Epilepsy Research News: November 2020

This month’s research news includes a study that highlights the importance of adherence to antiepileptic drug regimens and controlling seizures to reduce the risk of sudden unexplained death in epilepsy (SUDEP). We also highlight an advancement in understanding and preventing temporal lobe epilepsy, utilizing an animal model.

Additionally, we share a study that highlights the difficulty that can be faced in diagnosing sometimes subtle seizures associated with focal epilepsy, and we present findings on the development of a new tool to help ease what can be a challenging transition from pediatric/adolescent to adult care for individuals with epilepsy.

In other news, a new FDA alert was issued to avoid the use of lamotrigine/Lamictal in people with cardiac conduction disorders, ventricular arrhythmias, or cardiac disease or abnormality.

These studies and the FDA alert are summarized below.

Research Highlights

Preventing SUDEP
Polytherapy, especially the use of three or more antiepileptic drugs, is correlated with a substantially decreased risk for SUDEP according to a nationwide study conducted in Sweden. The study also demonstrated a link between statin use and a decreased risk for SUDEP. “These results provide support for the importance of medication adherence and intensified anti-epileptic drug treatment for patients with poorly controlled generalized tonic-conic seizures in the efforts to reduce SUDEP risks and suggest that comedication with statins may reduce risks,” the researchers wrote.

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Understanding & Treating Temporal Lobe Epilepsy
A team of researchers has found that an amino acid produced by the brain could play a crucial role in preventing cell loss and seizures associated with temporal lobe epilepsy. Utilizing an animal model of temporal lobe epilepsy, the research team found that administration of the amino acid D-serine prevented cell loss characteristic of temporal lobe epilepsy and reduced the number and severity of seizures.

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Focal Epilepsy & Delayed Diagnosis
A new study shows that it can take on average two years for physicians to recognize the early signs of focal epilepsy, particularly in patients with seizures that do not involve uncontrolled movements of their arms and legs. Subtler cases are often not diagnosed until they have progressed to disruptive “motor” seizures, say the study authors, which can cause the unrestrained, whole-body spasms often portrayed in popular culture. Researchers believe the impact of earlier diagnosis in focal epilepsy patients goes beyond more timely treatment of patients; some study participants reported having one or more car accidents before their diagnosis. The researchers estimate that for every 13 early diagnoses, one car accident, equating to an estimated 1,816 annually worldwide, could be prevented.

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Transitioning to Adulthood with Epilepsy
Clinicians at Michigan Medicine have developed an assessment tool to help doctors ensure adolescents and young adults with epilepsy have the skills and confidence they need to take control of seizures and health care. Through a customized screening tool for 16 to 26-year-olds, doctors are effectively able to monitor their patients’ development of knowledge and self-management skills regarding their condition. This tool allows providers to proactively address gaps in readiness that may impact long term health outcomes.

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FDA Alert for Lamotrigine
The FDA has issued a new warning advising against the use of lamotrigine/Lamictal in people with cardiac conduction disorders, ventricular arrhythmias, or cardiac disease or abnormality. People currently taking lamotrigine should consult their healthcare provider. Do not stop taking lamotrigine without talking to your healthcare provider as doing so can cause serious problems.

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Generalized, Focal, and Combined Epilepsies in Families: New Evidence for Distinct Genetic Factors

Abstract, originally published in Epilepsia

Objective: To determine the roles of shared and distinct genetic influences on generalized and focal epilepsy operating in individuals who manifest features of both types (combined epilepsies), and in families manifesting both generalized and focal epilepsies in separate individuals (mixed families).

Methods: We analyzed the deeply phenotyped Epi4K cohort of multiplex families (≥3 affected individuals per family) using methods that quantify the aggregation of phenotypes within families and the relatedness of individuals with different phenotypes within family pedigrees.

Results: The cohort included 281 families containing 1021 individuals with generalized (n = 484), focal (304), combined (51), or unclassified (182) epilepsies. The odds of combined epilepsy was higher in relatives of participants with combined epilepsy than in relatives of those with other epilepsy types (odds ratio [OR] 5.2, 95% confidence interval [CI] 1.7-16.1, P = .004). Individuals with combined epilepsy co-occurred in families more often than expected by chance (P = .03). Within mixed families, individuals with each type of epilepsy were more closely related to relatives with the same type than to relatives with other types (P < .001).

Significance: These findings suggest that distinct genetic influences underlie the recently recognized entity of combined epilepsies, just as generalized epilepsies and focal epilepsies each have distinct genetic influences. Mixed families may in part reflect chance co-occurrence of these distinct genetic influences. These conclusions have important implications for molecular genetic studies aimed at identifying genetic determinants of the epilepsies.

Epilepsy Research News: October 2020

This month’s research news features two studies advancing Dravet syndrome research, both utilizing mouse models mimicking the disorder. One study, featuring the work of former CURE Grantee Dr. Lori Isom, tested a new type of drug and found that it decreased the frequency of Sudden Unexplained Death in Epilepsy (SUDEP) in these mice.

In other news, a recent study has increased our understanding of the unique way epilepsy can affect women, showing that women who have seizures that increase in frequency during their menstrual cycle are also more likely to have drug-resistant epilepsy.

Finally, research has helped pinpoint individuals with epilepsy who may be at risk for obstructive sleep apnea, a finding that may help physicians identify who is most at risk and who would likely benefit from treatment.

Summaries of these research discoveries and more are below.

Research Discoveries

Dravet Syndrome (Featuring the work of former CURE Grantee, Dr. Lori Isom)
A new treatment curbs deadly seizures in a mouse model of Dravet syndrome, a severe form of epilepsy, according to a new study. This new drug counteracts the effects of mutations in a gene known as SCN1A, which cause Dravet syndrome. In this study, the drug significantly decreased the overall frequency of SUDEP, lowering the likelihood of a fatal seizure. A clinical trial is evaluating the drug’s safety in children with the syndrome.

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Dravet Syndrome
A study has utilized a gene therapy technique to reduce seizures and improve behaviors in a mouse model of Dravet syndrome. Researchers used the technique to activate the SCN1A gene, a gene with decreased activity in individuals with Dravet syndrome. The authors note that although more work must be done before the technique can be tested in people, the study supports a potential new approach to treating this cause of epilepsy.

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Epilepsy Genetics
Researchers have identified a critical new step in how brain cells function in people with one of the most common forms of epilepsy. Using mice, researchers found certain changes in gene activity and regulation in an area of the brain important in temporal lobe epilepsy. The researchers note that the study could eventually lead to targeted treatments that prevent a person from developing epilepsy.

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Epilepsy and Fetal Alcohol Spectrum Disorder
A study has found a much higher prevalence of epilepsy or history of seizures in individuals with fetal alcohol spectrum disorder (FASD), a disorder that refers to a range of developmental problems that result from maternal drinking during pregnancy. Although more research is needed to establish a direct cause-effect relationship between FASD and epilepsy, the study, which examined the medical histories of individuals from two FASD clinics, supports the link between maternal drinking during pregnancy and a wide array of health impacts to the child.

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Drug Resistant Epilepsy and Women
More frequent seizures during the menstrual cycle in women with genetic generalized epilepsy have been linked for the first time to drug-resistant epilepsy. Women with catamenial epilepsy, a generalized epilepsy characterized by increased seizure frequency during the menstrual cycle, were nearly four times more likely to have drug-resistant epilepsy than women who experience no changes in frequency.

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Epilepsy and Sleep Apnea
People with generalized epilepsy who have seizures arising from both sides of the brain simultaneously have a higher risk of obstructive sleep apnea than those who have focal epilepsy where seizures emanate from one area of the brain, according to a new study. These findings may help physicians better understand who is most at risk for obstructive sleep apnea and, therefore, who will benefit most from treatment.

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The Path to a Cure: Improving Genetic-Based Outcomes

Dr. Heather Mefford is a current CURE Grantee who is as dedicated to driving science toward cures for epilepsy as she is to treating people in her clinical practice. As Associate Professor of Pediatrics at the University of Washington and attending physician at Seattle Children’s Hospital, Dr. Mefford is making an impact both in and out of the laboratory.

Severe Pediatric Epilepsy is Often Genetic

Dr. Heather Mefford, 2019 CURE Epilepsy Grantee

As a physician who cares for pediatric patients living with severe epilepsy syndromes, Dr. Mefford has firsthand knowledge of the devastating impacts of seizures in children. These treatment-resistant epilepsy syndromes are usually caused by a genetic mutation and knowing what that mutation is can potentially inform the treatment plan. As such, genetic testing is a critical part of the epilepsy diagnosis and care process. Dr. Mefford describes what genetic testing involves and what kinds of tests are available in an episode of our Seizing Life® podcast. Watch or listen to learn more.

The DNA of Dr. Mefford’s Genetic Research
When not seeing patients, Dr. Mefford heads a research laboratory at the University of Washington. Over the last 10 years, Dr. Mefford’s team has identified many new epilepsy-related genes and mutations. Dr. Mefford’s lab is currently investigating a type of genetic change that does not alter the sequence of the gene itself but instead affects how the gene functions. This field of research, known as epigenetics, is relatively new and now, excitingly, is being applied to epilepsy. For her CURE-funded project, Dr. Mefford is studying a type of epigenetic change called methylation, in people with severe early-onset, treatment-resistant seizure disorders known as developmental and epileptic encephalopathies (DEE). Despite advanced genetic testing, more than 50% of people with DEE still do not have a genetic diagnosis and work like Dr. Mefford’s could ultimately improve the prognosis for children with these epilepsies.

Leading the Next Generation
To support the future of research, Dr. Mefford has helped launch the careers of the next generation of epilepsy scientists. One of her former trainees, Dr. Gemma Carvill, is also making a big impact on the field of epilepsy research. Dr. Carvill was awarded a CURE grant early in her career and now leads her own independent research program at Northwestern University in Chicago, where she also investigates the underlying genetic and epigenetic mechanisms of epilepsy.


Your support makes this research possible. Our researchers’ important work continues through the current public health crisis and beyond thanks to generous donors who, like us, envision a world without epilepsy.

Epilepsy Research News: September 2020

In this month’s research news, we highlight studies suggesting that unprovoked seizure onset in US veteranspsychogenic nonepileptic seizure (PNES), and socioeconomic status can have severe impacts on people with epilepsy. We also feature a study that states antiepileptic drugs (AEDs) do not increase the risk of a fetus developing genetic mutations. Finally, we report on a non-invasive treatment for severe pediatric, treatment resistant seizures.

Summaries of these research studies are presented below.

Research Discoveries

  • Seizure Onset and Dementia: US military veterans over the age of 73 who developed unprovoked seizures of unknown cause were twice as likely to develop dementia compared to veterans without seizures. Veterans who developed these seizures were more likely to be younger, black, have lower income, and a higher prevalence of co-existing illnesses. Learn more
  • PNES Misdiagnoses and Death: Almost 25% of people who are admitted to a hospital for uncontrolled seizures actually do not have epilepsy. Instead, they have psychogenic nonepileptic seizures (PNES), which resemble epileptic seizures but have a psychological cause rather than a neurological one. Researchers found that patients with PNES are 2.5 times more likely to die compared to people of their same age, and this risk is even greater for people under 30 years of age. Learn more
  • SUDEP and Socioeconomic Status: Lower socioeconomic status is associated with higher rates of Sudden Unexpected Death in Epilepsy (SUDEP), according to a review of medical records from three geographically diverse areas in the US. People with epilepsy living in the poorest communities were found to be more than twice as likely to suffer from SUDEP than those living in more affluent areas. Learn more
  • Differing Interpretations of Genetic Data: Different genetic testing laboratories may show conflicting interpretations of genetic data. Because genomic testing has become routine in the diagnosis, management, and treatment of pediatric epilepsy, consistency in data interpretation is important. Learn more
  • Antiepileptic Drugs and Birth Defects: A small study found that antiepileptic drugs (AEDs) taken during pregnancy do not increase the risk of a fetus’ developing new genetic mutations, i.e., those that arise in the sperm, egg, or fertilized egg rather than being inherited from one or both of  parents. Learn more
  • Body Cooling and Refractory Seizures: A treatment that lowers the body’s temperature called “therapeutic hypothermia” can shorten long-lasting seizures and improve outcomes in children with severe and treatment-resistant forms of epilepsy. Learn more

New CURE-Funded Research Projects to Drive Science Forward

We are delighted to announce new CURE grants awarded to three innovative epilepsy researchers, Drs. Detlev Boison, Chris McGraw, and James Gugger! Each researcher has a unique perspective and focus; Dr. Boison has been researching ways to prevent epilepsy for 25 years; Dr. McGraw, is a physician-scientist who is currently an epilepsy research fellow at Boston Children’s Hospital studying epilepsy genetics; Dr. Gugger is an epilepsy fellow at the University of Pennsylvania exploring a novel way to assess a person’s risk of developing post-traumatic epilepsy (PTE). We are honored to support the exciting work of these researchers.

To date, CURE has raised over $70 million dollars and funded more than 240 grants to support our mission of finding a cure for epilepsy. Read on to learn about the newest promising projects we’ve funded with the Catalyst Award, Taking Flight Award, and our partnership with the American Epilepsy Society (AES).

Catalyst Award Grantee
$250,000 for two years

The Catalyst Award supports translational research, where findings from basic research (studies that increase our general knowledge and understanding) are “translated” into the next phase of study to prepare potential new treatments for clinical trials.

Detlev Boison, PhDDetlev Boison, PhD
Rutgers University

For 25 years, Dr. Boison and his team have studied ways to prevent epilepsy. During that time, they have found that some individuals develop epilepsy when a substance in the brain called adenosine (ADO) is reduced.

Dr. Boison’s Catalyst Award project builds on a prior CURE-funded study which demonstrated that in an animal model of acquired epilepsy, ADO levels can be increased with a drug that blocks the enzyme responsible for reducing it, called adenosine kinase (ADK). The team’s goal is to optimize and test this potential epilepsy-preventing drug in the hopes of creating disease-modifying treatment options.

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Taking Flight Award Grantee
$100,000 for one year

The Taking Flight Award seeks to promote the careers of young epilepsy investigators, allowing them to develop a research focus independent of their mentors.

Chris McGraw MD, PhDChris McGraw MD, PhD
Massachusetts General Hospital

Dr. McGraw is developing a zebra fish model to enable the rapid screening of genes that enhance seizure resistance. This system integrates the latest advances in genetic engineering (Crispr/Cas9 technology) and non-invasive neural activity monitoring. Dr. McGraw predicts that by systematically discovering which genes underlie seizure-resistance in zebra fish, researchers can identify potential targets for the next generation of antiepileptic drugs for people with epilepsy.

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AES/CURE Training Fellowship for Clinicians
$50,000 for one year, funded 50% by CURE

These research dollars support trainees, fellows, and newly independent investigators working across the spectrum of epilepsy research.

James Gugger, MD, PharmDJames Gugger, MD, PharmD
University of Pennsylvania

Epilepsy can develop following a brain injury such as a stroke, brain infection, or head injury; however, there is currently no way to predict who will develop epilepsy following these insults to the brain. Dr. Gugger’s goal is to address this gap by using a special type of brain scan called diffusion tensor imaging (DTI) to identify changes in the brain that indicate an increased risk of epilepsy following a head injury. By better understanding why some people develop epilepsy after injury and by identifying which individuals are at risk, diagnostic tests may be created to predict epilepsy.

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Utility of Genetic Testing for Therapeutic Decision-Making in Adults with Epilepsy

Abstract, published in Epilepsia

Objective: Genetic testing has become a routine part of the diagnostic workup in children with early onset epilepsies. In the present study, researchers sought to investigate a group of adult patients with epilepsy, to determinate the diagnostic value, and explore the gain of personalized treatment approaches in adult patients.

Methods: Two hundred patients (age span = 18-80 years) referred for diagnostic gene panel testing at the Danish Epilepsy Center were included. The vast majority (91%) suffered from comorbid intellectual disability. The medical records of genetically diagnosed patients were examined for data on epilepsy syndrome, cognition, treatment changes, and seizure outcome following the genetic diagnosis.

Results: The team found a genetic diagnosis in 46 of 200 (23%) patients. Mutations in genes that make proteins involved in neuronal communication accounted for the greatest number of positive findings (48%). More rare genetic findings included those that make proteins involved in sugar transport and those that make proteins responsible for turning other genes on or off. Gene-specific treatment changes were initiated in 11 of 46 (17%) patients following the genetic diagnosis. Ten patients improved, with seizure reduction and/or increased alertness and general well-being.

Significance: With this study, researchers show that routine diagnostic testing is highly relevant in adults with epilepsy. The diagnostic value is similar to that previously reported in pediatric patients, and the genetic findings can be useful for therapeutic decision-making, which may lead to better seizure control, ultimately improving quality of life.

Mutations in an Important Ion Channel in the Brain are Not the Cause of a Common Childhood Epilepsy

Featuring the work of former CURE Grantee, Dr. Gemma Carvill

Summary of Abstract

Mutations in a channel, known as CACNA1H, which allows calcium ions into nerve cells, were originally reported in a group of children with absence epilepsy, a disorder in which the seizures involve brief staring spells or repetitive movements like mouth chewing. Although this initial finding resulted in the gene’s being included in genetic tests offered by commercial laboratories, its status as a singular cause of epilepsy is controversial.

The authors analyzed published variants and those reported in ClinVar, a freely-available public database of genetic mutations, and found none would be classified as disease-causing. Moreover, these mutations did not change seizure propensity in mouse models.

Overall, the authors conclude that there is limited evidence that mutations in this channel are responsible for epilepsy in humans and that the gene should be removed from commercial genetic testing panels to reduce the burden of mutations of uncertain significance for healthcare providers, families and patients with epilepsy.

A blonde woman in a lab coat is conducting genetic research in the lab.

CURE Discovery: Researchers use “Big Data” to Identify a Protein that Protects Against Epileptogenesis

Key Points

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  • Dr. Avtar Roopra and his team used a “big data” approach to understand how an injured brain may develop epilepsy. To do so, the team analyzed a vast amount of data to identify a protein called EZH2, which determines when thousands of genes are “turned on” or “turned off.”
  • The research team found that inhibiting EZH2 activity increased the frequency and severity of seizures in rodent models of acquired epilepsy, suggesting that EZH2 protects against the development of seizures and may be a potential new therapeutic target.
  • Because of this CURE-funded work, Dr. Roopra was able to secure a grant from the National Institutes of Health (NIH) to continue his promising study on EZH2.

Deep Dive

There are many antiepileptic drugs (AEDs) commercially available, but they only treat the seizures rather than cure or even prevent epilepsy. To develop curative or preventative AEDs, researchers must first understand the biological mechanisms underlying epileptogenesis, the process by which an initial “insult” to the brain, such as a head injury or even a period of recurrent seizures, leads to epilepsy.1 A particularly critical stage of epileptogenesis is called the latent period, a poorly understood span of time between the initial insult and the onset of epilepsy.1 Dr. Roopra’s CURE-funded project set out to better understand what happens in the brain during this period.2

Key Terms DefinedThe researchers turned to a potentially powerful method, which involves identifying possible proteins, known as transcription factors, that activate (“turn on”) or suppress (“turn off”) specific genes. Some transcription factors control thousands of genes and are therefore known as “master” regulators. Unfortunately, finding these master regulators can be a challenging task given the large quantity of genomic data to analyze.

Dr. Roopra’s work overcame these challenges through a collaboration with Dr. Raymond Dingledine’s team at Emory University. They collected data from numerous laboratories and worked together to construct a large database of detailed gene expression profiles3 of brain cells from different rat models of acquired epilepsy, collected at multiple time points during the latent period.4 Dr. Roopra’s team then developed a high-powered computer algorithm5 to identify potential master regulators from this database.

Gene Expression ProfileUsing these tools, Dr. Roopra and his team uncovered evidence for increased levels of EZH2 in these samples.2 In addition, when the team inhibited EZH2 activity in rodent models of acquired epilepsy, the frequency and severity of daily seizures increased significantly, suggesting that EZH2 serves to dampen seizure activity during the latent period. 2

This discovery could lead to the development of novel treatments that could potentially cure or even prevent epilepsy rather than offer only symptomatic treatment of the seizures.

Since completing his CURE-funded grant, Dr. Roopra and his co-investigators have parlayed their initial results to obtain a much larger grant from the NIH to further explore the role of EZH2 in the generation of epilepsy. CURE is proud to have played a part in propelling Dr. Roopra’s groundbreaking work to the next stage. Such success highlights the importance of funding innovative ideas that one day will lead to developing treatments with “no seizures, no side effects” for every person with epilepsy.

Literature Cited

1Lukawski, K. et al. Mechanisms of epileptogenesis and preclinical approach to antiepileptogenic therapies. Pharmacol. Rep. 2018; 70(2): 284-293.
2 Khan, N. et al. A systems approach identifies Enhancer of Zeste Homolog 2 (EZH2) as a protective factor in epilepsy. PLoS One 2019; 14(12): e0226733.
3 Casamassimi, A. et al. Transcriptome profiling in human diseases: new advances and perspectives. Int. J. Mol. Sci. 2017; 18(8): 1652.
4 Dingledine. R. et al. Transcriptional profile of hippocampal dentate granule cells in four rat epilepsy models. Sci. Data 2017; 4: 170061
5 Roopra, A. MAGIC: A tool for predicting transcription factors and cofactors driving gene sets using ENCODE data. PLoS Comput. Biol. 2020; 16(4): e1007800.


Your support makes this research possible. Our researchers’ important work continues through the current public health crisis and beyond, thanks to generous donors who, like us, envision a world without epilepsy.

A visibly pregnant woman looks at a prescription, which her doctor is handing to her.

A First Step towards Understanding Anti-Epileptic Medications with Birth Defects

A study, led by Associate Professor Piero Perucca from Monash University’s Department of Neuroscience, is the first to investigate whether antiepileptic drugs (AEDs) taken during pregnancy can increase new mutations in a baby’s genes, which were previously thought to be related to birth defects associated with the drugs.

A ‘new mutation’ is a genetic change seen for the first time in one family member. This change might have occurred in a germ cell (egg or sperm) of one of the parents, or it may have arisen in the fertilized egg during the development of the embryo.

The study, recently published in the prestigious journal Annals of Neurology, found that AEDs taken during pregnancy do not increase the number of de novo variants in the baby, irrespective of whether the baby had birth defects or not, indicating that AEDs were not a major contributor.