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.

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

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

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

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 ligand-
gated cation channels.

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

 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.

Neural Plasticity
 The capacity of the nervous system to
change—generally 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.

 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).

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

 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.

 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
long-lasting 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.

 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 plasticity—those 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) .

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.

 This layer is divided into several distinct
regions, the major ones being CA1 and
CA3.
 “CA” refers to cornu Ammon , the Latin
for Ammon’s horn—the ram’s horn that
resembles the shape of the hippocampus.

 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.

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.

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.

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 ).

If a single weak stimulus to the Schaffer
collaterals—paired 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,


 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

 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.

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

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).

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
high-frequency stimulation will cause a
prolonged depolarization that results in Mg
2+ being expelled from the NMDA
channel (Right of next figure).

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.

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

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.

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.

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.

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 .

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

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 into the postsynaptic spine,
thereby increasing the sensitivity to glutamate

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 rate—about 1 Hz—for
long periods (10–15 minutes).

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 collateral-
CA1 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 .

Alterations postulated in
epilepsy

Alterations
1- Inherited predisposition for fast or long-
lasting 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 AMPA-
type 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

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.

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 GABA-
A 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.

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

 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
 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
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.

 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.

 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 T-
calcium 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
 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.

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

 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

Generalized Onset
A) seizures with tonic–clonic manifestations
I) Clonic seizures: clonic seizures are fast
rhythmic events (1–2 Hz), often associated
with impaired consciousness.

Generalized Onset
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
Lennox–Gastaut syndrome and occasionally
in epilepsy with myoclonic astatic (or
myoclonic-atonic) seizures.

Generalized Onset
III) Generalized tonic–clonic seizures
(GTCSs) have sudden onset with immediate
loss of consciousness.

Generalized Onset
 There is a brief tonic phase (10–30
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
 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
 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

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 (5–12
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,
ﬂushing, tachycardia, change in blood
pressure).

Generalized Onset
D) Epileptic spasms
 These consist of a brief (0.5–2 second)
tonic contraction of the neck and trunk in
ﬂexion, extension or in a mixed ﬂexed-
extended 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 ﬁrst 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 0.5–2 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.

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
 Automatisms—complex motor
phenomena, but with impaired awareness
and no recollection afterwards, varying
from primitive oral (lip smacking,
chewing, swallowing) or manual
(fumbling, ﬁddling, 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 phenomena—déjà 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 ﬁnd yourself not
believing your patient’s bizarre story—eg
“Canned music at Tesco’s 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 Todd’s palsy

Parietal lobe
 Sensory disturbances—tingling, numbness,
pain (rare)
 Motor symptoms (due to spread to the pre-
central gyrus).

Occipital lobe
 Visual phenomena such as spots, lines,
ﬂashes.

Classiﬁcation of The Epilepsies
And of Epilepsy Syndrome

Partial & Generalized
 In 1981 the International League Against
Epilepsy (ILAE) Commission on
Classification and Terminology proposed
an International Classification of Epileptic
Seizures .
 Seizures were classified as partial and
generalized (Next table) .

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

 Seizures were considered as generalized if
the ﬁrst 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 ﬁndings and, often,
outcome (Next table ) .

 According to symptoms, epilepsies were
classiﬁed as generalized and partial (or
focal).
 Generalized epilepsies were deﬁned as
characterized by generalized seizures,
bilateral motor manifestations, and
generalized interictal and ictal EEG
discharges.

 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 Classiﬁcation also divided the
epilepsies by aetiology, into two broad
categories: idiopathic and symptomatic
epilepsies.

 Idiopathic epilepsies were deﬁned 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 speciﬁc mode
of inheritance.

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

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 long-
term 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 ﬁrst-ever seizure, consider
also:
1- Is it really the ﬁrst? Ask the family and
patient about past funny turns/odd behaviour.
2- Déjà 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 (3–10%,
unless the cause is irreversible, eg an infarct
or glioma); if it was unprovoked, recurrence
rates are 30–50%.

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 don’t do one if simple syncope is the
likely diagnosis (often false +ve).

EEG
 In 1st unprovoked ﬁts, 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 non-
convulsive 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

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
second-line 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 3–4% 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 ‘ﬁt’
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.

Epilepsy

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