EPILEPSY

Background
Epileptic seizures are only one manifestation of neurologic or metabolic diseases. Epileptic
seizures have many causes, including a genetic predisposition for certain seizures, head
trauma, stroke, brain tumors, alcohol or drug withdrawal, and other conditions. Epilepsy is a
medical condition with recurrent, unprovoked seizures. Therefore, repeated seizures due to
alcohol withdrawal are not epilepsy.
Definitions
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,
psychologic, and social consequences of this condition. [1] Traditionally, the diagnosis of
epilepsy requires the occurrence of at least 2 unprovoked seizures 24 hours apart. Some
clinicians are also diagnosing epilepsy when one unprovoked seizure occurs in the setting of
a predisposing cause such as a focal cortical injury or a generalized interictal discharge that
suggests a persistent genetic predisposition. 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.
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%.
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%).
Studies in several countries have shown incidences and prevalences of seizures similar to
those in the United States. In some countries, parasitic infections account for the increased
incidence of seizures and epilepsy.
See Classification of Epileptic Seizures and Classification of Epileptic Syndromes.
Historical information
Epileptic seizures have been recognized for millennia. One of the earliest descriptions of a
secondarily 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 that caused
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. They 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. An excellent historical
review of seizures and epilepsy, written by E. Goldensohn, was published in the
journalEpilepsia to commemorate the 50th anniversary of the creation of the American
Epilepsy Society in 1997. A more recent review discusses the foundation of this professional
society.[2]
This article reviews the classifications, pathophysiology, clinical manifestations, and
treatment of epileptic seizures and some common epileptic syndromes. See below for links to
several articles related to epileptic syndromes and their treatment that are not reviewed in this
introductory article.
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
Shuddering Attacks
First Adult Seizure
First Pediatric Seizure
Epilepsia Partialis Continua
Status Epilepticus
Preeclampsia and 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
Epileptic and Epileptiform Encephalopathies
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
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. 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 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 and are therefore discussed
separately.
For a review, see the epilepsy book of Rho, Sankar, and Cavazos.[3]
Pathophysiology of Focal Seizures
The clinical neurophysiologic hallmark of focal-onset seizures is the focal interictal
epileptiform spike or sharp wave. The cellular neurophysiologic correlate of an interictal
focal epileptiform discharge in single cortical neurons is the paroxysmal depolarization shift
(PDS). The PDS is characterized by a prolonged calcium-dependent depolarization that
results in multiple sodium-mediated action potentials during the depolarization phase, and it
is followed by a prominent after hyperpolarization, which is a hyperpolarized membrane
potential beyond the baseline resting potential. Calcium-dependent potassium channels
mostly mediate the after-hyperpolarization phase. When multiple neurons fire PDSs in a
synchronous manner, the extracellular field recording shows an interictal spike.
If the number of discharging neurons is more than several million, they can usually be
recorded with scalp electrographic (EEG) electrodes. Calculations show that the interictal
spikes need to spread to about 6 cm 2 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. When any of the mechanisms that underlie an acute seizure become a
permanent alteration, patients are assumed to then develop a propensity for recurrent seizures
(ie, epilepsy).
The mechanisms discussed below may coexist in different combinations to cause focal-onset
seizures. If the mechanisms leading to a net increased excitability become permanent
alterations, patients develop pharmacologically intractable focal-onset epilepsy. Current
available medications were screened using acute models of focal-onset or generalized-onset
convulsions. In clinical use, they 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.
Mechanisms leading to decreased inhibition and those leading to increased excitation are
discussed in this section.
Mechanisms leading to decreased inhibition include the following:

Defective gamma-aminobutyric acid (GABA)A inhibition

Defective GABA-B inhibition

Defective activation of GABA neurons

Defective intracellular buffering of calcium
Defective GABA-A inhibition
GABA is the main inhibiting 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
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 -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 to the neuronal membrane potential
increases as the neuron becomes more depolarized by the summation of the excitatory
postsynaptic potentials (EPSPs). In this manner, they 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 the anticonvulsant topiramate. Benzodiazepines increase
the frequency of openings of chloride channels, whereas barbiturates increase the duration of
openings of these channels. Topiramate increases the frequency of channel openings, but it
binds to a site different from the benzodiazepine-receptor site. Either benzodiazepines or
barbiturates, but not both, appear to modulate individual chloride channels. Whether
combining topiramate with either class of agents increases the chloride currents is unknown.
Alterations in the normal state of the chloride channels might increase membrane
permeability and conductance of chloride ions. In the end, the behavior of all individual
chloride channels sum up to form a large chloride-mediated hyperpolarizing current that
counterbalances the depolarizing currents created by summation of excitatory postsynaptic
responses (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 release in the postsynaptic neuron: N -methyl-Daspartic acid (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid
(AMPA)/kainate, and metabotropic, which are coupled by means of different mechanisms to
several depolarizing channels. Inhibitory postsynaptic potentials (IPSPs), mediated mainly by
the release of GABA in the synaptic cleft with postsynaptic activation of GABA-A receptors,
temper these effects.
All channels in the nervous system (and essentially any living organism) 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 molecularly related but different proteins.

The heterogeneity of electrophysiologic responses of different GABA-A receptors is due to

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; therefore, more than 1000 receptor types theoretically exist.
In practice, only about 20 of these combinations have been found in the normal mammalian
brain. Some epilepsies may be due to mutations or lack of expression of the different GABAA receptor complex subunits, the molecules that govern their assembly, or the molecules that
modulate their electrical properties. For example, hippocampal pyramidal neurons might 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 electricalkindling, chemical-kindling, and pilocarpine models. In the last model, decreased
concentrations of mRNA for the alpha 5 subunit of the surviving interneurons were observed
in the CA1 region of the rat hippocampus.[4]
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. Therefore, release of
GABA from the interneuron terminal inhibits the postsynaptic neuron by means of 2
mechanisms: (1) direct induction of an 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. Once again,
alterations or mutations in the different subunits or in the molecules that regulate their
function might affect the seizure threshold or the propensity for recurrent seizures.
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 neuron
output of the network, such as 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 timely
inhibit 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. In the last few years, experimental evidence has
indicated that some other kind of interneuron might 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. However, in certain circumstances they appear highly vulnerable to seizure-related
neuronal loss.
After some of the mossy cells are lost, activation of GABAergic neurons is impaired.
[5]
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, but as the epilepsy
progresses, 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
Recurrent seizures induced by a variety of methods result in a pattern of interneuron loss in
the hilar polymorphic region in rodents, with striking loss of the neurons that lack calciumbinding proteins parvalbumin and calbindin. In rat hippocampal sections, these interneurons
demonstrate a progressive inability to maintain a hyperpolarized resting membrane potential;
eventually, they die. An experiment in which researchers used microelectrodes containing the
calcium chelator BAPTA demonstrated reversal of the deterioration in the membrane
potential as the calcium chelator was allowed to diffuse in the interneuron [6] ; the experiment
demonstrated the critical role of adequate concentrations of calcium-binding proteins for
neuronal survival in settings with sustained rises of intracellular calcium, such as in status
epilepticus and other brain insults. This mechanism might be a possible contributor 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)
might have remarkably dissimilar outcomes: One may have completely normal development,
and the other may have intractable focal-onset epilepsy after a few years.
Mechanisms leading to increased excitation include the following:

Increased activation of NMDA receptors

Increased synchrony between neurons due to ephaptic interactions
Increased synchrony and/or activation due to recurrent excitatory collaterals

Increased activation of NMDA receptors

Glutamate is the major excitatory neurotransmitter in the brain. The release of glutamate
causes an EPSP in the postsynaptic neuron by activating the glutaminergic receptors
AMPA/kainate and NMDA and the metabotropic receptor. Fast neurotransmission is achieved
with the activation of the first 2 types of receptors. The metabotropic receptor alters cellular
excitability by means of a second-messenger system with later onset but a prolonged
duration. The major functional difference between the 2 fast receptors is that the
AMPA/kainate receptor opens channels that primarily allow the passage of monovalent
cations (ie, sodium and potassium), whereas the NMDA type is coupled to channels that also
allow passage of divalent cations (ie, calcium).
Calcium is a catalyst for many intracellular reactions that lead to changes in phosphorylation
and gene expression. Thus, it is in itself a second-messenger system. NMDA receptors are
generally assumed to be associated with learning and memory. The activation of NMDA
receptors is increased in several animal models of epilepsy, such as kindling, kainic acid,
pilocarpine, and other focal-onset epilepsy models. Some patients with epilepsy may have an
inherited predisposition for fast or long-lasting activation of NMDA channels that alters their
seizure threshold. Other possible alterations include the ability of intracellular proteins to
buffer calcium, increasing the vulnerability of neurons to any kind of injury that otherwise
would not result in neuronal death.
Increased synchrony between neurons due to 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. Other possible nonsynaptic interactions
include electrotonic interactions due to gap junctions or changes in extracellular ionic
concentrations of potassium and calcium. Increased coupling of neurons due to permanent
increases in the functional availability of gap junctions might be a mechanism that
predisposes to seizures or status epilepticus.
Increased synchrony and/or activation due to 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 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 might contribute to the development
of hippocampal sclerosis.[7]
A situation more subtle and apparently more common than overt hippocampal sclerosis is
mossy-fiber sprouting.[8] 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 due to 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.
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 primarily generalized-onset
seizures. The thalamic relay neurons receive ascending inputs from 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.[9]
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 gamma aminobutyric acid (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 release from the NRT
projection to the thalamic relay neuron. The result is a hyperpolarization that switches the Tcalcium 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 GABAB agonists worsen these seizures.[10] Anticonvulsants that prevent absence seizures, such as
valproic acid and ethosuximide, suppress the T-calcium current, blocking its channels. One
clinical problem is that some anticonvulsants that increase GABA levels (eg, gabapentin,
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.
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.
Regarding morbidity, trauma is not uncommon among people with generalized tonic-clonic
seizures. Injuries such as ecchymosis; hematomas; abrasions; and tongue, facial, and limb
lacerations often develop as a result of the repeated tonic-clonic movements. Atonic seizures
are also frequently associated with facial and neck injuries. Worldwide, burns are the most
common serious injury associated with epileptic seizures.
Regarding mortality, seizures cause death in a small proportion of individuals. Most deaths
are accidental due to impaired consciousness. However, sudden unexpected death in
epilepsy (SUDEP) is a risk of having 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 increase risk of death is mostly seen in people with long-standing
focal-onset epilepsy but is also present in those with primary generalized epilepsy. The risk of
SUDEP increases in the setting of uncontrolled seizures and in people with poor compliance.
The risk increases further in people with uncontrolled secondarily 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 the same as the general population.
Patient Education
To prevent injury, educate patients who have lapses of consciousness during wakefulness and
in whom seizures are suspected about seizure precautions. 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 in 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 the state laws for driving before
making recommendations.
Epilepsy Foundation of America has a large library of educational materials that are available
to health care professionals and the general public. The American Epilepsy Society is the
professional organization of people who take care of patients with epilepsy. Their Web site
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 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?
Physical Examination
The clinical diagnosis of seizures is based on the history obtained from the patient and, most
important, the observers. Physical examination helps in the diagnosis of specific epileptic
syndromes that cause abnormal findings, such as dermatologic abnormalities. For example,
patients with intractable generalized tonic-clonic seizures for years are likely to have 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 the semiologic classification advanced by Luders and others,
have been proposed.[11] A refinement of this semiologic classification led to a 5-dimensional
(5-D) patient-oriented classification of epilepsy.[12] The ILAE commission on classification
has developed additional reports.[13, 14] In 2006, a new proposed classification of seizures was
published.[13, 14] 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 of using the changes in terminology.[15]
Focal-Onset Seizures
Focal-onset seizures are further classified as simple focal seizures, complex focal seizures, or
secondarily generalized tonic-clonic seizures.
Simple and complex focal seizures
The defining element of simple focal seizures is a seizure with preserved consciousness.
Many patients with complex focal seizures have an aura warning them of their seizure. An
aura 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 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 focalonset seizure or a secondarily 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.
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
might 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. Automatisms frequently consist of 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. They have more prominent motor features than those of
complex focal seizures of temporal-lobe onset. Frontal lobe onset complex focal seizures may
have a fast postictal recovery to baseline, and they often appear in clusters of seizures. 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.
Secondarily generalized seizures
Secondarily 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, 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 secondarily 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 EEG manifestations. On occasion,
classifying seizures is difficult despite videotape review of the data.
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. Facial automatisms are most common, and repetitive blinking is the most
common facial automatism. Hyperventilation or photic stimulation often precipitates these
seizures which typically begin during childhood or adolescence, although they may persist
into adulthood.
A diagnosis of new-onset absence seizures in adulthood is incorrect in the vast majority of
cases. Adults often have complex focal seizures with relatively minor automatisms. In
children, absence seizures are often unrecognized until a child develops a generalized tonicclonic seizure, and then the child is brought to medical attention. Sudden decreased
performance in school or overall attention might be a subtle manifestation of frequent
absence seizures.
The classic ictal electroencephalogram (EEG) correlate of absence seizures consists of 3.5-Hz
generalized spike-andslow wave complexes. Twin studies have demonstrated a significant
inherited predisposition for typical childhood absence seizures. 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, they are less well formed, and
they are of lesser amplitude.
Myoclonic, clonic, and tonic seizures
Myoclonic seizures consist of brief, arrhythmic, jerking, motor movements that last less than
1 second. Myoclonic seizures often cluster within a few minutes. If they 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 in
the EEG consists of fast polyspike-andslow wave complexes.
Clonic seizures consist of rhythmic, motor, jerking movements with or without impairment of
consciousness. Clonic seizures can have a focal origin with or without impaired
consciousness. 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 the person falls asleep, or just after he or she awakens. They 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-and-wave 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 secondarily
generalized tonic-clonic seizures is that these seizures lack an aura. However, the aura
preceding the secondarily generalized seizure is often forgotten because of postictal amnesia.
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 occur in people with clinically significant neurologic abnormalities. These
seizures consist of brief loss of postural tone, often resulting in falls and injuries. The ictal
EEG correlate is similar to abnormalities observed in tonic seizures.
Classification of Epileptic Syndromes
Epileptic seizures are symptoms of neurologic dysfunction and are but one manifestation of
many neurologic diseases. Like 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. A task force is revising this syndromic classification. 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 Task Force on Classification and Terminology of the International League
Against Epilepsy (ILAE) 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[16] :

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 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 partialonset or localization-related seizure or epilepsy for the term focal. The 2006 review of
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 of probably symptomatic.
However, cryptogenic remains an accepted term.
Despite the fact that psychiatrists have successfully used for many years 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 [2003][17] and its discussion by Engel, Luders et al, Berg and
Blackstone, and Avanzini. Similarly, see Fisher et al [2005][1] and its 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.[18]
Diagnostic Considerations
The diagnosis of seizures is based on the clinical history. Because many types of seizures are
associated with impairment of consciousness, patients are unaware of their occurrence; thus,
the history as related by a witness is of high importance.
The clinical diagnosis can be confirmed by abnormalities on the interictal
electroencephalogram (EEG), but these abnormalities could 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)
Migraine (eg, migrainous aura, migraine equivalent)
Vascular conditions (eg, transient ischemic attacks)
Sleep disorder (eg, cataplexy, narcolepsy, night terror)
Movement disorder (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
Confusional States and Acute Memory Disorders
Febrile Seizures
First Seizure in Adulthood: Diagnosis and Treatment
First Seizure: Pediatric Perspective
Frontal Lobe Epilepsy
Idiopathic Orthostatic Hypotension and other Autonomic Failure Syndromes
Migraine Headache
Somnambulism (Sleep Walking)
Transient Global Amnesia
Approach Considerations
Two imaging studies must be performed after a seizure. They are neuroimaging evaluation
(eg, brain magnetic resonance imaging [MRI], head computed tomography [CT] scanning)
and electroencephalography (EEG).
Lumbar puncture for cerebrospinal fluid (CSF) examination has a role in the patient with
obtundation or in patients in whom meningitis or encephalitis is suspected.
Epileptic seizures have many causes, and some epileptic syndromes have specific
histopathologic abnormalities. Discussion of these abnormalities are beyond the scope of this
article. For more information, see the articles about specific epileptic syndromes listed in the
Background section.
Prolactin Study
Prolactin levels obtained shortly after a seizure have been used to assess the etiology
(epileptic or nonepileptic) of a spell. However, the considerable variability of prolactin levels
has precluded routine clinical use of such testing. levels are typically elevated 3- or 4-fold
and more likely to occur with generalized tonic-clonic seizures than with other seizure types.
Serum Studies of Anticonvulsant Agents
Obtaining serum levels of anticonvulsants may help to improve the care for patients with
seizures and epilepsy and to answer a clinical question. In practice, some authors do not
advise routine measurement of serum levels. The following situations are 5 recommended
indications for the use of serum levels.

Baseline: After seizures are controlled, determine the drug levels needed to achieve
seizure-free effectiveness.
Toxicity: Determine the maximal anticonvulsant dose that the patient can tolerate
without toxic effects.
Lack of efficacy: Before an anticonvulsant agent is deemed a failure, knowing
whether the patient has achieved an adequate drug level is imperative.
Noncompliance: Approximately 30% of patients miss at least 1 dose of their
medication every month.

Autoinduction or pharmacokinetic change: After an anticonvulsant is 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 medications might substantially change the clearance of some
anticonvulsants.
Like any medical test, serum concentrations of anticonvulsants help in making clinical
decisions, 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. Therefore,
clinical judgment regarding how well the patient is doing (ie, no seizures, no adverse effects)
should prevail over a laboratory reading.
The usual therapeutic ranges include peak and trough levels of a group of adult patients. If
the problem under study is toxicity, a peak level is desirable. However, in most
circumstances, a trough level is the best indication of efficacy.
Neuroimaging Studies
A neuroimaging study, such as brain magnetic resonance imaging (MRI) or head computed
tomography (CT) scanning, provides evidence about structural abnormalities that could be
the cause for 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, the preferred study is a brain MRI
because of its resolution to depict subtle abnormalities.
Brain MRIs obtained with thin coronal sections by using fast spin-echo (FSE) or inversion
recovery (IR) sequences from the presumed region of epileptogenic aura are useful for
assessing cortical lesions, which may be amenable to potentially curative surgery.
Not every brain MRI study provides the same quality of information. Studies obtained at 3.0
Tesla scanners might show better resolution than conventional 1.5 T scanners, or the "opensided" scanners of 0.5 T.
For more information, see Presurgical Evaluation of Medically Intractable Epilepsyregarding
imaging studies.
Electroencephalography
Interictal epileptiform discharges or focal abnormalities on electroencephalogram (EEG)
strengthen the diagnosis and provide some help in determining the prognosis. Although the
criterion standard for diagnosis and classification of epileptic seizures includes the
interpretation of sleep-deprived EEG, the clinical history remains the cornerstone for the
diagnosis of epileptic seizures.
Video-Electroencephalography
Video-electroencephalographic (EEG) monitoring is the criterion standard for classifying the
type of seizure or syndrome or to diagnose pseudoseizures; that is to establish 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 should
undergo video-EEG. Referral to an epilepsy center should be reserved for patients whose
seizures are refractory to treatment. Some frontal-lobe seizures are considered pseudoseizures
for many years until appropriate diagnosis is made by means of video-EEG