This presentation provides a brief overview of factors involved in epileptogenesis

1. Basic mechanisms of
epilepsy
Dr Pramod Krishnan
Consultant Neurologist and Epileptologist
HOD Neurology,
Manipal Hospital, Bengaluru

2. Outline of the presentation
• Introductions and definitions.
• Histology of cerebral cortex.
• Neurotransmitters involved.
• Neuronal excitability.
• Genetic mechanism of epilepsy.
• Neuroinflammation and epilepsy.
• Conclusion.

3. Why is this topic important?
• To understand how varied etiological factors result in epilepsy.
• To understand the basis of the electro-clinical features of different
epilepsies.
• To identify potential therapeutic targets for anti seizure medications.
• To prevent epileptogenesis (ultimate goal).

4. Definition:
Seizure: The clinical manifestation of an abnormal and excessive excitation and
synchronization of a population of cortical neurons.
Epilepsy:
• ≥2 unprovoked (or reflex) seizures occurring > 24 hours apart, or
• A single unprovoked (or reflex) seizure and a probability of further seizures
similar to the general recurrence risk (atleast 60%) after 2 unprovoked seizures
occurring over the next 10 years, or
• Diagnosis of an epilepsy syndrome.
Epileptogenesis: Sequence of events that converts a normal neuronal network
into a hyperexcitable network.

7. • Archipallium is 3 layered, eg
Hippocampus.
Hippocampus consists of:
1. Subiculum
2. Hippocampus proper (Ammon's
horn)
3. Dentate gyrus.
• Hippocampus and dentate gyrus
have a three layered cortex.
• Subiculum is the transition zone
from the 3 to the 6 layered cortex.
• Important regions of the
hippocampus proper include CA1,
CA 2, CA3.

8. Babb TL, Brown WJ. In: Engel J. Jr. Ed. Surgical Treatment of the Epilepsies. New York: Raven Press 1987: 511-540.
Cortex includes two classes of
neurons:
1. Projection or principal neurons
(e.g., pyramidal cells)
• They "project" to neurons
located in distant brain areas.
• They form excitatory synapses
on post-synaptic neurons.
2. Interneurons (eg, basket cells):
• They are local-circuit cells which
influence the activity of nearby
neurons.
• Most interneurons form
inhibitory synapses on principal
cells or other inhibitory neurons.
Dentate Gyrus

9. Etiology of Seizures/ Epilepsy
Neonates Infants, children
Perinatal hypoxia, ischemia Developmental disorders
Intracerebral hemorrhage Genetic disorders
Trauma Trauma
CNS infection CNS infection
Genetic disorders Unknown
Disorders of metabolism Disorders of metabolism
Adolescents, young adults Older adults
Trauma Trauma
Genetic disorders Cerebrovascular disease
CNS infections Metabolic diseases
Substance abuse Degenerative brain
diseases
Neoplasms Neoplasms
Unknown Substance abuse
Unknown

10. Inhibition
Excitation
Mechanism of acute symptomatic/ provoked seizures
Mechanism of epilepsy
• In epilepsy there is predisposition to recurrent seizures.
• Seizures are unpredictable and relatively rare.
• Many known mutations and models do not affect excitation or inhibition.
• Mechanism of epilepsy is not just about excitation- inhibition imbalance.
• It should also explain the episodic nature of seizures and the varied etiology.

11. Excitation
Ions: Na and Ca
influx
Neurotransmitters:
Glutamate, Aspartate
Inhibition
Ions: Cl influx, K
efflux
Neurotransmitters:
GABA
A hyperexcitable state can also result when several synchronous subthreshold excitatory
stimuli occur, allowing their temporal summation in the post synaptic neurons.
Increased excitatory
neurotransmission
Decreased inhibitory
neurotransmission
Alteration in voltage
gated ion channels
Alteration in intra or
extra cellular ion
concentrations

12. Role of neurotransmitters
Glutamate
Major excitatory neurotransmitter.
Inotropic receptors
Fast synaptic transmission.
NMDA, AMPA, Kainate: Na influx.
NMDA: Ca influx. Can cause excitotoxicity
and cell death due to excessive stimulation
(eg in status).
Agonists trigger seizures.
Metabotropic receptors
Slow synaptic transmission.
Signal transduction involving membrane-
associated G-proteins.
Stimulation results in variable effects.
GABA
Major inhibitory neurotransmitter.
GABAA
Post synaptic.
Causes Cl influx and hyperpolarisation.
Agonists suppress seizures (BZD,
barbiturates).
GABAB
Presynaptic autoreceptors.
Can modulate synaptic release.
Associated with second messenger systems.
Causes K channel opening and
hyperpolarizing current.

13. Inotropic receptors and their
associated ion channels form one
complex (top). Each iGluR is formed
from the co-assembly of multiple (4-
5) subunits.
Metabotropic receptors are coupled to
their associated ion channels by a
second messenger cascade (top). Each
mGluR is composed of one polypeptide,
which is coupled to a G- protein.

15. Glutamate and GABA reuptake
• Relevant to epilepsy, glutamate and GABA both require active reuptake
to be cleared from the synaptic cleft.
• Transporters for both glutamate and GABA exist on both neurons and
glia (primarily astrocytes).
• Interference with transporter function has also been shown to activate
or suppress epileptiform activity in animal models, depending on which
transporter is being blocked.

16. Neuronal excitability
Extra- neuronal/ Extrinsic
factors
Neuronal/ Intrinsic factors
(neurons, glia, vascular
endothelial cells)
• Changes in extra-cellular ion
concentration.
• Remodelling of synapse
location or configuration by
afferent input.
• Modulation of transmitter
metabolism or uptake by glial
cells.
• Ion channel type, number and
distribution.
• Biochemical modification of
receptors.
• Activation of second
messenger systems.
• Modulation of gene
expression (eg receptor
proteins).

17. Ion channel type, number and
distribution.
Intrinsic factors affecting neuronal excitability
Biochemical modification of
receptors.
Activation of second
messenger systems.
Modulation of gene
expression
This decides the direction, degree, and rate of changes in the
transmembrane potential.
E.g, Phosphorylation of the NMDA receptor increases
permeability to Ca++, resulting in increased excitability.
E.g, Binding of norepinephrine to its alpha receptor activates
cGMP, in turn activating G-proteins which open K+ channels,
thereby decreasing excitability.
E.g, editing a single base pair of mRNA encoding a specific
glutamate receptor subunit can change the ion selectivity of the
assembled channel.

18. Changes in extra cellular ion
concentration.
Extrinsic factors affecting neuronal excitability
Remodelling of synapse
location or configuration by
afferent input.
Modulation of transmitter
metabolism or uptake by glial
cells.
E.g, decreased extracellular volume leads to increased extracellular
K+ concentration, resisting the outward movement of K+ ions
needed to repolarize the cell, thereby effectively increasing
excitability.
E.g, previous synaptic experience such as a brief burst of high
frequency stimulation (e.g., long-term potentiation) increases the
efficacy of such synapses, increasing their excitability.
E.g, Excitability increases if glial metabolism or uptake of
excitatory transmitters such as glutamate or ACh decreases.

19. Final common pathway of ictogenesis
• Diverse set of pathways leading
to a final common
pathophysiology of episodic
shifts in the excitation-inhibition
balance which are self-reinforcing
through activity-dependent
disinhibition.
Episodic shifts in network state
(excitation inhibition imbalance)
Increased network activity/
excitation leading to network
instability
Crosses seizure threshold,
leading to seizures
Self reinforcing through activity
dependent disinhibition

20. Results in activity dependent
disinhibition
Episodic surges in network activity
may rarely cross a “seizure
threshold” of activity level.
Positive feedback
mechanism
Rapid degradation of inhibition in the epileptic
network and increased network activity
If transient imbalances in inhibition and excitation
promoted further imbalance, this could occasionally
build to the point of engendering a seizure.

21. Timing of seizures
• This is due to episodic shifts in the balance of excitation and inhibition.
• Change in network (brain) states:
1. ADNFLE occurring in NREM sleep.
2. Catamenial epilepsy occurring at specific stages of menstrual cycle.
• However, seizures do not occur in most of the at-risk periods. So other
additional factors are at play during the at-risk period.
• Low-probability ictal transitions and ictal stability (stereotyped seizure
duration) can be explained by positive feedback mechanism.

22. Neuronal homeostasis: process by which
neurons regulate their excitability
Neuronal loss, leading to
loss of connectivity and
network instability
Wiring and rewiring
of circuits
Downregulation of
excitatory and upregulation
of inhibitory conductances
Excitable networks
Seizures/ Epilepsy
Recovery without
development of epilepsy
FailsSuccessful
TBI, CVA, infections,
neurodegeneration
Network activity
crosses seizure
threshold
Self reinforcing through
activity dependent disinhibition
Excitatory axonal sprouting
Loss of inhibitory neurons
Loss of excitatory neurons-
driving inhibitory interneurons

23. Perinatal insult
Alteration in ion channels and receptors
Induction of immediate early genes
Changes in neurotransmission
leading to hyperexcitable or
hypoexcitable circuits
Neuronal death
Microglial activation
Neurotrophic factor
expression
Modulation of synaptic
plasticity
Transcriptional changes
Axonal sprouting
Neurogenesis
Gliosis
Neonatal seizures
Epileptic
network
Two hit hypothesis
Acute stage
Subacute stage
Chronicstage

24. Role of neuro inflammation
• Epilepsy is a proinflammatory state: high IL-1β, HMGB1, IL-2, TNF-α,
IFN-α, IL-17, IL-6, NF-kβ.
• Neurologic inflammation can precipitate and perpetuate seizures.
• Inflammatory process can be peripheral or central.
• Persistent inflammation can explain drug refractoriness.
• Steroids can control seizures in some patients.
HMGB1: high mobility group box 1
Neuro
inflammation
Epilepsy

25. Dravet syndrome
SCN1A mutation
Loss of function mutation
Hyperexcitable networks
and epilepsy
Reduced activity in
inhibitory interneurons
(fast firing GABA ergic
basket cells)
Altered activity of sodium
channels in the membrane
due to impaired feedback
mechanisms
Genetic mechanisms in epilepsy
Dysregulation of sodium
current
Lower density of
Nav1.1 channels
Lower density of
Nav1.1 channels
Principal neurons

26. mTOR pathway:
Essential for outgrowth of afferent
and efferent neural processes
ARX gene
Encodes a transcription factor
necessary for neuronal migration
Excessive neuronal outgrowth and
unnecessary neuronal connectivity
Epilepsy
Failure of interneuron
migration
Inadequate disinhibition of
cortical networks especially
during peak network activity
A host of signals regulate interneuron differentiation and migration, and
mutations in many of these signals are associated with severe epilepsy.
Hyperexcitable
networks
Mutation Mutation

27. Mechanism of delayed epileptogenesis
Kindling model: repeated subconvulsive stimuli resulting in electrical
after-discharges
• Eventually lead to stimulation-induced clinical seizures
• In some cases, lead to spontaneous seizures (epilepsy)
• Applicability to human epilepsy uncertain
B-Slide 27

28. Conclusion
• Epilepsy can arise due to various causes.
• Final common pathway is disturbance of excitation- inhibition balance
(neuronal homeostasis) resulting in self reinforcing episodic shifts in
neuronal and network excitability.
• This involves multiple neurotransmitters (primarily GABA and
Glutamate), ion conductance (primarily Na, K, Ca, Cl) and genetic
factors.
• Major role for interneurons and glial cells in epileptogenesis.
• Neuroinflammation plays a role in epileptogenesis.

29. THANK YOU

30. Recommended articles
• Staley K. Molecular mechanisms of epilepsy. Nat Neurosci. 2015
Mar;18(3):367-72. doi: 10.1038/nn.3947. Epub 2015 Feb 24.
• Vitaliti G, et al. Molecular mechanisms involved in the pathogenesis of
early onset epileptic encephalopathy. Front Mol Neurosci. 2019 May
15;12:118. doi: 10.3389/fnmol.2019.00118.
• Nikkola E, et al. Genetic mechanisms of epilepsy. Practical Neurology
Oct 2019; 56-59.
• Goldberg EM, et al. Mechanisms of epileptogenesis: a convergence on
neural circuit dysfunction. Nat Rev Neurosci. 2013 May;14(5):337-49.
doi: 10.1038/nrn3482