What is epilepsy?

How can you see a generalised seizure on an

EEG?
What percentage of the adult population have
active epilepsy?
What percentage of children experience one or
more seizures?
What percentage of children who have had
seizure in childhood develop epilepsy in
adulthood?
Is epilepsy higher in men or women?
At which age ranges is the incidence of epilepsy
at its highest?
What do the symptoms (presentation of
epilepsy) of epilepsy depend on?

When is a seizure partial?

When is a seizure primarily generalised?

When is a seizure secondarily generalised?

What are the two types of partial seizure?

What is an aura?

What can trigger epileptic fits?

Describe an absence seizure (petit mal)

Describe tonic-clonic seizures (grand mal)

A disorder of the CNS characterised by

recurrent, sudden, large increases in the
electrical activity (electrical seizures) that may
be localised or generalised
You will see seizure activity across the cortex
(at all/most of the electrodes)
0.5 1%
2 5% (usually benign febrile convulsions)
10%

Men
Very young and very old
1. The CNS region(s) in which the
electrical seizure occurs
2. Whether the seizure is localised or
generalised
3. If localised initially, whether the seizure
then spreads to other regions of the
CNS
(Localised, focal)
If the seizure is restricted to a limited
region
If most of the CNS is involved but no
focus can be distinguished
If most of the CNS is involved
eventually but the excitation has
spread from an initial focus
1. Simple if the subject remains
conscious and aware
2. Complex if consciousness is impaired
Seizures are frequently preceded by an
aura: a feeling or experience that
warns the subjects of an impending
seizure
Repetitive sensory stimuli, especially visual
stimuli such as flashing lights
A primarily generalised seizure that is
common in children
Characterised by sudden loss of
awareness lasting up to about 30
seconds
A generalised seizure lasting 2 5
minutes that is characterised by sudden
stiffening (tonic) of muscles, a fall,
followed by jerking (clonic)
movements

Describe simple partial seizures (example:

Jacksonian)

Describe temporal lobe epilepsy (psychomotor

epilepsy)

Describe status epilepticus

Why are seizures not immediately associated

with epilepsy?

What three things can cause one-off seizures?

What is an epilepsy syndrome?

An example would be a focal cortical

seizure characterized by jerking
movements that begin in the
extremities and spread throughout the
body (Jacksonian march)
Affects motor cortex and moves across
the motor cortex
May be sensory symptoms rather than
motor
A partial seizure of the temporal lobe
that may be a simple partial seizure
characterised by emotional, sensory or
memory-related phenomena (deja-vu is
a minor localised benign seizure)
Or a complex partial seizure where the
seizure spreads throughout the
temporal lobe impairing consciousness
and may be secondarily generalised to
provoke a tonic-clonic seizure
The commonest tonic-clonic seizures
are those secondary to a temporal lobe
seizure
This is the commonest form of epilepsy
When a seizure does not spontaneously
stop but continues or repeats for a
period of 30 minutes or more the
condition is termed status epilepticus
and is life threatening
Seizures of themselves do not
immediately indicate a diagnosis of
epilepsy
It may be a one-off seizure related to
stress or seizures associated with
specific circumstances such as
hypoglycaemia, dehydration or alcohol
withdrawal syndrome
Epilepsies, especially childhood
epilepsies, can sometimes be further
classified as syndrome which are
collections of signs and symptoms that
more closely identify the particular
conditions
Better definition helps to achieve the
optimum therapeutic approach
Factors that are considered on defining
a syndrome include:
o The type and pattern of
seizures
o The frequency
o The location of the focus
o Physical and mental symptoms

What are the causes of epilepsy?

Which mutations are associated with benign
febrile epilepsy?
Which mutations are associated with familial
generalised epilepsy with febrile seizures?
What % are idiopathic?
What % are symptomatic?
What is the fold increase of developing epilepsy
if you have a close relative with epilepsy?
What is the last cause of epileptic fits?

Describe the major animal models used to

study epilepsy
Where are the injections given?
Where is the electrical stimulation given?
What have the studies shown that are the
problems in the brain which lead to epilepsy?

o The age of onset

o The gender of the patient
o The prognosis
There are at least 40 identified epilepsy
syndromes
In most cases the cause of epilepsy is
not known (idiopathic) or cannot be
proven (cryptogenic)
About 30% of cases are symptomatic
o i.e. the seizures occur following
head injury (often after a
delay), stroke, an infection,
tumour growth, drug abuse
There is a 2 3 fold increase in the
chances of developing epilepsy if you
have a close relative who suffers from
the disease but clear genetic links have
been difficult to trace suggesting
multiple genes or environmental
factors are involved
o Benign febrile epilepsy is linked
to mutations in KCNQ2 and
KCNQ3: genes that encode
voltage gated potassium
channels
o Familial generalised epilepsy
with febrile seizures plus is
linked to mutations in SCN1B: a
gene that encodes an accessory
subunit of the voltage-gated
sodium channel
Some epilepsy may be drug-induced:
many drugs have pro-convulsant
effects
1. Kainic acid (KA) injection
a. Binds to a subtype of glutamate
receptors (Kainate receptors)
b. After binding it causes neurons
to be excitable and depolarise
quickly and can even die
c. Therefore Kainate is excitotoxic
d. Local (e.g. intrahippocampal) or
systemic injections of KA can
induce seizures in animals and
lead to chronic epileptic
behaviour
2. Kindling
a. Repeated low intensity
electrical stimulation (usually in
the amygdala or hippocampus)
of some brain regions leads,

after a delay, to development

of chronic epileptic behaviour
b. The frequency of the kindling
stimulus is critical
c. Several mechanisms have been
proposed

Describe the initiation of a seizure

What does the rise (depolarising phase) depend

on?

What curtails seizures?

What causes epilepsy according to this theory?

Studies using these (any many other:

pentylenetetrazol injection,
electroshock etc) models and looking at
the data coming from these models (by
looking at changes in brain tissue)
suggest that the focal synchronous
excitation that occurs to initiate a
seizure involves:
o Increased synaptic transmission
o Decreased surround inhibition
The cellular event that initiates a focal
seizure is called a paroxysmal
depolarising shift (PDS)
The rise (depolarising phase) of the
cellular PDS depends on activation of
ionotropic glu receptors (AMPA and
NMDA), and opening of voltage gated
calcium channels (increased glutamate
synaptic transmission)
Curtailment (the action of reducing
something) of PDS and repolarization
depends on opening of voltage gated
potassium channels and activation of
ionotropic GABA receptors (inhibitory
interneurons)
During the extended period of time
(time period may vary) that the neuron
is depolarised, it will fire many action
potentials
This doesnt necessarily give rise to a
seizure unless it spreads
It is thought that auras are the
sensations perceived when this is
happening in a small focal point (it
hasnt spread yet)
The mechanism by which PDS is
initiated is not known (it is a
spontaneous event) but the ability of
the PDS to spread to neighbouring cells
to generate a synchronous focus
implies a failure of inhibitory feedback
through local interneurons
Epilepsy is often described as being due
to an imbalance between glutamate-

Describe surround inhibition

Describe the therapeutic drug treatments

which can treat tonic-clonic, partial and
temporal lobe seizures (may provoke absences)
What are the two broad types
Name the 4 subtypes in number 1
Name the 3 drugs in number 2

mediated excitation and GABAmediated inhibition which has led to

attempts to develop drugs that inhibit
glutamate or enhance GABA as
potential therapeutic agents
Diverging synaptic connections of
neurons in a relay nucleus can lead to
spreading as well as blending of
information flowing out of the nucleus
Surround inhibition mediated by
interneurons through feedback
pathways has the effect of limiting the
spread of the input signalling (i.e. it has
a focusing effect) each neuron will
inhibit its neighbour via the inhibitory
interneuron
This focuses the signalling of
information through the centre of the
network
It will control the flow of information
Surround inhibition will localize
discharges (e.g. due to PDS) and
prevent their spread but reduction or
loss of surround inhibition will allow
spread of excitation through networks
So that is how the seizure spreads
1. Enhance the activity of GABAergic
systems (increase surround inhibition
prevents spread and may prevent
initiation of seizure)
a. Benzodiazepines (e.g.
diazepam, clonazepam) are
drugs that enhance the activity
of GABA. They bind to a
regulatory site on the GABAA
receptor and increase the
affinity of the receptor for
GABA benzodiazepines are
given intravenously to treat
status epilepticus but are
usually too sedative for
prophylactic use in other
epilepsies although oral BDZs
are used sometimes in patients
who do not respond well to
other treatments (clonazepam)
b. Barbiturates (phenobarbitone)
prolong the time that GABAactivated Cl- channels say open
when the GABAA receptor is
occupied

Describe how voltage-gated sodium channels

work in the brain
What are the two gates that they have?
What are the stages when depolarisation
occurs?

How do use-dependent blockers of sodium

channels suppress high frequency AP activity?
When these bind what does AP frequency
depend on?

c. Vigabatrin inhibits GABA

transaminase (decreases
metabolism of GABA)
d. Tiagabin inhibits GABA uptake
(increases the concentration of
GABA in the extracellular
space)
2. Use-dependent block of voltage-gated
sodium channels
a. Carbamazepine, phenytoin,
lacosamide (very common
prophylactic treatments):
These drugs will reduce the
likelihood of action potentials
firing at high frequencies but
have relatively little effect at
low frequencies. Their binding
(and hence blocking action) to
the voltage-gated sodium
channels is state-dependent
VGSCs have two gates
o Activation gate which is shut at
negative membrane potentials
o Inactivation gate which is open
at negative potentials
When something depolarises a cell, the
activation gate opens and allows
sodium influx causes further
depolarisation
Once depolarisation has occurred, the
inactivation gate shuts which prevents
further sodium influx and therefore
prevents further
depolarisation/sustained depolarisation
Then voltage gated potassium channels
open which repolarise the cell due to
efflux of potassium
There are a few more stages then the
neuron resets and can depolarise again
(refractory period)
Use-dependent sodium channels bind
to and stabilize the inactivated state of
the channel which increases the
refractoriness of the cell and limits the
maximum frequency at which the cell
can fire
So the drug doesnt bind to sodium
channels at rest or in the activated
state but only in the inactivated state
thus prolonging refractoriness
You cannot have another AP while the

Describe the therapeutic drug treatments

which can treat absence seizures only?

What is the mechanism which is thought the be

the main one?
What effect does this have on the CNS?

Describe the therapeutic drug treatments

which can treat absence seizures and tonicclonic seizures

1.

2.

Describe some miscellaneous drugs for treating

epilepsy

1.

7 drugs
5 points
2.

drug is bound, so the frequency

depends on how quick the drug
dissociates from the channel
They are state-dependent blockers
Therefore, they are good for treating
the high frequency activity of epileptic
seizures and do not affect relatively low
frequency activity of normal cortical
activity
Some drugs may also have affinity for
the open state of the channel and
combine and open-channel blocking
action with prolongation of inactivation
Ethosuximide:
o Mechanism uncertain
o Thought to work by blocking Ttype voltage-gated Ca2+
channels in thalamic neurons
(best guess)
o The thalamus and cortex drive
each other in a sort-of loop
o Maintenance of the loop is
important for awareness
o Ethosuximide binds to the ion
channels to interfere with the
loop and synchronisation of
thalamo-cortical activity
o These channels are important
for the generation of rhythmic
activity in the neurones. Not
useful for tonic-clonic seizures
Sodium valproate (solvent)
a. Mechanism uncertain
b. Combines a weak blocking
action on voltage-gated sodium
channels with a weak inhibition
of GABA transaminase
Lamotrigine
a. Probably a use-dependent
sodium channel blocker
Gabapentin, pregabalin:
a. Mechanism is uncertain but the
molecular target is known to be
the alpha2gamma subunit of
voltage-gated calcium channels
so they probably work by
compromising NT release
Retigabine (Ezogabine in USA):
a. Acts by provoking the opening
of K+ channels of the KCNQ
type (one of the channels

3.

4.

5.
How do we know which anti-epileptic drug to
give?

Describe some other treatments for epilepsy

1.

2.

implicated in genetic febrile

seizures) so the anticonvulsant
effect is probably due to
stabilisation of the resting
membrane potential of
neurones
Perampanel (approved in EU not USA)
a. Thought to act as antagonists
of AMPA receptors
Levetiracetam:
a. Levetiracetam binds to a
synaptic vesicle protein called
SV2A so it may affect
neurotransmission
Topiramate, zonisamide
a. Mechanism uncertain
The usefulness of individual agents for
different epileptic conditions if varied
and based on clinical experience
general rules are difficult to define or
apply
Many drugs are useful given alone
(monotherapy e.g. carbamazepine,
phenobarbitone, ethosuximide, sodium
valproate, Topiramate, lamotrigine)
whilst others are recommended for
adjunctive therapy (e.g. tiagabine,
vigabatrine, gabapentin, retigabine)
Drugs that are useful for tonic-clonic
seizures are not always useful for
absence seizures and may even make
them worse (carbamazepine,
phenobarbitone, phenytoin)
Conversely, ethosuximide is useful for
absence seizures but is not effective for
tonic-clonic seizures
Sodium valproate and lamotrigine are
potentially useful for both classes of
seizure
Monitoring dose and the potential for
drug interactions is very important
Ketogenic diet
a. It is argued that a high fat, low
carb diet (normal protein) is
beneficial for the control of
epileptic seizures in children (at
least)
b. Sometimes used when
conventional therapy is not
sufficiently effective
Vagal stimulation

3.

State two ways in which animal models can be

created for studying epilepsy

Focal seizures can be triggered by a paroxysmal

depolarising shift. Explain what this means.

Name five types of epilepsy treatment. Give an

example of a treatment for each.

1.
2.

3.

4.
5.

a. A surgically implanted device

stimulates the vagus nerve by
applying regular electrical
stimuli
b. The device can also be
activated by a magnet to
deliver a predefine program of
stimuli to abort and ongoing or
impending attack
c. The device is effect but the
mechanism by which it works is
not known
Surgery
a. Removal of tissue that
harbours a recurrent focus or
to limit spread of excitation
Local or systemic injections of kainic
acid can induce seizures and cause
chronic epileptic behaviour
Kindling repeated low intensity
stimulation, usually of the amygdala or
hippocampus, causes chronic epileptic
behaviour after a delay.
Paroxysmal means a sudden attack.
Depolarising shift means theres a flow
(shift) of electrolytes across cell
membranes which causes
depolarisations.
The initiation mechanism for these is
not known, but the ability to spread
suggests a failure of inhibitory
interneurones
Enhance GABA activity e.g.
Benzodiazepines
Block voltage-gated Na+ channels in a
use-dependent way, e.g.
Carbamazepine, phenytoin
Drugs for absence seizures e.g.
Ethosuxamide, sodium valproate.
Mechanism isnt clear for these.
Other drug treatments include
gabapentin and pregabalin
Non-drug treatments, e.g. ketogenic
diet, vagal stimulation and surgery
(remove tissue that is a recurrent
focus)