Repurposed Molecules for Antiepileptogenesis: Missing an Opportunity to Prevent Epilepsy?

Prevention of epilepsy is a great unmet need. Acute central nervous system (CNS) insults such as traumatic brain injury (TBI), cerebrovascular accidents (CVA), and CNS infections account for 15%-20% of all epilepsy. Following TBI and CVA, there is a latency of days to years before epilepsy develops. This allows treatment to prevent or modify post-injury epilepsy. No such treatment exists. In animal models of acquired epilepsy, a number of medications in clinical use for diverse indications have been shown to have antiepileptogenic or disease-modifying effects, including medications with excellent side effect profiles. However, except for vigabatrin, there have been almost no translation studies to prevent or modify epilepsy using these potentially “repurposable” medications. Doctors may be missing an opportunity to develop preventive treatment for epilepsy by not evaluating these medications clinically.

One reason for the lack of translation studies is that the preclinical data for most of these medications are disparate in terms of types of injury, models within different injury type, dosing, injury – treatment initiation latencies, treatment duration, and epilepsy outcome evaluation mode and duration. This makes it difficult to compare the relative strength of antiepileptogenic evidence across the molecules, and difficult to determine which drug(s) would be the best to evaluate clinically. Furthermore, most preclinical antiepileptogenic studies lack information needed for translation, such as dose – blood level relationship, brain target engagement, and dose-response, and many use treatment parameters that cannot be applied clinically, for example, treatment initiation before or at the time of injury and dosing higher than tolerated human equivalent dosing.

Here, this research team reviews animal and human antiepileptogenic evidence for these medications. The team highlights the knowledge gaps for each molecule that need to be filled in order to consider clinical translation, and we suggest a platform of preclinical antiepileptogenesis evaluation of potentially repurposable molecules or their combinations going forward.

CURE Initiative: Defending Against Post-Traumatic Epilepsy

Post-traumatic epilepsy (PTE) is a seizure disorder resulting from injury to the brain. It is a devastating complication of traumatic brain injury (TBI), which can occur as a result of car accidents, sports-related injuries, or military combat. PTE can develop weeks, months, or even years after TBI, offering a window of opportunity for interventions to prevent seizures. Unfortunately, there is currently no way to predict who will develop epilepsy following TBI, and there are no therapies to prevent it.

CURE’s collaborative, multi-investigator PTE research program aims to develop better models to study PTE and discover methods to predict who is at risk as a way to intervene early and prevent PTE. With a $10 million grant from the US Department of Defense, this initiative brings together leading scientists in the field from around the world. This groundbreaking initiative, which launched in 2018, involves six primary investigators and their research teams for a total of over 60 scientists. To further encourage collaboration and scientific rigor, CURE has contracted with the Laboratory of Neuro Imaging (LONI) at the University of Southern California to create a database to house data from the teams and make it accessible for cross-comparison and analysis.

These teams are enhancing knowledge about PTE by researching what changes occur in the brain, as well as by developing robust animal models to study PTE. In addition, the researchers are investigating how different types of head injury can contribute to seizure onset and occurrence, and they are identifying potential EEG, MRI, or blood biomarkers to predict PTE in humans.

One exciting, ongoing PTE project is led by Dr. Jeffrey Loeb of the University of Illinois at Chicago. Dr. Loeb’s team project will focus on a type of bleeding commonly caused by TBI called subarachnoid hemorrhage. This kind of bleeding occurs when there is blood between the brain and the protective tissue surrounding the brain. By studying both rat models and in-patient instances of subarachnoid hemorrhage, Dr. Loeb’s data-driven approach will hopefully lead to methods or guidelines to help doctors take steps to prevent the development of epilepsy. Check out our recent interview with him to learn more.

We’ve also seen significant achievements over the course of the past two years. These includes a publication from Dr. Harald Sontheimer’s team at Virginia Tech University on a new mouse model for PTE,1 and a manuscript in preparation by Dr. Victoria Johnson’s team at the University of Pennsylvania on neuropathology in humans after TBI. The investigators have presented abstracts of their work at scientific meetings including the 2019 National Neurotrauma Society meeting in Pittsburgh, PA and the 2019 American Epilepsy Society Meeting in Baltimore, MD.

This collaborative, team-science approach has the potential to develop innovative ways to study PTE, build understanding of the neural mechanisms behind PTE, and ultimately help us understand who is at the greatest risk. This research can pave the way for the development of therapies to prevent and/or treat PTE, having a positive impact on the lives of all affected by TBI and PTE.

1 Shandra O., Robel S. Inducing Post-Traumatic Epilepsy in a Mouse Model of Repetitive Diffuse Traumatic Brain Injury. J Vis Exp. 2020 Feb 10;(156)

Learn More about PTE

Mike and Kim Adamle smiling as they are being interviewed for an episode of Seizing Life, a CURE podcast

Podcast: Former football star and broadcaster Mike Adamle discusses developing and managing PTE resulting from sports injuries.

Watch or Listen Now

Woman sitting at a laptop participating in a CURE webinar.

Webinar: Watch a free webinar on what triggers seizures in people who sustain traumatic brain injury.

Watch Now

Dr. Graffman being interviewed by Kelly Cervantes, CURE Board Member and Seizing Life podcast host.

Podcast: Explore the relationship between TBI and PTE, particularly in Vietnam veterans, in this Seizing Life podcast episode.

Watch or Listen Now

Woman standing in a research lab wearing a white coat with her back to the camera.

CURE Discovery: Discover the results of an innovative CURE-funded study aiming to find a way to prevent PTE.

Learn More

Epilepsy Research Findings: March 2020

This month’s research highlights feature promising work by former CURE Grantees and CURE partners.

Former CURE Grantee Dr. Kristina Simeone’s recent research has uncovered a potential predictive biomarker for Sudden Unexpected Death in Epilepsy (SUDEP). Dr. Simeone’s work was supported by the Benninghoven family in memory of Cameron Benninghoven.

We also feature research by another former CURE Grantee, Dr. Angelique Bordey, who along with her research team published exciting findings showing that targeting a particular protein in the brain can reduce or prevent seizures in mouse models of difficult-to-treat epilepsy.

We are also highlighting research by Dr. Daniel Correa and his work through the EpiBioS4Rx Public Engagement Core, a project in which CURE participates. Dr. Correa’s research indicates that greater efforts should be made to ensure online epilepsy health education materials are more easily understandable to the general population to increase epilepsy literacy.

These findings, as well as others, can be found below:

Research Discoveries & News

  • SUDEP: Research featuring the work of former CURE Grantee Dr. Kristina Simeone found a potential time-based biomarker of impending SUDEP. Dr. Simeone found cardiac and respiratory dysfunction that changed over time in mice at risk for SUDEP and may serve as a biomarker to indicate who is at risk for SUDEP. She also found that this dysfunction could be lessened by blocking a particular type of receptor in the brain, the orexin receptorLearn More

    This research was supported by the Benninghoven family in memory of Cameron Benninghoven.

  • Uncontrolled Epilepsy Treatment: Former CURE Grantee Dr. Angelique Bordey and her research team utilized an experimental drug to reduce seizures in mouse models of tuberous sclerosis complex (a rare genetic epilepsy) and a subset of focal cortical dysplasia type II (a brain malformation causing epilepsy). The team found that seizures can be prevented or reduced by targeting a protein called actin-cross linking protein filament A which is often elevated in the brains of humans with these epilepsies. Learn More
  • Online Epilepsy Education: Researcher Dr. Daniel Correa found that the majority of online health education materials related to traumatic brain injury (TBI), epilepsy, and post-traumatic epilepsy (PTE) do not meet the sixth-grade reading level recommendation from most health organizations. This study was published as part of the CURE-supported EpiBioS4Rx Public Engagement Core, an NINDS initiative focused on ensuring successful future clinical trials to prevent the development of PTE following TBI. This study suggests that improving the readability of health education materials may increase epilepsy-related health literacy, leading to more effective recruitment efforts for future clinical trials, as well as better patient-centered results. Learn More
  • New Treatment: Valtoco (diazepam), a nasal spray intended to treat seizure emergencies in patients 6 years of age and older, is now commercially available in the US. Learn More
  • Clinical Trial: Engage Therapeutics announced that its Phase 2b StATES study of Staccato® alprazolam, an orally inhaled therapy designed to terminate an active epileptic seizure, met its primary endpoint. This endpoint was a proportion of responders achieving cessation of seizure activity within two minutes of treatment administration and no recurrence within two hours. Learn More
  • Post-Traumatic Epilepsy: Research suggests that rats treated with certain drugs within a few days of a traumatic brain injury have a dramatically reduced risk of developing epilepsy later in life. Researchers found that suppressing an immune system receptor called Toll-like receptor 4 shortly after brain injury reduces seizure susceptibility and neuronal excitability in an important part of the brain called the hippocampus. Learn More
  • SCN8A Encephalopathy: A therapy that enables researchers to control gene expression in the brain, called antisense oligonucleotides (ASOs), has been utilized to stop seizures in a mouse model of SCN8A encephalopathy, a rare childhood epilepsy. By using ASOs, researchers delayed seizure activity and increased the lifespan of these mice. Learn More

The CURE Epilepsy Research Mobile App delivers research news to the palm of your hand! With frequent updates, you’ll always be in-the-know about the latest in epilepsy science. Download today. iOS | Android

Doctor wearing a white coat typing at a computer

Study Finds Need for Improved Readability of Online Health Education Materials to Improve Health Literacy Around TBI, Epilepsy and PTE

Objective: The use of the internet for health-related questions is increasing, but it is not clear whether individuals can understand the information available online. Most health organizations recommend that health educational materials (HEMs) be written below the sixth grade reading level. This study was designed to evaluate the readability level of available online HEMs pertaining to traumatic brain injury (TBI), epilepsy, and posttraumatic epilepsy (PTE).

Methods: This cross-sectional readability assessment included HEMs from TBI and epilepsy stakeholder organizations and those obtained from four internet searches. The search strategy was designed to replicate a nonmedical individual’s keyword searches. Each HEM was assessed with an online automated readability tool using three indices (Flesch Reading Ease Score, Flesch-Kincaid Grade Level, and Simple Measure of Gobbledygook). Findings were compared as a function of organization type (journalistic news or health organization), targeted medical condition (TBI, epilepsy, or PTE), or content topic (patient health education, clinical research education, or both).

Results: Readability analysis of 405 identified HEMs revealed scores above the sixth grade reading level recommendation. Only 6.2% of individual HEMs met the sixth grade recommendation. Journalistic news organizations’ HEMs had similar readability levels to health organizations’ HEMs. PTE-related HEMs required the highest readability level, >11th grade (P < .001). There were significant differences in the readability scores (P < .01 for all indices) among HEMs with information on health education, research education, or both topics. The highest required readability level (>12 grade level) was for HEMs that included both health and research education.

Significance: The majority of TBI-, epilepsy-, and PTE-related online health education materials do not meet the sixth grade reading recommendation. Improving the readability of health education materials may advance health literacy around TBI, epilepsy, and PTE, leading to more effective participant recruitment/retention strategies for future antiepileptogenesis trials in persons with TBI and perhaps better patient-centered outcomes.

Dr. Viji Santhakumar in her lab

Early Intervention Following Traumatic Brain Injury Reduces Epilepsy Risk

UC Riverside-led rat study finds an immune receptor in the hippocampus is responsible for the onset of the disease after brain injuries

A research team led by a scientist at the University of California, Riverside, has found that brain treated with certain drugs within a few days of an injury have a dramatically reduced risk of developing epilepsy later in life.

The development of epilepsy is a major clinical complication after brain injury, and the disease can often take years to appear.

“Working on rats, whose immune response system models that of humans, we identified that after brain injury a certain immune system receptor makes the brain more excitable, which promotes development of epilepsy,” said Viji Santhakumar, an associate professor of molecular, cell, and systems biology at UC Riverside and the lead author of the study that appears in the Annals of Neurobiology. “If this receptor can be suppressed, preferably within a day after injury, the future development of epilepsy can be reduced if not entirely prevented.”

The receptor in question is the Toll-like receptor 4, or TLR4, an innate immune receptor. Following a brain injury, TLR4 increases excitability in the dentate gyrus of the hippocampus, the brain structure that plays a major role in learning and memory.

“What our rat studies on traumatic brain injury show is that if we target early changes in excitability, we can alter long-term pathology,” Santhakumar said. “Blocking TLR4 signaling shortly after brain injury reduces neuronal excitability in the hippocampus and seizure susceptibility. This seizure susceptibility is not reduced if we delay the blocking of TLR4 signaling after injury.”

Paradoxically, Santhakumar’s team found that drugs such as Resatorvid, which block TLR4 in the injured brain, caused epilepsy in uninjured brains.

“This paradox is difficult to understand,” Santhakumar said. “We are currently looking at molecular signaling pathways in injured and uninjured brains to make sense of it.”

Epilepsy Research Findings: December 2019

This month, the FDA approved XCOPRI, a new medication to treat partial-onset seizures in adults. This type of seizure is often difficult to control, so we are thrilled to see this treatment advancement.

Additional promising research news includes the advancement of a method of predicting seizure risk. Also, for individuals affected by Lennox-Gastaut syndrome, a new Amazon Alexa skill offers engaging, interactive play options.

Summaries of these research discoveries and news highlights are below.

Research Discoveries & News

  • New Treatment: The FDA approved SK Lifescience’s XCOPRI (cenobamate tablets) to treat partial-onset seizures in adults. Learn More
  • Seizure Prediction: The new seizure risk assessment tool from Rice University, EpiSAT, received its first validation. The automated machine-learning algorithm correctly identified changes in seizure risk — improvement, worsening, or no change — in more than 87% of cases by analyzing seizure diaries. This prediction rate is as good or better than specialized epilepsy clinicians predicting seizure risk using patient histories. Learn More
  • New Technology: Eisai Inc. launched Ella the Jellyfish, the first Amazon Alexa skill designed for those affected by Lennox-Gastaut syndrome. This skill features capabilities such as interactive play, listening, and creative activities. Learn More
  • Status Epilepticus: New findings from a team, which included CURE Scientific Advisory Members Dr. Jaideep Kapur and Dr. Dan Lowenstein, reveal that levetiracetam (Keppra), fosphenytoin (Cerebyx), and valproate (Depakote) are equally safe and effective in treating patients with status epilepticus. Learn More
  • Post-Traumatic Epilepsy: Researchers from the University of California, Irvine (UCI) developed a cell therapy to improve memory and prevent seizures in mice following traumatic brain injury. In the study, the UCI team transplanted a cell type that can generate inhibitory brain activity into mouse brains. This process formed new connections with injured brain cells and prevented the mice from developing seizures. Learn More
  • Febrile Seizures: A study examined the cognitive functioning in children ages 4-5 who experienced febrile seizures. The research found that children with early onset of febrile seizures (especially those with recurrent febrile seizures) may be at heightened risk for poorer verbal and processing speed function, and possibly at risk for other cognitive dysfunctions. The findings suggest that these children would likely benefit from neuropediatric and neuropsychological follow-up, regardless of if they are still having febrile seizures. Learn More

Introducing the CURE Epilepsy Research Mobile App for research updates in the palm of your hand! Download today. iOS | Android

New Cell Therapy Improves Memory and Stops Seizures Following TBI

Researchers from the University of California, Irvine developed a breakthrough cell therapy to improve memory and prevent seizures in mice following traumatic brain injury. The study, titled “Transplanted interneurons improve memory precision after traumatic brain injury,” was published in Nature Communications.

Traumatic brain injuries affect 2 million Americans each year and cause cell death and inflammation in the brain. People who experience a head injury often suffer from lifelong memory loss and can develop epilepsy.

In the study, the UCI team transplanted embryonic progenitor cells capable of generating inhibitory interneurons, a specific type of nerve cell that controls the activity of brain circuits, into the brains of mice with traumatic brain injury. They targeted the hippocampus, a brain region responsible for learning and memory.

The researchers discovered that the transplanted neurons migrated into the injury where they formed new connections with the injured brain cells and thrived long term. Within a month after treatment, the mice showed signs of memory improvement, such as being able to tell the difference between a box where they had an unpleasant experience from one where they did not. They were able to do this just as well as mice that never had a brain injury. The cell transplants also prevented the mice from developing epilepsy, which affected more than half of the mice who were not treated with new interneurons.

Review Examines Advances and Limitations in Imaging Biomarkers of Post Traumatic Epilepsy

Traumatic brain injury (TBI) affects 2.5 million people annually within the United States alone, with over 300,000 severe injuries resulting in emergency room visits and hospital admissions. Severe TBI can result in long-term disability. Post traumatic epilepsy (PTE) is one of the most debilitating consequences of TBI, with an estimated incidence that ranges from 2% to 50% based on severity of injury. Conducting studies of PTE poses many challenges, because many subjects with TBI never develop epilepsy, and it can be more than 10 years after TBI before seizures begin. One of the unmet needs in the study of PTE is an accurate biomarker of epileptogenesis, or a panel of biomarkers, which could provide early insights into which TBI patients are most susceptible to PTE, providing an opportunity for prophylactic anticonvulsant therapy and enabling more efficient large-scale PTE studies. Several recent reviews have provided a comprehensive overview of this subject (Neurobiol Dis, 123, 2019, 3; Neurotherapeutics, 11, 2014, 231).

In this review, researchers describe acute and chronic imaging methods that detect biomarkers for PTE and potential mechanisms of epileptogenesis. They also describe shortcomings in current acquisition methods, analysis, and interpretation that limit ongoing investigations that may be mitigated with advancements in imaging techniques and analysis.

Dealing a Therapeutic Counterblow to Traumatic Brain Injury

A blow to the head or powerful shock wave on the battlefield can cause immediate, significant damage to a person’s skull and the tissue beneath it. But the trauma does not stop there. The impact sets off a chemical reaction in the brain that ravages neurons and the networks that supply them with nutrients and oxygen.

It is the secondary effects of traumatic brain injury (TBI), which can lead to long-term cognitive, psychological and motor system damage [as well as post-traumatic epilepsy], that piqued the interest of a team of NJIT biomedical engineers. To counter them, they are developing a therapy, to be injected at the site of the injury, which shows early indications it can protect neurons and stimulate the regrowth of blood vessels in the damaged tissue.

The challenge, researchers say, is that brain cells don’t regenerate as well as other tissues, such as bone, which may be an evolutionary strategy for preserving the synaptic connections that retain memories. To date, there is no effective treatment for restoring damaged neurons. The body’s protective mechanisms also make it difficult to penetrate the blood-brain barrier, which hampers the delivery of medications.

“Nerve cells respond to trauma by producing excessive amounts of glutamate, a neurotransmitter that under normal conditions facilitates learning and memory, but at toxic levels overexcites cells, causing them to break down. Traumatic brain injury can also result in the activation and recruitment of immune cells, which cause inflammation that can lead to short- and long-term neural deficits by damaging the structure around cells and creating a chronic inflammatory environment,” says Biplab Sarkar, a post-doctoral fellow in biomedical engineering and member of the team that presented this work at a recent American Chemical Society conference.

The team’s treatment consists of a lab-created mimic of ependymin, a protein shown to protect neurons after injury, attached to a delivery platform — a strand of short proteins called peptides, contained in a hydrogel — that was developed by Vivek Kumar, director of NJIT’s Biomaterial Drug Development, Discovery and Delivery Laboratory. After injection, the peptides in the hydrogel reassemble at the localized injury site into a nanofibrous scaffold that mimics extracellular matrix, the supporting structure for cells. These soft materials possess mechanical properties similar to brain tissue, which improves their biocompatibility. They promote rapid infiltration by a variety of stem cells which act as precursors for regeneration and may also provide a biomimetic niche to protect them.

Now in preclinical animal trials, rats injected with the hydrogel retained twice as many functioning neurons at the injury site as compared to the control group. They also formed new blood cells in the region.

“The idea is to intervene at the right time and place to minimize or reverse damage. We do this by generating new blood vessels in the area to restore oxygen exchange, which is reduced in patients with a TBI, and by creating an environment in which neurons that have been damaged in the injury are supported and can thrive,” Kumar says. “While the exact mechanism of action for these materials is currently under study, their efficacy is becoming apparent. Our results need to be expanded, however, into a better understanding of these mechanisms at the cellular level, as well as their long-term efficacy and the resulting behavioral improvements.”

Collaborators James Haorah, an associate professor of biomedical engineering, and his graduate student Xiaotang Ma at NJIT’s Center for Injury Biomechanics, Materials and Medicine have shown how a number of TBI-related chemical effects can disrupt and destroy integral brain vasculature in the blood-brain barrier, the brain’s protective border, promoting chronic inflammation that can lead to symptoms such as post-traumatic stress disorder and anxiety, among others. Their current work provides insights into the potential neuroprotective and regenerative response guided by the Kumar lab’s materials, while future studies will attempt to analyze other mediators of inflammation and blood flow in the brain.

Epilepsy Research Findings: August 2019

The past month has been filled with interesting research discoveries, including work done by CURE Grantee Dr. William Nobis and colleagues to advance our understanding of the areas of the brain that may be important in Sudden Unexpected Death in Epilepsy (SUDEP). In the field of epilepsy genetics, a large-scale study identified new epilepsy-associated genetic variants by examining the genetic make-up of more than 17,000 people with epilepsy. There is also intriguing research news looking at why cilantro, used in traditional medicine, may work to combat seizures.

Summaries of these research discoveries are below.

Plus, get epilepsy research news all month by downloading the new CURE mobile app! Find the details here.

Research Discoveries

  • SUDEP: A study featuring the work of CURE Grantee Dr. William Nobis and colleagues suggests that an area of the brain called the amygdala plays a role in dysfunctional breathing during seizures and possibly SUDEP. Learn More
  • Epilepsy Genetics: In one of the largest studies of its kind to examine the genetic make-up of individuals with epilepsy, scientists discover rare genetic variants associated with epilepsy. Learn More
  • Herbal Treatments: A study examines how the molecular action of cilantro, which is used as a traditional anticonvulsant medication, can help combat seizures. Learn More
  • Dementia and Epilepsy: Patients with dementia who are registered in the Swedish dementia registry were found to have increased rates of epilepsy. Learn More
  • Multiple Sclerosis and Epilepsy: Patients with multiple sclerosis have a higher risk of developing seizures compared with the general population. Learn More
  • SCN8A-Related Epilepsy: A study featuring the work of CURE Grantee Dr. Gemma Carvill and colleagues identified a set of neurons in the brains of mice that have a SCN8A gene mutation similar to humans that may be critical targets for therapeutic intervention. Learn More

Introducing the CURE Epilepsy Research Mobile App for research updates in the palm of your hand! Download today. iOS | Android