of Epilepsy n Seizures
5/44
B-SlideB-Slide 5 5
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
8/19/2019 Basic Mechanism of Epilepsy n Seizures
6/44
B-SlideB-Slide 6 6
Epilepsy—Basic Neurophysiology Epilepsy—Basic Neurophysiology
(a)or *eurotransmitters in the brain:
# +lutamate
# +,,
# ,cetylcholine
# .opamine
# Serotonin
# "istamine
# /ther modulators: neuropeptides hormones
8/19/2019 Basic Mechanism of Epilepsy n Seizures
7/44
B-SlideB-Slide 7 7
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
8/19/2019 Basic Mechanism of Epilepsy n Seizures
8/44
B-SlideB-Slide 8 8
Epilepsy—Glutamate Epilepsy—Glutamate
Diagram of the
various glutamatereceptorsubtypes andlocationsFrom Takumi et al, 1998
8/19/2019 Basic Mechanism of Epilepsy n Seizures
9/44
B-SlideB-Slide 99
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
8/19/2019 Basic Mechanism of Epilepsy n Seizures
10/44
B-SlideB-Slide 10 10
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
8/19/2019 Basic Mechanism of Epilepsy n Seizures
11/44
B-SlideB-Slide 1111
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+,,
8/19/2019 Basic Mechanism of Epilepsy n Seizures
12/44
B-SlideB-Slide 12 12
Normal NS !unction Normal NS !unction
Excitation 'nhibition
glutamate
aspartate +,,
(odified from 7hite 899
8/19/2019 Basic Mechanism of Epilepsy n Seizures
13/44
B-SlideB-Slide 1313
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
8/19/2019 Basic Mechanism of Epilepsy n Seizures
14/44
B-SlideB-Slide 1414
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
8/19/2019 Basic Mechanism of Epilepsy n Seizures
15/44
B-SlideB-Slide 15 15
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
8/19/2019 Basic Mechanism of Epilepsy n Seizures
16/44
B-SlideB-Slide 16 16
%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)
8/19/2019 Basic Mechanism of Epilepsy n Seizures
17/44
B-SlideB-Slide 17 17
%on hannel ' Neurotransmitter %on hannel ' Neurotransmitter
(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)
8/19/2019 Basic Mechanism of Epilepsy n Seizures
18/44
8/19/2019 Basic Mechanism of Epilepsy n Seizures
19/44
B-SlideB-Slide 1919
%on hannel ' Neurotransmitter %on hannel ' Neurotransmitter
(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
8/19/2019 Basic Mechanism of Epilepsy n Seizures
20/44
B-SlideB-Slide 20 20
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
8/19/2019 Basic Mechanism of Epilepsy n Seizures
21/44
B-SlideB-Slide 2121
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
8/19/2019 Basic Mechanism of Epilepsy n Seizures
22/44
B-SlideB-Slide 22 22
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&
8/19/2019 Basic Mechanism of Epilepsy n Seizures
23/44
B-SlideB-Slide 2323
*ormal
8/19/2019 Basic Mechanism of Epilepsy n Seizures
24/44
B-SlideB-Slide 2424
!hang and ?owenstein 899A
Hippocampal ircuit hanges .ith Hippocampal ircuit hanges .ith
Hippocampal Sclerosis Hippocampal Sclerosis
8/19/2019 Basic Mechanism of Epilepsy n Seizures
25/44
B-SlideB-Slide 25 25
!avazos and !ross 899@
Epileptogenesis Epileptogenesis
8/19/2019 Basic Mechanism of Epilepsy n Seizures
26/44
B-SlideB-Slide 26 26
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;
8/19/2019 Basic Mechanism of Epilepsy n Seizures
27/44
B-SlideB-Slide 27 27
/0120 System of EEG Electrode/0120 System of EEG Electrode
3lacement 3lacement
8/19/2019 Basic Mechanism of Epilepsy n Seizures
28/44
B-SlideB-Slide 28 28
3hysiological Basis of the EEG 3hysiological Basis of the EEG
Extracellular dipole generated
by excitatory post-synaptic
potential at apical dendrite of
pyramidal cell
8/19/2019 Basic Mechanism of Epilepsy n Seizures
29/44
B-SlideB-Slide 2929
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
8/19/2019 Basic Mechanism of Epilepsy n Seizures
30/44
B-SlideB-Slide 30 30
Electroencephalogram $EEG& Electroencephalogram $EEG&
!linical applications
# SeizuresCepilepsy
# Sleep
# ,ltered consciousness
# Focal and diffuse disturbances in
cerebral functioning
8/19/2019 Basic Mechanism of Epilepsy n Seizures
31/44
B-SlideB-Slide 3131
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
8/19/2019 Basic Mechanism of Epilepsy n Seizures
32/44
B-SlideB-Slide 32 32
EEG !re5uencies EEG !re5uencies
8/19/2019 Basic Mechanism of Epilepsy n Seizures
33/44
B-SlideB-Slide 3333
EEG !re5uencies EEG !re5uencies
8/19/2019 Basic Mechanism of Epilepsy n Seizures
34/44
B-SlideB-Slide 3434
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
8/19/2019 Basic Mechanism of Epilepsy n Seizures
35/44
B-SlideB-Slide 35 35
!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
8/19/2019 Basic Mechanism of Epilepsy n Seizures
36/44
B-SlideB-Slide 36 36
Sharp .a6es Sharp .a6es
,n example of aleft temporal
lobe sharp wave
$arrow&
8/19/2019 Basic Mechanism of Epilepsy n Seizures
37/44
B-SlideB-Slide 37 37
-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
8/19/2019 Basic Mechanism of Epilepsy n Seizures
38/44
B-SlideB-Slide 38 38
Generalized Spi,e .a6e DischargeGeneralized Spi,e .a6e Discharge
8/19/2019 Basic Mechanism of Epilepsy n Seizures
39/44
B-SlideB-Slide 3939
EEG9 A#sence Seizure EEG9 A#sence Seizure
8/19/2019 Basic Mechanism of Epilepsy n Seizures
40/44
B-SlideB-Slide 40 40
ircuitry Underlying Generalizedircuitry Underlying Generalized
Epilepsies Epilepsies
(c!ormick and !ontreras 899
8/19/2019 Basic Mechanism of Epilepsy n Seizures
41/44
auses of Ac5uired Epilepsyauses of Ac5uired Epilepsy
# Seere head in4ury
# Cerebral hemorrhage
# +rain tumor
#
C,S infection
# 5 Early life febrile seizures
B-SlideB-Slide 4141
8/19/2019 Basic Mechanism of Epilepsy n Seizures
42/44
De6elopment of ac5uired epilepsy De6elopment of ac5uired epilepsy
B-SlideB-Slide 42 42
8/19/2019 Basic Mechanism of Epilepsy n Seizures
43/44
De6elopment of ac5uired epilepsy De6elopment of ac5uired epilepsy
B-SlideB-Slide 4343
8/19/2019 Basic Mechanism of Epilepsy n Seizures
44/44
B-SlideB-Slide 4444
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