Epilepsy

An estimated 40 million individuals

worldwide have epilepsy.
This estimate is based on epidemiological
data gathered as part of the Global Burden
of Disease (GBD)

Epidemiology
Mortality data from GBD, a traditional
measure of burden of disease, indicates
that 142,000 persons with epilepsy die
annually, equating to 0.2% of all deaths
worldwide.

Epidemiology
Acknowledging the need to define burden
beyond mortality, the GBD study
introduced a new measure of burden of
diseases, injuries, and risk factors, the
DALY (disability adjusted life year).

Epidemiology
One DALY equates to 1 year of healthy
life lost due to disability or poor health.
Epilepsy is estimated to contribute
7,854,000 DALYs (0.5%) to the global
burden of disease.

Epidemiology
A clear pattern emerges from the GBD data
whereby over half of all deaths and half of
all years of healthy life lost to epilepsy
occur in low-income countries.

Epidemiology
Moreover, almost one in five of all deaths
and almost one in four of all years of
healthy life lost to epilepsy worldwide
occur among children living in low-income
countries.

Epidemiology
A major contributor in low-income
countries is the treatment gap, that is, the
difference between the number of
individuals with active epilepsy and the
number who are being appropriately
treated at a given point in time.

Epidemiology
Estimates suggest that up to 90% of people
with epilepsy in resource-poor countries
are inadequately treated .

Epidemiology
The burden of epilepsy, however, extends
beyond physical health status. Stigma and
discrimination are common features of the
condition worldwide.

Epidemiology
Profound social isolation, feeling of shame
and discomfort, and higher risk of
psychiatric disorder are among a host of
variables contributing to a compromised
quality of life.

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DEFINITIONS
A seizure is a paroxysmal event due to
abnormal, excessive, hypersynchronous
discharges from an aggregate of central
nervous system (CNS)neurons (cortical
neurons).
Have various manifestations.

DEFINITIONS
A seizure that occurs in the absence of an
acute provoking event is considered
unprovoked
An acute provoked seizure is one that
occurs in the context of an acute brain
insult or systemic disorder, such as, but not
limited to, stroke, head trauma, a toxic or
metabolic insult, or an intracranial infection

DEFINITIONS
Epileptic seizure:
Is a transient occurrence of signs and/or
symptoms due to abnormal excessive or
synchronous neuronal activity in the brain.

DEFINITIONS
Epileptic seizures must be distinguished from
nonepileptic seizures and from other
conditions that may produce clinical
manifestations that are highly similar to
those caused by epileptic seizures.

DEFINITIONS
Epilepsy :
(recurrent, unprovoked seizures) individual
have at least two unprovoked seizures on
separate days, generally 24 hours apart.

DEFINITIONS
An individual with a single unprovoked
seizure or with two or more unprovoked
seizures within a 24-hour period is
typically not at that time considered to
have met the criteria for labeling him with
the diagnosis of epilepsy per se

Epilepsy Syndromes
Epilepsy, like cancer, is not a single disorder,
and the efforts to identify specific forms of
epilepsy reflect the importance of the
diversity within the epilepsies.

Epilepsy Syndromes
The epilepsy syndromes represent forms of
epilepsy that have different causes, different
manifestations, different implications for
short- and long-term management and
treatment, and different outcomes

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PATHOPHYSIOLOGY
Those questions were as follows:
(i)what are the long-term consequences of
seizures? Can these be modified?
(ii)what is the best anticonvulsant therapy?
(iii) What is the best antiepileptogenic
therapy?

PATHOPHYSIOLOGY
From these questions, the mechanisms of
seizure initiation, prolongation, and termination
must be addressed, and their sequelae defined.
Further, the mechanisms underlying the
development of spontaneous repetitive seizures
(SRS) (epileptogenesis) and associated
cognitive dysfunction must begin to be
addressed.

PATHOPHYSIOLOGY
Focal-Onset
Seizures

The following mechanisms may coexist in

different combinations to cause focal-onset
seizures:
1- Increased activation
2- Decreased inhibition
3-Defective activation of (GABA) neurons

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PATHOPHYSIOLOGY
Beginning with receptor activation, followed
by alterations in membrane polarization,
potentially loops around to result in
alterations of the properties of the initial
trigger of receptor activation.

PATHOPHYSIOLOGY
Such a loop likely underlies normal plasticity
associated with processes like learning and
memory, but perhaps becomes unstable with
seizures and epileptogenesis, leading to
aberrant plasticity that could result in both
seizures and cognitive dysfunction

PATHOPHYSIOLOGY

Glutamatergic Ion Channels

Glutamate is the major excitatory
neurotransmitter in the brain.
The release of glutamate causes an EPSP
in the postsynaptic neuron by activating
the families of glutamate-activated ligandgated cation channels.

Glutamatergic Ion Channels

classified according to their preferred
agonists:
1- kainate, -amino-3-hydroxy-5-methyl-4isoxazole propionate (AMPA) = (GluR1-4)
and (GluR5-7)
2- N-methyl-D-aspartate (NMDA) = (NR1,
NR2A-D)

Glutamatergic Ion Channels

Calcium influx through NRs is thought to
mediate the calcium-activated processes
involved in long-term potentiation and
depression (LTP and LTD) which are
thought to be synaptic models of learning
and memory .
They participate in the induction of
plasticity in this fashion.

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Neural Plasticity
The capacity of the nervous system to
changegenerally referred to as neural
plasticity
plasticity is so fundamental that its
essential cellular and molecular
underpinnings are likely to be conserved in
the nervous systems of very different
organisms.

Epilepsy & Neural Plasticity

It seems likely that abnormal activity
generates plastic changes in cortical circuitry
that are critical to the pathogenesis of the
disease.
The importance of neuronal plasticity in
epilepsy is indicated most clearly by an
animal model of seizure production called
kindling.

Epilepsy & Neural Plasticity

To induce kindling, a stimulating electrode
is implanted in the brain, often in the
amygdala (a component of the limbic
system that makes and receives
connections with the cortex, thalamus, and
other limbic structures, including the
hippocampus).

Epilepsy & Neural Plasticity

At the beginning, weak electrical
stimulation, in the form of a low-amplitude
train of electrical pulses, has no discernible
effect on the animals behavior or on the
pattern of electrical activity in the brain
(laboratory rats or mice have typically
been used for such studies).

Epilepsy & Neural Plasticity

As this weak stimulation is repeated once a
day for several weeks, it begins to produce
behavioral and electrical indications of
seizures.
By the end of the experiment, the same
weak stimulus that initially had no effect
now causes full-blown seizures.

Epilepsy & Neural Plasticity

This phenomenon is essentially permanent; even
after an interval of a year, the same weak
stimulus will again trigger a seizure.
Thus, repetitive weak activation produces longlasting changes in the excitability of the brain
that time cannot reverse.
The word kindling is therefore quite appropriate:
A single match can start a devastating fire.

Epilepsy & Neural Plasticity

The changes in the electrical patterns of
brain activity detected in kindled animals
resemble those in human epilepsy.
The behavioral manifestations of epileptic
seizures in human patients range from mild
twitching of an extremity to loss of
consciousness and uncontrollable
convulsions.

The short-term forms of

plasticity
Synaptic plasticity mechanisms occur on
time scales ranging from milliseconds to
days, weeks, or longer. The short-term
forms of plasticitythose lasting for
minutes or less

The short-term forms of

plasticity
Facilitation of the EPP occurs at the
beginning of the stimulus train and is
followed by depression of the EPP.
After the train of stimuli ends, EPPs are
larger than before the train.
This phenomenon is called post-tetanic
potentiation.

The Long-term forms of

plasticity
Some patterns of synaptic activity in the
CNS produce a long-lasting increase in
synaptic strength known as long-term
potentiation (LTP) , whereas other patterns
of activity produce a long-lasting decrease
in synaptic strength, known as long-term
depression (LTD) .

The Long-term forms of

plasticity
LTP and LTD are broad terms that describe
only the direction of change in synaptic
efficacy; in fact, different cellular and
molecular mechanisms can be involved in
producing LTP or LTD at different
synapses.

The Long-term Potentiation of

Hippocampal Synapses
The arrangement of neurons allows the
hippocampus to be sectioned such that
most of the relevant circuitry is left intact.
In such preparations, the cell bodies of the
pyramidal neurons lie in a single densely
packed layer that is readily apparent in the
next figure.

The Long-term Potentiation of

Hippocampal Synapses
This layer is divided into several distinct
regions, the major ones being CA1 and
CA3.
CA refers to cornu Ammon , the Latin
for Ammons hornthe rams horn that
resembles the shape of the hippocampus.

The Long-term Potentiation of

Hippocampal Synapses

The Long-term Potentiation of

Hippocampal Synapses
The dendrites of pyramidal cells in the
CA1 region form a thick band (the stratum
radiatum), where they receive synapses
from Schaffer collaterals, the axons of
pyramidal cells in the CA3 region.

The Long-term forms of

plasticity
Electrical stimulation of Schaffer
collaterals generates excitatory
postsynaptic potentials (EPSPs) in the
postsynaptic CA1 cells .
If the Schaffer collaterals are stimulated
only two or three times per minute, the size
of the evoked EPSP in the CA1 neurons
remains constant.

The Long-term forms of

plasticity
However, a brief, high-frequency train of
stimuli to the same axons causes LTP, which is
evident as a long-lasting increase in EPSP
amplitude .
LTP occurs not only at the excitatory synapses
of the hippocampus shown, but at many other
synapses in a variety of brain regions, including
the cortex, amygdala, and cerebellum.

The Long-term forms of

plasticity

Characteristics of LTP
First, LTP is state-dependent :
The state of the membrane potential of the
postsynaptic cell determines whether or
not LTP occurs ( next figure ).

Characteristics of LTP
If a single weak stimulus to the Schaffer
collateralspaired with strong depolarization
of the postsynaptic CA1 cell, the activated
Schaffer collateral synapses undergo LTP.
The increase occurs only if the paired activities
of the presynaptic and postsynaptic cells are
tightly linked in time,

Characteristics of LTP

Characteristics of LTP
LTP also exhibits the property of input
specificity :
When LTP is induced by the stimulation of one
synapse, it does not occur in other, inactive
synapses that contact the same neuron .
Thus, LTP is restricted to activated synapses
rather than to all of the synapses on a given cell

Characteristics of LTP
Another important property of LTP is
associativity :
As noted, weak stimulation of a pathway will
not by itself trigger LTP.
However, if one pathway is weakly activated at
the same time that a neighboring pathway
onto the same cell is strongly activated, both
synaptic pathways undergo LTP.

Molecular mechanism of
LTP
NMDA receptor channel is permeable to
Ca 2+ , but is blocked by physiological
concentrations of Mg 2+ .
This property provides a critical insight
into how LTP is induced.

Molecular mechanism of
LTP
During low-frequency synaptic
transmission, glutamate released by the
Schaffer collaterals binds to both NMDAtype and AMPA/kainate-type glutamate
receptors.

Molecular mechanism of
LTP
While both types of receptors bind
glutamate, if the postsynaptic neuron is at
its normal resting membrane potential, the
NMDA channels will be blocked by Mg 2+
ions and no current will flow (Left of next
figure).

Molecular mechanism of
LTP
Because blockade of the NMDA channel by
Mg 2+ is voltage-dependent, the function of the
synapse changes markedly when the
postsynaptic cell is depolarized. Thus,
conditions that induce LTP, such as highfrequency stimulation will cause a prolonged
depolarization that results in Mg 2+ being
expelled from the NMDA channel (Right of
next figure).

Molecular mechanism of
LTP

Molecular mechanism of
LTP
Removal of Mg 2+ allows Ca 2+ to enter
the postsynaptic neuron and the resulting
increase in Ca 2+ concentration within the
dendritic spines of the postsynaptic cell
turns out to be the trigger for LTP.

Molecular mechanism of
LTP
The NMDA receptor thus behaves like a
molecular and gate: The channel opens
(to induce LTP) only when glutamate is
bound to it and the postsynaptic cell is
depolarized to relieve the Mg 2+ block of
the receptor.
Thus, the NMDA receptor can detect the
coincidence of two events

Molecular mechanism of
LTP
These properties of the NMDA receptor
can account for many of the characteristics
of LTP.
The specificity of LTP can be explained by
the fact that NMDA channels will be
opened only at synaptic inputs that are
active and releasing glutamate, thereby
confining LTP to these sites.

Molecular mechanism of
LTP
With respect to associativity a weakly
stimulated input releases glutamate, but
cannot sufficiently depolarize the
postsynaptic cell to relieve the Mg 2+ block.
If neighboring inputs are strongly stimulated,
however, they provide the associative
depolarization necessary to relieve the block.

Molecular mechanism of
LTP
Rise in the concentration of Ca 2+ in the
postsynaptic CA1 neuron, due to Ca 2+ ions
entering through NMDA receptors, serves as
a second messenger signal that induces LTP.
Cuz injection of Ca 2+ chelators blocks LTP
induction, whereas elevation of Ca 2+ levels
in postsynaptic neurons potentiates synaptic
transmission.

Molecular mechanism of
LTP
Ca 2+ induces LTP by activating complicated
signal transduction cascades that include
protein kinases in the postsynaptic neuron.
At least two Ca 2+-activated protein kinases
have been implicated in LTP induction Ca 2+
/calmodulin-dependent p rotein kinase
(CaMKII) and protein kinase C .

Molecular mechanism of
LTP
CaMKII seems to play an especially important
role: This enzyme is the most abundant
postsynaptic protein at Schaffer collateral
synapses, and pharmacological inhibition or
genetic deletion of CaMKII prevents LTP.
The downstream targets of these kinases are
not yet fully known, but apparently include the
AMPA class of glutamate receptors.

Mechanisms underlying LTP. During glutamate release, the

NMDA channel opens only if the postsynaptic cell is
sufficiently depolarized.
The Ca 2+ ions that enter the cell through the channel
activate postsynaptic protein kinases. These kinases may
act in postsynaptic neurons to insert new AMPA receptors

Molecular mechanism of
LTP
LTP arises from changes in the sensitivity
of the postsynaptic cell to glutamate by
adding new AMPA receptors to silent
synapses that did not previously have
postsynaptic AMPA receptors.
Such rapid insertion of new AMPA
receptors also can occur at non-silent
excitatory synapses.

LTD
If synapses simply continued to increase in
strength as a result of LTP, eventually they
would reach some level of maximum
efficacy, making it difficult to encode new
information. Thus, to make synaptic
strengthening useful, other processes must
selectively weaken specific sets of
synapses.

LTD
Long-term depression (LTD) is such a
process.
Whereas LTP at these synapses requires
brief, high-frequency stimulation, LTD
occurs when the Schaffer collaterals are
stimulated at a low rateabout 1 Hzfor
long periods (1015 minutes).

LTD

LTD
This pattern of activity depresses the EPSP
for several hours and, like LTP, is specific
to the activated synapses
Moreover, LTD can erase the increase in
EPSP size due to LTP, and, conversely,
LTP can erase the decrease in EPSP size
due to LTD.

LTD
LTP and LTD at the Schaffer collateralCA1 synapses actually share several key
elements. Both require activation of
NMDA-type glutamate receptors and the
resulting entry of Ca 2+ into the
postsynaptic cell.

LTD
The major determinant of whether LTP or
LTD arises appears to be the amount of
Ca 2+ in the postsynaptic cell:
Small rises in Ca 2+ lead to depression,
whereas large increases trigger potentiation.

LTD
LTD, appears to result from activation of Ca
2+-dependent phosphatases that cleave
phosphate groups from these target molecules
.
Just as LTP at this synapse is associated with
insertion of AMPA receptors, LTD is often
associated with a loss of synaptic AMPA
receptors.

LTD
This loss probably arises from internalization
of AMPA receptors into the postsynaptic cell,
due to the same sort of clathrin dependent
endocytosis mechanisms important for
synaptic vesicle recycling in the presynaptic
terminal .

LTD

Glutamatergic Ion Channels

Alterations postulated in
epilepsy

Alterations
1- Inherited predisposition for fast or longlasting activation of NMDA channels that
alters their seizure threshold.
2- Other possible alterations include the
ability of intracellular proteins to buffer
calcium, increasing the vulnerability of
neurons to any kind of injury that otherwise
would not result in neuronal death.

GluR2 hypothesis
whereby preferential removal of GluR2 (with
no changes in GluR1) can lead to AMPAtype glutamate receptors that flux calcium.

Alterations
It has now been shown that AMPA-type glutamate receptors
can not only participate in calcium-dependent plasticity, but
can also, as a result of plasticity, alter their subunit
composition .
It has been known that GluR2-lacking receptors flux calcium,
allowing for this to occur. Either downregulation of GluR2 or
upregulation of GluR1 would potentially lead to more
homomeric, calcium-permeable GluRs. This contributed to
the GluR2 hypothesis (53,54) whereby preferential removal
of GluR2 (with no changes in GluR1) can lead to AMPA-type
glutamate receptors that flux calcium.

Alterations
It has been known that GluR2-lacking
receptors flux calcium, allowing for this to
occur, either:
A- down regulation of GluR2 or,
B- up regulation of GluR1.
would potentially lead to more homomeric,
calcium-permeable GluRs.

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PATHOPHYSIOLOGY
The release of GABA from the interneuron
terminal inhibits the postsynaptic neuron by
means of 2 mechanisms:
(1) direct induction of an inhibitory
postsynaptic potential (IPSP), which a
GABA-A chloride current typically mediates,
and

PATHOPHYSIOLOGY
(2) indirect inhibition of the release of excitatory
neurotransmitter in the presynaptic afferent
projection, typically with a GABA-B potassium
current.
Alterations or mutations in the different chloride
or potassium channel subunits or in the molecules
that regulate their function may affect the seizure
threshold or the propensity for recurrent seizures.

PATHOPHYSIOLOGY
Properties of the chloride channels
associated with the GABA-A receptor are
often clinically modulated by using
benzodiazepines (eg, diazepam, lorazepam,
clonazepam), barbiturates (eg,
phenobarbital, pentobarbital), or
topiramate.

PATHOPHYSIOLOGY
Benzodiazepines increase the frequency of
openings of chloride channels, whereas
barbiturates increase the duration of
openings of these channels. Topiramate
also increases the frequency of channel
openings, but it binds to a site different
from the benzodiazepine-receptor site.

Defective GABA-A inhibition

Some epilepsies may involve mutations or
lack of expression of the different GABAA receptor complex subunits, the
molecules that govern their assembly, or
the molecules that modulate their electrical
properties.

 For example, hippocampal pyramidal

neurons may not be able to assemble alpha
5 beta 3 gamma 3 receptors because of
deletion of chromosome 15 (ie, Angelman
syndrome).

Defective activation of GABA

neurons

Feedforward Inhibition
GABAergic cells receive a collateral
projection from the main afferent
projection that activates the CA1 neurons,
namely, the Schaffer collateral axons from
the CA3 pyramidal neurons.

Feedforward Inhibition
This feedforward projection activates the
soma of GABAergic neurons before or
simultaneously with activation of the
apical dendrites of the CA1 pyramidal
neurons.

Feedforward Inhibition
The results in an IPSP on the soma or axon
hillock of the CA1 pyramidal neurons
almost simultaneously with the EPSP from
the apical dendrites to the axon hillock,
thus primes the inhibitory system in a
manner that allows it to inhibit, in a timely
fashion, the pyramidal cell's depolarization
and firing of an action potential.

Alteration
Synaptic reorganization is a form of brain
plasticity induced by neuronal loss,
perhaps triggered by the loss of the
synaptic connections of the dying neuron,
a process called deafferentation.

Alteration
Formation of new sprouted circuits
includes excitatory and inhibitory cells,
and both forms of sprouting have been
demonstrated in many animal models of
focal-onset epilepsy and in humans with
intractable temporal-lobe epilepsy.

Alteration
Most of the initial attempts of hippocampal
sprouting are likely to be attempts to restore
inhibition. As the epilepsy progresses, however,
the overwhelming number of sprouted synaptic
contacts occurs with excitatory targets, creating
recurrent excitatory circuitries that permanently
alter the balance between excitatory and
inhibitory tone in the hippocampal network.

Pathophysiology
Generalized Seizures
The best-understood example of the
pathophysiologic mechanisms of
generalized seizures is the thalamocortical
interaction that may underlie typical
absence seizures.

Pathophysiology
Generalized Seizures
The thalamocortical circuit has normal
oscillatory rhythms, with periods of
relatively increased excitation and periods
of relatively increased inhibition.
It generates the oscillations observed in
sleep spindles.

Pathophysiology
Generalized Seizures
The thalamocortical circuitry includes:
The pyramidal neurons of the neocortex.
The thalamic relay neurons .
The neurons in the nucleus reticularis of the
thalamus (NRT).

Thalamic Relay Neurons

Receive ascending inputs from the spinal
cord and project to the neocortical
pyramidal neurons. Cholinergic pathways
from the forebrain and the ascending
serotonergic, noradrenergic, and
cholinergic brainstem pathways
prominently regulate this circuitry.

Thalamic Relay Neurons

They can have oscillations in the resting
membrane potential, which increases the
probability of synchronous activation of
the neocortical pyramidal neuron during
depolarization and which significantly
lowers the probability of neocortical
activation during relative
hyperpolarization.

Thalamic Relay Neurons

The key to these oscillations is the
transient low-threshold calcium channel,
also known as T-calcium current.
Inhibitory inputs from the NRT control the
activity of thalamic relay neurons.

T-calcium current
Have 3 functional states: open, closed, and
inactivated.
Calcium enters the cells when the Tcalcium channels are open. Immediately
after closing, the channel cannot open
again until it reaches a state of inactivation.

T-calcium current
The thalamic relay neurons have GABA-B
receptors in the cell body and receive tonic
activation by GABA released from the
NRT projection.
The result is a hyperpolarization that
switches the T-calcium channels away from
the inactive state into the closed state,
which is ready for activation when needed.

T-calcium current
The switch to closed state permits the
synchronous opening of a large population
of the T-calcium channels every 100
milliseconds or so, creating the oscillations
observed in the EEG recordings from the
cerebral cortex.

T-calcium current
Findings in several animal models of absence
seizures, have demonstrated that GABA-B
receptor antagonists suppress absence seizures,
whereas GABA-B agonists worsen these
seizures.
Anticonvulsants that prevent absence seizures,
such as valproic acid and ethosuximide,
suppress the T-calcium current, blocking its
channels.

Pathophysiology
Generalized Seizures
A clinical problem is that some
anticonvulsants that increase GABA levels
(eg, tiagabine, vigabatrin) are associated with
an exacerbation of absence seizures. An
increased GABA level is thought to increase
the degree of synchronization of the
thalamocortical circuit and to enlarge the pool
of T-calcium channels available for activation.

Natural History of Seizures

At least 60% of newly diagnosed patients
can expect complete seizure control.
Approximately 50% of these patients can
discontinue medication.
Up to one third of premature deaths can be
directly or indirectly attributable to
epilepsy.

 Mortality is significantly higher if :

1- Symptomatic epilepsy.
2- In the first 5 to 10 years after diagnosis of
epilepsy
3- younger pt.

Natural History of Seizures

Major contributors to death in patients with
epilepsy are :
1- Neoplasia.
2- Cerebrovascular disorders.
3- Pneumonia in elderly or institutionalized
patients.

Natural History of Seizures

Natural History of Seizures

SUDEP is the most important cause of
epilepsy-related deaths, particularly in the
young, and people with frequent seizures
and/or suboptimal AED treatment.
Appropriate postmortem investigations
should be conducted in order to accurately
classify the cause of death.

AURA
The aura, of course, is the start, not the
cause, of a seizure.
The aura usually lasts seconds to minutes
and immediately precedes the signs of an
attack.
On occasion, auras can be long-lasting,
continuous, or recurrent with short
intervening breaks.

Somatosensory
Tingling, numbness, and an electrical
feeling are common, whereas absence of
sensation or a sensation of movement is
less.

Cephalic
Ill-defined sensations felt within the head,
such as dizziness, electrical shock,
tingling, fullness, or pressure.
No specific site, and related to an alteration
of circulation.

Psychical
certain psychical states during the onset
of epileptic seizures that included
intellectual aura dreamy feelings ...
dreams mixing up with present thoughts ...
double consciousness ... as if I went back
to all that occurred in my childhood.
psychic auras can occur with focal seizures
from anywhere in the brain

Visual
Spots, stars, blobs, bars, or circles of light,
monochromatic or variously colored,
implicate seizure activity in the visual
areas of the occipital lobes

Auditory
ringing, booming, buzzing, chirping, or
machinelike .
A lateralized sound is usually contralateral
to the side of stimulation. At other times,
partial deafness may occur.
Auras with such unformed auditory
hallucinations suggest seizure activity in the
superior temporal neocortex

Olfactory
The smell of an olfactory aura is often
unpleasant or disagreeable.
Other than the medial temporal lobe, the
olfactory bulb is the only structure that can
produce an olfactory sensation on
electrical stimulation.

Vertiginous
Stimulation of the superior temporal gyrus
can elicit feelings of displacement or
movement, including rotatory sensations

Others
Gustatory
Sexual
Autonomic
Emotional

Epileptic Seizures

Generalized Onset
A) seizures with tonicclonic manifestations
I) Clonic seizures: clonic seizures are fast
rhythmic events (12 Hz), often associated
with impaired consciousness.

Generalized Onset
A) seizures with tonicclonic manifestations
II) Tonic seizures: the mechanism of tonic
seizures is probably not the same as that of
the tonic phase of generalized tonic clonic
seizures.
Generalized tonic seizures typically occur in
LennoxGastaut syndrome and occasionally
in epilepsy with myoclonic astatic (or
myoclonic-atonic) seizures.

Generalized Onset
A) seizures with tonicclonic manifestations
III) Generalized tonicclonic seizures
(GTCSs) have sudden onset with immediate
loss of consciousness.

Generalized Onset
A) seizures with tonicclonic manifestations
There is a brief tonic phase (1030
seconds) with whole body tonic
contraction, associated with a loud scream
and vegetative symptoms such as
tachycardia, mydriasis, increased blood
pressure, and apnoea.

Generalized Onset
A) seizures with tonicclonic manifestations
Tongue biting if present, is produced at this
stage.
The clonic phase lasts around 30 seconds
1 minute and is characterized by
bilateral clonic jerks that gradually
decrease in intensity and frequency.

Generalized Onset
A) seizures with tonicclonic manifestations
The postictal phase, which can last for several
minutes up to hours, is characterized by initial
mydriasis, body relaxation, hypotonia, and sleep.
Urination if present, takes place at this stage.
Finally the patient gradually recovers and
appears confused, presenting sometimes with
automatisms, headache, and muscle aches.

Generalized Onset
B) Myoclonic seizures
Myoclonic seizures are manifested as brief
symmetrical muscular jerks of variable
intensity.
Proximal muscles such as girdle muscles are
mostly involved.
During stronger attacks, there is possibility
of the patient falling over, but quickly
recovering.

Generalized Onset
B) Myoclonic seizures
The patient is usually conscious during the
jerks. Myoclonic seizures may often be
triggered by photic stimulation.

Generalized Onset
C) Absences
Typical absence seizures are brief (512
seconds).
They appear mostly in children and are
clinically characterized by sudden
interruption of ongoing activity and staring
straight ahead or drifting upwards.
There is complete loss of awareness during
the seizure.

Generalized Onset
C) Absences
The onset and offset is sharp.
Absence seizures can be easily produced if
the child is asked to hyperventilate.
Concomitant EEG abnormalities are
typical generalized spike-and wave
discharge at 3 Hz.

Generalized Onset
C) Absences
Possible associated manifestations include
slight rhythmic (3 Hz) eyelid myoclonus,
slight decrement or increment of muscle
tone, simple gestural automatisms (if the
absence is of long duration), and, rarely,
vegetative symptoms (urinary incontinence,
pupil dilatation, pallor, ushing,
tachycardia, change in blood pressure).

Generalized Onset
D) Epileptic spasms
These consist of a brief (0.52 second)
tonic contraction of the neck and trunk in
exion, extension or in a mixed exedextended posture.
They occur most commonly in clusters
upon awakening.

Generalized Onset
D) Epileptic spasms
Each cluster consists of several spasms the
intensity and frequency of which follow an
increasing-plateau-decreasing pattern.
Therefore the rst spasms in a cluster can
be barely visible, presenting a forced
opening of the eyes or slight nodding of
the head.

Generalized Onset
D) Epileptic spasms
Ictal EEG is characterized by pseudo-periodic
slow polyphasic EEG discharges that are
concomitant to spasms.
EEG activity related to spasms can also be a
bilateral electrodecremental pattern.
Electromyographic activity from deltoid and neck
muscles shows a characteristic rhomboid pattern
during the spasm, usually lasting 0.52 seconds

Generalized Onset
E) Atonic seizures
Atonic seizures are characterized by
decrease or complete inhibition of postural
tone.
They manifest as head nodding, dropping
of the jaw or of a limb, or falls.

Generalized Onset
E) Atonic seizures
The patient can then lie motionless on the
ground or promptly resume the posture.
Pure atonic seizures are rare.
Ictal EEG is usually characterized by a
generalized slow spike-and-wave
discharge.

Focal Onset
A) Focal sensory seizures.
I) With elementary sensory
(visual, somatosensory, vestibular, olfactory,
gustatory, or auditory) symptoms as
produced by activation of primary sensory
cortices (e.g. occipital and parietal lobe
seizures).

Focal Onset
A) Focal sensory seizures.
II) With experiential symptoms.
These are complex, formed, distorted and/or multimodal
sensory symptoms, usually implying seizure initiation in
association cortices, such as the temporo-parieto-occipital
junction.
B) Focal motor seizures.
I) With elementary clonic
motor signs. II) With asymmetric tonic motor seizures (e.g.
supplementary motor seizures). III) With typical (temporal
lobe) automatisms (e.g. mesial temporal lobe seizures). IV)
With hyperkinetic automatisms. V) With focal negative
myoclonus. VI) With inhibitory motor seizures.

Focal Onset
B) Focal motor seizures.
I) With elementary clonic motor signs.
II) With asymmetric tonic motor seizures (e.g.
supplementary motor seizures).
III) With typical (temporal lobe) automatisms (e.g.
mesial temporal lobe seizures).
IV) With hyperkinetic automatisms.
V) With focal negative myoclonus.
VI) With inhibitory motor seizures.

Lobar epilepsy
Temporal lobe
Automatismscomplex motor
phenomena, but with impaired awareness
and no recollection afterwards, varying
from primitive oral (lip smacking,
chewing, swallowing) or manual
(fumbling, ddling, grabbing) movements,
to complex actions (singing, kissing,
driving a car and violent acts)

Lobar epilepsy
Temporal lobe
Abdominal rising sensation or pain ( ictal
vomiting; or rarely episodic fevers.
Dysphasia (ictal or post-ictal)
Memory phenomenadj vu (when
everything seems strangely familiar), or
jamais vu (everything seems strangely
unfamiliar)

Lobar epilepsy
Temporal lobe
Hippocampal involvement may cause
emotional disturbance, eg sudden terror,
panic, anger or elation, and derealization
(out-of-body experiences), which in
combination may manifest as excessive
religiosity.

Lobar epilepsy
Temporal lobe
Uncal involvement may cause
hallucinations of smell or taste and a
dreamlike state, and seizures in auditory
cortex may cause complex auditory
hallucinations, eg music or conversations.
Delusional behaviour;

Lobar epilepsy
Temporal lobe
Finally, you may nd yourself not
believing your patients bizarre storyeg
Canned music at Tescos always makes
me cry and then pass out, unless I wear an
earplug in one ear or I get orgasms when
I brush my teeth (right temporal lobe
hyper- and hypo perfusion, respectively).

Frontal lobe
Motor features such as posturing,
movements of the head and eyes,or
peddling movements of the legs
Jacksonian march (a spreading focal motor
seizure with retained awareness, often
starting with the face or a thumb)
Motor arrest

Frontal lobe
Subtle behavioural disturbances (often
diagnosed as psychogenic)
Dysphasia or speech arrest
Post-ictal Todds palsy

Parietal lobe
Sensory disturbancestingling, numbness,
pain (rare)
Motor symptoms (due to spread to the precentral gyrus).

Occipital lobe
Visual phenomena such as spots, lines,
ashes.

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Partial & Generalized

In 1981 the International League Against
Epilepsy (ILAE) Commission on
Classication and Terminology proposed
an International Classication of Epileptic
Seizures .
Seizures were classied as partial and
generalized (Next table) .

Partial & Generalized

Seizures were dened as partial if the rst
clinical and electroencephalographic (EEG)
signs indicated that initial activation was
limited to part of one cerebral hemisphere.
Partial seizures were classied in simple or
complex on the basis of whether or not
awareness was impaired during the attack.

Partial & Generalized

Seizures were considered as generalized if
the rst clinical and EEG changes
indicated the initial involvement of both
hemispheres.

Syndromic Classification
The Commission adopted a syndromic
classification.
A syndrome was considered as a group of
signs and symptoms customarily occurring
in association, including seizure types,
clinical background, neurophysiological
and neuroimaging ndings and, often,
outcome (Next table ) .

Syndromic Classification
According to symptoms, epilepsies were
classied as generalized and partial (or
focal).
Generalized epilepsies were dened as
characterized by generalized seizures,
bilateral motor manifestations, and
generalized interictal and ictal EEG
discharges.

Syndromic Classification
Partial epilepsies were those characterized
by seizures originating from a
circumscribed brain region, and by clinical
manifestations consistent with a focal onset
of the epileptic discharge, with or without
subsequent spread, and by focal ictal or
interictal EEG abnormalities.

Idiopathic VS Symptomatic
The 1989 Classication also divided the
epilepsies by aetiology, into two broad
categories: idiopathic and symptomatic
epilepsies.

Idiopathic VS Symptomatic
Idiopathic epilepsies were dened by
absence of any brain lesions, normal
background EEG activity and interictal
generalized spike and wave discharges.
They were considered to be due to a
genetic predisposition or to a specic mode
of inheritance.

Idiopathic VS Symptomatic
Symptomatic epilepsies were considered
the expression of a focal or diffuse brain
lesion as demonstrated by clinical history,
structural neuroimaging, EEG ndings, or
biological tests.

Unclassified Seizures

B. UNCLASSIFIED SEIZURES
i. Neonatal seizures
ii. Infantile spasms

Neonatal Seizure
Less than 1 month of age.
Brief episodes of apnea, eye deviation, eye
blinking, or repetitive movements of the
arms and legs.

Infantile Spasms
Infants under 12 months.
Abrupt movements of the head, trunk, or
limbs.
The classic spasm is a sudden flexion of
the neck and abdomen with extension of
the limbs.

Differential diagnoses of
epilepsy

Ultimately, the rationale for diagnostic studies is to provide the patien

with effective therapy. The goals of therapy are no seizures, no side
effects, and no lifestyle limitations.

General Considerations
The initial diagnostic approach to the
patient with epilepsy and related episodic
disorders has importance for both longterm prognosis and treatment, including
the determination of:
1- whether treatment is necessary
2- The type(s) of therapy to be considered.

General Considerations
When evaluating a patient with possible
epilepsy, the basic approach is as follows: Is this
epilepsy, and, if so, is it focal or generalized,
Any triggers?
Once a seizure is determined to be a
manifestation of epilepsy, a diagnostic workup
must be performed to understand the underlying
cause(s) and epilepsy syndrome type when
possible

Essential for the diagnosis

1) Recurrent seizures.
2) Characteristic electroencephalographic
changes accompany seizures.
3) Mental status abnormalities or focal
neurologic symptoms may persist for
hours postictally.

First Seizure
In assessing a rst-ever seizure, consider
also:
1- Is it really the rst? Ask the family and
patient about past funny turns/odd behaviour.
2- Dj vu and odd episodic feelings of fear
may well be relevant.

First Seizure
3- Was the seizure provoked? Provoked 1st
seizures are less likely to recur (310%,
unless the cause is irreversible, eg an infarct
or glioma); if it was unprovoked, recurrence
rates are 3050%.

First Seizure
provocations are different to triggers: most
people would have a seizure given sufficient
provocation, but most people do not have
seizures however many triggers they are
exposed to, so triggered seizures suggest
epilepsy.

First Seizure
Triggered attacks tend to recur.
Admit to substantiate ideas of
pseudoseizures, or for recurrent seizures.

Laboratory studies

Electrolytes
Glucose
Ca
Mg
Liver and renal function test
Urianalysis
Toxicology screen
Lumbar puncture

EEG Clinical Applications

1- Diagnosis of epilepsy.
2- Selection of AED therapy.
3- Evaluation of response to treatment.
4- Determination of candidacy for drug
withdrawal.
5- Surgical localization.

EEG
An EEG cannot exclude or refute epilepsy;
it forms part of the context for diagnosis,
so dont do one if simple syncope is the
likely diagnosis (often false +ve).

EEG
In 1st unprovoked ts, unequivocal
epileptiform activity on EEG helps assess
risk of recurrence, based on studies in both
adults and children, with recurrence rates
that range from 30% to 70% in the first
year.

 Therefore, when the EEG shows an

epileptiform discharge after a single
seizure, treatment may be considered even
before a diagnosis of epilepsy is
established.
Only do emergency EEGS if nonconvulsive status is the problem .

EEG
Epileptiform abnormalities usually appear
as spikes, sharp waves, or spike-wave
discharges that are distinct from the normal
background activity and indicate an
increased seizure tendency.

 The spike discharges are predominantly

negative transients with steep ascending
and descending limbs and a duration of 20
ms to 70 ms.
A sharp wave is a broader potential with a
duration of 70 ms to 200 ms.

Sensitivity & Specificity

The sensitivity of a single EEG study to
record an epileptiform abnormality may be
50% or less in people with epilepsy so
normal interictal EEG studies do not
exclude the presence of a seizure disorder.
The diagnostic yield increases to 80% to
90% if three or more serial EEGs are
performed.

EEG
Ultimately, epilepsy is a clinical diagnosis
and the EEG serves to provide supporting
evidence; in other words, you treat the
patient and not the EEG.

The presence of an epileptiform abnormality

does not always indicate a seizure disorder
Interictal epileptiform discharges are seen
rarely in adults or children without
epilepsy (0.2% to 3%).
Healthy airline personnel who underwent
EEG studies.
Occipital spikes have been observed in
blind people.

The presence of an epileptiform abnormality

does not always indicate a seizure disorder
Generalized spikes have been reported in
relatives of patients with genetic
generalized epilepsies.
Interictal epileptiform discharges may also
be seen in patients receiving bupropion,
cefepime, clozapine, lithium, and tramadol,
and in pt with renal failure or an acute
encephalopathy.

Factors That May Affect The

Diagnostic Yield of EEG
(1) The age of the patient
(2) Seizure classification and epileptic
syndrome diagnosis
(3) Presence of AED therapy
(4) Proximity of the EEG recording to seizure
activity (since patients with more recent
seizures more frequently have diagnostic EEG
recordings).

Indications for video-EEG

Evaluation of spells.
Seizure classification.
Seizure quantification.
Assessment of seizure precipitating factors.
Surgical localization in drug-resistant
focal epilepsy.

MRI
Is the structural neuroimaging procedure of
choice in people with epilepsy.
All individuals with seizures should undergo
an MRI study unless the patient has a
confirmed genetic generalized epilepsy
syndrome (eg, childhood absence epilepsy) or
a contraindication exists that does not permit
this imaging procedure to be done safely

MRI Help In
Identification of the pathologic findings
associated with focal or generalized
seizures.
Localization of the epileptogenic zone.
Determination of surgical localization in
drug-resistant focal epilepsy

t
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The basic goals of treatment for

epilepsy are to:
1- Help the patient achieve freedom from
further seizures without adverse effects of
therapies.
2- Minimize the frequency of disabling or
potentially injurious seizure types when seizure
freedom is not achieved.

3- Address any relevant interictal

comorbidities of epilepsy to maximize
quality of life for people with epilepsy.

Starting treatment
Single seizures: No treatment unless there
is a high risk of recurrence, e.g. abnormal
EEG as in JME or an abnormal MRI. If
precipitating factors (e.g. alcohol)
identified, avoidance may prevent
recurrence

Starting treatment
After a single unprovoked seizure, risk of
recurrence is 24% with no cause and
normal EEG. and 65% if associated with a
neurological abnormality + abnormal
EEG.

Starting treatment
Prophylaxis : No indication for starting
treatment in patients with head injuries,
craniotomy, brain tumours, unless seizures
occur.

 Drug treatment Aim of treatment is to

render patient seizure-free with minimal
side-effects.
Other factors include sudden unexpected
death in epilepsy (SUDEP) 1/200/year
in refractory epilepsy.

 Factors to be taken into account:

- age;
- sex;
- type of epilepsy;
- other drugs, e.g. contraceptive pill; - other
medical conditions, e.g. liver or renal
dysfunction.

 Treatment is initiated at low dose gradually

titrating to an effective level to avoid side-effects
(start low, go slow).
- If seizures continue, increase dose to maximum
tolerated.
- If seizures continue, withdraw first drug and try
another first-line drug.
- If unsuccessful, adjunctive treatment with a secondline drug should be considered.

Surgery
Should be considered, and patients referred
to a specialist centr, in cases with:
- Surgically resectable lesion.
- Temporal lobe seizures in whom there is
evidence of mesial temporal sclerosis
- In such patients seizure-free rates 80%, with
34% permanent neurological deficit and 1%
mortality rates.

Vagus nerve stimulation

is an option with no serious side-effects in
those with refractory epilepsy, and
unsuitable for surgery.

Counselling After any t

Advise about dangers (eg swimming,
driving, heights) until the diagnosis is
known; then give individualized counselling
on employment, sport, insurance and
conception .
Avoid driving until seizure free for >1yr.