Curing the 

Epilepsies 

The Promise of 

Research 

National Institute of 

Neurological Disorders 

and Stroke 

National Institutes of Health 
II 

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Curing the Epilepsies: The Promise of Research Curing Epilepsy: The Promise of Research

Contents 

Introduction ___________________________________________________________1 

1 About the Epilepsies _______________________________________________________ 2 

Seizures __________________________________________________________________ 2 

Epilepsies with Childhood Onset ______________________________________________ 2 

Causes ___________________________________________________________________ 4 

2 Research Progress on the Epilepsies ____________________________________ 5 

What New Discoveries Have Been Made About the Causes of the Epilepsies? _________ 6 

n Genetic Mutations_________________________________________________________ 8 

n Identify Biomarkers of Seizure Onset and Epileptogenesis _____________________________ 9 

n Develop New Animal Models for Studying Epileptogenesis and for Testing Treatments _______ 11 

Develop New Treatment Strategies and Optimize Existing Treatments _____________ 12 

n Surgery _______________________________________________________________ 14 

n Brain Stimulation_________________________________________________________ 16 

n Diet __________________________________________________________________ 17 

n Gene and Cell Therapies ___________________________________________________ 18 

Preventing the Development of the Epilepsies _________________________________ 19 

3 Reducing the Risk of Conditions that Co-occur with the Epilepsies____20 

Psychiatric, Neurodevelopmental, and Sleep Disorders _______________________________ 20 

Sudden Unexpected Death in Epilepsy (SUDEP) ____________________________________ 21 

Progress in Managing Specific Populations ____________________________________ 22 

n Pregnancy and the Epilepsies ________________________________________________ 22 

n Infants and Children ______________________________________________________ 23 

n Older Adults ____________________________________________________________ 23 

n Diagnosing, Treating, and Preventing Non-epileptic Seizures _________________________ 23 

4 Furthering Research on the Epilepsies _______________________________ 24 

Conclusion ___________________________________________________________ 25 

For individuals living with a treatment resistant 

form of the seizure disorders known as “the 

epilepsies,” each day can bring debilitating 

seizures as well as challenges from co occurring 

conditions that dramatically impair quality 

of life. This brochure, for people with the 

disorders, their caregivers, and advocates, 

outlines the state of progress made in the past 

decade toward achieving the Epilepsy Research 

Benchmarks, a set of widely recognized 

objectives aimed at prioritizing the efforts of 

scientists and health care providers to find cures 

for the epilepsies. Much of this work has been 

funded by grants from the National Institute 

of Neurological Disorders and Stroke (NINDS), 

part of the National Institutes of Health (NIH). 

1 

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. 
Curing Epilepsy 

 

2 Curing Epilepsy: The Promise of Research : The Promise of Research 3

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. 

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 LennoxGastaut 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. 

Curing the Epilepsies: The Promise of Research 3 

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. 

The Role of the National 

Institutes of Health 

1. About the 

Epilepsies 

2 Curing the Epilepsies: The Promise of Research
g Epile sy: The Promise of Research Curing Epilepsy

 

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. 

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 or illness—can lead to 

seizures and epilepsy. 

4 Curin p Curing the Epilepsies: The Promise of Research 5

Neurons communicate with each other by using signaling chemicals called 

neurotransmitters to send information across tiny spaces between neurons called 

synapses (see inset illustration). Neurotransmitters collect in sacs called vesicles. 

When the nerve receives a signal, these sacs release their neurotransmitters into 

the synapse. Receptors on the receiving neuron bind to the neurotransmitters, 

triggering a new electrical impulse, which in turn prompts neurotransmitters 

to be released into the synapse with the next neighboring neuron. 

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 

2. Research 

Progress 

on the 

Epilepsies 

I

n 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. 

Curing the Epilepsies: The Promise of Research 
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). n	 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. 

The white, star-shaped cells in this photo are swollen astrocytes 

in brain tissue from a mouse model of epilepsy. This condition is 

called reactive gliosis. Astrocytes are the most common cells in the 

brain. Normally, they help the brain to function. However, they also 

produce the nerve-signaling chemical glutamate, which can trigger 

seizures. When reactive gliosis develops, astrocytes stop functioning 

correctly and may contribute to the development of epilepsy. n	 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: n	 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. 

n	 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. 

n	 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. 

n	 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. 

6 Curing the Epilepsies: The Promise of Research Curing the Epilepsies: The Promise of Research Curing Epilepsy: The Promise of Research7
8 Curing Epilepsy: The Promise of Research Curing Epilepsy: The Promise of Research 9

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. 

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. 

Curing the Epilepsies: The Promise of Research 9 

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. 

Collaborations 

NINDS-sponsored programs aim to coordinate 

research efforts with the goal of accelerating 

advances in prevention, diagnosis, or treatment 

of the epilepsies and co-occurring conditions. 

For example, the Epilepsy Centers without 

Walls program brings together investigators 

from multiple disciplines, regardless of geographic 

location, and uses innovative approaches to 

address challenges identified by the Epilepsy 

Research Benchmarks. Among the first of such 

centers to be awarded funding, “Epi4K” aims to 

determine the genetic basis of human epilepsies 

in order to improve the well-being of individuals 

and family members living with these disorders. 

Epi4K investigators are working as a team in 

order to analyze the genomes of at least 4,000 

people with well-characterized epilepsy. Among 

Epi4K’s first discoveries is the identification of 

de novo mutations involved in infantile spasms 

and Lennox-Gastaut syndrome. These epileptic 

encephalopathies are characterized as severe 

epilepsies that are typically resistant to medication 

and that involve developmental delay and 

cognitive and behavioral disabilities. 

8 Curing the Epilepsies: The Promise of Research
10 Curing the Epilepsies: The Promise of Research Curing Epilepsy

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 brain 

activity during seizures. Using 

microelectrodes, researchers 

are able to better characterize 

high-frequency oscillations. 

The zebrafish, a member of the minnow family, is making waves in genetic research. The fish can be bred to express mutations known to be associated with particular 

types of epilepsy, as well as other diseases. 

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. 

Curing the Epilepsies: The Promise of Research 11 
g Epile sy: The Promise of Research

Paramedics stopped status epilepticus seizures earlier thanks to drug 

Curing the Epilepsies: The Promise of Research Curing Epilepsy: The Promise of Research 13 

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. 

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), 

Curing the Epilepsies: The Promise of Research 

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. 

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. 

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. 

12 
Curing Epilepsy

Researchers continue to refine surgical 

techniques to make them less invasive and to 

prevent cognitive and other neurological deficits 

that can result from surgery. 

n	 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. NIHfunded researchers are aiming to verify 

whether fMRI actually improves surgical 

outcomes and to standardize best practices 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). 

for its use. 

n 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. 

14 Curing the Epilepsies: The Promise of Research

f

n	 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. 

n	 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. 

Functional MRI (fMRI) provides a means for surgeons to more precisely target areas 

in the brain that, once removed, will control seizures, while also preserving language 

and memory function. Prior to surgery, fMRI results from a single patient (figures A 

and B) identify areas vital for language processing. 

A structural MRI scan obtained after surgery (figure C) shows the anterior temporal 

lobe tissue removed (grey area). A 3D image of this surgically removed region 

(shown in pink in figure D) is digitally constructed. 

Curing the Epilepsies: The Promise of Research 15 
16 Curin p Curing the Epilepsies: The Promise of Research g Epile sy: The Promise of Research Curing Epilepsy: The Promise of Research 17

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. 

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 

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-glycemic

index 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. 

Optogenetics delivers light-sensitive proteins to targeted brain cells. 

Once in place, the proteins can be inhibited or stimulated by exposure 

to light transmitted via fiber optics. Animal studies suggest that such 

an approach provides an exquisitely sensitive and highly targeted way 

of regulating of brain activity. 

A responsive or closed-loop stimulation system involves the 

implantation of electrodes on or adjacent to the area of the brain 

where seizures begin. The electrodes are attached to a neurostimulator 

implanted in the skull. With the detection of abnormal electrical 

activity, the neurostimulator sends a signal that disrupts that activity 

to prevent the seizure. Photo credit: Neurosurgical Focus, 2012. 

Curing the Epilepsies: The Promise of Research 17 
18 Curing the Epilepsies: The Promise of Research Curing Epilepsy

Gene and Cell Therapies	 Cell therapy differs from gene therapy in that 

instead of introducing genetic material, it The discovery of genetic mutations that are involves the transplantation of whole cells linked to specific epilepsy syndromes suggests into a brain. In animal studies, for example, the possibility of using gene-directed therapies NINDS-funded researchers have successfully to counter the effects of these mutations. Gene 

controlled seizures in mice by grafting special therapies remain the subject of many studies types of neurons that produce the inhibitory in animal models of epilepsy, and the number neurotransmitter GABA into the hippocampus of potential approaches continues to expand. of their brains. 

A common approach in gene therapy research, 

called transfection, uses modified components Gene and cell therapies remain attractive and of viruses to introduce new genes into brain cells, promising strategies for treating, and potentially which then act as “factories” to produce potentially curing, some forms of epilepsy. However, their therapeutic proteins. advancement as a viable treatment option 

in people will require new technologies and Several proteins have been targeted for transfection. methods that can target specific neurons in Animal studies have shown that it is possible to the brain. These approaches need to be introduce a new protein into a cell, and in some able to create more long-lasting changes. cases, there has been an associated reduction in 

the frequency, duration, and severity of seizures. 

Viruses are introduced into brain cells, 

which then act as “factories” to produce 

potentially therapeutic proteins. 

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. 

n	 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. 

n	 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. 

Curing the Epilepsies: The Promise of Research 19 
g Epile sy: The Promise of Research Curing Epilepsy

 

20 Curin p Curing the Epilepsies: The Promise of Research

3. Reducing 

the Risk of 

Conditions 

that Co-occur 

with 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. 

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. 

Curing the Epilepsies: The Promise of Research 21 

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. 
22 Curing the Epilepsies: The Promise of Research Curing Epilepsy

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: n	 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. 

n	 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. 

n	 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. 

n	 Levetiracetam appears to have a lower risk of 

major congenital malformations than other 

antiseizure drugs. 

n	 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. 

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. 

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. 

Curing the Epilepsies: The Promise of Research 23 
 

 

Curing the Epilepsies: The Promise of Research Curing Epilepsy: The Promise of Research 25 

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. 

PHOTO CREDITS 

Page 4: National Institute on Aging/National Institutes 

of Health; Page 6: Nancy Ann Oberheim and Maiken 

Nedergaard (University of Rochester); Page 8: Jack M. Parent 

(University of Michigan); Page 11: Lynn Ketchum, Oregon 

State University; Page 14: (bottom) Carrie R. McDonald 

(University of California, San Diego); Page 15: Jeffrey R. 

Binder (Medical College of Wisconsin); Page 16: (bottom)

illustrated by Jovany Cruz (Baylor College of Medicine), 

used with permission from the Journal of Neurosurgery 

Publishing Group. 

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: n	 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. 

n	 To learn more about why clinical trial research 

is important, visit the Human Epilepsy 

Research Opportunities (HERO) website 

at www.epilepsyhero.org. 

Curing the Epilepsies: The Promise of Research 

n	 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 www.massgeneral.org/aed. 

n	 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: 

NICHD Brain and Tissue Bank for 

Developmental Disorders 

University of Maryland School of Medicine 

Department of Pediatrics 

655 West Baltimore Street, 13-013 BRB 

Baltimore, MD 21201-1559 

800-847-1539 

www.btbank.org 

University of Miami Brain Endowment Bank 

University ofMiami Department of Neurology 

1951 NW 7th Avenue, Suite 240 

Miami, FL 33136 

305-243-6219 or 800-862-7246 

www.brainbank.med.miami.edu

National Disease Research Interchange/ 

National Human Tissue Resource Center 

8 Penn Center, 15th Floor 

1628 JFK Boulevard 

Philadelphia, PA 19103 

215-557-7361 or 800-222-6374 

www.ndriresource.org 

The Human Brain and Spinal Fluid 

Resource Center 

11301 Wilshire Boulevard (127A) 

Building 212, Room 16 

Los Angeles, CA 90073 

310-268-3536 

www.brainbank.ucla.edu 

24 
NIH Publication No. 13 6120 - • September 2013