A Hit, a Hit-A Very Palpable Hit: Mild TBI and the Development of Epilepsy

In the United States, almost 3 million people sustain a traumatic brain injury (TBI) every year. The vast majority of these injuries are categorized as mild (?90%) and do not require hospitalization. Mild TBI is also frequently categorized as concussion, and it remains controversial as to whether, and to what extent mild TBI is a risk for the development of post-traumatic epilepsy.

It is well established, on the other hand, that severe TBI can lead to the development of a range of negative sequela in humans, including epilepsy. Moreover, the epileptogenic effects of severe TBI have been confirmed in rodents following controlled cortical impact and fluid percussion injury. In both rodent models [of PTE], a craniectomy is performed to expose the dura, and injury is induced either by a rigid impact device or hydraulically induced pressure. Both models can produce severe injuries, including neuronal loss, hemorrhage, extensive inflammatory changes, and mortality. These models have provided a wealth of data about potential epileptogenic mechanisms of severe TBI, but do not provide insight into the effects of mild TBI on epileptogenesis.

To address this gap in knowledge, Shandra and colleagues developed a closed-head model of post-traumatic epilepsy in mice following repetitive, mild TBI.

Epilepsy Research Findings: June 2019

This month’s round-up of epilepsy news features an announcement about a new antiepileptic rescue medication, NAYZILAM®. This therapy is the first FDA-approved nasal treatment option for people with epilepsy who experience episodes of frequent seizure activity.

We also highlight many research advances, from the discovery of a compound found in fruit and honey which can inhibit seizures to the development of a new drug to treat Dravet syndrome. Research in the cannabidiol (CBD) space has also advanced, with the creation of a synthetic form of CBD which may be easier to purify and does not need to be cultivated from hemp plants.

In more sobering news, reports over the past month show that one-third of epilepsy cases go without appropriate treatment for up to three years following diagnosis. In addition, people with psychogenic nonepileptic seizures (PNES) as well as epileptic seizures may be at a higher risk for sudden unexpected death in epilepsy (SUDEP)during the years immediately following diagnosis with PNES.

Summaries of all highlighted studies follow below. I’ve organized the findings into three categories: Treatment Advances, Research Discoveries, and Also Notable.

Treatment Advances

FDA Approves NAYZILAM® Nasal Spray to Treat Intermittent, Stereotypic Episodes of Frequent Seizure Activity in People Living with Epilepsy in the US
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The FDA has approved a New Drug Application for UCB’s newest antiepileptic drug NAYZILAM® (midazolam) nasal spray. This therapy is a benzodiazepine indicated for the acute treatment of intermittent, stereotypic episodes of frequent seizure activity (i.e., seizure clusters, acute repetitive seizures) distinct from a patient’s usual seizure pattern in individuals with epilepsy who are 12 years of age and older.

Study Advances More Effective Laser Ablation and Standard Epilepsy Surgery 
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In the largest study of its kind to date, researchers across 11 centers analyzed data on a relatively new minimally invasive alternative surgery for epilepsy. These researchers discovered changes that could make the procedure more effective in both laser ablation and standard surgery.

Research Discoveries

Brain Network Activity can Improve in Epilepsy Patients after Surgery
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Successful epilepsy surgery can improve brain connectivity similar to patterns seen in people without epilepsy, according to a new study published in the journal Neurosurgery. The study of 15 people with temporal lobe epilepsy is the first to show improvements in brain networks after surgery compared to a group of healthy subjects.

New Drug Could Help Treat Neonatal Seizures
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A new drug that inhibits neonatal seizures in rodent models could open new avenues for epilepsy treatment in human newborns. Researchers have found that gluconate—a small organic compound found in fruit and honey—acts as an anticonvulsant, inhibiting seizures by targeting the activity of channels that control the flow of chloride ions in and out of neonatal neurons.

Research Looks to Halt Stress-Induced Seizures Following Brain Injury
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The likelihood of developing epilepsy increases significantly with a traumatic brain injury. Stress and anxiety increase that likelihood even more dramatically. Researchers have been able to demonstrate that an injured brain responds differently to stress hormones than a healthy brain. The research team showed abnormal electrical activity in the brain tied to these stress-induced seizures and, most importantly, found a way to stop this activity from occurring.

Synthetic Version of Cannabidiol (CBD) Treats Seizures in Rats
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A synthetic, non-intoxicating analogue of CBD was found to be effective for treating seizures in rats. Researchers note the synthetic CBD alternative is easier to purify than a plant extract, eliminates the need to use agricultural land for hemp cultivation, and could avoid legal complications associated with cannabis-related products.

AZD7325 Has Seizure-Protective Effect in Mouse Model of Dravet Syndrome, Study Says
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Treatment with AZD7325, a compound that stimulates an inhibitory receptor in the brain, has a seizure-protective effect in a mouse model of Dravet syndrome. This treatment significantly increased the temperature threshold animals could withstand without experiencing any seizures during a hyperthermia-induced seizure test.

Children’s Brains Reorganize after Epilepsy Surgery to Retain Visual Perception
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Children can keep their full ability to process and understand visual information after brain surgery for severe epilepsy, according to a study funded by the National Eye Institute, part of the National Institutes of Health. This new report from a study of children who underwent epilepsy surgery and suggests that the lasting effects on visual perception can be minimal, even among children who lost tissue in the brain’s visual centers.

One-Third of Epilepsy Cases Go Untreated up to 3 Years After Diagnosis
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A small yet substantial subset of patients with newly diagnosed epilepsy go without appropriate treatment approximately 3 years after diagnosis. This gap in treatment may be increasing the risk for medical events and hospitalization in these patients.

Study Suggests ‘High Risk Period’ for SUDEP for People with Psychogenic Nonepileptic Seizures in Addition to Epileptic Seizures 
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Findings of a recently published study suggest that patients with comorbid epileptic seizures (ES) and Psychogenic Nonepileptic Seizures (PNES) can die from SUDEP and that there may be a high?risk period after the diagnosis of PNES is made. The authors state such patients should be closely monitored and provided with coordinated care of both their epilepsy and psychiatric disorder(s).

Also Notable

Fralin Biomedical Research Institute Neuroscientist Awarded Grant to Study Epilepsy
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Featuring CURE Grantee Dr. Sharon Swanger

Dr. Sharon Swanger of the Fralin Biomedical Research Institute was recently awarded a $1.7 million grant through the National Institute of Neurological Disorders and Stroke to study the role of glutamate receptors in the thalamus – an area of the brain involved in seizure generation. “If we can figure out how each [receptor] subtype functions and modulate select subtypes, then maybe we can target therapies to the circuit where the disease originated while leaving healthy circuits intact,” said Dr. Swanger.

Tool Helps GPs Predict Risk of Seizures in Pregnancy
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Doctors, midwives, and others can use a new risk calculator to identify those pregnant women at high-risk of seizures and to plan early referral for specialist input. The specialist could determine the need for close monitoring in pregnancy, labor, and after birth, and assess antiepileptic drug management, according to new research in PLOS Medicine. The study authors added that the model’s performance is unlikely to vary with the antiepilepsy drug dose management strategy – and that it could save maternal and infant lives.

Development of Epilepsy Prediction Device to Improve Independence for People with Epilepsy
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The University of Sydney’s Faculty of Engineering and Information Technologies is developing a system, NeuroSyd, which aims at real-time monitoring and processing of brain-signals while driving in a group of people living with epilepsy. NeuroSyd will be developed to deliver an early warning of the likelihood of an epileptic seizure.

Pfizer’s Lyrica at Doses 5mg and 10mg Fails Phase 3 Trial in Epilepsy
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Pfizer’s Lyrica has failed to meet its primary endpoint in a phase 3 trial in primary generalized tonic-clonic (PGTC) seizures. The study evaluated two doses of the drug – 5 mg and 10 mg – over a period of 12 weeks. Treatment with the drug did not result in a statistically significant reduction in seizure frequency versus placebo. Another phase 3 trial in May 2018 was successful, showing that a 14 mg dose of Lyrica resulted in a statistically significant reduction in seizure frequency versus placebo.

Epilepsy Research Findings: May 2019

In this month’s research news, treatments, genetic analysis, and preclinical work offer hope to those impacted by hard-to-treat or difficult-to-diagnose forms of epilepsy.

Exciting treatment developments include a positive Phase 3 clinical trial outcomefor the cannabidiol-based drug EPIDIOLEX® for the treatment of seizures associated with tuberous sclerosis complex. In addition, an improved treatment regimen targeting the severe, prolonged seizures that make up status epilepticus has been created.

In promising genetics news, a report from CURE’s own Epilepsy Genetics Initiativeunderscores the value of continued reanalysis of genetic information from people with epilepsy to increase their chances of obtaining a genetic diagnosis for their epilepsy.

Additionally, important preclinical work led by CURE Grantees Dr. Chris Dulla and Dr. Janice Naegele uncovers a potential drug to treat post-traumatic epilepsy and a way to restore the balance of brain activity and reduce seizures in temporal lobe epilepsy, respectively.

Summaries of all highlighted studies follow below. I’ve organized the findings into four categories: Treatment Advances, Diagnostic Advances, Research Discoveries, and Also Notable.

Treatment Advances

GW Pharmaceuticals Reports Reduction in Seizure Frequency for EPIDIOLEX® (cannabidiol) Oral Solution in Patients with Seizures Associated With Tuberous Sclerosis Complex
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GW Pharmaceuticals and Greenwich Biosciences announced positive top-line results of a Phase 3 clinical trial of EPIDIOLEX® (cannabidiol or CBD) in the treatment of seizures associated with Tuberous Sclerosis Complex (TSC). TSC is a rare and severe form of childhood-onset epilepsy. In this trial, EPIDIOLEX met its primary endpoint, which was a reduction in seizure frequency in the group given EPIDIOLEX compared to the placebo group.

Breakthrough for Children with Serious Epileptic Seizures
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A new treatment regimen of administering levetiracetam and phenytoin one after the other has given emergency medicine doctors a better way to treat severe, prolonged epileptic seizures in children. These treatment modifications will lower the chances of intubation and intensive care, as well as increase the chances of children recovering more quickly.

Diagnostic Advances

The Epilepsy Genetics Initiative: Systematic Reanalysis of Diagnostic Exomes Increases Yield
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Featuring CURE’s Epilepsy Genetics Initiative

Results from CURE’s Epilepsy Genetics Initiative (EGI) show that when the genetic information of a person with epilepsy is systematically reanalyzed, there is an increase in the return of a genetic diagnosis. Eight new diagnoses were made as a result of updated annotations or the discovery of novel epilepsy genes after the initial diagnostic analysis was performed. One novel epilepsy gene was discovered through dual interrogation of research and clinically generated whole-exome sequencing. According to this recently-published report, EGI’s contributions to gene discovery underscore the importance of data sharing and the value of collaborative enterprises.

Research Discoveries

Using a Drug that Mimics the Ketogenic Diet to Help Prevent Epilepsy after Traumatic Brain Injury
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Featuring the work of CURE Grantee Dr. Chris Dulla

Neuroscientists led by CURE Grantee Dr. Chris Dulla at Tufts University School of Medicine prevented the development of epileptic activity in mice after traumatic brain injury by using a drug that mimics the metabolic effects of the ketogenic diet.

Neural Stem Cell Transplantation May Reduce Abnormal Increases in New Cells in the Brains of Mice with Temporal Lobe Epilepsy
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Featuring the work of CURE Grantee Dr. Janice Naegele

According to a new, CURE-funded study featuring the work of grantee Dr. Janice Naegele, the transplantation of inhibitory cells into the brains of mice with temporal lobe epilepsy may reduce the abnormal growth of new neurons in an area of the brain called the hippocampus. This in turn could reduce brain hyperexcitability that leads to seizures.

Stimulating the Epileptic Brain Breaks Up Neural Networks to Prevent Seizures
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Responsive neurostimulation treats epilepsy by detecting seizures and intervening with a jolt of electric current. Over time, most patients find their seizures become fewer and further between. New evidence suggests responsive neurostimulation can remodel the brain to be less susceptible to seizures.

Scientists Discover Trigger Region for Absence Epileptic Seizures
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Scientists have discovered a neurological origin for absence seizures – a type of seizure characterized by very short periods of lost consciousness in which people appear to stare blankly at nothing. Using a mouse model of childhood epilepsy, a group of scientists has shown that absence epilepsy can be triggered by impaired communication between two brain regions: the cortex and the striatum.

Autism-Related Memory and Seizures Improved through Gene Repair in Adults
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Scientists have shown that correcting the protein deficiency caused by a genetic form of autism spectrum disorder in adult mice can improve behavioral and electrophysiological measures of both memory and seizure. The evidence suggests this is true even when the treatment is carried out well past what has traditionally been thought of as the critical window of early brain development.

Drug Used to Treat Multiple Sclerosis May Be Beneficial for Individuals with Epilepsy 
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A drug commonly used to treat multiple sclerosis may, after necessary modifications, one day be used to treat patients with epilepsy, according to research from the laboratory of Dr. Inna Slutsky.

Study Reveals How Glial Cells May Play Key Epilepsy Role
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A study provides potential new targets for treating epilepsy and novel fundamental insights into the relationship between neurons and their glial “helper” cells. This study reports finding a key sequence of molecular events in which the genetic mutation in a fruit fly model of epilepsy leaves neurons vulnerable to becoming hyper-activated by stress, leading to seizures.

Ketogenic Diet May Reduce Sudden Unexpected Deaths in Epilepsy, Mouse Study Suggests
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Sudden unexpected death in epilepsy (SUDEP) occurs more frequently during the early evening and is significantly prevented by prolonged use of the ketogenic diet, research in a mouse model of Dravet syndrome suggests. The reasons why this happens are unclear and should be examined in more depth by future studies, but these findings may be useful to understand why most SUDEP episodes happen at night and how certain diets can benefit people with epilepsy, especially those with Dravet syndrome, researchers say.

Attention, Behavioral Problems Common in New, Recent-Onset Juvenile Myoclonic Epilepsy
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Children with new recent-onset juvenile myoclonic epilepsy are more likely to have difficulty with executive, attention, and verbal faculties than their healthy peers and are also more likely to use a greater number of academic services, researchers found.

Also Notable

Zogenix Receives Refusal to File Letter from FDA for FINTEPLA® New Drug Application
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Zogenix announced that it received a Refusal to File letter from the FDA regarding its New Drug Application (NDA) for FINTEPLA® for the treatment of seizures associated with Dravet syndrome. Upon its preliminary review, the FDA determined that the NDA was not sufficiently complete to permit a substantive review.

CURE Discovery: Predicting Acquired Epilepsy Following a Brain Infection

A potential method of predicting who will get epilepsy following a brain infection, such as that brought on by malaria, has been discovered. This breakthrough is the result of work by two CURE grantees, Dr. Bruce Gluckman and Dr. Steven Schiff of Pennsylvania State University.

Individuals who contract cerebral malaria (malaria accompanied by a coma, typically spread by mosquitos) are at a substantially increased risk of developing epilepsy.1 Malaria is especially widespread in non-industrialized areas of the world and often affects children.2 Because malaria is so widespread, it may be the most significant cause of post-infection epilepsy in the world today. Currently, there are no methods to predict who will develop epilepsy, or any means of preventing epilepsy after such an infection.

This makes Dr. Gluckman and Dr. Schiff’s discovery so critical. Together with their team members Fatemeh Bahari and Dr. Paddy Sstentongo, they found a combination of brain and heart activity in mice that could accurately predict which animals would develop seizures and epilepsy after infection with malaria.3

Using their CURE grant, Drs. Gluckman and Schiff studied the connection between cerebral malaria and epilepsy by first developing a mouse “model” replicating malaria-induced epilepsy. In addition, they investigated possible ways to determine which mice would go on to develop epilepsy after infection.

Using the mice which developed epilepsy after infection with malaria, the research team measured two important variables often associated with epilepsy: the activity of the brain and heart. They found abnormal brain activity immediately followed by abnormal heart activity – but only in the animals which went on to develop epilepsy.

This discovery represents a possible biomarker for predicting epilepsy following infection with malaria. In other words, these may be measurable indicators to determine the infected individuals who will develop epilepsy. Furthermore, the abnormal brain and heart activity was detectable as early as 14 weeks before the first seizure, opening a potential window during which therapeutic interventions might be used to prevent epilepsy.

Drs. Gluckman and Schiff plan to continue this work, using these findings to develop treatment methods for people who contract cerebral malaria to prevent them from developing epilepsy. They are hopeful their discovery will lead to a means to eliminate not only post-malarial epilepsy, but also epilepsy caused by other types of brain injuries.

1 Ngoungou and Preux. Cerebral malaria and epilepsy. Epilepsia 2008; 49(s6):19-24.
2 World Health Organization. World malaria report 2017. http://www.who.int/malaria/publications/world-malaria-report-2017/report/en/.
3 Bahari et al. A brain-heart biomarker for epileptogenesis. J Neurosci 2018; pii: 1130-18.

Epilepsy Research Findings: December 2018

Exciting epilepsy research discoveries include two groundbreaking studies. Dr. Steven Petrou created “minibrains” using stem cells to better understand how neurons behave in children with epilepsy. Dr. Harald Sontheimer discovered the previously unknown function of perineuronal nets, which may lead to new treatments for acquired epilepsy. Both Dr. Petrou and Dr. Sontheimer are CURE grantees, and we’re thrilled to see these innovations from them beyond the work they do with us!

In diagnostic news regarding children with epilepsy, scientists are calling for parents to have their children’s genes reviewed at least every two years. This is to ensure their diagnoses and treatments are based on the latest discoveries.

Summaries of all highlighted studies follow below. I’ve organized the findings into four categories: Treatment Advances, Diagnostic Advances, Research Discoveries, and Also Notable.

Treatment Advances

Diacomit Add-On Therapy More Effective in Children with Dravet Syndrome Who Carry Pathogenic SCN1A Mutations, Study Shows

Diacomit (stiripentol) add-on therapy is more effective in children with Dravet syndrome who have pathogenic (disease-causing) SCN1A mutations than in those with variants of unknown significance and benign SCN1A mutations, a study has found.

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GW Pharmaceuticals Announces Second Positive Phase 3 Pivotal Trial for EPIDIOLEX® (Cannabidiol) Oral Solution CV in Patients with Dravet Syndrome

GW Pharmaceuticals announces positive top-line results of the second randomized, double-blind, placebo-controlled Phase 3 clinical trial of EPIDIOLEX® (cannabidiol or CBD) CV in the treatment of seizures associated with Dravet syndrome, a rare and severe form of childhood-onset epilepsy.

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Aquestive Therapeutics Announces FDA Approval for SYMPAZAN™ (clobazam) Oral Film

The FDA approved SYMPAZAN™ (clobazam) oral film for the adjunctive treatment of seizures associated with Lennox-Gastaut syndrome (LGS) in patients 2 years of age or older. SYMPAZAN is the first and only oral film FDA-approved to treat seizures associated with LGS. Previously, clobazam was marketed as ONFI® and offered in two formulations – either tablet or oral suspension.

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Diagnostic Advances

Reanalyzing Gene Tests Prompts New Diagnoses in Kids

A new study from UT Southwestern quantifies for the first time how quickly rapid advancements in genomics may benefit patients. Research published in JAMA Pediatrics includes a five-year review of more than 300 epilepsy cases showing nearly a third of children had a change in diagnosis based on new data.

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Research Discoveries

Could Lab-Grown Human Minibrains Help Treat Alzheimer’s and Epilepsy?

Featuring the work of CURE Grantee Dr. Steven Petrou

Florey Institute Director Dr. Steven Petrou leads research creating organoids to mimic the behavior of children’s brains with rare, debilitating forms of epilepsy. Replicating the way neurons behave in children with epilepsy using stem cells in a dish allowed the researchers to tailor a treatment; Petrou is on the verge of announcing a clinical trial of a gene therapy to treat one variant of the disorder.

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Scientists Solve Century-Old Neuroscience Mystery; Answers May Lead to Epilepsy Treatment

Featuring the work of CURE Grantee Dr. Harald Sontheimer

A research team led by Dr. Harald Sontheimer determined that perineuronal nets, whose function was previously unknown, modulate electrical impulses in the brain. Seizures can occur if the nets are dissolved. This discovery may lead to a potential treatment for acquired epilepsy.

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Epidemiology of Status Epilepticus in Adults: A Population-Based Study on Incidence, Causes, and Outcomes

The first population-based study using the International League Against Epilepsy 2015 definition and classification of status epilepticus found an increase of incidence of 10% compared to previous definitions. The study also provides epidemiologic evidence that different patterns of status evolution and level of consciousness have strong prognostic implications.

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Can Genetic Therapy Help Kids with Angelman Syndrome Overcome Seizures?

Scientists at the UNC School of Medicine found evidence that genetic therapy may prevent the enhanced seizure susceptibility common in children with Angelman Syndrome. The research marks the first time scientists reduced seizure susceptibility in mice by activating a dormant copy of the UBE3A gene, so it could replace the faulty mutant version.

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Also Notable

Parents and Researchers Work to Find Cause of Neonatal Epilepsy

Three US families aim to help researchers develop better treatments for neonatal-onset epilepsy with a US-wide study called Early Recognition of Genetic Epilepsy in Neonates (ERGENT). This study provides free-of-charge genetic testing to babies who have features suggestive of a genetically-caused epilepsy.

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Alzheimer’s and Epilepsy: Intimate Connections

Like people with Alzheimer’s disease, people with epilepsy can experience memory loss or confusion. As part of an aura, they may hear or see things that aren’t there. When older adults display these symptoms, they may be misdiagnosed with Alzheimer’s disease, when in fact they are having (or just had) a seizure.

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Bhanu Tewari and Harald Sontheimer

Scientists Solve Century-Old Neuroscience Mystery; Answers May Lead to Epilepsy Treatment

Featuring Work by CURE Grantee Dr. Harald Sontheimer

Scientists at the Virginia Tech Carilion Research Institute have solved a 125-year-old mystery of the brain, and, in the process, uncovered a potential treatment for acquired epilepsy.

Since 1893, scientists have known about enigmatic structures called perineuronal nets wrapped around neurons, but the function of the nets remained elusive.

Now, a research team led by Harald Sontheimer has determined the nets modulate electrical impulses in the brain. What’s more, brain seizures can occur if the nets are dissolved.

The discovery, published Friday, November 9 in Nature Communications, has implications in various forms of acquired epilepsy, a type of seizure disorder that results from brain lesions caused by trauma, infection, or tumors in the brain.

Study: Phenotypic Spectrum in Families with Mesial Temporal Lobe Epilepsy Probands

Purpose: The traditional perception of mesial temporal lobe epilepsy (MTLE) as a predominantly acquired disorder is challenged due to emerging evidence of familial aggregation. In this study, we ascertained the extent of familial occurrence of epilepsy in MTLE patients, as well as phenotypic heterogeneity in affected relatives.

Methods: We identified and reevaluated patients with MTLE, treated at Epilepsy Department for a period of two years. All eligible putatively affected relatives were asked to participate in the study. In addition to comprehensive epilepsy interview, they underwent EEG and MRI studies.

Results: 52 patients with MTLE were included; nine of them (17%) had at least one family member with epilepsy. Subsequently, we analyzed nine probands with MTLE and a total of 15 relatives with seizures. Among affected relatives, spectrums of clinical manifestations were observed. Typical MTL seizures were described in five individuals, while other types of focal or generalized tonic-clonic seizures were reported in other ten relatives. A total of seven individuals had febrile seizures. Hippocampal sclerosis was found in three probands and none of the relatives. Two of affected family members had a traumatic brain injury in addition to febrile seizures, prior to the occurrence of their epilepsy.

Conclusion: We demonstrate that familiar occurrence of epilepsy and subsequently putative genetic background, accounts for a substantial proportion MTLE patients. In addition, we foreground the remarkable intra- and interfamilial phenotypic heterogeneity than usually described, displaying the complexity of the genotype-phenotype correlations.

UC granted $1.75 million to develop potential cures for acquired epilepsy

Research scientist Jianxiong Jiang, PhD, doesn’t just want to treat acquired epilepsy…he hopes to prevent it.

“Epilepsy is a common neurological condition that afflicts nearly three million Americans and 50 to 60 million people globally. The disease is featured by epileptic seizures due to unusual hypersynchronization and hyperexcitability of a group of brain neurons,” says Jiang, an assistant professor at the University of Cincinnati (UC) James L. Winkle College of Pharmacy.

Jiang is the principal investigator on a $1.75 million grant from the National Institute of Neurological Disorders and Stroke (#R01NS100947) for a five-year preclinical study on the signaling pathways underlying the development of acquired epilepsy. Unlike the genetic forms of epilepsy, acquired epilepsy often directly results from neurological insults such as strokes, traumatic brain injuries, brain infections and brain tumors.

Jiang will track the alterations of some key inflammatory mediators within the brain in animal models and study their potential roles in the development of acquired epilepsy. Jiang says he feels confident that the goal of “no seizures, no side effects, no comorbidities” in the management of epilepsy will be ultimately achieved one day through the collaborative efforts among the epilepsy research community: “Successful completion of this study might lead to the identification of novel molecular targets for the prevention strategies of acquired epilepsy.”

Stopping Acquired Epilepsy Before It Starts? CURE Researcher Identifies a Possible Biomarker

Early intervention, in response to rising biomarker levels, could delay the onset of epilepsy, block the progression of the disease, and eliminate impairments in memory

(Chicago – February 6, 2018) New research, funded by Citizens United for Research in Epilepsy (CURE), has discovered a ‘smoking gun’ biomarker that could result in treatments that stop some epilepsies before they even start.

“Being able to identify that a person is likely to develop epilepsy following a brain injury is one of the most important focus areas in modern-day epilepsy research,” says Dr. Laura Lubbers, CURE’s Chief Scientific Officer. “With 3.4 million Americans suffering from epilepsy and seizures in the U.S., this discovery of a predictive biomarker for a certain form of epilepsy could prevent unpredictable seizures from taking over the lives of millions of Americans and their families.”

Using a rat model of brain injury and epilepsy, CURE-funded researcher Dr. Annamaria Vezzani and her team at the Mario Negri Institute for Pharmacological Research in Milan, Italy have identified that, prior to the development of epilepsy, high levels of the protein high-mobility group box 1 – also known as HMGB1 – have been found in both the brain and blood of rats. This means that high levels of the biomarker HMGB1 may predict the impending onset of epilepsy.

The CURE-funded research team also discovered that a combination of existing medications not only prevent an increase in HMGB1 levels, but delay the onset of epilepsy, halt the disease’s progression, and eliminate memory impairments associated with epilepsy.

“This discovery suggests that early intervention could slow, or potentially stop, the development of epilepsy in those at risk,” says Dr. Lubbers. “Epilepsy costs the United States approximately $15.5 billion each year, and prevention could result in ripple effects that go far beyond the millions who may receive early treatment.”

HMGB1 is normally released in the brain in response to neuroinflammation, the brain’s response to injury. Targeting the neuroinflammation that leads to increased HMGB1 with drugs that are already in clinical use could create an entirely new therapeutic area to prevent epilepsy from developing or improve its outcomes.

“With this research, Dr. Vezzani and her team have provided hope that a treatment for preventing acquired epilepsy before it occurs is on the horizon,” says CURE CEO Kate Carr. “We thank both Dr. Vezzani as well as our supporters who have made such research possible through their generous donations.”

CURE Conversations: Dr. Avtar Roopra

Get to know our researchers! CURE Conversations features interviews with our scientists and discusses the focus of their work as well as recent breakthroughs in the field of epilepsy research. These investigators are the people behind the scenes who work diligently in the labs to unravel the mysteries of epilepsy, studying the science that will one day lead to cures for the epilepsies.

Can you share some details about what you do?
I run a lab in the Department of Neuroscience at the University of Wisconsin at Madison. We study the role of genes in epilepsy and breast cancer. We focus on one master regulator of genes called REST. My lab uses computational approaches to study how large patterns of gene expression in disease can be used to predict how patients will fare. We use insights from these studies to guide experiments in mouse models of cancer and epilepsy and to test novel treatments.

What motivated you to become interested in this area of research?
I have been interested in how genes are controlled since I was a graduate student. It became clear that a key controller of many genes, REST, plays a major role in epilepsy. Later we found that it also played a role in cancer. So the lab split into two subgroups to chase both these findings. The subgroups synergize very well together, such that findings in the brain color how we look at cancer, and vice versa.

What is your current research focus?
Genes are stretches of DNA that encode information required by cells to perform certain tasks. A major focus of our lab is the study of how genes in the brain are controlled by neuronal activity. How do seizures alter the patterns of genes in neurons and how do these changes alter the brain functions after a seizure? Are there long-term alterations in gene patterns after a seizure that make the brain prone to further seizures in the future? Can this long-term alteration (a process called “epigenetics”) be controlled to prevent the development of epilepsy?

Can you share some of the latest findings?
Some epilepsies are caused by environmental factors such as a head trauma. These are acquired or evoked epilepsies. Other forms of epilepsy are caused by gene mutations and are termed genetic epilepsies. We have found that we can control seizures in both genetic and acquired epilepsies with drugs that control epigenetic processes. Whereas some work has already been published showing a role for epigenetics in acquired epilepsies, our findings with genetic epilepsies were totally unexpected, novel, and exciting.

What is the ultimate goal for the research and how will it impact patients with epilepsy?
Ultimately, it is hoped that tools will be invented that can repair or fix mutated genes and cure epilepsy. However, that goal is still far in the future. Our goal is to find ways to leave the mutations alone but use epigenetics to cover up and hide the effects of the mutation. We predict that this goal can be achieved with currently available drugs and in a much shorter time frame that genetic engineering.

What accomplishment—personal or professional—are you most proud of?
I get to hang out and speak with some of the brightest people on the planet on a daily basis. I have friends across the globe who lead their fields in the sciences and humanities. As a scientist, I have achieved the position of being paid to work on my very favorite hobby! I get to witness the uncovering and discovery of new knowledge, totally unseen to any other human in the history of mankind, everyday. As a teacher, I have altered the course of young peoples’ trajectories into science. My lab has generated findings that could change clinical practice in the fields of epilepsy and breast cancer.