Curing the Epilepsies: The

Promise of Research

Introduction
At least 2.3 million adults and nearly 500,000 children in the U.S. currently
live with some form of epilepsy, a disorder in which clusters of nerve cells, or
neurons, in the brain sometimes signal abnormally, causing seizures. Each
year, another 150,000 people are diagnosed with epilepsy. The disorders
affect both males and females and can develop at any age. In the U.S. alone,
the annual costs associated with the epilepsies are estimated to be $15.5
billion in direct medical expenses and lost or reduced earnings and
productivity.

The disturbances of neuronal activity that occur during seizures may cause
strange sensations, emotions, and behaviors. They also sometimes cause
convulsions, abnormal movements, and loss of consciousness. In some
people, seizures happen only occasionally. Other people may experience
hundreds of seizures a day. There are many different forms of epilepsy, and
symptoms vary greatly from one person to another. Recent adoption of the
term “the epilepsies” underscores the diversity of types and causes.

About three-quarters of the individuals diagnosed with the epilepsies can

control their seizures with medicine or surgery. However, about 25 to 30
percent will continue to experience seizures even with the best available
treatment. Doctors call this treatment-resistant epilepsy. In some cases,
people experience a type of seizure called status epilepticus, defined as
seizures that last for more than five minutes or seizures that recur without
recovery of consciousness. Prolonged status epilepticus can damage the
brain and may be life-threatening.

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Section 1: About Epilepsies
Seizures
Seizures can be classified as focal or generalized. Focal seizures begin in one
area of the brain and may or may not spread to other areas. Generalized
seizures are the result of abnormal neuronal (nerve cell) activity on both
sides of the brain from the beginning of the seizure.

About 60 percent of people with epilepsy have focal seizures. Some focal
seizures cause unusual sensations, feelings, or movements, but do not cause
loss of consciousness. Other focal seizures cause a change in or loss of
consciousness and may produce a dreamlike experience or strange,
repetitive behavior. Focal seizures are often named for the area of the brain
in which they originate. For example, temporal lobe epilepsy, or TLE, begins
in the temporal lobe located on either side of the brain. TLE is the most
common type of epilepsy to feature focal seizures and can sometimes be
difficult to treat with available medications.

Generalized seizures impair consciousness and distort electrical activity of

the whole or a large portion of the brain, leading to falls or abnormal
movements. There are several different types of generalized seizures. In
absence seizures, which usually begin in childhood or adolescence, an
individual may appear to be staring into space or may have jerking or
twitching muscles. Tonic seizures cause stiffening of muscles. Clonic seizures
cause repeated jerking movements of muscles on both sides of the body.
Myoclonic seizures cause jerks or twitches of the upper body, arms, or legs.
Atonic seizures cause a loss of normal muscle tone, which may lead to falls or
sudden drops of the head. Tonic-clonic seizures cause a combination of
symptoms, including stiffening of the body and repeated jerks of the arms or
legs as well as loss of consciousness.

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Epilepsies with Childhood Onset

Compared to adults, infants and children have a relatively high risk of
developing the epilepsies. Many epilepsy syndromes, such as infantile
spasms, Lennox-Gastaut syndrome, and Rasmussen’s encephalitis, begin in
childhood. Infantile spasms usually begin before the age of six months and
may cause a baby to bend forward and stiffen. Children with Lennox-Gastaut
syndrome have severe epilepsy with several different types of seizures,
including atonic seizures, which cause sudden falls called drop attacks.
Rasmussen’s encephalitis is a rare, chronic inflammatory neurological disease
that usually affects only one hemisphere of the brain. It causes frequent and
severe seizures and a loss of motor skills, and can lead to severe intellectual
disability. Hypothalamic hamartomas can cause another rare form of
epilepsy that presents during childhood and is associated with
malformations in the hypothalamus at the base of the brain. People with
hypothalamic harmatomas have seizures that can resemble laughing
(gelastic) or crying (dacrystic). Such seizures frequently go unrecognized or
are difficult to diagnose.

Some childhood epilepsy syndromes, such as childhood absence epilepsy,

may go into remission or stop entirely as a child matures, although this is not
true in all cases. Other syndromes, such as juvenile myoclonic epilepsy and
Lennox-Gastaut syndrome, are usually present for the rest of the person’s
life.

Children with delayed brain development and neurological disorders are

more likely to have seizures. Seizures are more common, for example,
among children with autism spectrum disorder, cerebral palsy, tuberous
sclerosis complex (TSC), or Rett, Aicardi, or Down syndromes. In one study,
one-third of children with autism spectrum disorder had treatmentresistant
epilepsy.

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Causes
For about half of all people with an epilepsy, a cause for the disorder is not
identified. In other cases, the epilepsies are clearly linked to genetic factors,
infection, head trauma, stroke, brain tumors, or other identifiable problems.

The epilepsies have many possible causes. Almost anything that disturbs the
normal pattern of brain circuit activity—from abnormal brain development to
traumatic brain injury (TBI) or illness—can lead to seizures and epilepsy. For
example, seizures may develop because of an abnormality in brain wiring
that occurs during brain development, an imbalance of neuronsignaling
chemicals called neurotransmitters, or a combination of these factors.
Researchers believe that some people with epilepsies have abnormally high
levels of responsiveness to excitatory neurotransmitters, chemicals that
increase the activity of nerve cells. Other people may have an abnormally low
level of responsiveness to neurotransmitters that inhibit nerve cell activity.
Either situation can result in too much neuronal activity and cause epilepsy.
In some cases, inflammation and neuronal damage after a head injury,
stroke, or other trauma may lead to epilepsy. In addition, the brain’s
attempts to repair itself after such injury may inadvertently generate
abnormal nerve connections that lead to seizures. Supportive cells (known as
glial cells) in the brain may play a role in certain types of epilepsy.

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Sidebar: The Role of the National Institutes of

Health
The U.S. Federal government supports research to better understand the
epilepsies and to reduce their burden through improved treatments and
prevention. Much of this research support comes from the National Institutes of
Health (NIH). The National Institute of Neurological Disorders and Stroke (NINDS)
is the lead NIH institute for research on the epilepsies. Several other NIH Institutes
also fund epilepsy-related research. Representatives from NIH institutes, the
Centers for Disease Control and Prevention (CDC), the Department of Defense, the
Department of Veterans Affairs, and the U.S. Food and Drug Administration (FDA)
work together as part of the Interagency Collaborative to Advance Research in
Epilepsy (ICARE), which was formed to facilitate communication and opportunities
for coordination among institutes and agencies sponsoring research related to
the epilepsies.

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Section 2: Research Progress on the

Epilepsies
In 2000, NINDS and epilepsy research and advocacy organizations co-
sponsored a White House initiated conference, “Curing Epilepsy: Focus on the
Future.” The conference has been viewed as a turning point for research on
the epilepsies by shifting the focus from treating seizures to identifying cures,
defined as “no seizures, no side effects, and the prevention of epilepsy in
those at risk.” The first Epilepsy Research Benchmarks grew out of the
momentum created by this conference, as a way to communicate and
address important research priorities and as a framework for periodically
“benchmarking” progress. A second conference in 2007, “Curing Epilepsy:
Translating Discoveries into Therapies,” reassessed the state of research on
the epilepsies and revised the Epilepsy Research Benchmarks, adding
emphasis to the conditions that co-occur with the epilepsies and sudden
unexpected death in epilepsy (SUDEP). A third conference in 2013, “Curing
the Epilepsies: Pathways Forward,” provided an update on the state of
research and will result in another revision of the Benchmarks.

Today, more than a decade since they were first developed, the Benchmarks
are increasingly embraced by the entire epilepsy community, including NIH,
researchers, and professional and advocacy organizations. While the ultimate
goal of curing the epilepsies has not yet been achieved, researchers have
made substantial progress. Research on the epilepsies has yielded exciting
advances across all areas of the Benchmarks.

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What New Discoveries Have Been Made About

the Causes of the Epilepsies?
To understand how to prevent, treat, and cure the epilepsies, researchers
first must learn how they develop. Where, how, when, and why do neurons
begin to display the abnormal firing patterns that cause epileptic seizures?
This process, known as epileptogenesis, is the key to understanding the
epilepsies. Researchers are learning more about the fundamental processes
—known as mechanisms—that lead to epileptogenesis. The discovery of each
new mechanism involved in epileptogenesis has the potential to yield new
targets that can be affected by medications or other therapies to block that
mechanism. Among this growing list of candidate mechanisms, two stand out
as being closest to yielding potential targets for drug therapy: 1) the mTOR
(mammalian target of rapamycin) signal transduction pathway; and 2)
activation of the cytokine protein interleukin-1ß (IL-1ß).

 The mTOR pathway is a master regulator that is involved in several

genetic and acquired forms of epilepsy. An inhibitor of the mTOR
pathway is being studied for the prevention of seizures related to
tuberous sclerosis complex (TSC), a rare genetic disease that causes
 the growth of noncancerous tumors in the brain and in other organs
such as the kidney, heart, eyes, lungs, and skin.
 In various types of epilepsy, inflammatory processes may play a key
role. Cytokines are signaling molecules that, among other functions,
help regulate the body’s inflammatory responses. Researchers are
exploring why IL-1ß appears to be activated in different types of
epilepsy. An inhibitor of IL-1ß synthesis is being tested in people with
treatment-resistant epilepsy.

Other Areas of Epileptogenesis Research Include:

 Proteins in the cell membrane are crucial for generating the electrical
impulses that neurons use to communicate with one another. For this
reason, researchers are studying the membrane structure and the
channels that allow molecules like sodium, calcium, and potassium to
move across them to generate electrical impulses. A disruption in any
of these processes can cause changes that may lead to epilepsy.
 Studies have suggested how a breakdown of the blood-brain barrier
may lead to seizures. When proteins from the blood cross this
important barrier between the circulatory system and fluid
surrounding the brain, they trigger a reaction that leads to
hyperactivity of neurons in the area of the brain surrounding the
breakdown.
 Glial cells are non-neuronal cells that play a critical supportive role in
the brain. For example, astrocytes are a type of glial cell that acts as a
“housekeeper” by removing excessive levels of glutamate, a major
neurotransmitter that mediates excitatory signals in the central
nervous system. When astrocytes are impaired, levels of glutamate rise
excessively in the spaces between brain cells, which may then
contribute to the onset of seizures. In animal studies, the introduction
of ceftriaxone, an antibiotic that supports the housekeeping role of
astrocytes, has been shown to reduce seizure frequency.
 The body’s immune system may contribute to the development of
certain forms of epilepsy. In aggressive forms of the disorders,
antibodies may impair the function of brain receptors, leading to
abnormal neuronal activity. Testing for many of these antibodies is
already available, and findings from early-stage clinical trials suggest
that strategies aimed at adjusting the body’s immune system may
 provide a means of treating these otherwise untreatable forms of
epilepsy.

Researchers are studying the membrane structure and the channels that allow
molecules like sodium, calcium, and potassium to move across them to generate
electrical impulses. A disruption in any of these processes can cause changes that
may lead to epilepsy.

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Genetic Mutations
Recent studies have yielded substantial progress in the identification of
genetic mutations involved in the epilepsies. Several types of epilepsy have
been linked to defective genes for ion channels, the “gates” that control the
flow of ions in and out of cells and that regulate neuronal activity.

Mutations in single genes have been found among family members affected
by certain epilepsy syndromes. For example, some infants with Dravet
syndrome, a type of epilepsy associated with seizures that begin before the
age of one year, carry a mutation in the SCN1A gene that is believed to cause
seizures by affecting sodium channels in the brain. Surprisingly, the SCN1A
mutations and other epilepsy mutations are often de novo mutations,
meaning that they are not present in the parents. Building on that genetic
discovery, researchers have created models of Dravet syndrome in the fruit
fly, zebrafish, and mouse that are now being used to test potential therapies
for controlling seizures. In addition, researchers have successfully taken
connective tissue cells from individuals with Dravet syndrome,
reprogrammed them to create induced pluripotent stem cells (cells that can
become any type of cell in the body), and differentiated them into neurons
that also can be used to test potential drugs and to study the mechanisms
that lead to Dravet syndrome.

Continued progress in the identification of genetic causes of the epilepsies

could guide the care and medical management of individuals. In the case of
heritable mutations, this will help affected families understand their risks.

A major driver of success on the genetics front is the advent of next-

generation sequencing—highthroughput methods of genetic sequencing that
have revolutionized the search for the genetic underpinnings of diseases and
disorders. Next-generation sequencing has significantly cut the time and
costs required to identify genes involved with the epilepsies, as well as other
diseases.

Major collaborative efforts have enabled researchers to efficiently investigate

the effects of many risk factors, including genetic ones, among large
populations of people affected by the epilepsies.

Researchers have taken skin cells from people with Dravet syndrome, turned
them into stem cells, and then turned those stem cells into brain cells. Electrical
activity among the brain cells can be measured, creating a testing ground for
studying the disorder.

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Identify Biomarkers of Seizure Onset and

Epileptogenesis
Researchers see a potential opportunity to prevent the epilepsies before the
onset of recurrent spontaneous seizures. Surrogate measures of
epileptogenic processes, or biomarkers, could aid in the development of
interventions that would prevent epilepsy in at-risk individuals. Other types
of biomarkers could help researchers and health care providers better
identify and monitor seizure-onset zones or predict seizure occurrence,
which could enable more targeted treatments. The identification of reliable
biomarkers for the epilepsies is one of the more critical areas in need of
research advances.

A number of changes in the brain shown on imaging and

electroencephalography (EEG) are known to be associated with epilepsy-
related processes. The challenge is that people without epilepsy also can
have similar brain changes and there is little evidence to show clearly which
of these changes is predictive of someone who will develop a form of
epilepsy.

Newer technologies are allowing researchers to map epileptic networks and

track seizure generation with increasing resolution. Implantable
“microelectrodes” are revealing complex brain activity during seizures. Using
microelectrodes, researchers are able to better characterize high-frequency
oscillations (HFOs). Abnormal HFOs have been linked to seizureonset zones
and may serve as a biomarker of epileptogenesis; this could help identify
people at risk for developing epilepsy after an initial insult to the brain, such
as a stroke or TBI.

Investigators also have improved devices for measuring electrical activity in

the brain. New electrode arrays are flexible enough to mold to the brain’s
complex surface, providing unprecedented access for recording and
stimulating brain activity. While these arrays have not yet been used in
humans, they are a promising advance toward expanded options for epilepsy
diagnosis and treatment.

Epilepsy researchers have increasingly explored how connections between

different brain regions—structurally and functionally—may explain how
seizures start in the first place. Much of this research grows out of
observations that seizures are not merely the result of focal areas of
hyperactivity, but arise from the complex interactions of the network. A
better understanding of how this network operates may explain, for example,
why some people do not improve even after focal areas of hyperactivity,
which appeared to be the source of seizure, are surgically removed.

Diffusion tensor imaging, a type of magnetic resonance imaging (MRI) that

shows microstructural detail of tissues based on the diffusion of water
molecules, has shown abnormal structural connectivity during focal and
generalized seizures. Advances in MRI have shown that functional
connectivity patterns in people with epilepsy differ from those of normal
controls. Interestingly, patterns of abnormal functioning occur both during
seizures and during the “resting-state” period between seizures.

Newer technologies are allowing researchers to map epileptic networks and

track seizure generation with increasing resolution. Implantable
“microelectrodes” are revealing complex brainactivity during seizures. Using
microelectrodes, researchers are able to better characterize high-frequency
oscillations.

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Develop New Animal Models for Studying

Epileptogenesis and for Testing Treatments
The diversity of epilepsy syndromes and their causes precludes investigators
from using any single animal model system for learning about the epilepsies
and for testing potential therapies. Multiple syndrome-specific models are
therefore needed to advance research on the epilepsies.

Several substantial advances in the development of animal models have

occurred over the last few years, including new models of Dravet syndrome,
infantile spasms, cortical dysplasia, and viral encephalitis, as well as for
stroke, TBI, and other conditions that can lead to acquired forms of epilepsy.

The zebrafish has emerged as a promising model for screening new drug
compounds for antiseizure activity. Fish that are bred to express mutations
known to be associated with particular types of epilepsy can be quickly and
cost-effectively produced for research. The drosophila, or fruit fly, is another
model developed to investigate the cellular mechanisms of the epilepsies.

Paramedics stopped status epilepticus seizures earlier thanks to drug delivery

with an autoinjector. Similar to the EpiPen used by people with serious allergic
reactions, the autoinjector may someday be on hand for people with epilepsy and
their families.

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Develop New Treatment Strategies and

Optimize Existing Treatments
There have been several key advances in diagnostics, therapeutics, and
technologies that are either approved or in various stages of approval in the
U.S. and Europe. New chemical entities have been developed for treatment-
resistant epilepsy. For example, ezogabine (also called retigabine) was
approved by the U.S. Food and Drug Administration (FDA) in 2011 for the
prevention of focal seizures by a novel mechanism of action. Several other
potential drugs and chemical compounds (brivaracetam, perampanel,
YKP3089, VX-765) are in development and also are aimed at preventing
seizures by novel mechanisms.

In addition, several agents have been approved for specific seizure types or
syndromes: rufinamide (Lennox-Gastaut syndrome), stiripentol (Dravet
syndrome), adrenocorticotropic hormone also known as ACTH (infantile
spasms), and vigabatrin (infantile spasms). mTOR inhibitors (such as
everolimus) are being tested for the treatment of seizures and other
manifestations of tuberous sclerosis complex (TSC). The drug everolimus has
been approved by the FDA for preventing the growth of tumors in individuals
with TSC.

Progress has been made in determining the best single-agent therapy for
childhood absence epilepsy (CAE), the most common pediatric epilepsy
syndrome, occurring in 10 to 17 percent of all children with epilepsy. People
with CAE tend to have several seizures each day. In the interest of finding a
drug regimen that would limit an individual’s exposure to drug-related side
effects, researchers compared ethosuximide, lamotrigine, and valproic acid
to treat CAE. Ethosuximide was found to be the best single-agent therapy
because of its optimal balance between effectiveness and relatively few side
effects.

NINDS-funded researchers have made significant strides in improving the

management of individuals with status epilepticus seizures. These prolonged
seizures can be particularly challenging to treat given the difficulty of
establishing an intravenous line (IV) when a person is having convulsions. The
results of the randomized controlled trial, known as Rapid Anticonvulsant
Medication Prior to Arrival Trial (RAMPART), showed that seizures stopped
significantly earlier in people treated with midazolam delivered by an
autoinjector compared to individuals treated with lorazepam by IV. The
autoinjector is similar to the EpiPen drug delivery system used to treat
serious drug reactions. Faster resolution of seizures also translated into
fewer people requiring hospitalization.

Ongoing basic research efforts continue to identify targets for therapy

development. For example, studies have focused on the role of gamma-
aminobutyric acid (GABA), a key neurotransmitter that inhibits activity in the
central nervous system. Other studies are investigating ways of blocking the
activity of the excitatory neurotransmitter glutamate.

Given that the epilepsies involve so many different underlying mechanisms,

the development of a single therapy is unlikely. Instead, management
approaches will need to be tailored for specific syndromes.

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Sidebar: Anticonvulsant Screening Program

In 1975, NINDS established the Anticonvulsant Screening Program (ASP) to
promote the development and evaluation of new antiseizure drugs. At the time,
few incentives existed for the pharmaceutical industry to support epilepsy
research on the development of therapeutic agents. Since its launch, the ASP has
been instrumental in bringing new antiseizure medications to the marketplace by
giving researchers a common platform for submitting potential therapeutic
agents to standardized testing in animal models. The resources provided to
researchers through the ASP can save years in development time.

ASP’s priorities have evolved to focus on the development of therapies aimed at

preventing epileptogenesis, modifying the course of disease progression, finding
therapies for the cases that do not respond to currently available treatments, and
identifying specific epilepsy subtypes and their unmet needs. The ASP maintains a
database of more than 30,000 submitted compounds, and plans are underway to
improve the usefulness of the data for researchers pursuing novel compounds.
NINDS continues to look for new ways to improve the ASP. New assays and
procedures are being developed and implemented to significantly expand the
sensitivity of the traditional screening approach to identify novel
pharmacotherapies targeting the major unmet medical needs in epilepsy.

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Surgery
Surgery remains an effective option for individuals with treatment-resistant
epilepsies. The most common type of surgery involves the removal of a
seizure focus, the small area of the brain where seizures originate. In some
extremely severe cases, surgeons perform a procedure called multiple
subpial transection, which involves making cuts designed to prevent seizures
from spreading into other parts of the brain while leaving the person’s
normal abilities intact. Doctors also may use surgical procedures called
corpus callosotomy (severing of the nerve fibers that connect the two sides of
the brain) or hemispherectomy (removal of half of the brain). Researchers
continue to refine surgical techniques to make them less invasive and to
prevent cognitive and other neurological deficits that can result from surgery.

 New imaging technologies are key advances for localizing the effects of
surgery and minimizing adverse events. Many epilepsy centers have
begun to use functional magnetic resonance imaging (fMRI) to “map”
language and memory zones prior to surgery. NIH-funded researchers
are aiming to verify whether fMRI actually improves surgical outcomes
and to standardize best practices for its use.
  Researchers also are looking for ways to combine imaging modalities
to more accurately map language zones. In one study, for example,
diffusion tensor imaging (DTI) is being used along with fMRI and
magnetoencephalography (MEG), another brain mapping technique
based on magnetic fields, to evaluate preoperative language
processing and preserve key language zones during surgery for
temporal lobe epilepsy.
 Evidence suggests that high-frequency oscillations (HFOs) measured in
the neocortex and temporal lobe may be biomarkers of epileptic
networks, and can therefore help in surgical mapping and predicting
outcomes after epilepsy surgery. Retrospective studies show that the
removal of zones generating HFOs is associated with improved results
following surgery.
 Minimally invasive MRI-guided laser surgery is being studied for the
treatment of epilepsies associated with tumors, such as hypothalamic
hamartomas and tuberous sclerosis complex. The technique involves
drilling a very small hole in the skull through which a thermal laser is
inserted to ablate an epileptogenic zone under MRI-guidance.

New imaging technologies are key advances for localizing the effects of surgery
and minimizing adverse events. Many epilepsy centers have begun to use
functional magnetic resonance imaging to “map” language and memory zones
prior to surgery.

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Brain Stimulation
Electrical stimulation of the brain remains a therapeutic strategy of interest.
The types of stimulation include: deep brain, intracranial cortical, peripheral
nerve, vagal nerve, and trigeminal nerve. So far, deep brain stimulation has
involved either the thalamus or the hippocampus, and only thalamic
stimulation has been tested in a large clinical trial.

A clinical trial of deep brain stimulation in the anterior thalamic nucleus

showed significant seizure reduction over the long term, and the majority of
participants saw benefit. Thalamic stimulation has been cleared for use in
Europe, but not in the U.S.

A report on trigeminal nerve stimulation showed efficacy rates similar to

those for vagal nerve stimulation, with about half of the people responding (a
responder is defined as having greater than a 50 percent reduction in seizure
frequency). Freedom from seizures, although reported, remains rare for both
methods.

NINDS-supported investigators are developing methods to predict seizures

by analyzing brain activity patterns that precede their onset. A promising
application of this research is the development of implantable devices that
can detect a forthcoming seizure. Once detected, the implanted device
administers an intervention, such as electrical stimulation or a fast-acting
drug to prevent the seizure from occurring. The first generation of seizure
control devices in clinical trials uses such seizure prediction technology. The
NeuroPace RNS system is among these devices, known as responsive
stimulation or closed-loop devices.

Optogenetics is an emerging experimental technique that may eventually

lead to future generations of closed-loop devices. It involves the genetic
delivery of light-sensitive proteins to specific populations of brain cells. The
lightsensitive proteins can be inhibited or stimulated by exposure to light
delivered by fiber optics. Although optogenetic methods are not currently
used in humans, such an approach could allow highly targeted regulation of
network excitability, providing a means for intervening at or before the onset
of a seizure.

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Diet
A high-fat, very low carbohydrate ketogenic diet is an age-old treatment for
medicationresistant epilepsies and there has been a renewed interest in
recent years in how it works. The diet effectively reduces seizures for some
people, especially children with certain forms of epilepsy. Studies have
shown that more than 50 percent of people who try the ketogenic diet have a
greater than 50 percent improvement in seizure control and 10 percent
experience seizure freedom. However, for some people, the regimen is
difficult to maintain.

Researchers are trying to learn exactly how the ketogenic diet prevents
seizures. They hope to find ways to mimic its seizure-blocking effects without
the dietary restrictions. Studies have advanced the understanding of the
connection between energy metabolism and neuronal excitability, and in the
process and may contribute to a better understanding of how the ketogenic
diet promotes seizure control.

In addition, researchers are looking at modified versions of and alternatives

to the ketogenic diet. For example, studies show promising results for a
modified Atkins diet and for a low-glycemicindex diet, both of which are less
restrictive and easier to follow than the ketogenic diet. However, well-
controlled randomized controlled trials have yet to assess the approaches,
and many questions remain about the optimal circumstances of their use.

Researchers are trying to learn exactly how the ketogenic diet prevents seizures.
They hope to find ways to mimic its seizure-blocking effects without the dietary
restrictions. Studies have advanced the understanding of the connection between
energy metabolism and neuronal excitability..

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Gene and Cell Therapies

The discovery of genetic mutations that are linked to specific epilepsy
syndromes suggests the possibility of using gene-directed therapies to
counter the effects of these mutations. Gene therapies remain the subject of
many studies in animal models of epilepsy, and the number of potential
approaches continues to expand. A common approach in gene therapy
research, called transfection, uses modified components of viruses to
introduce new genes into brain cells, which then act as “factories” to produce
potentially therapeutic proteins.

Several proteins have been targeted for transfection. Animal studies have
shown that it is possible to introduce a new protein into a cell, and in some
cases, there has been an associated reduction in the frequency, duration,
and severity of seizures.

Cell therapy differs from gene therapy in that instead of introducing genetic
material, it involves the transplantation of whole cells into a brain. In animal
studies, for example, NINDS-funded researchers have successfully controlled
seizures in mice by grafting special types of neurons that produce the
inhibitory neurotransmitter GABA into the hippocampus of their brains.

Gene and cell therapies remain attractive and promising strategies for
treating, and potentially curing, some forms of epilepsy. However, their
advancement as a viable treatment option in people will require new
technologies and methods that can target specific neurons in the brain.
These approaches need to be able to create more long-lasting changes.

Viruses are introduced into brain cells, which then act as “factories” to produce
potentially therapeutic proteins.

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Preventing the Development of the Epilepsies

Until recently, therapy development for the epilepsies focused largely on
treating seizures in people already affected by the disorders. Now, in addition
to efforts to develop new and improved antiseizure treatments, researchers
are striving to prevent the epilepsies among people at risk.

Measures that reduce the risk of head injury and trauma—such as

improvements in automobile safety and the use of seat belts and bicycle
helmets—can prevent epilepsies related to TBI. Good prenatal care, including
treatment of high blood pressure and infections during pregnancy, can
prevent brain damage in developing babies that may lead to epilepsy and
other neurological problems later in life. Treating cardiovascular disease,
high blood pressure, infections, and other disorders that affect the brain
during adulthood and aging also may prevent some types of epilepsy.

However, while such measures can prevent brain damage from occurring in
the first place, there are currently no interventions known to specifically
reduce the risk of seizure onset once damage to the brain has occurred.
None of the available antiseizure medications have been shown to modify
the development of the epilepsies in people. Researchers are working to
change this.

 Recent animal studies have helped clarify the mechanisms of hypoxic-

ischemic encephalopathy (HIE) seizures (caused by a lack of oxygen in
the brain), and clinical studies involving newborns have begun to
assess potential treatment strategies. These include drugs both alone
and in combination with each other or in combination with a strategy
that involves deliberately cooling babies with HIE for the prevention of
epilepsy.
 Adenosine is an inhibitory neuromodulator that is believed to promote
sleep and suppress arousal. Studies in animal models have shown that
 increasing adenosine levels in the brain can inhibit the development of
spontaneous recurrent seizures after an initial injury.

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Section 3: Reducing the Risk of

Conditions that Co-occur with the
Epilepsies
Psychiatric, Neurodevelopmental,and Sleep
Disorders
Co-occurring psychiatric conditions are relatively common in individuals with
epilepsy. In adults, depression and anxiety disorders are the two most
frequent psychiatric diagnoses. Attention Deficit Hyperactivity Disorder and
anxiety frequently affect children with epilepsy.

Therapies commonly used to treat depression in the general population have

been shown in randomized controlled trials to be effective in treating
depression in people with epilepsy. In those trials, depression medications
did not appear to be associated with an increased risk of seizures. However,
larger trials with longer followup would be required to provide reliable
estimates of seizure exacerbation risk.

Basic research investigations currently are exploring the possibility that the
development of depression, anxiety, and seizures may involve similar causes.
In addition, studies of antiseizure drugs have focused on determining
whether there may be an increased risk of suicide associated with specific
medications.

People with neurodevelopmental disabilities, such as autism spectrum

disorder, attention deficit disorder, and learning disabilities are known to be
at higher risk for epilepsy. Further investigation is needed to better
understand these associations and if there is a shared mechanism between
these neurodevelopmental disabilities and the epilepsies. Sleep disorders are
common among people
with the epilepsies. By one estimate, fully 70 percent of people with epilepsy
had some form of disordered breathing during sleep. In another study,
researchers found that certain types of seizures were associated with
sleeping, while others were more common during times of wakefulness—
suggesting that more research is needed on how these patterns might
inform medication adjustment.

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Sudden Unexpected Death in Epilepsy (SUDEP)

Some people with epilepsy are at risk of SUDEP, which for years was largely
unrecognized. Estimates of SUDEP risk vary, but some studies suggest that
each year approximately one case of SUDEP occurs for every 1,000 people
with the epilepsies. For some, this risk can be higher, depending on several
factors. People with more difficult-to-control seizures tend to have a higher
incidence of SUDEP.

One study suggested that use of more than two antiseizure drugs at one time
is a risk factor for SUDEP. However, it is not clear whether the use of multiple
drugs causes SUDEP, or whether people who use multiple antiseizure drugs
have a greater risk of death because their epilepsy is more severe or more
difficult to control. People with tonic-clonic seizures, uncontrolled seizures, or
epilepsy combined with other neurological disorders also have an elevated
risk for SUDEP.

Findings from an analysis of four studies showed that the highest risk of
SUDEP can be seen in men younger than 60 years of age with at least a 15-
year history of epilepsy from unexplained causes, who had frequent
generalized tonicclonic seizures, and who were taking multiple antiseizure
drugs. Although SUDEP is considered rare in children, some evidence
suggests that children with certain types of epilepsies, such as Dravet
syndrome, may have an elevated risk for SUDEP.

Seizures are known to alter breathing and cardiac activity. Research suggests
that drug therapies that address respiratory arrest and implantation of
cardiac devices may reduce the risk of SUDEP in some individuals.

Early studies have described certain EEG patterns that may help identify
people at elevated risk for SUDEP. In addition, several devices in the early
stages of development aim to provide a warning when a seizure has the
potential to put someone at risk for SUDEP.

NINDS, nonprofit lay and professional organizations, and the CDC are
providing significant funding toward studies aimed at better understanding
SUDEP risk factors and mechanisms, which may yield strategies for screening
and prevention. Plans are underway for an Epilepsy Center without Walls
initiative devoted to multi-disciplinary research on SUDEP and increased
surveillance and epidemiology studies.

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Progress in Managing Specific Populations

Pregnancy and the Epilepsies
Understanding how to treat epilepsy in pregnant women and the impact of
antiseizure medications on an unborn child are of paramount importance
and have been the focus of several studies. The American Academy of
Neurology and the American Epilepsy Society conducted evidence-based
systematic reviews of pregnancy-related studies among women with
epilepsy.

Emerging data from the NINDS-funded Maternal Outcomes and

Neurodevelopmental Effects of Antiepileptic Drugs study, as well as multiple
hospital- and population-based registries, are helping to better characterize
the risk of birth defects associated with antiseizure medications. In general,
higher doses of these
medications are associated with an increased risk of major congenital
malformations. Findings from the registries and other studies include:

 Valproate is consistently associated with an increased risk of major

congenital malformations, and studies suggest a specific increased risk
of neural tube defects, such as spina bifida. Prenatal exposure to
valproate has been shown to be associated with symptoms of autism
in humans and animals. Valproate exposure in utero also has been
shown to adversely affect a child’s cognitive function, particularly
verbal abilities.
 Carbamazepine may increase the risk of neural tube defects, but this is
not a consistent finding. Verbal cognitive skills also have been shown to
be impaired among children who were exposed to carbamazepine
during gestation.
 Topiramate increases the risk of oral clefts (birth defects in which the
tissues of the lip or mouth do not form correctly during fetal
development) as demonstrated in multiple studies. The FDA has
classified it as a category D drug in pregnancy, meaning that evidence
 shows that the drug involves risk to a developing fetus, but the
potential benefits from the drug may warrant its use in pregnant
women despite potential risks.
 Levetiracetam appears to have a lower risk of major congenital
malformations than other antiseizure drugs.
 Motor, adaptive, and emotional behavioral functioning were impaired
in children of mothers who had taken phenytoin, lamotrigine,
valproate, or carbamazepine during pregnancy, with dose-response
effects seen with valproate and carbamazepine. Breastfeeding did not
affect cognitive health of the studied children.

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Infants and Children

Febrile seizures occur in infants and young children and involve convulsions
brought on by high fever. The vast majority of febrile seizures are brief and
harmless. In rare cases, however, some children—including those with
cerebral palsy, delayed development, or other neurological abnormalities—
have an increased risk of developing epilepsy.

Results from an ongoing NINDS-funded study suggested that MRI and EEG
may help determine which children with febrile seizures are subsequently at
increased risk of developing epilepsy.

Older Adults
Epidemiological studies demonstrate that the elderly are at a substantially
higher risk for the development of the epilepsies. In addition to stroke
(hemorrhagic and ischemic), seizures in the elderly may be associated with
brain tumors, TBI, and Alzheimer’s disease.

NIH-funded researchers have found that blood concentrations of antiseizure

medications fluctuate markedly among many residents of nursing homes
even when there is no change in dosage and no change in other medications
the resident may be taking. Prospective studies will continue to follow older
adults in nursing homes to help determine optimal levels of antiseizure drugs
and to identify factors that may contribute to such fluctuations in drug
levels.

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Diagnosing, Treating, and Preventing Non-epileptic Seizures
An estimated five to 20 percent of people diagnosed with epilepsy actually
have nonepileptic seizures (NES) which outwardly resemble epileptic seizures
but are not associated with seizure-like electrical discharges in the brain. A
history of traumatic events is among the known risk factors for psychogenic
nonepileptic seizures, which are largely thought to be psychological in origin.

A NINDS-funded pilot trial showed a reduction in NES frequency when

individuals with psychogenic non-epileptic seizures were treated with
sertraline compared with a placebo. Two other studies showed a reduction in
seizures and fewer comorbid symptoms following treatment with cognitive
behavioral therapy.

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Section 4: Furthering Research on the

Epilepsies
There are several ways in which individuals with epilepsy and their families
can help move research forward. Resources include:

 People with epilepsy can help researchers test new medications,

surgical techniques, and other treatments by enrolling in clinical
studies. Information about finding and participating in clinical studies
can be found at the NIH Clinical Trials and You website
(www.nih.gov/health/clinicaltrials). Additional studies can be found at
www.clinicaltrials.gov and through many pharmaceutical and biotech
companies, universities, and other organizations. A person who wishes
to participate in a clinical trial must ask his or her physician to work
with the doctor in charge of the trial and to forward all necessary
medical records.
 To learn more about why clinical trial research is important, visit the
Human Epilepsy Research Opportunities (HERO) website at
www.epilepsyhero.org.
 Pregnant women with epilepsy who are taking antiseizure drugs can
help researchers learn how these drugs affect unborn children by
participating in the Antiepileptic Drug Pregnancy Registry. This registry
is maintained by the Genetics and Teratology Unit of Massachusetts
General Hospital. For more information, call 1-888-233-2334 or visit the
 website at
http://www.massgeneral.org/research/researchlab.aspx?
id=1493&display=overview.
 People with epilepsies can help further research by making
arrangements to donate tissue either at the time of surgery for
epilepsy or at the time of death. Researchers utilize the tissue to study
epilepsy and other disorders so they can better understand what
causes seizures. Some brain banks accept tissue from individuals with
epilepsy. Each brain bank may have different protocols for registering a
potential donor. Individuals are strongly encouraged to contact a brain
bank directly to learn what needs to be done ahead of the time of
tissue donation. These banks include:

Conclusion
The pace of research on the epilepsies has accelerated considerably over the
past few decades. Progress has been made in understanding how and why
the epilepsies develop and how they might be prevented. Investigators have
identified a variety of potential new treatments, and they may soon be able
to use knowledge about genetic variations and other individual differences to
tailor treatment for each person. With time and continued work, the missing
pieces of the puzzle will be filled in to form a complete picture of how to treat
and prevent all types of epilepsy