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Epilepsy and Seizures

 Author: David Y Ko, MD; Chief Editor: Selim R Benbadis, MD more...

 

Updated: Oct 14, 2013 

Practice Essentials

Epilepsy is defined as a brain disorder characterized by an enduring predisposition to generate epileptic seizures

and by the neurobiologic, cognitive, psychological, and social consequences of this condition.[1]

Essential update: Immunotherapy for epilepsy resistant to conventional antiepileptic agents

Immunotherapy may be a viable treatment strategy in a subset of epileptic patients whose seizures are refractory

to management with conventional antiepileptic drugs (AEDs) and whose poor seizure control may result from the

presence of neural-specific antibodies.[2, 3] Iorio et al found autoantibodies specific to neural antigen in 2 of 29

patients with epilepsy and other neurologic symptoms and/or autoimmune diseases (group 1) and in 9 of 30

patients with AED-resistant epilepsy (group 2).

Of the patients in group 2 who received (1) immunotherapy with intravenous (IV) steroids and IV immunoglobulin for 

6 months, (2) IV methylprednisolone, IV immunoglobulin, and rituximab, or (3) IV steroids, 5 cycles of 

plasmapheresis, and oral steroids, 75% had a reduction in seizure frequency of 50% or greater. [3] The remainingpatients in group 2 who received immunotherapy were evenly distributed between those who had a reduction in

seizure frequency of 20-50% and those with a reduction of less than 20%. [3]

Signs and symptoms

The clinical signs and symptoms of seizures depend on the location of the epileptic discharges in the cerebral

cortex and the extent and pattern of the propagation of the epileptic discharge in the brain. A key feature of 

epileptic seizures is their stereotypic nature.

Questions that help clarify the type of seizure include the following:

Was any warning noted before the spell? If so, what kind of warning occurred?What did the patient do during the spell?

Was the patient able to relate to the environment during the spell and/or does the patient have recollection

of the spell?

How did the patient feel after the spell? How long did it take for the patient to get back to baseline

condition?

How long did the spell last?

How frequent do the spells occur?

 Are any precipitants associated with the spells?

Has the patient shown any response to therapy for the spells?

See Clinical Presentation for more detail.

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Diagnosis

The diagnosis of epileptic seizures is made by analyzing the patient's detailed clinical history and by performing

ancillary tests for confirmation. Physical examination helps in the diagnosis of specific epileptic syndromes that

cause abnormal findings, such as dermatologic abnormalities (eg, patients with intractable generalized tonic-clonic

seizures for years are likely to have injuries requiring stitches).

Testing 

Potentially useful laboratory tests for patients with suspected epileptic seizures include the following:

Prolactin levels obtained shortly after a seizure to assess the etiology (epileptic vs nonepileptic) of a spell;

levels are typically elevated 3- or 4-fold and more likely to occur with generalized tonic-clonic seizures than

with other seizure types; however, the considerable variability of prolactin levels has precluded their routine

clinical use

Serum levels of anticonvulsant agents to determine baseline levels, potential toxicity, lack of efficacy,

treatment noncompliance, and/or autoinduction or pharmacokinetic change

CSF examination in patients with obtundation or in patients in whom meningitis or encephalitis is

suspected

Imaging studies

The following 2 imaging studies must be performed after a seizure:

Neuroimaging evaluation (eg, MRI, CT scanning)

EEG

The clinical diagnosis can be confirmed by abnormalities on the interictal EEG, but these abnormalities could be

present in otherwise healthy individuals, and their absence does not exclude the diagnosis of epilepsy.

Video-EEG monitoring is the standard test for classifying the type of seizure or syndrome or to diagnose

pseudoseizures (ie, to establish a definitive diagnosis of spells with impairment of consciousness). This technique

is also used to characterize the type of seizure and epileptic syndrome to optimize pharmacologic treatment and

for presurgical workup.

See Workup for more detail.

Management

Pharmacotherapy 

The goal of treatment is to achieve a seizure-free status without adverse effects. Monotherapy is important,

because it decreases the likelihood of adverse effects and avoids drug interactions.

Standard of care for a single, unprovoked seizure is avoidance of typical precipitants (eg, alcohol, sleep

deprivation). No anticonvulsants are recommended unless the patient has risk factors for recurrence.

Special situations that require treatment include the following:

Recurrent unprovoked seizures: The mainstay of therapy is an anticonvulsant; if a patient has had more

than 1 seizure, administration of an anticonvulsant is recommended

Having an abnormal sleep-deprived EEG that includes epileptiform abnormalities and focal slowing, diffuse

background slowing, and intermittent diffuse intermixed slowing

Selection of an anticonvulsant medication depends on an accurate diagnosis of the epileptic syndrome. Although

some anticonvulsants (eg, lamotrigine, topiramate, valproic acid, zonisamide) have multiple mechanisms of action,

and some (eg, phenytoin, carbamazepine, ethosuximide) have only one known mechanism of action,

anticonvulsant agents can be divided into large groups based on their mechanisms, as follows:

Blockers of repetitive activation of the sodium channel: Phenytoin, carbamazepine, oxcarbazepine,

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lamotrigine, topiramate

Enhancer of slow inactivation of the sodium channel: Lacosamide, rufinamide

Gamma aminobutyric acid (GABA)–A receptor enhancers: Phenobarbital, benzodiazepines, clobazam

NMDA receptor blockers: Felbamate

 AMPA receptor blockers: Perampanel, topiramate

T-calcium channel blockers: Ethosuximide, valproate

N- and L-calcium channel blockers: Lamotrigine, topiramate, zonisamide, valproate

H-current modulators: Gabapentin, lamotrigine

Blockers of unique binding sites: Gabapentin, levetiracetam

Carbonic anhydrase inhibitors: Topiramate, zonisamideNeuronal potassium channel (KCNQ [Kv7]) opener: Ezogabine

Nonpharmacologic therapy 

The following are 2 nonpharmacologic methods in managing patients with seizures:

 A ketogenic diet

Vagal nerve stimulation

Surgical options

The 2 major kinds of brain surgery for epilepsy are palliative and potentially curative. The use of a vagal nerve

stimulator (VNS) for palliative therapy in patients with intractable atonic seizures has reduced the need for anterior callosotomy. Lobectomy and lesionectomy are among several possible curative surgeries.

See Treatment and Medication for more detail.

Background

Epileptic seizures are only one manifestation of neurologic or metabolic diseases. Epileptic seizures have many

causes, including a genetic predisposition for certain types of seizures, head trauma, stroke, brain tumors, alcohol

or drug withdrawal, repeated episodes of metabolic insults, such as hypoglycemia, and other conditions. Epilepsy

is a medical disorder marked by recurrent, unprovoked seizures. Therefore, repeated seizures with an identified

provocation (eg, alcohol withdrawal) do not constitute epilepsy.

 As proposed by the International League Against Epilepsy (ILAE) and the International Bureau for Epilepsy (IBE) in

2005, epilepsy is defined as a brain disorder characterized by an enduring predisposition to generate epileptic

seizures and by the neurobiologic, cognitive, psychological, and social consequences of this condition.[1]

Traditionally, the diagnosis of epilepsy requires the occurrence of at least 2 unprovoked seizures. Some clinicians

also diagnose epilepsy when 1 unprovoked seizure occurs in the setting of a predisposing cause, such as a focal

cortical injury, or a generalized interictal discharge occurs that suggests a persistent genetic predisposition. (See

Clinical Presentation.)

Seizures are the manifestation of abnormal hypersynchronous or hyperexcitable discharges of cortical neurons.

The clinical signs or symptoms of seizures depend on the location of the epileptic discharges in the cerebral

cortex and the extent and pattern of the propagation of the epileptic discharge in the brain. Thus, seizure

symptoms are highly variable, but for most patients with 1 focus, the symptoms are usually very stereotypic.

It should not be surprising that seizures are a common, nonspecific manifestation of neurologic injury and disease,

because the main function of the brain is the transmission of electrical impulses. The lifetime likelihood of 

experiencing at least 1 epileptic seizure is about 9%, and the lifetime likelihood of receiving a diagnosis of epilepsy

is almost 3%. However, the prevalence of active epilepsy is only about 0.8%. (See Epidemiology.)

This article reviews the classifications, pathophysiology, clinical manifestations, and treatment of epileptic

seizures and some common epileptic syndromes. (See Pathophysiology, Presentation, DDx, and Treatment.)

For more information regarding seizure types and other conditions, see the following topics:

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 Absence Seizures

Complex Partial Seizures

Generalized Tonic-Clonic Seizures

Psychogenic Nonepileptic Seizures

Pediatric First Seizure

Epilepsia Partialis Continua

Status Epilepticus

Preeclampsia

Eclampsia

See the following articles for more information regarding epileptic syndromes and epilepsy treatment:

Benign Childhood Epilepsy

Benign Neonatal Convulsions

EEG in Common Epilepsy Syndromes

Pediatric Febrile Seizures

Neonatal Seizures

Frontal Lobe Epilepsy

Temporal Lobe Epilepsy

Juvenile Myoclonic Epilepsy

Lennox-Gastaut Syndrome

Posttraumatic EpilepsyReflex Epilepsy

Vagus Nerve Stimulation

Women's Health and Epilepsy

Partial Epilepsies

Pediatric Status Epilepticus

Myoclonic Epilepsy Beginning in Infancy or Early Childhood

Historical information

Epileptic seizures have been recognized for millennia. One of the earliest descriptions of a secondary generalized

tonic-clonic seizure was recorded over 3000 years ago in Mesopotamia. The seizure was attributed to the god of 

the moon. Epileptic seizures were described in other ancient cultures, including those of China, Egypt, and India. An ancient Egyptian papyrus described a seizure in a man who had previous head trauma.

Hippocrates wrote the first book about epilepsy almost 2500 years ago. He rejected ideas regarding the divine

etiology of epilepsy and concluded that the cause was excessive phlegm leading to abnormal brain consistency.

Hippocratic teachings were forgotten, and divine etiologies again dominated beliefs about epileptic seizures during

medieval times.

Even at the turn of the 19th century, excessive masturbation was considered a cause of epilepsy. This hypothesis

is credited as leading to the use of the first effective anticonvulsant (ie, bromides).

Modern investigation of the etiology of epilepsy began with the work of Fritsch, Hitzig, Ferrier, and Caton in the

1870s. These researchers recorded and evoked epileptic seizures in the cerebral cortex of animals. In 1929,

Berger discovered that electrical brain signals could be recorded from the human head by using scalp electrodes;this discovery led to the use of electroencephalography (EEG) to study and classify epileptic seizures.

Gibbs, Lennox, Penfield, and Jasper further advanced the understanding of epilepsy and developed the system of 

the 2 major classes of epileptic seizures currently used: localization-related syndromes and generalized-onset

syndromes. An excellent historical review of seizures and epilepsy, written by E. Goldensohn, was published in

the journal Epilepsia to commemorate the 50th anniversary of the creation of the American Epilepsy Society in

1997. A decade later, another review in Epilepsia discussed the foundation of this professional society. [4]

Pathophysiology

Seizures are paroxysmal manifestations of the electrical properties of the cerebral cortex. A seizure results when

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a sudden imbalance occurs between the excitatory and inhibitory forces within the network of cortical neurons in

favor of a sudden-onset net excitation.

The brain is involved in nearly every bodily function, including the higher cortical functions. If the affected cortical

network is in the visual cortex, the clinical manifestations are visual phenomena. Other affected areas of primary

cortex give rise to sensory, gustatory, or motor manifestations. The psychic phenomenon of déjà-vu occurs when

the temporal lobe is involved.

The pathophysiology of focal-onset seizures differs from the mechanisms underlying generalized-onset seizures.

Overall, cellular excitability is increased, but the mechanisms of synchronization appear to substantially differ 

between these 2 types of seizure and are therefore discussed separately. For a review, see the epilepsy book of 

Rho, Sankar, and Cavazos.[5] For a more recent review, see Kramer and Cash.[6]

Pathophysiology of focal seizures

The electroencephalographic (EEG) hallmark of focal-onset seizures is the focal interictal epileptiform spike or 

sharp wave. The cellular neurophysiologic correlate of an interictal focal epileptiform discharge in single cortical

neurons is the paroxysmal depolarization shift (PDS).

The PDS is characterized by a prolonged calcium-dependent depolarization that results in multiple sodium-

mediated action potentials during the depolarization phase, and it is followed by a prominent after-

hyperpolarization, which is a hyperpolarized membrane potential beyond the baseline resting potential. Calcium-

dependent potassium channels mostly mediate the after-hyperpolarization phase. When multiple neurons fire

PDSs in a synchronous manner, the extracellular field recording shows an interictal spike.

If the number of discharging neurons is more than several million, they can usually be recorded with scalp EEG

electrodes. Calculations show that the interictal spikes need to spread to about 6 cm2 of cerebral cortex before

they can be detected with scalp electrodes.

Several factors may be associated with the transition from an interictal spike to an epileptic seizure. The spike has

to recruit more neural tissue to become a seizure. When any of the mechanisms that underlie an acute seizure

becomes a permanent alteration, the person presumably develops a propensity for recurrent seizures (ie,

epilepsy).

The following mechanisms (discussed below) may coexist in different combinations to cause focal-onset seizures:

Decreased inhibition

Defective activation of gamma-aminobutyric acid (GABA) neurons

Increased activation

If the mechanisms leading to a net increased excitability become permanent alterations, patients may develop

pharmacologically intractable focal-onset epilepsy.

Currently available medications were screened using acute models of focal-onset or generalized-onset

convulsions. In clinical use, these agents are most effective at blocking the propagation of a seizure (ie, spread

from the epileptic focus to secondary generalized tonic-clonic seizures). Further understanding of the mechanisms

that permanently increase network excitability may lead to development of true antiepileptic drugs that alter the

natural history of epilepsy.

Decreased inhibition

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 (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.

Mechanisms leading to decreased inhibition include the following:

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Defective GABA-A inhibition

Defective GABA-B inhibition

Defective activation of GABA neurons

Defective intracellular buffering of calcium

Normal GABA-A inhibitory function

GABA is the main inhibitory neurotransmitter in the brain, and it binds primarily to 2 major classes of receptors:

GABA-A and GABA-B. GABA-A receptors are coupled to chloride (negative anion) channels, and they are one of 

the main targets modulated by the anticonvulsant agents that are currently in clinical use.

The reversal potential of chloride is about negative 70 mV. The contribution of chloride channels during resting

potential in neurons is minimal, because the typical resting potential is near -70 mV, and thus there is no

significant electromotive force for net chloride flux. However, chloride currents become more important at more

depolarized membrane potentials.

These channels make it difficult to achieve the threshold membrane potential necessary for an action potential.

The influence of chloride currents on the neuronal membrane potential increases as the neuron becomes more

depolarized by the summation of the excitatory postsynaptic potentials (EPSPs). In this manner, the chloride

currents become another force that must be overcome to fire an action potential, decreasing excitability.

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. 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.

 Alterations in the normal state of the chloride channels may increase the membrane permeability and

conductance of chloride ions. In the end, the behavior of all individual chloride channels sum up to form a large

chloride-mediated hyperpolarizing current that counterbalances the depolarizing currents created by the

summation of EPSPs induced by activation of the excitatory input.

The EPSPs are the main form of communication between neurons, and the release of the excitatory amino acid

glutamate from the presynaptic element mediates EPSPs. Three main receptors mediate the effect of glutamate in

the postsynaptic neuron: N   -methyl-D-aspartic acid (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazole

propionic acid (AMPA)/kainate, and metabotropic. These are coupled by means of different mechanisms to several

depolarizing channels.

IPSPs temper the effects of EPSPs. IPSPs are mediated mainly by the release of GABA in the synaptic cleft with

postsynaptic activation of GABA-A receptors.

 All channels in the nervous system are subject to modulation by several mechanisms, such as phosphorylation

and, possibly, a change in the tridimensional conformation of a protein in the channel. The chloride channel has

several phosphorylation sites, one of which topiramate appears to modulate. Phosphorylation of this channel

induces a change in normal electrophysiologic behavior, with an increased frequency of channel openings but for 

only certain chloride channels.

Each channel has a multimeric structure with several subunits of different types. Chloride channels are noexception; they have a pentameric structure. The subunits are made up of molecularly related but different

proteins.

The heterogeneity of electrophysiologic responses of different GABA-A receptors results from different

combinations of the subunits. In mammals, at least 6 alpha subunits and 3 beta and gamma subunits exist for the

GABA-A receptor complex. A complete GABA-A receptor complex (which, in this case, is the chloride channel

itself) is formed from 1 gamma, 2 alpha, and 2 beta subunits. The number of possible combinations of the known

subunits is almost 1000, but in practice, only about 20 of these combinations have been found in the normal

mammalian brain.

Defective GABA-A inhibition

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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).

Changes in the distribution of subunits of the GABA-A receptor complex have been demonstrated in several animal

models of focal-onset epilepsy, such as the electrical-kindling, chemical-kindling, and pilocarpine models. In the

pilocarpine model, decreased concentrations of mRNA for the alpha 5 subunit of the surviving interneurons were

observed in the CA1 region of the rat hippocampus. [7]

Defective GABA-B inhibition

The GABA-B receptor is coupled to potassium channels, forming a current that has a relatively long duration of 

action compared with the chloride current evoked by activation of the GABA-A receptor. Because of the long

duration of action, alterations in the GABA-B receptor are thought to possibly play a major role in the transition

between the interictal abnormality and an ictal event (ie, focal-onset seizure). The molecular structure of the

GABA-B receptor complex consists of 2 subunits with 7 transmembrane domains each.

G proteins, a second messenger system, mediate coupling to the potassium channel, explaining the latency and

long duration of the response. In many cases, GABA-B receptors are located in the presynaptic element of an

excitatory projection.

Defective activation of GABA neurons

GABA neurons are activated by means of feedforward and feedback projections from excitatory neurons. These 2

types of inhibition in a neuronal network are defined on the basis of the time of activation of the GABAergic neuron

relative to that of the principal neuronal output of the network, as seen with the hippocampal pyramidal CA1 cell.

In 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.

 Activation of the GABAergic neurons results in an IPSP that inhibits the soma or axon hillock of the CA1

pyramidal neurons almost simultaneously with the passive propagation of the excitatory potential (ie, EPSP) fromthe apical dendrites to the axon hillock. The feedforward projection thus primes the inhibitory system in a manner 

that allows it to inhibit, in a t imely fashion, the pyramidal cell's depolarization and firing of an action potential.

Feedback inhibition is another system that allows GABAergic cells to control repetitive firing in principal neurons,

such as pyramidal cells, and to inhibit the surrounding pyramidal cells. Recurrent collaterals from the pyramidal

neurons activate the GABAergic neurons after the pyramidal neurons fire an action potential.

Experimental evidence has indicated that some other kind of interneuron may be a gate between the principal

neurons and the GABAergic neurons. In the dentate gyrus, the mossy cells of the hilar polymorphic region appear 

to gate inhibitory tone and activate GABAergic neurons. The mossy cells receive both feedback and feedforward

activation, which they convey to the GABAergic neurons.

In certain circumstances, the mossy cells appear highly vulnerable to seizure-related neuronal loss. After some of the mossy cells are lost, activation of GABAergic neurons is impaired.[8]

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. 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.

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.

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Defective intracellular buffering of calcium

In rodents, recurrent seizures induced by a variety of methods result in a pattern of interneuron loss in the hilar 

polymorphic region, with striking loss of the neurons that lack the calcium-binding proteins parvalbumin and

calbindin. In rat hippocampal sections, these interneurons demonstrate a progressive inability to maintain a

hyperpolarized resting membrane potential; eventually, the interneurons die.

In an experiment, researchers used microelectrodes containing the calcium chelator BAPTA and demonstrated

reversal of the deterioration in the membrane potential as the calcium chelator was allowed to diffuse in the

interneuron.[9] These findings showed the critical role of adequate concentrations of calcium-binding proteins for 

neuronal survival in settings with sustained rises of intracellular calcium, such as in status epilepticus and other 

brain insults. This mechanism may contribute to medical intractability in some epilepsy patients.

The vulnerability of interneurons to hypoxia and other insults also correlates to the relative presence of these

calcium-binding proteins. The premature loss of interneurons alters inhibitory control over the local neuronal

network in favor of net excitation. This effect may explain, for example, why 2 patients who have a similar event (ie,

simple febrile convulsion) may have remarkably dissimilar outcomes; that is, one may have completely normal

development, and the other may have intractable focal-onset epilepsy after a few years.

Increased activation

Mechanisms leading to increased excitation include the following:

Increased activation of NMDA receptors

Increased synchrony between neurons due to ephaptic interactions

Increased synchrony and/or activation due to recurrent excitatory collaterals

Increased activation of NMDA receptors

Glutamate is the major excitatory neurotransmitter in the brain. The release of glutamate causes an EPSP in the

postsynaptic neuron by activating the glutaminergic receptors AMPA/kainate and NMDA and the metabotropic

receptor.

Fast neurotransmission is achieved with the activation of the first 2 types of receptors. The metabotropic receptor 

alters cellular excitability by means of a second-messenger system with later onset but a prolonged duration. The

major functional difference between the 2 fast receptors is that the AMPA/kainate receptor opens channels that

primarily allow the passage of monovalent cations (ie, sodium and potassium), whereas the NMDA type is coupled

to channels that also allow passage of divalent cations (ie, calcium).

Calcium is a catalyst for many intracellular reactions that lead to changes in phosphorylation and gene

expression. Thus, it is in itself a second-messenger system. NMDA receptors are generally assumed to be

associated with learning and memory. The activation of NMDA receptors is increased in several animal models of 

epilepsy, such as kindling, kainic acid, pilocarpine, and other focal-onset epilepsy models.

Some patients with epilepsy may have an inherited predisposition for fast or long-lasting activation of NMDA

channels that alters their seizure threshold. 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.

Increased synchrony between neurons caused by ephaptic interactions

Electrical fields created by synchronous activation of pyramidal neurons in laminar structures, such as the

hippocampus, may increase further the excitability of neighboring neurons by nonsynaptic (ie, ephaptic)

interactions. Changes in extracellular ionic concentrations of potassium and calcium are another possible

nonsynaptic interaction, as is increased coupling of neurons due to permanent increases in the functional

availability of gap junctions. This last may be a mechanism that predisposes to seizures or status epilepticus.

Increased synchrony and/or activation from recurrent excitatory collaterals

Neuropathologic studies of patients with intractable focal-onset epilepsy have revealed frequent abnormalities in

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the limbic system, particularly in the hippocampal formation. A common lesion is hippocampal sclerosis, which

consists of a pattern of gliosis and neuronal loss primarily affecting the hilar polymorphic region and the CA1

pyramidal region. These changes are associated with relative sparing of the CA2 pyramidal region and an

intermediate severity of the lesion in the CA3 pyramidal region and dentate granule neurons.

Prominent hippocampal sclerosis is found in about two thirds of patients with intractable temporal-lobe epilepsy.

 Animal models of status epilepticus have reproduced this pattern of injury; however, animals with more than 100

brief convulsions induced by kindling seizures had a similar pattern, suggesting that repeated temporal lobe

seizures may contribute to the development of hippocampal sclerosis. [10]

More subtle and apparently more common than overt hippocampal sclerosis is mossy-fiber sprouting. [11] The

mossy fibers are the axons of the dentate granule neurons, and they typically project into the hilar polymorphic

region and toward the CA3 pyramidal neurons. As the neurons in the hilar polymorphic region are progressively

lost, their synaptic projections to the dentate granule neurons degenerate.

Denervation resulting from loss of the hilar projection induces sprouting of the neighboring mossy fiber axons. The

net consequence of this phenomenon is the formation of recurrent excitatory collaterals, which increase the net

excitatory drive of dentate granule neurons.

Recurrent excitatory collaterals have been demonstrated in human temporal lobe epilepsy and in all animal models

of intractable focal-onset epilepsy. The effect of mossy-fiber sprouting on the hippocampal circuitry has been

confirmed in computerized models of the epileptic hippocampus. Other neural pathways in the hippocampus, such

as the projection from CA1 to the subiculum, have been shown to also remodel in the epileptic brain.

For further reading, a review by Mastrangelo and Leuzzi addresses how genes lead to an epileptic phenotype for 

the early age encephalopathies.[12]

Pathophysiology of generalized seizures

The best-understood example of the pathophysiologic mechanisms of generalized seizures is the thalamocortical

interaction that may underlie typical absence 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. The thalamocortical circuitry includes the pyramidal neurons of the

neocortex, the thalamic relay neurons, and the neurons in the nucleus reticularis of the thalamus (NRT).

 Altered thalamocortical rhythms may result in primary generalized-onset seizures. The 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.[13]

The thalamic relay neurons 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.

In animal studies, inhibitory inputs from the NRT control the activity of thalamic relay neurons. NRT neurons are

inhibitory and contain GABA as their main neurotransmitter. They regulate the activation of the T-calcium channelsin thalamic relay neurons, because those channels must be de-inactivated to open transitorily.

T-calcium channels 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.

The thalamic relay neurons have GABA-B receptors in the cell body and receive tonic activation by GABA

released from the NRT projection to the thalamic relay neuron. 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.

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.

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Findings in several animal models of absence seizures, such as lethargic mice, have demonstrated that GABA-B

receptor antagonists suppress absence seizures, whereas GABA-B agonists worsen these seizures.[14]

 Anticonvulsants that prevent absence seizures, such as valproic acid and ethosuximide, suppress the T-calcium

current, blocking its channels.

 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.

Etiology

In a substantial number of cases, the cause of epilepsy remains unknown. Identified causes tend to vary with

patient age. Inherited syndromes, congenital brain malformations, infection, and head trauma are leading causes

in children. Head trauma is the most common known cause in young adults. Strokes, tumors, and head trauma

become more frequent in middle age, with stroke becoming the most common cause in the elderly, along with

 Alzheimer disease and other degenerative conditions.

The genetic contribution to seizure disorders is not completely understood, but at the present time, hundreds of 

genes have been shown to cause or predispose individuals to seizure disorders of various types. Seizures are

frequently seen in patients that are referred to a genetics clinic. In some cases, the seizures are isolated in an

otherwise normal child. In many cases, seizures are part of a syndrome that may also include intellectualdisability, specific brain malformations, or a host of multiple congenital anomalies.

For the sake of brevity and clarity, genetic disorders that can cause seizures will be broken into the following

categories:

Syndromes in which seizures are common

Chromosomal deletion or duplication syndromes that cause seizures

Metabolic diseases

Mitochondrial diseases

Seizure disorders caused by single-gene mutations

Genetic syndromes with seizure disorder 

 A number of genetic syndromes are known to causes seizures; therefore, this list is not meant to be authoritative.

However, a number of more common syndromes should be considered in the patient who presents with seizures

and other findings.

 Angelman syndrome

 Angelman syndrome is an inherited disorder that is most frequently (68%) caused by a deletion in the maternally

inherited region of chromosome 15q11.2-q13. Approximately 7% of cases are caused by paternal disomy of the

same region. An additional 11% of cases of Angelman syndrome are due to sequence variants in the maternally

inherited UBE3A gene.

Patients with Angelman syndrome generally have a normal prenatal and birth history, with the first evidence of developmental delay occurring between 6 and 12 months of age. Seizures occur in over 80% of patients with

 Angelman syndrome, with onset before age 3 years.

Patients generally have deceleration of head growth, resulting in microcephaly by early childhood. Dysmorphic

facies are typical and include a protruding tongue, prognathia, and a wide mouth with widely-spaced teeth.

Patients with a deletion also have hypopigmentation. Intellectual impairments are typically severe and speech

impairment is quite severe, with most patients having few or no words. Patients also have ataxia and frequent

laughter with a happy demeanor.

Rett syndrome

Rett syndrome in its classical form is caused by mutations in the MECP2  gene, although other similar forms

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caused by different genes are described. Additionally, although Rett syndrome has generally been described only

in female patients (with the supposition that this would be a lethal disease in males), rare cases have been

described in males.

Patients with Rett syndrome have a normal prenatal and birth history and normal psychomotor development for the

first 6 months, followed by deceleration of head growth in most patients, loss of hand skills over the first 2-3 years

of life, hand stereotypies, social withdrawal, communication dysfunction, loss of acquired speech, cognitive

impairment, and impairment of movement.[15]

Seizures are reported in greater than 90% of females with Rett syndrome. Seizures may be of any type, but

generalized tonic-clonic and complex partial seizures are the most common.[16]

Pitt-Hopkins syndrome

Pitt-Hopkins syndrome is classically caused by mutations in the TCF4 gene, although several forms of Pitt-

Hopkins–like syndrome have been described. Patients with Pitt-Hopkins syndrome have severe intellectual

disability, microcephaly, and little or no speech. They also have an unusual breathing pattern characterized by

intermittent hyperventilation followed by periods of apnea.

Patients with Pitt-Hopkins also have distinctive facies, which may not be apparent in early childhood. These

features include microcephaly with a coarse facial appearance, deeply set eyes, upslanting palpebral fissures, a

broad and beaked nasal bridge with a downturned nasal tip, a wide mouth and fleshy lips, and widely spaced

teeth. There is also a tendency toward prognathism.

Seizures are seen in this syndrome, with one study reporting a frequency of 20%.[17] Earlier studies suggested

that around 50% of patients with Pitt-Hopkins have seizures.

Tuberous sclerosis

Tuberous sclerosis complex is caused by mutations in the TSC1 or TSC2  genes. Major features of this disease

include the following[18] :

Facial angiofibromata

Ungual or periungual fibromas

Hypopigmented macules

Connective tissue nevi

Retinal hamartomas

Cortical tubers

Subependymal nodules or giant cell astrocytomas

Cardiac rhabdomyomas

Lymphangiomyomatosis

Renal angiomyolipomas

Minor features include the following:

Dental enamel pits

Rectal hamartomas

Bone cystsCerebral white matter migration lines

Gingival fibromas

Nonrenal hamartomas

Retinal achromic patches

Confetti skin lesions

Renal cysts

 A definite diagnosis of tuberous sclerosis requires 2 major features or 1 major and 2 minor features. A probable

diagnosis of tuberous sclerosis requires 1 major and 1 minor feature.

More than 80% of patients with tuberous sclerosis are reported to have seizures, although this may be an

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overestimate. However, this diagnosis should always be strongly considered in the case of infantile spasms.

Prader-Willi syndrome

Prader-Willi syndrome is most frequently (70%) caused by a deletion in the paternal inherited portion of 

chromosome 15q11.2-q13. The remainder of cases are caused by maternal uniparental disomy of chromosome

15, complex chromosomal rearrangements, or defects in specific imprinting centers.

Patients with Prader-Willi syndrome have neonatal hypotonia and failure to thrive during infancy. Patients have

hyperphagia, and onset of weight gain occurs between age 1 and 6 years. Affected individuals also have mild-

moderate intellectual impairment, hypogonadism, and characteristic facies consisting of a narrow bifrontaldiameter, almond-shaped eyes, a round face, and downturned corners of the mouth. Hands and feet will tend to be

small for size. Seizures occur in approximately 10-20% of patients.

Sturge-Weber syndrome

Sturge-Weber syndrome has an unknown cause and appears to occur in a sporadic fashion. This disorder is

characterized by intracranial vascular anomalies called arteriovenous malformations and port-wine stains on the

face. Patients with Sturge-Weber syndrome also have seizures and glaucoma. The seizures can be very difficult to

control in some of these patients.

Chromosomal deletion or duplication syndromes with seizures

Chromosomal 22q deletion syndrome is a spectrum of findings caused by a deletion on chromosome 22q11.2.

This disorder has previously been known by a variety of names, including DiGeorge syndrome, velocardiofacial

syndrome, Shprintzen syndrome, Opitz G/BBB syndrome, and Cayler asymmetrical crying facies, among others.

The most common features of this syndrome are congenital heart disease, palate anomalies, hypocalcemia,

immune deficiencies, and learning difficulties. Seizures occur in 7% of patients with chromosomal 22q deletion

syndrome.[19]

Wolf-Hirschhorn syndrome is caused by deletions of chromosome 4p16.3. Typical facies in these patients include

a broad nasal bridge continuing to the forehead (the “Greek warrior helmet” appearance), microcephaly, high

forehead, hypertelorism, and highly arched eyebrows. The mouth tends to be turned downward. Growth retardation

is seen, as is a variable degree of intellectual disability. Although seizures are present in between 50-100% of 

patients with Wolf-Hirschhorn syndrome, they tend to improve with age.[20]

Chromosomal 1p36 deletion syndrome is characterized by dysmorphic facies, including straight eyebrows, deeply

set eyes, a long philtrum, and microcephaly. All patients with this syndrome have developmental delay and

hypotonia, and 44-58% have seizures. [21]

Metabolic disorders that can cause seizures

Many different metabolic disorders can cause seizures, some as a result of a metabolic disturbance such as

hypoglycemia or acidosis and some as a primary manifestation of the seizure disorder. Some seizures are

responsive to administration of certain vitamins (eg, pyridoxine-responsive or folinic acid-responsive seizures).

Peroxisomal biogenesis disorders, which can cause seizures, result from homozygosity for mutation in one of the

many PEX  genes. One of these disorders, Zellweger syndrome, presents in the neonatal period as hypotonia,

seizures, and hepatic dysfunction. Death typically occurs from respiratory failure within the first year of life.

Congenital disorders of glycosylation are a group of disorders that (as their name suggests) involve malfunction in

one of the many enzymes involved in the pathway that attaches certain oligosaccharides to proteins. These

disorders vary significantly in their severity and characteristic manifestations. Hypotonia, intellectual disability,

failure to thrive/feeding difficulties, and unusual fat distribution are common. Seizures occur in some cases.

Other rare diseases also commonly cause seizures, including the following:

Neuronal ceroid lipofuscinosis

Disorders of metal and metal cofactor deficiency

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Disorders of neurotransmitter metabolism

Lysosomal storage diseases

Mitochondrial diseases

Mitochondrial disorders are underdiagnosed but often involve seizures and other neurologic manifestations.

Mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes (MELAS) syndrome is a mitochondrial

disorder that is associated with seizures; often, seizures are the presenting manifestation. Patients can also have

recurrent headache and vomiting.

Myoclonic epilepsy with ragged red fibers (MERRF) is characterized by myoclonus, seizures, and ataxia;

myopathy, hearing loss, and vision loss can also occur. Genetic tests are available for these disorders.

Seizure disorders caused by single-gene mutations

 Autosomal dominant nocturnal frontal lobe epilepsy is caused by mutations in the CHRNA4, CHRNB2 , or 

CHRNA2  genes. It is characterized by nocturnal motor seizures. The severity of autosomal dominant nocturnal

frontal lobe epilepsy can be variable, can include awakening episodes, and can result in impressive dystonic

effects. Affected individuals are generally otherwise normal, and the attacks tend to become less severe with age.

 Autosomal dominant juvenile myoclonic epilepsy is caused by a mutation in one of a number of genes. Patients

report myoclonic jerks, most commonly in the morning, but they can also have both generalized tonic-clonic

seizures and absence seizures. The onset of this disorder is typically in late childhood or early adolescence.

Benign familial neonatal seizures are caused by mutations in the KCNQ2  or KCNQ3 genes and are inherited in an

autosomal dominant manner. Neonates with this disorder will experience tonic-clonic seizures a few days after 

birth, and these seizures will remit within 1 month. Most infants will have normal development, but there is a 10-

15% risk of seizure disorder later in life.

Mutations in other genes, such as SCN1A, can cause a range of seizure syndromes. At the mild end of this

spectrum, patients may have familial febrile seizures and may otherwise be normal. At the severe end, patients

may have severe myoclonic epilepsy of infancy (also known as Dravet syndrome).

Mutations in SCN2A and SCN1B are known to cause generalized epilepsy with febrile seizures.

Mutations in SCN9A, GPA6 , and GPR98  are known to cause familial febrile seizures.

Mutation in GABRG2  is known to cause generalized epilepsy with febrile seizures, and familial febrile seizures.

Epidemiology

Hauser and collaborators demonstrated that the annual incidence of recurrent nonfebrile seizures in Olmsted

County, Minnesota, was about 100 cases per 100,000 persons aged 0-1 year, 40 per 100,000 persons aged 39-40

years, and 140 per 100,000 persons aged 79-80 years. By the age of 75 years, the cumulative incidence of 

epilepsy is 3400 per 100,000 men (3.4%) and 2800 per 100,000 women (2.8%). [22]

Studies in several developed countries have shown incidences and prevalences of seizures similar to those in theUnited States. In some countries, parasitic infections account for an increased incidence of epilepsy and seizures.

Prognosis

The patient's prognosis for disability and for a recurrence of epileptic seizures depends on the type of epileptic

seizure and the epileptic syndrome in question. Impairment of consciousness during a seizure may unpredictably

result in morbidity or even mortality.

Regarding morbidity, trauma is not uncommon among people with generalized tonic-clonic seizures. Injuries such

as ecchymosis; hematomas; abrasions; tongue, facial, and limb lacerations; and even shoulder dislocation can

develop as a result of the repeated tonic-clonic movements. Atonic seizures are also frequently associated with

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facial injuries, as well as injuries to the neck. Worldwide, burns are the most common serious injury associated

with epileptic seizures.

SUDEP

Regarding mortality, seizures cause death in a small proportion of individuals. Most deaths are accidental and

result from impaired consciousness. However, sudden, unexpected death in epilepsy (SUDEP) is a risk in persons

with epilepsy, and it may occur even when patients are resting in a protected environment (ie, in a bed with rail

guards or in the hospital).

The incidence of SUDEP is low, about 2.3 times higher than the incidence of sudden death in the general

population. The increased risk of death is seen mostly in people with long-standing focal-onset epilepsy, but it is

also present in individuals with primary generalized epilepsy. The risk of SUDEP increases in the setting of 

uncontrolled seizures and in people with poor medication compliance. The risk increases further in people with

uncontrolled secondary generalized tonic-clonic seizures.

The mechanism of death in SUDEP is controversial, but suggestions include cardiac arrhythmias, neurogenic

pulmonary edema, and suffocation during an epileptic seizure with impairment of consciousness. Treatment with

anticonvulsants decreases the likelihood of an accidental seizure-related death, and successful epilepsy surgery

decreases the risk of SUDEP to that of the general population.

In 2011, the National Institutes of Health (NIH) convened a workshop on SUDEP to focus research efforts and to

determine benchmarks for further study.[23] A summary of their report can be found at:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3115809/.

Patient Education

To prevent injury, provide education about seizure precautions to patients who have lapses of consciousness

during wakefulness and in whom seizures are suspected. Most accidents occur when patients have impaired

consciousness. This is one of the reasons for restrictions on driving, swimming, taking unsupervised baths,

working at significant heights, and the use of fire and power tools for people who have epileptic seizures and other 

spells of sudden-onset seizures.

The restrictions differ for each patient because of the individual features of the seizures, the degree of seizurecontrol, and, in the United States, state laws. Other countries have more permissive or more restrictive laws

regarding driving. Check state driving laws before making recommendations.

Epilepsy Foundation of America has a large library of educational materials that are available to healthcare

professionals and the general public. The American Epilepsy Society is a professional organization for people who

take care of patients with epilepsy. Their Website provides a large amount of credible information.

For patient education information, see the Brain and Nervous System Center , as well as Epilepsy and Seizures

Emergencies.

 

Contributor Information and Disclosures

 Author David Y Ko, MD  Associate Professor of Clinical Neurology, Associate Director, USC Adult Epilepsy Program,

Keck School of Medicine of the University of Southern California

David Y Ko, MD is a member of the following medical societies:  American Academy of Neurology, American

Clinical Neurophysiology Society, American Epilepsy Society, and American Headache Society

Disclosure: GSK Honoraria Speaking and teaching; UCB Honoraria Speaking and teaching; Lundbeck

Consulting fee Consulting; Westward Consulting fee Consulting; Esai Consulting fee Consulting; Supernus

Consulting fee Consulting

Chief Editor 

Selim R Benbadis, MD  Professor, Director of Comprehensive Epilepsy Program, Departments of Neurology

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and Neurosurgery, Tampa General Hospital, University of South Florida College of Medicine

Selim R Benbadis, MD is a member of the following medical societies: American Academy of Neurology,

 American Academy of Sleep Medicine, American Clinical Neurophysiology Society, American Epilepsy

Society, and American Medical Association

Disclosure: UCB Pharma Honoraria Speaking, consulting; Lundbeck Honoraria Speaking, consulting;

Cyberonics Honoraria Speaking, consulting; Glaxo Smith Kline Honoraria Speaking, consulting;

Sleepmed/DigiTrace Honoraria Speaking, consulting; Sunovion Consulting fee None

 Additional Contributors

Jose E Cavazos, MD, PhD, FAAN, FANA, FACNS Professor with Tenure, Departments of Neurology,

Pharmacology, and Physiology, Assistant Dean for the MD/PhD Program, Program Director of the Clinical

Neurophysiology Fellowship, University of Texas School of Medicine at San Antonio; Co-Director, South Texas

Comprehensive Epilepsy Center, University Hospital System; Director, San Antonio Veterans Affairs Epilepsy

Center of Excellence and Neurodiagnostic Centers, Audie L Murphy Veterans Affairs Medical Center 

Jose E Cavazos, MD, PhD, FAAN, FANA, FACNS is a member of the following medical societies:  American

 Academy of Neurology, American Clinical Neurophysiology Society, American Epilepsy Society, American

Neurological Association, and Society for Neuroscience

Disclosure: LGCH, Inc Ownership interest Consulting

Ramon Diaz-Arrastia, MD, PhD Professor, Department of Neurology, University of Texas Southwestern

Medical Center at Dallas, Southwestern Medical School; Director, North Texas TBI Research Center,

Comprehensive Epilepsy Center, Parkland Memorial Hospital

Ramon Diaz-Arrastia, MD, PhD is a member of the following medical societies: Alpha Omega Alpha, American

 Academy of Neurology, New York Academy of Sciences, and Phi Beta Kappa

Disclosure: Nothing to disclose.

Mark Spitz, MD Professor, Department of Neurology, University of Colorado Health Sciences Center 

Mark Spitz, MD is a member of the following medical societies: American Academy of Neurology, American

Clinical Neurophysiology Society, and American Epilepsy Society

Disclosure: pfizer Honoraria Speaking and teaching; ucb Honoraria Speaking and teaching; lumdbeck Honoraria

Consulting

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center 

College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

References

1. Fisher RS, van Emde Boas W, Blume W, et al. Epileptic seizures and epilepsy: definitions proposed bythe International League Against Epilepsy (ILAE) and the International Bureau for Epilepsy (IBE).

Epilepsia. Apr 2005;46(4):470-2. [Medline].

2. Iorio R, Assenza G, Della Marca G, et al. Neural autoantibodies and immunotherapy-responsive epilepsy:

a prospective study [abstract 1956]. Presented at: XXI World Congress of Neurology (WNC), 2013;

September 22, 2013; Vienna, Austria. [Full Text].

3. Keller DM. Immunotherapy helps epileptic patients with neural antibodies. Medscape Medical News [serial

online]. September 27, 2013;Accessed October 7, 2013. Available at

http://www.medscape.com/viewarticle/811804 .

4. Goodkin HP. The founding of the American Epilepsy Society: 1936-1971. Epilepsia. Jan 2007;48(1):15-22.

8/14/2019 Epilepsy and Seizures.pdf

http://slidepdf.com/reader/full/epilepsy-and-seizurespdf 16/19

[Medline].

5. Rho JM, Sankar R, Cavazos JE. Epilepsy: Scientific Foundations of Clinical Practice. New York, NY:

Marcel Dekker; 2004.

6. Kramer MA, Cash SS. Epilepsy as a disorder of cortical network organization. Neuroscientist . Aug

2012;18(4):360-72. [Medline].

7. Houser CR, Esclapez M. Vulnerability and plasticity of the GABA system in the pilocarpine model of 

spontaneous recurrent seizures. Epilepsy Res. Dec 1996;26(1):207-18. [Medline].

8. Sloviter RS. Status epilepticus-induced neuronal injury and network reorganization. Epilepsia.

1999;40(suppl 1):S34-9; discussion S40-1. [Medline].

9. Scharfman HE, Schwartzkroin PA. Protect ion of dentate hilar cells from prolonged stimulation by

intracellular calcium chelation. Science. Oct 13 1989;246(4927):257-60. [Medline].

10. Cavazos JE, Das I, Sutula TP. Neuronal loss induced in limbic pathways by kindling: evidence for 

induction of hippocampal sclerosis by repeated brief seizures. J Neurosci . May 1994;14(5 pt 2):3106-21.

[Medline].

11. Sutula T, Cascino G, Cavazos J, et al. Mossy fiber synaptic reorganization in the epileptic human

temporal lobe. Ann Neurol . Sep 1989;26(3):321-30. [Medline].

12. Mastrangelo M, Leuzzi V. Genes of early-onset epileptic encephalopathies: from genotype to phenotype.

Pediatr Neurol . Jan 2012;46(1):24-31. [Medline].

13. McCormick DA. Cellular mechanisms underlying cholinergic and noradrenergic modulation of neuronal

firing mode in the cat and guinea pig dorsal lateral geniculate nucleus. J Neurosci . Jan 1992;12(1):278-89.

[Medline].

14. Hosford DA, Clark S, Cao Z, et al. The role of GABAB receptor activation in absence seizures of lethargic

(lh/lh) mice. Science. Jul 17 1992;257(5068):398-401. [Medline].

15. Hagberg B, Hanefeld F, Percy A, Skjeldal O. An update on clinically applicable diagnostic criteria in Rett

syndrome. Comments to Rett Syndrome Clinical Criteria Consensus Panel Satellite to European

Paediatric Neurology Society Meeting, Baden Baden, Germany, 11 September 2001. Eur J Paediatr Neurol . 2002;6(5):293-7. [Medline].

16. Steffenburg U, Hagberg G, Hagberg B. Epilepsy in a representative series of Rett syndrome. Acta

Paediatr . Jan 2001;90(1):34-9. [Medline].

17. Whalen S, Héron D, Gaillon T, Moldovan O, Rossi M, Devillard F, et al. Novel comprehensive diagnostic

strategy in Pitt-Hopkins syndrome: clinical score and further delineation of the TCF4 mutational spectrum.

Hum Mutat . Jan 2012;33(1):64-72. [Medline].

18. Roach ES, Sparagana SP. Diagnosis of tuberous sclerosis complex. J Child Neurol . Sep 2004;19(9):643-

9. [Medline].

19. Kao A, Mariani J, McDonald-McGinn DM, Maisenbacher MK, Brooks-Kayal AR, Zackai EH, et al.

Increased prevalence of unprovoked seizures in patients with a 22q11.2 deletion. Am J Med Genet A. Aug

15 2004;129A(1):29-34. [Medline].

20. Battaglia A, Filippi T, South ST, Carey JC. Spectrum of epilepsy and electroencephalogram patterns in

Wolf-Hirschhorn syndrome: experience with 87 patients. Dev Med Child Neurol . May 2009;51(5):373-80.

[Medline].

21. Battaglia A, Hoyme HE, Dallapiccola B, Zackai E, Hudgins L, McDonald-McGinn D, et al. Further 

delineation of deletion 1p36 syndrome in 60 patients: a recognizable phenotype and common cause of 

developmental delay and mental retardation. Pediatrics. Feb 2008;121(2):404-10. [Medline].

8/14/2019 Epilepsy and Seizures.pdf

http://slidepdf.com/reader/full/epilepsy-and-seizurespdf 17/19

22. Hauser WA, Annegers JF, Rocca WA. Descriptive epidemiology of epilepsy: contributions of population-

based studies from Rochester, Minnesota. Mayo Clin Proc . Jun 1996;71(6):576-86. [Medline].

23. [Best Evidence] Hirsch LJ, Donner EJ, So EL, Jacobs M, Nashef L, Noebels JL, et al. Abbreviated report

of the NIH/NINDS workshop on sudden unexpected death in epilepsy. Neurology . May 31

2011;76(22):1932-8. [Medline]. [Full Text].

24. Luders H, Acharya J, Baumgartner C, et al. Semiological seizure classification. Epilepsia. Sep

1998;39(9):1006-13. [Medline].

25. Loddenkemper T, Kellinghaus C, Wyllie E, Najm IM, Gupta A, Rosenow F. A proposal for a five-dimensional patient-oriented epilepsy classification. Epileptic Disord . Dec 2005;7(4):308-16. [Medline].

26. Engel J Jr. Report of the ILAE classification core group. Epilepsia. Sep 2006;47(9):1558-68. [Medline].

27. Wolf P. Basic principles of the ILAE syndrome classification. Epilepsy Res. Aug 2006;70 suppl 1:S20-6.

[Medline].

28. Berg AT, Berkovic SF, Brodie MJ, et al. Revised terminology and concepts for organization of seizures

and epilepsies: report of the ILAE Commission on Classification and Terminology, 2005-2009. Epilepsia.

 Apr 2010;51(4):676-85. [Medline].

29. Engel J Jr. A proposed diagnostic scheme for people with epileptic seizures and with epilepsy: report of 

the ILAE Task Force on Classification and Terminology. Epilepsia. Jun 2001;42(6):796-803. [Medline].

30. Wolf P. Of cabbages and kings: some considerations on classifications, diagnostic schemes, semiology,

and concepts. Epilepsia. Jan 2003;44(1):1-4; discussion 4-13. [Medline].

31. Beghi E. The concept of the epilepsy syndrome: how useful is it in clinical practice?. Epilepsia. May

2009;50 suppl 5:4-10. [Medline].

32. [Guideline] Chen DK, So YT, Fisher RS. Use of serum prolactin in diagnosing epileptic seizures: report of 

the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology.

Neurology . Sep 13 2005;65(5):668-75. [Medline].

33. First Seizure Trial Group (FIR.S.T Group). Randomized clinical trial on the efficacy of antiepileptic drugs in

reducing the risk of relapse after a first unprovoked tonic-clonic seizure. Neurology . Mar 1993;43(3 pt1):478-83. [Medline].

34. [Best Evidence] Glauser TA, Cnaan A, Shinnar S, et al, for the Childhood Absence Epilepsy Study

Group. Ethosuximide, valproic acid, and lamotrigine in childhood absence epilepsy. N Engl J Med . Mar 4

2010;362(9):790-9. [Medline].

35. Ng YT, Conry JA, Drummond R, Stolle J, Weinberg MA. Randomized, phase III study results of clobazam

in Lennox-Gastaut syndrome. Neurology . Oct 11 2011;77(15):1473-1481. [Medline].

36. [Best Evidence] Marson AG, Al-Kharusi AM, Alwaidh M, et al, for the SANAD Study group. The SANAD

study of effectiveness of valproate, lamotrigine, or topiramate for generalised and unclassifiable epilepsy:

an unblinded randomised controlled trial. Lancet . Mar 24 2007;369(9566):1016-26. [Medline].

37. US Food and Drug Administration. FDA approves Fycompa to treat seizures. October 22, 2012. Available

at http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm325038.htm . Accessed Sept 19,

2013.

38. Mattson RH, Cramer JA, Collins JF, et al. Comparison of carbamazepine, phenobarbital, phenytoin, and

primidone in partial and secondarily generalized tonic-clonic seizures. N Engl J Med . Jul 18

1985;313(3):145-51. [Medline].

39. Mattson RH, Cramer JA, Collins JF. A comparison of valproate with carbamazepine for the treatment of 

complex partial seizures and secondarily generalized tonic-clonic seizures in adults. The Department of 

Veterans Affairs Epilepsy Cooperative Study No. 264 Group. N Engl J Med . Sep 10 1992;327(11):765-71.

8/14/2019 Epilepsy and Seizures.pdf

http://slidepdf.com/reader/full/epilepsy-and-seizurespdf 18/19

[Medline].

40. [Best Evidence] Rowan AJ, Ramsay RE, Collins JF, et al, for the VA Cooperative Study 428 Group. New

onset geriatric epilepsy: a randomized study of gabapentin, lamotrigine, and carbamazepine. Neurology .

Jun 14 2005;64(11):1868-73. [Medline].

41. [Best Evidence] Marson AG, Al-Kharusi AM, Alwaidh M, et al, for the SANAD Study Group. The SANAD

study of effectiveness of carbamazepine, gabapentin, lamotrigine, oxcarbazepine, or topiramate for 

treatment of partial epilepsy: an unblinded randomised controlled trial. Lancet . Mar 24

2007;369(9566):1000-15. [Medline].

42. French JA, Kanner AM, Bautista J, et al, for the Therapeutics and Technology Assessment

Subcommittee of the AAN; Quality Standards Subcommittee of the AAN; and AES. Efficacy and

tolerability of the new antiepileptic drugs I: treatment of new onset epilepsy: report of the Therapeutics and

Technology Assessment Subcommittee and Quality Standards Subcommittee of the American Academy

of Neurology and the American Epilepsy Society. Neurology . Apr 27 2004;62(8):1252-60. [Medline].

43. French JA, Kanner AM, Bautista J, et al for the Therapeutics and Technology Assessment Subcommittee

of the AAN; Quality Standards Subcommittee of the AAN; and AES. Efficacy and tolerability of the new

antiepileptic drugs, II: treatment of refractory epilepsy. Report of the Therapeutics and Technology

 Assessment Subcommittee and Quality Standards Subcommittee of the American Academy of 

Neurology and the American Epilepsy Society. Neurology . Apr 27 2004;62(8):1261-73. [Medline].

44. Kwan P, Arzimanoglou A, Berg AT, Brodie MJ, Allen Hauser W, Mathern G, et al. Definition of drug

resistant epilepsy: consensus proposal by the ad hoc Task Force of the ILAE Commission on

Therapeutic Strategies. Epilepsia. Jun 2010;51(6):1069-77. [Medline].

45. Ramos-Lizana J, Rodriguez-Lucenilla MI, Aguilera-López P, Aguirre-Rodríguez J, Cassinello-García E. A

study of drug-resistant childhood epilepsy testing the new ILAE criteria. Seizure. May 2012;21(4):266-72.

[Medline].

46. [Guideline] Harden CL, Pennell PB, Koppel BS, et al, for the AAN and AES. Management issues for 

women with epilepsy--focus on pregnancy (an evidence-based review): III. Vitamin K, folic acid, blood

levels, and breast-feeding: Report of the Quality Standards Subcommittee and Therapeutics and

Technology Assessment Subcommittee of the American Academy of Neurology and the American

Epilepsy Society. Epilepsia. May 2009;50(5):1247-55. [Medline].

47. [Guideline] Birbeck GL, French JA, Perucca E, Simpson DM, Fraimow H, George JM, et al. Antiepileptic

drug selection for people with HIV/AIDS: evidence-based guidelines from the ILAE and AAN. Epilepsia.

Jan 2012;53(1):207-14. [Medline].

48. [Guideline] Harden CL, Hopp J, Ting TY, et al, for the AAN and AES. Management issues for women with

epilepsy-Focus on pregnancy (an evidence-based review): I. Obstetrical complications and change in

seizure frequency: Report of the Quality Standards Subcommittee and Therapeutics and Technology

 Assessment Subcommittee of the American Academy of Neurology and the American Epilepsy Society.

Epilepsia. May 2009;50(5):1229-36. [Medline].

49. [Guideline] Harden CL, Meador KJ, Pennell PB, et al, for the AAN and AES. Management issues for women with epilepsy-Focus on pregnancy (an evidence-based review): II. Teratogenesis and perinatal

outcomes: Report of the Quality Standards Subcommittee and Therapeutics and Technology

Subcommittee of the American Academy of Neurology and the American Epilepsy Society. Epilepsia.

May 2009;50(5):1237-46. [Medline].

50. Levy RG, Cooper PN, Giri P. Ketogenic diet and other dietary treatments for epilepsy. Cochrane

Database Syst Rev . Mar 14 2012;3:CD001903. [Medline].

51. Kossoff EH, Turner Z, Bluml RM, Pyzik PL, Vining EP. A randomized, crossover comparison of daily

carbohydrate limits using the modified Atkins diet. Epilepsy Behav . May 2007;10(3):432-6. [Medline].

52. Weber S, Mølgaard C, Karentaudorf, Uldall P. Modified Atkins diet to children and adolescents with

8/14/2019 Epilepsy and Seizures.pdf

http://slidepdf.com/reader/full/epilepsy-and-seizurespdf 19/19

 

Medscape Reference © 2011 WebMD, LLC

 

medical intractable epilepsy. Seizure. May 2009;18(4):237-40. [Medline].

53. Smith M, Politzer N, Macgarvie D, McAndrews MP, Del Campo M. Efficacy and tolerability of the modified

 Atkins diet in adults with pharmacoresistant epilepsy: a prospective observational study. Epilepsia. Apr 

2011;52(4):775-80. [Medline].

54. Anderson P. FDA approves extended-release once-daily epilepsy drug. Medscape Medical News [serial

online]. August 21, 2013;Accessed August 27, 2013. Available at

http://www.medscape.com/viewarticle/809719 .

55. Supernus Pharmaceuticals, Inc. Supernus announces final FDA approval and upcoming launch of Trokendi XR(TM) [press release]. August 19, 2013. Available at http://ir.supernus.com/releasedetail.cfm?

ReleaseID=785927. Accessed August 27, 2013.

56. Englot DJ, Chang EF, Auguste KI. Vagus nerve stimulation for epilepsy: a meta-analysis of efficacy and

predictors of response. J Neurosurg . Dec 2011;115(6):1248-55. [Medline].

57. Anderson P. FDA Panel Endorses Epilepsy Neurostimulator. Medscape Medical News. Available at

http://www.medscape.com/viewarticle/779901 . Accessed March 4, 2013.

58. [Best Evidence] Wiebe S, Blume WT, Girvin JP, Eliasziw M, for the Effectiveness and Efficiency of 

Surgery for Temporal Lobe Epilepsy Study Group. A randomized, controlled trial of surgery for temporal-

lobe epilepsy. N Engl J Med . Aug 2 2001;345(5):311-8. [Medline].

59. Hyslop A, Miller I, Bhatia S, Jayakar P. Functional lesionectomy: a minimally resective strategy effective

in children with MRI-negative, intractable epilepsy [abstract 1.280]. Presented at: 66th Annual Meeting of 

the American Epilepsy Society; December 1, 2012; San Diego, Calif.

60. Melville NA. Minimal resection effective for some patients with epilepsy. Medscape Medical News.

January 3, 2013;Accessed January 15, 2013. Available at http://www.medscape.com/viewarticle/777048 .

61. Engel J Jr, McDermott MP, Wiebe S, Langfitt JT, Stern JM, Dewar S, et al. Early surgical therapy for 

drug-resistant temporal lobe epilepsy: a randomized trial. JAMA. Mar 7 2012;307(9):922-30. [Medline].

62. Herman AO. Anti-seizure drug linked to retinal abnormalities, skin discoloration. Physician's First Watch

[serial online]. April 29, 2013;Accessed May 7, 2013. Available at

http://firstwatch.jwatch.org/cgi/content/full/2013/429/2.