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]

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.

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, 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, zonisamide
Neuronal 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:

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 Epilepsy
Reflex 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 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 dj-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 afterhyperpolarization 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:

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 chloridemediated 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-hydroxy5-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 no exception; 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

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) from the apical
dendrites to the axon hillock. The feedforward projection 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.

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 seizurerelated 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.

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 calciumbinding 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 focalonset 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 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 channels in
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.

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 intellectual disability, 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 15q11.2q13. 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 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-Hopkinslike 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 cysts

Cerebral 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 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 bifrontal diameter, 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 acidresponsive 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
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 the United 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 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 seizure control, 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.

History
The diagnosis of epileptic seizures is made by analyzing the patient's detailed
clinical history and by performing ancillary tests for confirmation. Someone who
has observed the patient's repeated events is usually the best person to provide
an accurate history. However, the patient also provides invaluable details about
auras, preservation of consciousness, and postictal states. A key feature of
epileptic seizures is their stereotypic nature.

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

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

Was the patient able to relate to the environment during the seizure and/or does
the patient have recollection of the seizure?
How did the patient feel after the seizure? How long did it take for the patient to
get back to baseline condition?
How long did the seizure last?
How frequently do the seizures occur?
Is anything known to precipitate the seizures?
Has the patient shown any response to therapy for the seizures?
Physical Examination
The clinical diagnosis of seizures is based on the history obtained from the
patient and, most importantly, the observers. Physical examination helps in the
diagnosis of specific epileptic syndromes that cause abnormal findings, such as
dermatologic abnormalities (eg, neurocutaneous syndromes such as SturgeWeber, tuberous sclerosis, and others). In addition, patients who for years have
had intractable generalized tonic-clonic seizures are likely to have suffered
injuries requiring stitches.

Overview of Epileptic Seizures Classification

In 1981, the International League Against Epilepsy (ILAE) developed an
international classification of epileptic seizures that divides seizures into 2 major
classes: partial-onset seizures and generalized-onset seizures. Partial-onset
seizures begin in a focal area of the cerebral cortex, whereas generalized-onset
seizures have an onset recorded simultaneously in both cerebral hemispheres.
Some seizures are difficult to fit into a single class, and they are considered
unclassified seizures. This classification is still widely accepted.

Other classifications, such as a semiologic classification advanced by Luders and

others, have been proposed.[24] A refinement of this semiologic classification led
to a 5-dimensional (5-D), patient-oriented classification of epilepsy.[25]

The ILAE commission on classification developed additional reports.[26, 27] In

2006, a new proposed classification of seizures was published.[26, 27] The 2
main changes in this classification are (1) the use of focal rather than partial and
(2) the proposal that a single seizure in the setting of a predisposition for further
seizures be considered epilepsy. In 2010, the ILAE commission on classification
explained in more detail the decision for using the changes in terminology in the
revised proposed classification.[28] Nevertheless, there remains controversy

over the classification of epileptic seizures among clinicians. A revised proposal is

expected after the 2013 ILAE meeting.

Focal-Onset Seizures
Focal-onset seizures are further classified as simple focal seizures, complex focal
seizures, and secondary generalized tonic-clonic seizures.

Simple and complex focal seizures

The defining element of simple focal seizures is a seizure with preserved
consciousness. A complex partial seizure is defined as one in which there is some
alteration or impairment of consciousness. Many patients with complex focal
seizures have an aura warning them of their seizure; the aura itself is a simple
focal seizure. The many kinds of simple focal seizures include sensory, motor,
autonomic, and psychic types. Any discrete experience that involves the cerebral
cortex could be a simple focal-onset seizure.

The diagnosis of the seizure type is based on the repeated, stereotypic

occurrence of the same experience in association with focal
electroencephalographic (EEG) changes or on recurrent auras leading to a
complex focal-onset seizure or a secondary generalized seizure. Resolution of the
recurrent clinical phenomena with anticonvulsants is presumptive but not
diagnostic evidence for epileptic seizures.

The clinical diagnosis is difficult, as many stereotypic auras may be induced in

areas of the cerebral cortex that are not recorded well on a typical EEG. About
20-40% of auras have an ictal correlate on the scalp EEG. Simple focal seizures
may last a few seconds to a few minutes. However, if the aura lasts longer than
30 minutes, it is considered simple focal status epilepticus by definition.

As noted above, consciousness is impaired during a complex focal seizure. In

practice, assessing the patient's history to determine whether consciousness was
impaired is difficult. The most common way to assess preserved consciousness is
asking patients if they remembered the event. Patients may be able to
remember their aura but are unaware that they were briefly unable to respond to
the environment.

A complex focal seizure typically begins with behavioral arrest and is followed by
staring, automatisms, and postictal confusion. Typical automatisms are chewing,

lip smacking, mumbling, and fumbling with the hands. Dystonic posturing of the
contralateral upper extremity is often seen when a complex partial seizure
originates from the mesial temporal lobe. A typical complex focal seizure lasts
about 60-90 seconds and is followed by brief postictal confusion. However,
generalized weakness, asthenia, and fatigue may last for a few days.

Complex focal seizures of frontal-lobe origin may feature bizarre motor behaviors
such as bicycling or a fencing posture, and they may have more of a nocturnal
occurrence. These seizures have more prominent motor features than those of
complex focal seizures of temporal-lobe onset. Frontal lobeonset complex focal
seizures may have a fast postictal recovery to baseline, and they often appear in
clusters.

The great majority of complex focal seizures have an ictal correlate on the EEG. A
normal alpha rhythm during behavioral impairment of consciousness is highly
suggestive of nonepileptic seizures, but this should be interpreted by an
experienced epileptologist, as some true seizures may not have surface EEG
changes, and some true seizures can have somewhat atypical features (eg,
bilateral motor activity is present, but the patient may be conscious from
supplementary motor seizures).

Secondary generalized seizures

Secondary generalized seizures often begin with an aura that evolves into a
complex focal seizure and then into a generalized tonic-clonic seizure. However,
a complex focal seizure may evolve into a generalized tonic-clonic seizure
without a preceding aura, or an aura may evolve into a generalized tonic-clonic
seizure without an obvious complex focal seizure.

Clinically classifying a generalized tonic-clonic seizure as being secondarily

generalized (focal onset) or primarily generalized is difficult on the basis of the
history alone. In most cases, the association with prominent amnesia for the aura
increases with the severity of a secondary generalized seizure.

Generalized-Onset Seizures
Generalized-onset seizures are classified into 6 major categories, as follows:

Absence seizures

Myoclonic seizures
Clonic seizures
Tonic seizures
Primary generalized tonic-clonic seizures
Atonic seizures
Each seizure type is classified by its clinical and electroencephalographic (EEG)
manifestations. Definitive classification of seizures is best made by ictal
recordings over a period of several days to capture seizures.

Absence seizures
Absence seizures are brief episodes of impaired consciousness with no aura or
postictal confusion. They typically last less than 20 seconds and are
accompanied by few or no automatisms. Of the automatisms that develop, the
facial ones are most common, with repetitive blinking occurring most often.
Hyperventilation or photic stimulation frequently precipitates these seizures,
which typically begin during childhood or adolescence and may persist into
adulthood.

A diagnosis of new-onset absence seizures in adulthood is not likely in the vast

majority of cases. (Adults often have complex focal seizures with relatively minor
automatisms.) Confusion arises when patients and some healthcare providers
incorrectly use the term absence seizure (or petit mal seizure) and petit
mal/absence seizure to describe a seizure that is not grand mal.

Twin studies have demonstrated a significant inherited predisposition for typical

childhood absence seizures. In children, the seizures are subtle, manifesting as
staring episodes and often going unrecognized until the child develops a
generalized tonic-clonic (previously known as grand mal) seizure. Sudden
decreased performance in school or overall attention may be a subtle
manifestation of frequent absence seizures.

The classic ictal EEG correlate of absence seizures consists of 3-Hz generalized
spike-andslow wave complexes that may be induced by activation during EEG
by hyperventilation and sometimes photic stimulation. EEG abnormalities may
persist into adulthood despite the absence of clinical seizures. However,
compared with the EEG discharges in children, those in adults occur less often,
are less well formed, and are of lesser amplitude.

Myoclonic, clonic, and tonic seizures

Myoclonic seizures consist of brief arrhythmic jerking motor movements that last
less than 1 second and often cluster within a few minutes. If the seizures evolve
into rhythmic jerking movements, they are classified as evolving into a clonic
seizure. Myoclonus is not always epileptic in origin. For example, the myoclonic
jerks during phase I of sleep are normal release phenomena. The classic ictal
correlate of myoclonic seizures on the EEG consists of fast polyspike-andslow
wave complexes.

Clonic seizures consist of rhythmic jerking motor movements with or without

impairment of consciousness; they can have a focal origin. The focal seizures are
classified as simple or complex partial seizures. The typical generalized clonic
seizures simultaneously involve the upper and lower extremities. The ictal EEG
correlate consists of bilateral, rhythmic, epileptiform discharges.

Tonic seizures consist of sudden-onset tonic extension or flexion of the head,

trunk, and/or extremities for several seconds. These seizures typically occur in
relation to drowsiness, shortly after patients fall asleep, or just after they
awaken. Tonic seizures are often associated with other neurologic abnormalities.

The ictal correlate of tonic seizures in the EEG includes an electrodecremental

response, which is a high-frequency electrographic discharge in the beta
frequency (also known as "beta buzz"), with a relatively low amplitude compared
with that of the background rhythm. This pattern may evolve into slow spike-andwave complexes or diffuse polyspikes.

Primary generalized tonic-clonic seizures

Tonic-clonic seizures are commonly referred to as grand mal seizures. They
consist of several motor behaviors, including generalized tonic extension of the
extremities lasting for few seconds followed by clonic rhythmic movements and
prolonged postictal confusion. On clinical evaluation, the only behavioral
difference between these seizures and secondary generalized tonic-clonic
seizures is that these seizures lack an aura, or there are partial seizure signs and
symptoms. However, the aura preceding the partial seizure with secondary
generalization is often forgotten because of postictal amnesia, and observers
may not see partial seizure signs and come upon the patient in the grand mal
phase.

The ictal correlate of generalized tonic-clonic seizures consists of generalized

(bilateral) complexes of spikes or polyspike and slow waves. These epileptiform
discharges often have increased amplitude in the frontal regions.

Atonic seizures
Atonic seizures are also called drop attacks. These seizures occur in people
with clinically significant neurologic abnormalities and consist of brief loss of
postural tone, often resulting in falls and injuries (hence, some patients need
helmets). The ictal EEG correlate is similar to EEG abnormalities observed in
tonic seizures.

Classification of Epileptic Syndromes

Epileptic seizures are symptoms of neurologic dysfunction, and they are but 1
manifestation of many neurologic diseases. As with any other syndrome in
medicine, an epileptic syndrome is a group of signs and symptoms that share a
common pathogenesis, prognosis, and response to treatment.

In 1989, the International League Against Epilepsy (ILAE) developed a

classification of epileptic syndromes, which is in the process of being revised.
The current system comprises 2 major categories: localization-related syndromes
and generalized-onset syndromes. Physicians would ideally classify their
patients' seizures by using the classification for seizure types and make a
syndromic diagnosis, if possible.

Localization-related epilepsies and syndromes include the following:

Idiopathic, with age-related onset

Benign childhood epilepsy with centrotemporal spikes
Childhood epilepsy with occipital paroxysms
Symptomatic
Mesial temporal lobe sclerosis
Generalized epilepsies and syndromes include the following:

Idiopathic, with age-related onset

Benign neonatal familial convulsions

Benign neonatal convulsions
Benign myoclonic epilepsy of infancy
Childhood absence epilepsy (pyknolepsy)
Juvenile absence epilepsy
Juvenile myoclonic epilepsy (JME)
Epilepsy with grand mal seizures on awakening
Idiopathic and/or symptomatic infantile spasms
Lennox-Gastaut syndrome
Epilepsy with myoclonic astatic seizures
Epilepsy with myoclonic absences
Symptomatic
In 2001, the ILAE Task Force on Classification and Terminology proposed that
rather than revising the entire classifications of seizures (1981) or epilepsy
syndromes (1989), a better strategy was to devise a 5-axis diagnostic scheme,
as follows[29] :

Axis 1: Descriptive ictal terminology

Axis 2: Seizure type, from the List of Epileptic Seizures, with specific brain
location (if known)
Axis 3: Syndrome, from the List of Epilepsy Syndromes; not always possible
Axis 4: Etiology, including specific genetic defects or pathologic substrates
Axis 5: Impairment; optional but useful parameter that can be derived from the
World Health Organization (WHO) revised International Classification of
Functioning, Disability and Health (ICIDH-2) impairment classification
The 2001 task force report also discussed the abandonment of the terms
partial-onset and localization-related seizure and epilepsy for the term
focal. The 2006 review of the terminology formalized the change from partial
to focal, but localization-related epilepsy remains an accepted term. In addition,
the task force recommended that the term cryptogenic be replaced for the
more precise wording probably symptomatic. However, cryptogenic remains an
accepted term.

Despite the fact that for many years psychiatrists have successfully used a
somewhat similar 5-axis diagnostic scheme, critics indicate that this system is
unnecessarily complex and its reliability, accuracy, and clinical use are uncertain.
(For a more complete description of these controversies see Wolf[30] and the
resultant discussions by Engel, Luders et al, Berg and Blackstone, and Avanzini.
Similarly, see Fisher et al[1] and its resultant discussion.)

To increase the controversy on this subject, there is evidence that epilepsy

syndromes are not static diagnoses but ones that may evolve over time. They
also have poor prognostic predictivity, and the interobserver reliability of
classifying epileptic syndromes is poor.[31]

Diagnostic Considerations
The diagnosis of seizures is based on the patients clinical history. The history as
related by a witness is of high importance, because many types of seizures are
associated with impairment of consciousness, and patients are unaware of their
occurrence.

The clinical diagnosis can be confirmed by abnormalities on the interictal

electroencephalogram (EEG). However, these abnormalities can be present in
otherwise healthy individuals, and their absence does not exclude the diagnosis
of epilepsy.

Not all spells are seizures. (See the Differentials section, below.) Other
conditions that should be considered include the following:

Syncope (eg, cardiac arrhythmia, vasovagal syncope, dysautonomia)

Metabolic conditions (eg, hypoglycemia, hyponatremia)
Migraine (eg, migrainous aura, migraine equivalent)
Vascular conditions (eg, transient ischemic attacks)
Sleep disorders (eg, cataplexy, narcolepsy, night terror)
Movement disorders (eg, paroxysmal dyskinesia)
Gastrointestinal conditions (eg, esophageal reflux in neonates and infants)
Psychiatric conditions (eg, conversion, panic attacks, breath-holding spells,
malingering, secondary gain)

Differential Diagnoses
Cardioembolic Stroke

First Adult Seizure

Frontal Lobe Epilepsy

Idiopathic Orthostatic Hypotension and other Autonomic Failure Syndromes

Migraine Headache

Pediatric Febrile Seizures

Pediatric First Seizure

Sleepwalking

Transient Global Amnesia

Approach Considerations
Two studies are often recommended after a seizure: neuroimaging evaluation
(eg, brain magnetic resonance imaging [MRI], head computed tomography [CT]
scanning) and electroencephalography (EEG). For neuroimaging, a CT scan is
often obtained in the emergency department to exclude an obvious structural
lesion, but an MRI is indicated if the patient continues to have seizures. In
addition, lumbar puncture for cerebrospinal fluid (CSF) examination has a role in
the patient with obtundation or in patients in whom meningitis, encephalitis, or
subarachnoid hemorrhage is suspected.

Epileptic seizures have many causes, and some epileptic syndromes have
specific histopathologic abnormalities. For more information, see the articles
about specific epileptic syndromes listed in the Background section.

Prolactin Study
Historically, prolactin levels obtained shortly after a seizure (within 20 min) have
been used to assess the etiology (epileptic or nonepileptic) of a spell. levels are
typically elevated 3- or 4-fold, and elevations are more likely to occur with
generalized tonic-clonic seizures than with other seizure types. However, not
only has the considerable variability of prolactin levels precluded routine clinical
use of such testing, but a baseline prolactin level is often obtained the next day
at the same time as when the seizure first occurred, which makes the testing
more cumbersome.

The American Academy of Neurology (AAN) recommends serum prolactin assays,

measured in the appropriate clinical setting at 10-20 minutes after a suspected
event as a useful adjunct for differentiating generalized tonic-clonic or complex
partial seizure from psychogenic nonepileptic seizure in adults and older
children.[32]

The AAN notes, however, that prolactin assays do not distinguish epileptic
seizures from syncope and have not been established in the evaluation of status
epilepticus, repetitive seizures, and neonatal seizures.[32] It should also be
noted that wider availability of bedside video electroencephalography (EEG), the
gold standard, has replaced prolactin testing for the evaluation of epileptic
versus nonepileptic episodes.

Serum Studies of Anticonvulsant Agents

Judicious testing of serum levels of antiepileptic drugs (AEDs) may help to
improve the care for patients with seizures and epilepsy. However, note that
many new AEDs do not have readily obtainable or established levels. The
following situations may be indications for obtaining serum AED levels:

Baseline measurements: After the seizures are controlled, the AED dose is then
established, and the levels needed to achieve seizure-free effectiveness if there
are expected changes in the levels, such as occurs with pregnancy, may be also
be obtained
Toxicity and efficacy: The toxicity and efficacy of an AED is a clinical decision not
based on levels per se but on how the patient is doing; an AED level may be
helpful if the patient is at the recommended maximum dose but the serum level
is not near that of the recommended maximum (thus, the clinician knows the
drug dose can be increased, as there is room to achieve a higher AED level)

Medication noncompliance: Approximately 30% of patients miss at least 1 dose

of their medication every month
Autoinduction or pharmacokinetic change, or patients who are unusual
metabolizers of a medication
After an anticonvulsant has been used for several weeks, the baseline trough
serum concentration slowly decreases because of hepatic autoinduction; this
phenomenon is most often seen with carbamazepine, oxcarbazepine, and
lamotrigine. Adding other medications with similar metabolic pathways may
substantially change the clearance of some anticonvulsants.

The usual therapeutic range for an AED includes peak and trough levels
measured in a group of adult patients. If a drugs toxicity is under study, the
peak level is desirable. In most circumstances, however, a trough level is the
best indication of efficacy.

As with any medical test, serum concentrations of AEDs help clinical decision
making, but the patient's individual response should be the main consideration.
For example, a patient with juvenile myoclonic epilepsy (JME) might be seizure
free with a valproic acid level of 30 mcg/mL, which is typically considered
subtherapeutic, but if the patient is seizure free, the level is therapeutic.
Therefore, clinical judgment regarding how well the patient is doing (ie, no
seizures, no adverse effects) should prevail over a laboratory reading. Again,
many new AEDs do not have a recommended level for testing, which is cost
saving for that AED relative to many other AEDs in which serum levels are
obtained reflexively (thus, adding to the cost of care).

Neuroimaging Studies
A neuroimaging study, such as brain magnetic resonance imaging (MRI) or head
computed tomography (CT) scanning, may show structural abnormalities that
could be the cause of a seizure. If the patient has normal findings on neurologic
examination and his or her condition (eg, cognitive, motor) returns to the usual
baseline level between seizures, the preferred study is a brain MRI because of its
resolution, which can depict subtle abnormalities.

Not every brain MRI study provides the same quality of information. Studies
obtained with 3.0 Tesla (T) scanners may show better resolution than do
conventional 1.5 T scanners or the "open-sided" scanners of 0.5 T. Brain MRIs
obtained for epilepsy should have thin coronal sections via fast spin-echo (FSE)
or fluid attenuation inversion recovery (FLAIR) sequences from the presumed

region of epileptogenic zone; these are useful for assessing cortical lesions,
which may be amenable to potentially curative surgery.

There are many new advances in MRI sequences to help in epilepsy presurgical
evaluation. For more information, see Identification of Potential Epilepsy Surgery
Candidates regarding imaging studies.

Electroencephalography and Video-Electroencephalography

Interictal epileptiform discharges or focal abnormalities on
electroencephalography (EEG) strengthen the diagnosis of epileptic seizures and
provide some help in determining the prognosis. Although the criterion standard
for diagnosis and classification of epileptic seizures includes the interpretation of
EEG, the clinical history remains the cornerstone for the diagnosis of epileptic
seizures.

Video-EEG monitoring is the criterion standard for classifying the type of seizure
or syndrome or for diagnosing pseudoseizures; that is, for establishing a
definitive diagnosis of spells with impairment of consciousness. This study can be
performed to rule out an epileptic etiology with a high degree of confidence if the
patient has demonstrable impairment of consciousness during the spell in
question. Video-EEG is also used to characterize the type of seizure and epileptic
syndrome to optimize pharmacologic treatment and for presurgical workup.

However, video-EEG monitoring is an expensive and laborious study; therefore,

monitoring all patients is impractical. Only those whose condition does not
respond to treatment or in whom pseudoseizures are suspected should undergo
video-EEG. Referral to an epilepsy center should be reserved for patients whose
seizures are refractory to treatment. There is now a formal definition of patients
who have medically refractory epilepsy: individuals who have tried 2 adequate
doses of AED without a clinical response. Some frontal-lobe seizures are
considered pseudoseizures for many years until appropriate diagnosis is made by
means of video-EEG.

Approach Considerations
The goal of treatment in patients with epileptic seizures is to achieve a seizurefree status without adverse effects. This goal is accomplished in more than 60%
of patients who require treatment with anticonvulsants. Many patients
experience adverse effects from these drugs, however, and some patients have
seizures that are refractory to medical therapy.

Monotherapy is desirable because it decreases the likelihood of adverse effects

and avoids drug interactions. In addition, monotherapy may be less expensive
than polytherapy, as many of the older anticonvulsant agents have hepatic
enzymeinducing properties that decrease the serum level of the concomitant
drug, thereby increasing the required dose of the concomitant drug.

People with seizures experience psychosocial adjustments after their diagnosis;

therefore, social and/or vocational rehabilitation may be needed. Many
physicians underestimate the consequences that an epilepsy diagnosis may have
on patients. For example, patients with epilepsy may live in fear of experiencing
the next seizure, and they may be unable to drive or work at heights.

Refer patients with intractable spells to a neurologist or an epileptologist for

further workup, including video-electroencephalographic (EEG) monitoring, to
characterize the etiology of their seizures. A neurosurgical consult is
recommended when the possibility of surgical management is considered.

Recurrence risk
For patients who have had more than 1 unprovoked seizure, treatment with an
anticonvulsant is recommended. However, the standard of care for a single
unprovoked seizure is avoidance of typical precipitants (eg, alcohol, sleep
deprivation); anticonvulsants are not recommended unless the patient has risk
factors for recurrence.

The risk of recurrence in the 2 years after a first unprovoked seizure is 15-70%.
Principal factors that increase the risk of recurrence are an abnormal brain
magnetic resonance image (MRI) study, an abnormal electroencephalogram
(EEG), and a partial-onset seizure.

On brain magnetic resonance imaging (MRI), a focal abnormality in the cortical or

limbic regions that indicates a possible substrate for an epileptogenic zone is the
finding that most often suggests increased risk for seizure recurrence. Diffuse
abnormalities, such as hydrocephalus, may increase the risk by injuring the
cerebral cortex.

Abnormalities on an EEG may include any of the following:

Epileptiform discharges
Focal slowing
Diffuse background slowing
Intermittent diffuse intermixed slowing
Epileptiform abnormalities and focal slowing are the EEG findings associated with
the highest risk of seizure recurrence. Nevertheless, even a normal EEG does not
eliminate recurrence risk.

The risk of recurrence in a person with 1 generalized tonic-clonic seizure, a

normal EEG, a normal brain MRI, and no evidence of focal onset is about 15%; in
this case, the patient is not treated. If a patient has all risk factors, the risk is
approximately 80%, and the patient is treated.

The major unresolved question is how to treat patients with 1 abnormality,

whose recurrence risk is 30-50%. One approach is to base the decision on a
discussion with the patient that includes the risk of seizure recurrence, the risk of
toxic effects from the anticonvulsant, and the benefits of avoiding another
seizure. The clinician should also describe seizure precautions, including not
driving for a specific time. Treatment with anticonvulsants does not alter the
natural history of seizure recurrence; it only reduces the risk for the duration of
treatment.

The First Seizure Trial Group randomly selected 397 patients with an unprovoked,
generalized tonic-clonic first seizure to either receive prophylaxis with a
conventional anticonvulsant (ie, carbamazepine, phenobarbital, phenytoin,
valproic acid) or to receive no treatment and reported that about 18% of treated
patients had seizure recurrence within 1 year, compared with 39% of untreated
patients.[33] Therefore, patients must be told that anticonvulsants can reduce
their risk of having another seizure but will not eliminate that risk.

Anticonvulsant Therapy
The mainstay of seizure treatment is anticonvulsant medication. The drug of
choice depends on an accurate diagnosis of the epileptic syndrome, as response
to specific anticonvulsants varies among different syndromes. The difference in
response probably reflects the different pathophysiologic mechanisms in the
various types of seizure and the specific epileptic syndromes.

Some anticonvulsants (eg, lamotrigine, topiramate, valproic acid, zonisamide)

have multiple mechanisms of action, and some (eg, phenytoin, carbamazepine,
ethosuximide) have only 1 known mechanism of action. Anticonvulsants can be
divided into large groups based on their mechanisms, as follows:

Blockers of repetitive activation of the sodium channel: Phenytoin,

carbamazepine, oxcarbazepine, eslicarbazepine, lamotrigine, topiramate
Enhancers of slow inactivation of the sodium channel: Lacosamide, rufinamide
Gamma-aminobutyric acid (GABA)A receptor enhancers: Phenobarbital,
benzodiazepines, clobazam
N -methyl-D-aspartic acid (NMDA) receptor blockers: Felbamate
Alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (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, perampanel
Carbonic anhydrase inhibitors: Topiramate, zonisamide
Neuronal potassium channel (KCNQ [Kv7]) opener: Ezogabine
For more information, see Antiepileptic Drugs.

Anticonvulsants for Specific Seizure Types

This section discusses the use of anticonvulsant agents for absence, tonic or
atonic, myoclonic, and tonic-clonic seizures. A discussion of treatment for focalonset seizures, including refractory cases, also follows, with some findings from
the Veterans Administration (VA) Cooperative Studies and Standard and New
Antiepileptic Drugs (SANAD) trial.

Absence seizures
If only absence seizures are present, most neurologists treat them with
ethosuximide. If absence seizures are present along with other seizure types (eg,
generalized tonic-clonic seizures, myoclonic seizures), the choices are valproic

acid, lamotrigine, or topiramate. Do not use carbamazepine, gabapentin or

tiagabine, because these drugs may exacerbate absence seizures. It is uncertain
whether pregabalin, a medication related to gabapentin, may also exacerbate
this type of seizure.

Investigators of a single, double-blind, randomized, controlled trial that

compared the efficacy, tolerability, and neuropsychologic effects of
ethosuximide, valproic acid, and lamotrigine in children with newly diagnosed
childhood absence epilepsy concluded that ethosuximide was the drug of choice
for this clinical scenario.[34] Valproate was equally as effective as ethosuximide
in newly diagnosed childhood absence epilepsy, but it was associated with more
adverse effects.

Tonic or atonic, myoclonic, and tonic-clonic seizures

Tonic or atonic seizures are dramatic seizures. Patients with Lennox-Gastaut
syndrome may have seizures, and this syndrome is best treated with broadspectrum drugs (eg, valproic acid, lamotrigine, topiramate) or felbamate as a last
resort. Other treatment modalities include the use of vagal nerve stimulation
(VNS). The US Food and Drug Administration (FDA) has approved several agents
rufinamide, clobazam,[35] and extended-release topiramate[36, 37, 38, 39]
as adjunctive therapies for seizures associated with Lennox-Gastaut syndrome.

Myoclonic seizures have a bimodal distribution. Infants with myoclonic epilepsies

usually have a poor prognosis; however, in late childhood and adolescence, the
syndrome of juvenile myoclonic epilepsy (JME) is often the cause of myoclonic
seizures. The seizures associated with JME are usually readily controlled with the
appropriate broad-spectrum antiepileptic drug (AED), but JME has a high
recurrence rate of approximately 80-90% after discontinuation of
anticonvulsants.

The best medications for JME and myoclonic seizures are valproic acid,
lamotrigine, and topiramate. Levetiracetam is approved by the FDA for
adjunctive therapy of JME; this is the first medication approved for this
syndrome. Anecdotal evidence suggests that zonisamide might be helpful in JME.
Note that if partial seizure medications, such as phenytoin and carbamazepine,
are used to treat JME, these agents may not only be ineffective, but in certain
cases they may exacerbate the seizures.

Primary generalized tonic-clonic seizures respond to valproic acid, topiramate, or

lamotrigine. Levetiracetam and perampanel are indicated as adjunctive therapy
for these seizures.

Generalized and unclassified epilepsies

The SANAD trial investigators concluded that valproate should remain the drug of
first choice for many patients with generalized and unclassified epilepsies, as it is
better tolerated than topiramate and more efficacious than lamotrigine.[40]
However, in women of childbearing age, the known potential adverse effects of
valproate during pregnancy (ie, black box warnings of severe birth defects and
impaired cognitive development) must be balanced against the benefits of
seizure control. Levetiracetam and zonisamide were not included in SANAD,
which tested only lamotrigine, topiramate, and valproate.

A 2014 study by Shallcross et al, however, indicated that whereas in utero

exposure to the AED valproate is associated with language and motor
development deficits in children, the same is not true for levetiracetam. In the
study, valproate exposure resulted in children having lower scores on tests of
comprehension, expressive language abilities, and motor skills compared with
children exposed to levetiracetam. In fact, children exposed to levetiracetam did
not differ from children unexposed to any AED on tests of thinking, movement,
and language when tested at age 36-54 months.[41, 42]

Focal-onset seizures
In focal-onset seizures, there are many AED choices with monotherapy
indications, including carbamazepine, lacosamide, lamotrigine, oxcarbazepine,
and topiramate. (see Anticonvulsants in Specific Patient Populations, below).
Adjunctive therapy with levetiracetam, tiagabine, gabapentin, pregabalin,
lacosamide, or ezogabine may be considered if the first or second monotherapy
trial with first-line treatments fails. Discussing the adverse-effect profiles of
anticonvulsants with patients is important, because the efficacies of
anticonvulsants appear to be similar.[43]

The VA Cooperative Study I clearly demonstrated similar efficacies for

carbamazepine, phenytoin, primidone, and phenobarbital.[44] However,
carbamazepine and phenytoin were tolerated better by men than women. The
VA Cooperative Study II findings showed that carbamazepine and valproic acid
had similar efficacies.[45] However, subset analysis for complex focal seizures
suggested that carbamazepine may be a better choice than valproate.[45]

In elderly subjects (patients aged 60 years) in the VA Cooperative Study,

lamotrigine and gabapentin were better tolerated than carbamazepine and were
similarly effective.[46] However, gabapentin caused more adverse effects than
lamotrigine. Those results led to the recommendation of lamotrigine as first-line
monotherapy in elderly patients.[46]

The focal seizures arm of the SANAD trial demonstrated that although
carbamazepine is the standard drug treatment, lamotrigine is clinically better
with respect to time to treatment failure.[47] This study also determined that
lamotrigine is a cost-effective alternative to carbamazepine for patients with
focal-onset seizures. Carbamazepine, gabapentin, lamotrigine, oxcarbazepine,
and topiramate were included for comparison.[47] However, the costeffectiveness of medications has changed, as many new AEDs also have generic
formulations.

All new medications have been tested as adjunctive therapy, and head-to-head
comparisons of new drugs with carbamazepine have been conducted in Europe.
In general, the new drugs have similar statistical efficacies but fewer adverse
effects than carbamazepine; this puts the results of the SANAD trial somewhat in
doubt, as the SANAD investigators did not find any important differences or
trends for scores on the Adverse Events Profile among the drugs.

Of the new anticonvulsants, lamotrigine and topiramate appear to have broad

spectrum of action in many seizure types.[48, 49] The American Academy of
Neurology and the American Epilepsy Society assembled a task force that
reviewed the literature and provided evidence-based recommendations for
monotherapy, adjunctive therapy, treatment of primary generalized seizures,
treatment in children, and treatment of subgroups of new-onset and refractory
epilepsy.[48, 49]

If carbamazepine fails to control the seizures, lamotrigine, topiramate, tiagabine,

gabapentin, levetiracetam, oxcarbazepine, pregabalin, and zonisamide are
considered for second- or third-line therapy. Several new anticonvulsants,
including lamotrigine, topiramate, and oxcarbazepine, are indicated as
monotherapy. Although the new anticonvulsants are considered second- or thirdline therapy, they can be used as first-line therapy in some patients, especially
as these medications have become generic.

In October 2013, the FDA approved labeling changes for ezogabine, including a
boxed warning, emphasizing increased risks for potentially permanent adverse

effects, such as retinal abnormalities, vision loss, and skin discoloration. The
agency recommended that the use of ezogabine be limited to patients who have
had an inadequate response to several other therapies and in whom the
treatment benefits outweigh the risks. The FDA also recommended eye
examinations for patients before they start on ezogabine, as well as every 6
months over the course of treatment.[50, 51, 52]

Medically refractory epilepsy

Although the term medically refractory epilepsy has been used for cases that fail
to respond to three antiepileptic drugs, the International League Against Epilepsy
(ILAE) has proposed defining drug-resistant epilepsy as the failure to achieve
sustained seizure freedom despite adequate trials of two antiepileptic drugs,
either as monotherapy or in combination.[53, 54] The drugs must have been
appropriately chosen and used, and failure must have occurred because of lack
of efficacy and not because of adverse effects.

A study of the ILAE criteria in pediatric epilepsy patients found that the
probability of achieving seizure freedom was 65%, 29%, 27% and 21%,
respectively, with trials of successive therapeutic regimens.[53, 54] Patients with
medically refractory epilepsy should be referred to an epileptologist.

Immunotherapy may be a viable treatment strategy in a subset of epileptic

patients whose seizures are refractory to management with conventional AEDs
and whose poor seizure control may result from the presence of neural-specific
antibodies.[55, 56] 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.
[56] The remaining patients 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%.[56]

Looking ahead

Future advances in AEDs will involve agents that alter the natural history of
epilepsy and modify disease as opposed to providing primarily symptomatic
treatment.

Anticonvulsants in Specific Patient Populations

The use of anticonvulsants is slightly different in several populations of patients,
including the following:

Neonates
Children
Elderly patients
Women on contraceptive agents
Pregnant women [57]
Patients with hepatic or renal insufficiency
Human immunodeficiency virus (HIV) infected patients [58]
Neonates, children, and elderly patients
In general, neonates and children require similar loading doses per kilogram of
body weight, but they tend to metabolize the drugs faster than adults. This
younger population also has rapid increases in the total volume of distribution.

In contrast, elderly patients need lower initial and maintenance doses, owing to
the following normal features of the aging process:

Slowed hepatic metabolism

Decreased renal clearance
Decreased volumes of distribution
Women on contraceptive agents
Anticonvulsants that induce hepatic enzymes, such as carbamazepine,
phenytoin, phenobarbital, primidone, felbamate, lamotrigine, topiramate, and
oxcarbazepine, decrease the efficacy of oral contraceptive pills. Some
anticonvulsants cause this drug interaction in a dose-dependent manner, with a
negligible effect at low doses. Some obstetricians use a high-dose estrogen-

progesterone contraceptive to counteract this effect. An alternative and possibly

preferable approach is to use a second method of contraception.

Women of childbearing age and pregnant women

In 2009, the American Academy of Neurology and the American Epilepsy Society
issued new guidelines for the management of antiepileptic drugs (AEDs) during
pregnancy.[57, 59, 60] These guidelines cover obstetric complications and
change in seizure frequency; teratogenesis and perinatal outcomes; and vitamin
K, folic acid, blood levels, and breastfeeding.

Woman of childbearing age should take folic acid, at least 0.4 mg per day, to
decrease the rate of neural-tube malformations in the fetus. In addition, evidence
strongly suggests that, during pregnancy, women should take the medication
that best controls their epilepsy. Switching medications during pregnancy is not
recommended, because of the risk of losing seizure control and because it
exposes the fetus to polypharmacy. Data from multiple studies show an
exponential risk of birth defects as anticonvulsants are added in polytherapy.

Frequent drug serum levels should be obtained because of the many physiologic
changes that take place during pregnancy, including changes in volume of
distribution, protein binding, and hepatic metabolism and erratic absorption. In
particular, decreased serum concentration of lamotrigine in the third trimester is
well documented, and the dose needs to be adjusted after delivery.

Whether to perform amniocentesis is a personal decision between the woman

and her obstetrician. The most important point is to have a clear idea about how
the information obtained will be useful for clinical decision making.

Patients with hepatic and renal insufficiency

Gabapentin, pregabalin, levetiracetam, and lacosamide are excreted mostly by
means of renal clearance, and their doses can be adjusted for renal insufficiency.
These agents are useful in patients with hepatic failure, especially when a druginduced etiology is suspected. Lamotrigine, which is metabolized by means of
glucuronidation, a phase II reaction, is also used in some patients with hepatic
insufficiency.

Considerable data are available on the use of phenytoin in the presence of

hepatic and renal insufficiency. However, phenytoin is not a preferred medication

because of its nonlinear kinetics, hepatic autoinduction, numerous drug

interactions, and high degree of protein binding. Among all anticonvulsants,
phenytoin, carbamazepine, valproic acid, and felbamate have been associated
with acute hepatic injury.

Discontinuing Anticonvulsant Agents

After a person has been seizure free for typically 2-5 years, the physician may
consider discontinuing that patients medication. Many patients outgrow many
epileptic syndromes of childhood and do not need to take anticonvulsants. The
relapse rate for seizures in adults is about 40-50%; for children, it is about 25%.
This difference probably reflects the different epileptic syndromes that are
prevalent in the 2 populations.

The recurrence rate during adulthood for patients with juvenile myoclonic
epilepsy (JME) is about 80-90% in 2 years, even in patients who have spent many
years being seizure free on low doses of appropriate anticonvulsants.

Risk of seizure recurrence

Many neurologists use the risk factors for new-onset seizures to assess patients
for discontinuation of anticonvulsants. Normal findings on an
electroencephalogram (EEG) and a brain magnetic resonance imaging (MRI) scan
lower the risk of relapse after drug discontinuation, whereas epileptiform or focal
abnormalities on an EEG and/or focal cortical or limbic abnormalities on a brain
MRI scan significantly increase the relapse risk.

Additional factors associated with an increased risk of seizure recurrence after

discontinuation include the following:

Several seizure types (eg, worse if tonic or atonic seizures are present)
High number and frequency of seizures
Long duration of epilepsy before the seizures were controlled
Short duration of seizure freedom
Seizure relapse
About 75% of seizure relapses after medication discontinuation occur in the first
year, and at least 50% of patients who have another seizure do so in the first 3
months. Therefore, advise patients to observe strict seizure precautions

(including not driving) during tapering and for at least 3 months after
discontinuation, depending on state laws. The need to drive is an impediment for
some patients, who may opt to continue therapy for that reason.

Some authors recommend that all anticonvulsants, except primidone,

phenobarbital, and benzodiazepines, be gradually discontinued over 6-10 weeks
if they were used for a long period. Discontinue primidone, phenobarbital, and
benzodiazepines over 10-16 weeks.

Nonpharmacologic Management
A ketogenic or modified Atkins diet and vagal nerve stimulation (VNS) are
nonpharmacologic methods for managing patients with seizures that are
unresponsive to antiepileptic drugs. The ketogenic diet is typically used in
children. The FDA has approved VNS stimulation for adolescents and adults with
refractory partial epilepsy, but clinical experience also suggests efficacy and
safety in children and in patients with generalized epilepsies.

Ketogenic diet and modified Atkins diet

The ketogenic diet, which relies heavily on the use of fat, such as hydrogenated
vegetable oil shortening (eg, Crisco), has a role in the treatment of children with
severe epilepsy. Support for the efficacy of these diets comes from large
observational studies rather than from randomized, controlled trials.[61]

Although this diet is unquestionably effective in some refractory cases of seizure,

a ketogenic diet is difficult to maintain; less than 10% of patients continue the
diet after a year. Furthermore, any small carbohydrate intake (eg, lollypop, piece
of candy) resets ketone metabolism for 2 weeks, thereby eliminating antiseizure
efficacy. Consequently, some authors do not consider using this treatment in
teenagers or adults unless all of the patients caloric intake is being delivered by
means of a gastric tube.

Preliminary data have been published about improvement of seizure frequency

following a modified Atkins (low-carbohydrate) diet that mimics the ketogenic
diet but does not restrict protein, calories, and fluids. In small studies of children
with intractable epilepsy, seizure reductions of more than 50% have been seen
within 3 months in some children placed on this diet, particularly with
carbohydrate limits of 10 g per day.[62, 63]

Preliminary studies of a modified Atkins diet have also been performed in adults.
For example, Smith et al found that this diet demonstrates modest efficacy as
adjunctive therapy for some adults with medically resistant epilepsy, and it may
be also helpful for weight loss but can pose financial and logistical difficulties.
[64]

Vagal nerve stimulation

VNS is a palliative technique that involves surgical implantation of a stimulating
device. VNS is FDA approved to treat medically refractory focal-onset epilepsy in
patients older than 12 years. Some studies demonstrate its efficacy in focalonset seizures and in a small number of patients with primary generalized
epilepsy. Randomized studies showed modest efficacy at 3 months, but
postmarketing experience showed delayed improvement in another group of
patients.

Guidelines on vagus nerve stimulation for epilepsy

In August 2013, the American Academy of Neurology issued an update to its

1999 guidelines on the use of VNS for epilepsy.[65, 66] VNS is currently indicated
for patients older than 12 years with medically intractable partial seizures who
are not candidates for potentially curative surgical resections, as well as for the
adjunctive long-term treatment of chronic or recurrent depression in patients
older than 18 years with a major depressive episode not adequately relieved by
4 or more antidepressant treatments. Recent reports also indicate long-term
efficacy and successful VNS use in pediatric epilepsy and other seizure types and
syndromes.

Key recommendations of the updated guidelines include the following[65, 66] :

VNS may be considered for (1) the adjunctive treatment of partial or generalized
epilepsy in children, (2) seizures associated with Lennox-Gastaut syndrome, and
(3) improving mood in adults with epilepsy
VNS may have improved efficacy over time
Children should be carefully monitored for site infection after VNS implantation
According to the manufacturer's registry, efficacy of the stimulating device at 18
months is 40-50%, where efficacy is defined as a seizure reduction of 50% or
more. Many patients report improvement in seizure intensity and general mood.

However, seizure-free rates for pharmacologically intractable focal-onset

epilepsy are less than 10%.

A meta-analysis of VNS clinical studies reported an average reduction in seizures

of at least 50% in approximately 50% of patients at last follow-up. Although VNS
was not initially FDA approved for children or patients with generalized epilepsy,
the authors also found that these groups benefitted significantly from VNS.

Positive predictors of a favorable outcome with VNS therapy include

posttraumatic epilepsy and tuberous sclerosis. Few patients achieve complete
seizure freedom with VNS, and about a quarter of patients receive no benefit in
their seizure frequency.[67] Some patients have clinical improvement in terms of
milder and shorter seizures.

Implantable neurostimulator
The NeuroPace RNS System, a device that is implanted into the cranium, senses
and records electrocorticographic patterns and delivers short trains of current
pulses to interrupt ictal discharges in the brain. The Neurological Devices panel
of the FDA concluded that this device was safe and effective in patients with
partial-onset epilepsy in whom other antiepileptic treatment approaches have
failed and that the benefits outweigh the risks.[68]

In November 2013, the FDA approved the NeuroPace RNS System for the
reduction of seizures in patients with drug-resistant epilepsy.[69, 70] Approval
was based on a clinical trial involving 191 subjects with drug-resistant epilepsy.
The neurostimulator was implanted in all of these patients but activated in only
half of them. After 3 months, the average number of seizures per month in
patients with the activated device fell by a median of 34%, compared with an
approximately 19% median reduction in patients with an unactivated device.

Lobectomy and Lesionectomy

The 2 major kinds of brain surgery for epilepsy are palliative and potentially
curative. In the past, the most common palliative surgery was anterior
callosotomy, which was indicated for patients with intractable atonic seizures,
who often sustain facial and neck injuries from falls. This surgery is still
performed as the use of vagal nerve stimulation (VNS) in such patients has good
efficacy.

Several curative surgeries are possible, including lobectomy and lesionectomy. In

general, the epileptogenic zone must be mapped by using videoelectroencephalographic (video-EEG) monitoring and, in some patients, with
intracranial electrodes.

Lobectomy
Outcomes of temporal-lobe surgeries are better than those for surgeries in other
areas. If a patient has unilateral temporal-lobe seizures (as observed on videoEEG) and unilateral hippocampal sclerosis (as observed on brain magnetic
resonance imaging [MRI]), the likelihood of a class I outcome (no seizures or only
auras) at 2 years is about 85%.

In a randomized, controlled trial of surgery in 80 patients with temporal lobe

epilepsy, 58% of patients in the group randomized to anterior temporal lobe
resective surgery were free from seizures impairing awareness at 1 year, as
compared with 8% in the group that received anticonvulsant treatment.[71]
Quality of life was also superior for patients in the surgical group.

According to research, MRI-guided selective laser amygdalohippocampectomy

(SLAH) is at least as effective as standard resection. In a study of 7 patients who
received SLAH and 10 patients who underwent standard resection (either open
anterior temporal lobectomy or selective amygdalohippocampectomy), 9 of 10
patients in the latter group showed a significant decline on visual/verbal memory
tasks (P < .002), compared with 1 of 7 patients in the former group.[41] Whereas
6 of 7 laser-ablation patients showed significant improvement on 1 or more
memory measures, only 4 of 10 standard-resection patients did (P < .02).[41]

Lesionectomy
In a study presented at the 66th Annual Meeting of the American Epilepsy
Society, investigators suggested that, in select pediatric patients, smaller
lesionectomy resections in the surgical treatment of seizures may be as effective
as larger resections, and they may spare children the functional and
developmental deficits associated with the larger resections.[72, 73]

The researchers reported on the outcomes of 25 children with MRI-negative,

intractable partial epilepsy who underwent focal corticectomies. Epileptogenic
regions were identified by 3-dimensional EEG, single-photon emission computed
tomography (SPECT) scanning, positron emission tomography (PET) scanning,
and invasive EEG data. Seizure-free outcomes occurred in 3 of 7 patients with

type I focal cortical dysplasia, 7 of 12 patients with type II focal cortical

dysplasia, and 3 of 6 patients with mild malformations of cortical development.
[72, 73]

Surgery for drug-resistant epilepsy

Although surgery for drug-resistant epilepsy is often considered a last resort,
results of a multicenter trial suggested that early surgery may be helpful in some
patients with newly intractable and disabling temporal lobe epilepsy. In this trial,
patients who had had no more than 2 consecutive years of disabling seizures
refractory to adequate trials of 2 anticonvulsant medications were randomized to
anteromesial temporal lobe resection plus continued medication (n = 15) or
continued medication alone (n = 23).[74]

At follow-up, 11 of the 15 surgery patients (73%) were seizure free during

postoperative year 2; none of the patients in the medication-only group were
seizure free over the same period. The researchers warned, however, that the
results must be interpreted cautiously, as the trial was halted prematurely
because of slow accrual.[62]

For more information on surgical management, see Identification of Potential

Epilepsy Surgery Candidates and Outcome of Epilepsy Surgery.

Activity Modification and Restrictions

The major problem for patients with seizures is the unpredictability of the next
seizure. Clinicians should discuss the following types of seizure precautions with
patients who have epileptic seizures or other spells of sudden-onset seizures:

Driving
Ascending heights
Working with fire or cooking
Using power tools or other dangerous equipment
Taking unsupervised baths
Swimming

These lifestyle precautions are clearly more applicable to some patients than to
others. Document on the patient's chart that driving and occupational hazards
for people with seizures were discussed.

Safety must be balanced with the risk for seizures. A patient with many poorly
controlled diurnal seizures may exercise more caution than a patient who has
only nocturnal seizures. Encourage the use of helmets to prevent head trauma
while the patient is biking, skiing, or participating in other high-risk activities.

Driving motorized vehicles

Driving restrictions differ for each patient because of the individual features of
their seizures, their degree of seizure control, and, in the United States, state
laws. US physicians should be aware of the state regulations regarding driving,
which vary considerably among states. If clinicians practice in a state that
requires mandatory reporting of patients with epilepsy to the Department of
Motor Vehicles, they must ensure they are compliant with state laws and have
documentation. International variation regarding reporting is also considerable;
some countries have more permissive or more restrictive laws regarding driving
than does the United States.

Aside from state laws, recommendations regarding driving motorized vehicles

also vary depending on whether the patient has seizures that occur exclusively
during sleep. Consult current state and federal laws and regulations. For
example, to resume commercial driving across state lines, a patient must have a
5-year seizure-free period. The recommendation for driving cars and trucks
extends to the operation of other motorized vehicles, such as boats and
motorcycles. Aircraft pilots are typically no longer permitted to fly.

Water precautions
Common sense dictates that patients with seizures should not swim alone, and
they should be particularly aware of the importance of the presence of an adult
lifeguard who can pull them out of the water if needed. Wearing a life jacket in a
boat is important. Activities as simple as taking a bath may be risky, because a
person can drown in as little as 1 inch of water during the flaccid postictal phase.
In addition, a patient who has a seizure while waiting for bath water to warm up
may suffer hot-water burns.

Heights, fire, and power tools

Patients with seizures may experience an episode in situations such as being up

on a roof or engaging in some activity at considerable height from the floor. In
addition, burns from injuries related to cooking are not uncommon, and injuries
can occur with the use of power tools and other dangerous equipment. Caution
in particular, supervisionis advised when power tools are used, and the use of
safety devices, such as an automatic shutoff switch, is recommended.

Medication Summary
Anticonvulsant medication is the mainstay of treatment for seizures, although
the choice of anticonvulsant drug varies with different seizure types and epileptic
syndromes. The number of anticonvulsants has increased, offering many more
medication choices for physicians and their patients. For more information, see
Antiepleptic Drugs.

Anticonvulsants, Other
Class Summary
These agents prevent seizure recurrence and terminate clinical and electrical
seizure activity. Anticonvulsants are normally reserved for patients who are at
increased risk for recurrent seizures.

View full drug information

Carbamazepine (Tegretol, Tegretol XR, Carbatrol, Epitol, Equetro)
Carbamazepine is indicated for the management of partial seizures and
generalized tonic-clonic seizures. It has an active metabolite, 10-11 epoxide,
which has anticonvulsant activity and can be measured in the serum. This agent
works by binding to voltage-dependent sodium channels and inhibiting the
generation of action potentials. Serum carbamazepine levels should be
measured frequently when initially starting this medication, with a goal of being
seizure free. Like phenytoin, carbamazepine has been associated with
osteopenia.

View full drug information

Clobazam (ONFI)
Clobazam is a 1,5-benzodiazepine that possesses potent anticonvulsant
properties. Its mechanism of action is binding to the gamma-aminobutyric acidA
(GABA-A) receptor. This agent is thought to potentiate GABAergic
neurotransmission. The active metabolite, N-demethylclobazam, is largely

responsible for its long duration of action. Clobazam is indicated for adjunctive
treatment of seizures associated with Lennox-Gastaut syndrome in patients older
than 2 years.

View full drug information

Ethosuximide (Zarontin)
Ethosuximide is a succinimide antiepileptic drug (AED) that is effective only
against absence seizures. It has no effect on generalized tonic-clonic, myoclonic,
atonic, or partial seizures.

The mechanism of action is based on reducing current in T-type calcium channels

on thalamic neurons. The spike-and-wave pattern during petit mal seizures is
thought to be initiated in thalamocortical relays by activation of these channels.
Ethosuximide is available in large 250-mg capsules, which may be difficult for
some children to swallow, and as a syrup (250 mg/5 mL).

Blood levels should be measured 1-3 weeks after starting ethosuximide. The
therapeutic concentration of ethosuximide is 40-100 mcg/mL. The major side
effects of the drug include nausea, vomiting, drowsiness, hyperactivity and sleep
disturbance.

View full drug information

Ezogabine (Potiga)
Ezogabine is a neuronal potassium channel opener that stabilizes neuronal KCNQ
(Kv7) channels in the open position, increasing the stabilizing membrane current
and preventing bursts of action potentials during the sustained depolarizations
associated with seizures. It is indicated as adjunctive therapy in partial-onset
seizures uncontrolled by current medications.

Owing to the presence of potassium channels in the bladder, there is a small risk
of urinary retention. In addition, in April 2013 the FDA issued a warning that
ezogabine can cause skin discoloration and abnormalities of the eye
characterized as changes in the pigment in the retina.[50] Whether these
changes are permanent and whether pigment changes in the retina have the
potential to cause loss of vision are unknown.

The FDA recommends that all patients taking ezogabine undergo baseline and
periodic eye examinations and discontinue the medication if changes are
observed, unless there is no other treatment option. Skin discoloration most
often appeared as blue around the lips and nail beds but was also reported to be
widespread on the face and legs.[50] In patients with skin discoloration,
alternative treatments should be considered, but the FDA warns of serious and
life-threatening reactions to the sudden discontinuance of the medication.[50]

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Felbamate (Felbatol)
Felbamate is approved by the FDA for medically refractory partial seizures and
Lennox-Gastaut syndrome. This agent has multiple mechanisms of action,
including (1) inhibition of N-methyl-D-aspartate (NMDA)associated sodium
channels, (2) potentiation of GABAergic activity, and (3) inhibition of voltagesensitive sodium channels. Felbamate is used only as a drug of last resort in
medically refractory cases because of the risk of aplastic anemia and hepatic
toxicity, which necessitates regular blood tests.

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Lamotrigine (Lamictal, Lamictal ODT, Lamictal XR)
Lamotrigine, a triazine derivative, is an antiepileptic drug with a very broad
spectrum of activity, like valproate. It is approved by the FDA for primary
generalized and partial-onset epilepsy. Other indications include adjunctive
therapy in the treatment of generalized seizures of Lennox-Gastaut syndrome,
treatment of juvenile myoclonic epilepsy (JME) and maintenance treatment of
bipolar I disorder. The mechanism of action is based on inhibiting the release of
glutamate and voltage-sensitive sodium channels, leading to stabilization of the
neuronal membrane.

Lamotrigine is quickly absorbed when given orally, and 55% is bound to plasma
proteins. The therapeutic serum levels have not been definitively established.

Side effects of lamotrigine include rash and nausea. The dose has to be
increased very slowly over several weeks to minimize the chance of rash,
especially if the patient is on valproic acid. The risk of developing StevensJohnson syndrome, toxic epidermal necrolysis, and angioedema is 1 in 1000
adults and higher in children, but this risk is decreased with slower titration.

View full drug information

Levetiracetam (Keppra, Keppra XR)
Levetiracetam is indicated for adjunctive therapy in the treatment of primary
generalized tonic-clonic seizures, JME, and partial-onset seizures in adults and
children. The mechanism of action is thought to be through modulation of
synaptic vesicle proteins. The metabolism of this drug is independent of the
CYP450 system, which limits the potential for interaction with other antiepileptic
drugs.

Levetiracetam has a rapid onset of action and is well tolerated. Common side
effects include fatigue, somnolence, dizziness, and irritability. This medication is
available in oral (including extended-release) and intravenous formulations.

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Phenytoin (Dilantin, Phenytek)
Phenytoin is used to treat patients with partial, generalized, or mixed seizures,
such as the tonic-clonic (grand mal) type. This agent works by blocking voltagedependent neuronal sodium channels. The therapeutic concentration range of
phenytoin in serum is 10-20 mcg/mL for patients who have normal renal function
and serum albumin levels.

The risk of osteopenia and cerebellar ataxia, both of which are long-term adverse
effects associated with phenytoin, now temper the drug's use by neurologists.
This agent is one of the most difficult AEDs to use because of its zero-order
kinetics and narrow therapeutic index. In addition, it can have significant
bidirectional drug interactions.

View full drug information

Primidone (Mysoline)
Primidone is indicated for the management of grand mal, psychomotor, and focal
seizures. In addition, it is commonly used for benign familial tremors. When
metabolized, primidone breaks down to phenobarbital, another active
antiepileptic drug. Primidone decreases neuron excitability and increases the
seizure threshold. Common side effects of this drug include sedation, drowsiness,
fatigue, and depression.

View full drug information

Rufinamide (Banzel)
Rufinamide modulates sodium channel activity, particularly prolongation of the
channel's inactive state. It significantly slows sodium channel recovery and limits
sustained, repetitive firing of sodium-dependent action potentials. Rufinamide is
indicated for adjunctive treatment of seizures associated with Lennox-Gastaut
syndrome. It is well tolerated, with the most common side effects being
somnolence and vomiting.

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Topiramate (Topamax)
Topiramate is an AED with a broad spectrum of antiepileptic activity. This agent is
approved for generalized, primary generalized, tonic-clonic, and partial-onset
seizures. Topiramate has multiple mechanisms of action, including statedependent sodium channel blocking action, enhancement of the inhibitory
activity of the neurotransmitter GABA, and antagonism of the NMDA-glutamate
receptor. It may block glutamate activity and is a weak carbonic anhydrase
inhibitor. Weight loss, impaired cognition, and mood problems are common side
effects of topiramate. The drug is also approved for migraine prevention.

View full drug information

Valproic acid (Depakote, Depakote ER, Depakene, Depacon, Stavzor)
Valproate, a broad-spectrum AED, is effective against most seizure types,
including myoclonic seizures. It can also be used alone or in combination for the
treatment of generalized or partial seizures. Valproate has multiple mechanisms
of anticonvulsant action, including increasing GABA levels in the brain, as well as
T-type calcium channel activity. The extended-release (ER) formulation allows for
once-a-day administration. Valproate also has FDA approval for migraine
prevention and prevention of mania in bipolar patients.

View full drug information

Zonisamide (Zonegran)
Zonisamide has been studied extensively in Japan and Korea and seems to have
broad-spectrum properties. It blocks T-type calcium channels, prolongs sodium
channel inactivation, and is a carbonic anhydrase inhibitor.

Dose adjustments may be required when zonisamide is given with other

anticonvulsants, such as carbamazepine, phenytoin, and phenobarbital. The
most common side effects of this drug include ataxia, anorexia, and fatigue.

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Perampanel (Fycompa)
Perampanel is a noncompetitive antagonist of the alpha-amino-3-hydroxy-5methyl-4-isoxazolepropionic acid (AMPA) glutamate receptor. It is indicated as
adjunct treatment for partial-onset seizures (with or without secondary
generalized seizures) and for primary generalized tonic-clonic seizures in adults
and children aged 12 years or older.

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Lacosamide (Vimpat)
Lacosamide selectively enhances slow inactivation of voltage-gated sodium
channels, resulting in stabilization of hyperexcitable neuronal membranes and
inhibition of repetitive neuronal firing. It is indicated as monotherapy or
adjunctive therapy for partial-onset seizures.

Anticonvulsants, Barbiturates
Class Summary
Like benzodiazepines, barbiturates bind to the gamma-aminobutyric acid (GABA)
receptor, enhancing the actions of GABA by extending GABA-mediated chloride
channel openings and allowing neuronal hyperpolarization. The principal
barbiturate used for status epilepticus is phenobarbital; for refractory cases,
pentobarbital is used.

View full drug information

Phenobarbital (Luminal)
Phenobarbital works at GABA receptors in the central nervous system (CNS) to
potentiate CNS inhibition. This agent is the best-studied barbiturate for the
treatment of status epilepticus.

In status epilepticus, achieving therapeutic levels as quickly as possible is

important. Intravenous dosing may require approximately 15 minutes to attain

peak levels in the brain. To terminate generalized convulsive status epilepticus,

administer up to 15-20 mg/kg. If the patient has received a benzodiazepine, the
potential for respiratory suppression significantly increases. Ventilation and
intubation may be necessary. Hypotension may require treatment.

In status epilepticus, phenobarbital is generally used after phenytoin or

fosphenytoin fails. However, it can be used in lieu of phenytoin in certain
circumstances. A trend is to recommend agents other than phenobarbital
(propofol, midazolam, other barbiturates) for refractory status epilepticus;
however, for super-refractory status epilepticus, phenobarbital should be used.