epilepsy

EpilepsyEpilepsy

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

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

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 activation2- Decreased inhibition 3-Defective activation of (GABA) neurons

Increased activation

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 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

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) .

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 Ammon’s horn—the ram’s 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 ).


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 ofLTP 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 ofLTP During low-frequency synaptic

transmission, glutamate released by the Schaffer collaterals binds to both NMDA-type and AMPA/kainate-type glutamate receptors.

Molecular mechanism ofLTP 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 ofLTP 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).

Molecular mechanism ofLTP

Molecular mechanism ofLTP 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 ofLTP 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 ofLTP 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 ofLTP 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 ofLTP 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 ofLTP 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 ofLTP 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 into the postsynaptic spine, thereby increasing the sensitivity to glutamate

Molecular mechanism ofLTP 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 .

Glutamatergic Ion Channels 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 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.

Decreased Inhibition

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 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 SeizuresThe 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 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.


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

Epileptic Seizures

Generalized OnsetA) seizures with tonic–clonic manifestations

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


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.


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


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.


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.


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 (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 OnsetE) 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 OnsetE) 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 OnsetA) 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 OnsetA) 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 OnsetB) 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 epilepsyTemporal 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 epilepsyTemporal 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 epilepsyTemporal 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 epilepsyTemporal 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 epilepsyTemporal 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.

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 patient 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

Management

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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