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Neurobiology of Epileptogenesisd2qrtshcpf0x30.cloudfront.net/nodes/58/Smith Neurobiology 2018.pdf · Epilepsia. 1997. Excitatory Center Inhibitory surround Basket cells ... •Potentiation

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Page 1: Neurobiology of Epileptogenesisd2qrtshcpf0x30.cloudfront.net/nodes/58/Smith Neurobiology 2018.pdf · Epilepsia. 1997. Excitatory Center Inhibitory surround Basket cells ... •Potentiation
Page 2: Neurobiology of Epileptogenesisd2qrtshcpf0x30.cloudfront.net/nodes/58/Smith Neurobiology 2018.pdf · Epilepsia. 1997. Excitatory Center Inhibitory surround Basket cells ... •Potentiation

Neurobiology of Epileptogenesis

Michael C. Smith, MDDirector, Rush Epilepsy Center

Professor and Senior Attending NeurologistRush University Medical Center

Chicago, IL

Page 3: Neurobiology of Epileptogenesisd2qrtshcpf0x30.cloudfront.net/nodes/58/Smith Neurobiology 2018.pdf · Epilepsia. 1997. Excitatory Center Inhibitory surround Basket cells ... •Potentiation

Lothman EW. Epilepsy: Models, Mechanisms, and Concepts. 1993.

Molecular, Synaptic, and Cellular Effects of Seizures

hours-to-daysweeks-months-years

seconds-to-minutes

SEIZURE

Ca++Enzyme Activity

Adenosine

K+

Intracellular

Extracellular

Presynaptic Element(Axon Terminals)

Postsynaptic Element(Receptors/Channels)

Presynaptic-Postsynaptic Functional Unit

Glutamate Excitation

GABA Inhibition

Glia

Neurons

Local Circuit

Projection Circuit

Facilitation

PTPLTP

Synaptogenesis

Necrosis

Neuron Loss

Apoptosis

Gene Expression

NerveGrowth Factors

Axon Proliferation, Growth

12 3

4

KainateReceptors

BZD Receptors

5

Gliosis

Excitation > Inhibition Imbalance

Disconnection Between Regions

Net

wo

rk M

ilieu

Cel

lula

r M

ilieu

Syn

apti

c M

ilieu

Mo

lecu

lar

Mili

eu

Page 4: Neurobiology of Epileptogenesisd2qrtshcpf0x30.cloudfront.net/nodes/58/Smith Neurobiology 2018.pdf · Epilepsia. 1997. Excitatory Center Inhibitory surround Basket cells ... •Potentiation

Basic Mechanisms of Seizures

• Neuronal short-circuit - PDS

• Paroxysmal Depolarization Shift

• Neuronal synchronization

• Gap junctions, ephaptic coupling, electrical fields, ionic concentrations

• Transition from interictal to ictus

• Failure of inhibition, excessive excitation

Page 5: Neurobiology of Epileptogenesisd2qrtshcpf0x30.cloudfront.net/nodes/58/Smith Neurobiology 2018.pdf · Epilepsia. 1997. Excitatory Center Inhibitory surround Basket cells ... •Potentiation

Paroxysmal Depolarization Shift

• Paroxysmal Depolarization Shift (PDS) is described in both experimental animal models of epilepsy and in human tissue obtained in epilepsy surgery

• Intracellular expression of epileptic spike

• Well-characterized with micro-electrode studies

Page 6: Neurobiology of Epileptogenesisd2qrtshcpf0x30.cloudfront.net/nodes/58/Smith Neurobiology 2018.pdf · Epilepsia. 1997. Excitatory Center Inhibitory surround Basket cells ... •Potentiation

Paroxysmal Depolarization Shift

Paroxysmal depolarizationshift

o

Vm

Vth

Vrest

-70mV

TIME Voltagedependent K+efflux

Ca+2dependent

200msec

Na+

infl

ux

Ca+2

infl

ux

Page 7: Neurobiology of Epileptogenesisd2qrtshcpf0x30.cloudfront.net/nodes/58/Smith Neurobiology 2018.pdf · Epilepsia. 1997. Excitatory Center Inhibitory surround Basket cells ... •Potentiation

Paroxysmal Depolarization Shift

• Pathophysiology of PDS

• Abnormal ionic conductance (Na+/Ca++)

• Due to increased number of ionic channels

• Excessive response to normal input

• Due to excessive excitatory input

• Giant EPSP (excitatory post-synaptic potential)

• Probably a combination of both

Page 8: Neurobiology of Epileptogenesisd2qrtshcpf0x30.cloudfront.net/nodes/58/Smith Neurobiology 2018.pdf · Epilepsia. 1997. Excitatory Center Inhibitory surround Basket cells ... •Potentiation

PDS Origin of Interictal Spike

Wong PK, et al. Prog Brain Res. 1984.

Intracellular recording

Extracellular recording

Paroxysmal depolarizing shift

Page 9: Neurobiology of Epileptogenesisd2qrtshcpf0x30.cloudfront.net/nodes/58/Smith Neurobiology 2018.pdf · Epilepsia. 1997. Excitatory Center Inhibitory surround Basket cells ... •Potentiation

PDS – Ionic Conductance

Westbrook G. Principles of Neuroscience. 2000.

A. Interictal PDS within seizure focus B. Basic cortical circuit

Feedback inhibition

Feed-forward inhibition

Page 10: Neurobiology of Epileptogenesisd2qrtshcpf0x30.cloudfront.net/nodes/58/Smith Neurobiology 2018.pdf · Epilepsia. 1997. Excitatory Center Inhibitory surround Basket cells ... •Potentiation

Epileptic Focus – Interplay Between Excitatory and Inhibitory Circuitry

Westbrook G. Principles of Neuroscience. 2000.

Page 11: Neurobiology of Epileptogenesisd2qrtshcpf0x30.cloudfront.net/nodes/58/Smith Neurobiology 2018.pdf · Epilepsia. 1997. Excitatory Center Inhibitory surround Basket cells ... •Potentiation

Neurobiology of Absence Seizures

Dichter MA. Epilepsia. 1997.

AEEG

Neuron

0-20-40-80

-100

GABA GABA GABA GABA

T-Ca++T-Ca++T-Ca++

1 sec

BCortex

ThalamusT

R

T

R

Re

Nu

Page 12: Neurobiology of Epileptogenesisd2qrtshcpf0x30.cloudfront.net/nodes/58/Smith Neurobiology 2018.pdf · Epilepsia. 1997. Excitatory Center Inhibitory surround Basket cells ... •Potentiation

Neuronal Synchronization

• Poorly understood and difficult to study

• Synchronization is necessary to reach the critical mass of neurons to overwhelm normal surround inhibition for transition to ictus

• There are multiple mechanisms responsible for neuronal synchronization

Page 13: Neurobiology of Epileptogenesisd2qrtshcpf0x30.cloudfront.net/nodes/58/Smith Neurobiology 2018.pdf · Epilepsia. 1997. Excitatory Center Inhibitory surround Basket cells ... •Potentiation

Neuronal Synchronization

• Neuronal synchronization may occur at dendritic and axonal levels, but not at cell body

• Gap junctions on these processes, when blocked, prevent fast ripple potentials that synchronize adjacent neurons

• Electrical field effects may synchronize adjacent neurons

• Alterations in extracellular space and ionic concentrations affect neuronal excitability and synchronization

Scharfman HE. Curr Neurol Neurosci Rep. 2007.

Page 14: Neurobiology of Epileptogenesisd2qrtshcpf0x30.cloudfront.net/nodes/58/Smith Neurobiology 2018.pdf · Epilepsia. 1997. Excitatory Center Inhibitory surround Basket cells ... •Potentiation

Interactions Between NMDA Activation, Extracellular Space and Potassium Concentration

Burst AHP

Ephapticcoupling

Depolarization

Spike threshold

NMDA receptor

Cell swelling

Larger [K+] transient duringinterictal burst

NEURONALFIRING

DURINGINTERICTAL

BURSTS

Seizure

ECspace

IPSP

RISE INBASELINE [K+]

Page 15: Neurobiology of Epileptogenesisd2qrtshcpf0x30.cloudfront.net/nodes/58/Smith Neurobiology 2018.pdf · Epilepsia. 1997. Excitatory Center Inhibitory surround Basket cells ... •Potentiation

Effects of Seizure on Extracellular Space and Ionic Concentration

Lothman EW. Epilepsy: Models, Mechanisms, and Concepts. 1993.

Page 16: Neurobiology of Epileptogenesisd2qrtshcpf0x30.cloudfront.net/nodes/58/Smith Neurobiology 2018.pdf · Epilepsia. 1997. Excitatory Center Inhibitory surround Basket cells ... •Potentiation

Glial Cell - Role in Generation and Spread of Seizures

• Impaired K+ buffering due to reduced gK(IR) in sclerotic epileptic hippocampus

• Enhanced expression of astroglial gap junction protein supports hypersynchronization

• Enhanced activation of metabotropic glutamate receptors with increased intracellular Ca++

Steinhäuser C. Eur J Pharmacol. 2002.

Page 17: Neurobiology of Epileptogenesisd2qrtshcpf0x30.cloudfront.net/nodes/58/Smith Neurobiology 2018.pdf · Epilepsia. 1997. Excitatory Center Inhibitory surround Basket cells ... •Potentiation

Astrocytic Ionic Regulatory Function

Steinhäuser C. Eur J Pharmacol. 2002.

Page 18: Neurobiology of Epileptogenesisd2qrtshcpf0x30.cloudfront.net/nodes/58/Smith Neurobiology 2018.pdf · Epilepsia. 1997. Excitatory Center Inhibitory surround Basket cells ... •Potentiation

Pathophysiology of Interictal Spike

Dichter MA. Epilepsia. 1997.

Excitatory Center

Inhibitory surround

Basket cells

Interictal dischargeOriginating in temporal lobe

PyramidalCells

Synaptic inhibition insurrounding neurons

DS

Hyperpolarization

Page 19: Neurobiology of Epileptogenesisd2qrtshcpf0x30.cloudfront.net/nodes/58/Smith Neurobiology 2018.pdf · Epilepsia. 1997. Excitatory Center Inhibitory surround Basket cells ... •Potentiation

Transition to Ictus

• Imbalance of excitation and inhibition

• Failure of inhibition:

• Activity dependent disinhibition

• Loss of the after hyperpolarization (AHP)

• Loss of surround inhibition

• Excessive glutamate stimulation

• Positive feedback

• Recurrent excitatory feedback circuitry

Staley K. Nat Neurosci. 2015; Scharfman HE. Curr Neurol Neurosci Rep. 2007.

Page 20: Neurobiology of Epileptogenesisd2qrtshcpf0x30.cloudfront.net/nodes/58/Smith Neurobiology 2018.pdf · Epilepsia. 1997. Excitatory Center Inhibitory surround Basket cells ... •Potentiation

Transition from Interictal State to Ictus

Lothman EW. Epilepsy: Models, Mechanisms, and Concepts. 1993.

Tonic Phase Clonic Phase

Seizure Focus Distant

Page 21: Neurobiology of Epileptogenesisd2qrtshcpf0x30.cloudfront.net/nodes/58/Smith Neurobiology 2018.pdf · Epilepsia. 1997. Excitatory Center Inhibitory surround Basket cells ... •Potentiation

GABA Desensitization Leading to Inhibitory Failure

Page 22: Neurobiology of Epileptogenesisd2qrtshcpf0x30.cloudfront.net/nodes/58/Smith Neurobiology 2018.pdf · Epilepsia. 1997. Excitatory Center Inhibitory surround Basket cells ... •Potentiation

Glutamate Neurotransmission

Dichter MA. Epilepsia. 1997.

Page 23: Neurobiology of Epileptogenesisd2qrtshcpf0x30.cloudfront.net/nodes/58/Smith Neurobiology 2018.pdf · Epilepsia. 1997. Excitatory Center Inhibitory surround Basket cells ... •Potentiation

Excessive Excitation Breaking Down Inhibition

Page 24: Neurobiology of Epileptogenesisd2qrtshcpf0x30.cloudfront.net/nodes/58/Smith Neurobiology 2018.pdf · Epilepsia. 1997. Excitatory Center Inhibitory surround Basket cells ... •Potentiation

Lothman EW. Epilepsy: Models, Mechanisms, and Concepts. 1993.

Seizure-induced Change in Neuron Function and Structure

Page 25: Neurobiology of Epileptogenesisd2qrtshcpf0x30.cloudfront.net/nodes/58/Smith Neurobiology 2018.pdf · Epilepsia. 1997. Excitatory Center Inhibitory surround Basket cells ... •Potentiation

An 18-month old male has a 25 minute convulsion followed by R-sided Todd’s Paralysis. The following may occur:

A. Excitotoxic damage to the dentate gyrus

B. Neuronal reorganization leading to hyperexcitable hippocampus

C. Increased risk of later seizures

D. All of the above

Page 26: Neurobiology of Epileptogenesisd2qrtshcpf0x30.cloudfront.net/nodes/58/Smith Neurobiology 2018.pdf · Epilepsia. 1997. Excitatory Center Inhibitory surround Basket cells ... •Potentiation

Example of Excitotoxicity in Hippocampus after Status Epilepticus

Page 27: Neurobiology of Epileptogenesisd2qrtshcpf0x30.cloudfront.net/nodes/58/Smith Neurobiology 2018.pdf · Epilepsia. 1997. Excitatory Center Inhibitory surround Basket cells ... •Potentiation

Brooks-Kayal AR, et al. J Neurosci. 1999; Stasheff SF, et al. Science. 1989; Sharfman HE. Prog Brain Res. 2007.

Important Factors in Epileptogenesis

• Alteration/expression/membrane localization in GABAA subunits resulting in changes in phasic/tonic inhibition and response to modulators (BZD/Zn)

• Up-regulation of NMDA and AMPA is seen in both models of epileptogenesis and from TLE pathology

• Reorganization of neuronal networks

Page 28: Neurobiology of Epileptogenesisd2qrtshcpf0x30.cloudfront.net/nodes/58/Smith Neurobiology 2018.pdf · Epilepsia. 1997. Excitatory Center Inhibitory surround Basket cells ... •Potentiation

Tauck DL, et al. J Neurosci. 1985; Sutula T, et al. Science. 1988.;Sharfman Prog Brain Res,2007

Synaptic Reorganization Resulting in Hyperexcitability and Epilepsy

• Seizures result in neuronal death of the hilar dentate neurons

• The hilar dentate neuron is the target of the dentate granule mossy fiber axon

• These fibers seek new synaptic contacts, at times, re-innervating themselves resulting in a recurrent positive feedback loop

Page 29: Neurobiology of Epileptogenesisd2qrtshcpf0x30.cloudfront.net/nodes/58/Smith Neurobiology 2018.pdf · Epilepsia. 1997. Excitatory Center Inhibitory surround Basket cells ... •Potentiation

Holmes MM, et al. Behav Neurosci. 2002.

Hippocampal Reorganization

Page 30: Neurobiology of Epileptogenesisd2qrtshcpf0x30.cloudfront.net/nodes/58/Smith Neurobiology 2018.pdf · Epilepsia. 1997. Excitatory Center Inhibitory surround Basket cells ... •Potentiation

Sloviter RS, et al. Science. 1989.

Synaptic Reorganization Resulting in Hyperexcitability and Epilepsy

• Hyperexcitability is due to the loss of feed forward inhibition due to loss of excitatory input to the inhibitory basket cell

• Loss of the inhibitory neurons feedback inhibition

• Probably all three mechanisms are involved

Page 31: Neurobiology of Epileptogenesisd2qrtshcpf0x30.cloudfront.net/nodes/58/Smith Neurobiology 2018.pdf · Epilepsia. 1997. Excitatory Center Inhibitory surround Basket cells ... •Potentiation

Sloviter RS, et al. Science. 1989.

Changes in Synaptic Connectivity in Epilepsy

Page 32: Neurobiology of Epileptogenesisd2qrtshcpf0x30.cloudfront.net/nodes/58/Smith Neurobiology 2018.pdf · Epilepsia. 1997. Excitatory Center Inhibitory surround Basket cells ... •Potentiation

Sloviter RS. Ann Neurol. 1994.

Hippocampal EpilepsyDentate Gyrus as ‘Gatekeeper’

Dentate gyrus

A - Normal circuitry

B -Temporal lobe epilepsy

Dentate gyrus

Hippocampus

Dentate gyrus

Dentate gyrus

Parahippocampal gyrus

Hippocampus

Parahippocampal gyrusBC BCG

Mossy cell

_ _+ +

+

BC BCG

Mossy cell

_ _+ +

+

Hippocampus

Dentate gyrus

Parahippocampal gyrus

1 2 3

1 2 3

Page 33: Neurobiology of Epileptogenesisd2qrtshcpf0x30.cloudfront.net/nodes/58/Smith Neurobiology 2018.pdf · Epilepsia. 1997. Excitatory Center Inhibitory surround Basket cells ... •Potentiation

Lothman EW. Epilepsy: Models, Mechanisms, and Concepts. 1993.

Receptor Activation During SeizureTonic-Clonic Electrographic Paroxysm

EEG

Neuron

PrimaryEpileptogenicZone

AMPA

GABA

NMDA

Non-T Ca++

1sec

Zone ofDissemination

0-20-40-60-80

-100

Page 34: Neurobiology of Epileptogenesisd2qrtshcpf0x30.cloudfront.net/nodes/58/Smith Neurobiology 2018.pdf · Epilepsia. 1997. Excitatory Center Inhibitory surround Basket cells ... •Potentiation

Inflammation in Experimental Models

• In many animal models of epilepsy and acute seizures there is up-regulation of inflammation with microglial activation and increased expression of transcription factors and cytokines that help coordinate the inflammatory response

• Toll-like receptor (TLR) family upregulated in microglia leading to transcriptional activation of cytokines, chemokines in the MHC class I and II

• This contributes to the seizure-related neuronal death and neuronal reorganization seen in hippocampal epilepsies

Zimmer LA, et al. J Comp Neurol. 1997; Turrin NP, et al. Neurobiol Dis. 2004.

Page 35: Neurobiology of Epileptogenesisd2qrtshcpf0x30.cloudfront.net/nodes/58/Smith Neurobiology 2018.pdf · Epilepsia. 1997. Excitatory Center Inhibitory surround Basket cells ... •Potentiation

Kim JV, et al. Nature. 2009. LCMV=lymphocytic choriomeningitis virus

• In mice, CNS infection with LCMV results in seizures and death

• CD8+ T cells recognize LCMV infected cells, bind to them and kill them

• CD8+ T cells secrete chemokines, which trigger influx of myeloid cells and breakdown of BBB

• Depleting the myeloid cells delays seizures and death, suggesting a causal role of inflammation, breakdown of BBB, and fatal seizures

Breakdown of BBB

Page 36: Neurobiology of Epileptogenesisd2qrtshcpf0x30.cloudfront.net/nodes/58/Smith Neurobiology 2018.pdf · Epilepsia. 1997. Excitatory Center Inhibitory surround Basket cells ... •Potentiation

Breakdown of BBB

• Pilocarpine model of experimental seizures and epilepsy

• Pilocarpine results in transient adherence between WBCs and endothelial cells of BBB resulting in a leaky BBB

• This permits albumin and other proteins to cross the BBB causing down regulation of astrocytic K+ channels, disrupting K+ homeostasis producing seizures and epilepsy. Seizures induce angiogenesis with porous BBB.

• Suppressing this interaction between WBC and endothelial cells and porous BBB prevented seizures and progression to epilepsy

Fabene PF, et al. Nat Med. 2008; Ivens S, et al. Brain. 2007; Rigau V, et al. Brain. 2007.

Page 37: Neurobiology of Epileptogenesisd2qrtshcpf0x30.cloudfront.net/nodes/58/Smith Neurobiology 2018.pdf · Epilepsia. 1997. Excitatory Center Inhibitory surround Basket cells ... •Potentiation

Paraneoplastic/Autoimmune Encephalitis

• Clinical phenotype

• Myelitis, limbic or brainstem encephalitis

• Antibodies intracellular proteins– ie, anti-Hu, anti-Ma2, anti CRMPs encephalomyelitis

• Antibodies to synaptic proteins– ie, anti-NMDA, anti-AMPA, LG1 antibody, anti-GABA A,B,

anti-Caspar2, anti-LGI1

• Treatment: Steroids, IVIG, PLEX, remove tumor. If no response rituximab, cyclophosphamide

Graus F, et al. Lancet Neurol. 2016.

Page 38: Neurobiology of Epileptogenesisd2qrtshcpf0x30.cloudfront.net/nodes/58/Smith Neurobiology 2018.pdf · Epilepsia. 1997. Excitatory Center Inhibitory surround Basket cells ... •Potentiation

Epilepsy and Other Chronic Convulsive Diseases

“Every fit, slight or severe, is in some degree the effect of those which precede

it, the cause of those that follow it.”

Gowers WR. 1881.

Page 39: Neurobiology of Epileptogenesisd2qrtshcpf0x30.cloudfront.net/nodes/58/Smith Neurobiology 2018.pdf · Epilepsia. 1997. Excitatory Center Inhibitory surround Basket cells ... •Potentiation

Pathophysiology of Epilepsy

EPILEPTOGENESIS

ONTOGENY

Lothman EW. Epilepsy: Models, Mechanisms, and Concepts. 1993.

Page 40: Neurobiology of Epileptogenesisd2qrtshcpf0x30.cloudfront.net/nodes/58/Smith Neurobiology 2018.pdf · Epilepsia. 1997. Excitatory Center Inhibitory surround Basket cells ... •Potentiation

Epileptogenesis

Genetics

Initiating Event

Critical modulators

Age

Structural/ Functional

changes

Clinical Seizures

CHRONIC EPILEPSY

Refractory Epilepsy?

Latent Period

Neurobehavioral changes, Cognitive impairment?

Page 41: Neurobiology of Epileptogenesisd2qrtshcpf0x30.cloudfront.net/nodes/58/Smith Neurobiology 2018.pdf · Epilepsia. 1997. Excitatory Center Inhibitory surround Basket cells ... •Potentiation

Gowers WR. 1881.

Basic Mechanisms of Epilepsy

• “Seizures beget seizures”

• Kindling model of epilepsy

• Model of partial epilepsy as well as neuronal learning

• Chronic epilepsy is maladaptive learning

• Prevent, rather than treat, intractable epilepsy

Page 42: Neurobiology of Epileptogenesisd2qrtshcpf0x30.cloudfront.net/nodes/58/Smith Neurobiology 2018.pdf · Epilepsia. 1997. Excitatory Center Inhibitory surround Basket cells ... •Potentiation

Anticonvulsant Agents

• Identified by maximal electroshock or metrazolmodels

• Stop expression or spread of seizures

• Na+ channel/GABA mechanism of action

• Little effect on interictal spiking

• No effect on epileptogenesis (development of seizures) as judged by the kindling model of epilepsy

Page 43: Neurobiology of Epileptogenesisd2qrtshcpf0x30.cloudfront.net/nodes/58/Smith Neurobiology 2018.pdf · Epilepsia. 1997. Excitatory Center Inhibitory surround Basket cells ... •Potentiation

Antiepileptogenic Agent

• Affects the development with variable effects on the expression of seizures

• Interferes with the development of kindling

• Suppresses interictal spiking

• Action via glutamate mechanisms/Ca++

• ? Protects neuronal circuits from the deleterious effects of epileptic discharges

Page 44: Neurobiology of Epileptogenesisd2qrtshcpf0x30.cloudfront.net/nodes/58/Smith Neurobiology 2018.pdf · Epilepsia. 1997. Excitatory Center Inhibitory surround Basket cells ... •Potentiation

Kindling Model of Epilepsy

Goddard GV. Nature. 1967.

• In 1967, Goddard reported on a new phenomenon he called “kindling”:

• Electrical stimulation in the rat amygdala that initially produced no clinical change in the animals behavior but did produce an after discharge (AD) if repeated daily

• 10-14 days produced a permanent epileptic condition

Page 45: Neurobiology of Epileptogenesisd2qrtshcpf0x30.cloudfront.net/nodes/58/Smith Neurobiology 2018.pdf · Epilepsia. 1997. Excitatory Center Inhibitory surround Basket cells ... •Potentiation

EEG: Kindling; Day 1-6-14Prolongation and Spread of the AD

Day 1

Day 6

Day 14

Page 46: Neurobiology of Epileptogenesisd2qrtshcpf0x30.cloudfront.net/nodes/58/Smith Neurobiology 2018.pdf · Epilepsia. 1997. Excitatory Center Inhibitory surround Basket cells ... •Potentiation

Kindling Model

Goddard GV. Nature. 1967; Bertram E. Epilepsia. 2007.

• Widespread effects on neurotransmitters, receptors, neuronal processes, and gene expression

• Potentiation EPSP in stimulated pathway

• Long term potentiation (LTP) occurs early in the kindling process

• This allows better coupling between EPSP and neuronal output

Page 47: Neurobiology of Epileptogenesisd2qrtshcpf0x30.cloudfront.net/nodes/58/Smith Neurobiology 2018.pdf · Epilepsia. 1997. Excitatory Center Inhibitory surround Basket cells ... •Potentiation

“This residual disposition to repetition of the same activity is the physical basis of memory, of muscular training, of all cerebral education and

it is the basis of the morbid education of the brain which underlies epilepsy.”

Gowers WR. 1901.

Page 48: Neurobiology of Epileptogenesisd2qrtshcpf0x30.cloudfront.net/nodes/58/Smith Neurobiology 2018.pdf · Epilepsia. 1997. Excitatory Center Inhibitory surround Basket cells ... •Potentiation

Kindling Model

• Only model to allow a quantitative analysis of epileptogenesis and its prevention with AEDs

• Study the effect of AED on AD length and the number of electrical stimulations to reach a certain seizure stage

• Model for SPS, CPS, and CPS with secondary generalization

Bertram E. Epilepsia. 2007.

Page 49: Neurobiology of Epileptogenesisd2qrtshcpf0x30.cloudfront.net/nodes/58/Smith Neurobiology 2018.pdf · Epilepsia. 1997. Excitatory Center Inhibitory surround Basket cells ... •Potentiation

AEDs Effect on Epileptogenesis

• Sodium channel blockers treat kindled seizure but do not inhibit the kindling process

• Sodium channel blockers (DPH,CBZ) offer no prophylaxis in the development of epilepsy

• Valproate, levetiracetam, and perhaps zonisamide, topiramate, and perampanel blunt the epileptogenic process as judged by the kindling model

• ? Prevents the development of epilepsy

Page 50: Neurobiology of Epileptogenesisd2qrtshcpf0x30.cloudfront.net/nodes/58/Smith Neurobiology 2018.pdf · Epilepsia. 1997. Excitatory Center Inhibitory surround Basket cells ... •Potentiation

Conclusions

• Understanding the basic mechanisms of seizures allows increased understanding of the MOA of our AEDS and offers additional treatment targets in the treatment of seizures (ie, gap junction blockers).

• Understanding basic mechanisms of epilepsy offers novel treatment options that may prevent the development of intractable epilepsy and its cognitive and behavioral sequelae.