Researcher Update: February 2023

In this Researcher Update you’ll find information on:


Participation Requested in an Important Community Survey from CURE Epilepsy

As we celebrate our 25th anniversary this year, we are looking ahead to continued progress in finding cures for epilepsy. To make sure we are meeting your needs at this organizational milestone, we are conducting a community survey to inform our 5-year strategic planning process. We want to better understand your interests and needs, our organizational strengths and weaknesses, and how we can better serve and communicate with the broader epilepsy community. There are specific questions around the research that we fund where we need feedback from the epilepsy research community.

The anonymous survey takes about 15 minutes to complete, and participants who fill out the survey by March 2 will be entered into a drawing to win one of ten (10) $75 Visa gift cards as a thank-you for participating.

We appreciate you sharing your thoughts and helping ensure that CURE Epilepsy incorporates feedback from researchers and clinicians in the community.

If you have any difficulties accessing or completing the survey, please email dana.vielmetti@cureepilepsy.org.

Take Survey


Funding Opportunity for Neurotech Devices from The Center for Innovative NeuroTech Advancement (CINTA) and NeuroTech Harbor (NTH)

CINTA and NTH seek groundbreaking, collaborative projects to improve the diagnosis and treatment of disorders of the nervous system or their sequelae. The technologies proposed in applications must have a pathway to a prototype ready for first-in-human testing within four years. If successful, projects should be viable candidates for commercial development or have a viable and sustainable financial plan for rare disorders. Pre-proposals are being accepted until March 16, 2023.

Learn More


American Epilepsy Society (AES) Now Accepting Applications from Established Investigators for Three Funding Opportunities

Applications are being accepted through Thursday, March 23, 2023, for three funding mechanisms by AES to support established investigators working in basic, translational, and clinical research for epilepsy, seizures, and related disorders.

Learn More


Join Project Echo

The Epilepsy Foundation, Rare Epilepsy Network (REN), and the American Academy of Pediatrics (AAP) are launching an ECHO to increase the knowledge and skills of providers to effectively diagnose and treat rare or genetic epilepsy, Developmental & Epileptic Encephalopathies (DEEs), and epilepsy syndromes as well as their comorbidities. They are recruiting neurologists (pediatric and adult), epileptologists, trainees, pediatricians, and other health professionals to join this learning collaborative.

The ECHO will run March – June 2023 and will meet twice monthly at 1 pm CT/2 pm ET for 1-hour on alternating Wednesdays and Fridays for a total of nine sessions. To learn more, view the attached flyer here. For more information, please contact Alexis Katzenbach, ECHO Manager.

Learn More


NINDS-Sponsored Workshop on Status Epilepticus After Benzodiazepines: Seizures and Improving Long-Term Outcomes

Register now for this NINDS-sponsored workshop taking place from February 28-March 1. The recent approval of intramuscular midazolam (Seizalam®) for acute treatment of status epilepticus (SE) is an important advancement for the treatment of epilepsy. However, effective treatments that improve neuropathic outcomes after SE becomes refractory to benzodiazepines are a common unmet medical need. This virtual workshop will convene preclinical and clinical researchers, as well as other relevant stakeholders to discuss and define potential therapeutics needed to improve outcomes following SE.

Register


National Workshop on Experimental Models of Post-Traumatic Epilepsy

Register now for this free workshop taking place both in-person at Texas A&M University and via Zoom on Friday, March 10. The Texas A&M Health Institute of Pharmacology and Neurotherapeutics (IPN) is hosting an AES-sponsored National Workshop on Experimental Models of Post-Traumatic Epilepsy (PTE). The IPN team invites you and your colleagues to learn the various facets of PTE research to discover and advance therapeutic agents for this form of epilepsy. The workshop will provide insights into animal models of PTE, laboratory protocols, biomarkers, and therapeutic interventions for traumatic brain injury-induced seizures and post-traumatic epileptogenesis.

Register

Epilepsy Research News: February 2023

This issue of Epilepsy Research News includes summaries of articles on:

 

Combining Diet with Drugs to Reduce Seizures

Following a modified Atkins diet that is high in fat and low in carbohydrates in addition to taking antiseizure medication(s) may reduce seizures in people with tough-to-treat epilepsy, according to a recently published study. The study involved 160 adults and adolescents who had epilepsy for more than 10 years on average and had at least 27 seizures per month, despite trying an average of four antiseizure medications at the maximum tolerated dose. After six months, researchers found that 26% of people who used drug therapy and followed the modified Atkins diet had more than a 50% reduction in seizures, compared to only 3% of the people who had drug therapy alone. Four people in the diet group were seizure free by the end of the study, while no one in the medication-only group was seizure free. A limitation of the study is that seizures were self-reported or reported by caregivers, so some seizures may not have been reported. Despite this important consideration, “for people with drug-resistant epilepsy, or those who have been unable to find effective treatment to reduce seizures, it’s encouraging to see that there are lifestyle changes that can be combined with standard drug therapy to reduce the number of seizures,” stated a study author.

Learn More

 

Parents Need Guidance Managing Sleep Issues in Children with Epilepsy

According to a new qualitative study that included interviews with nine mothers, sleep and epilepsy have a complex and bidirectional relationship. The aim of the study was to capture parental perceptions and experiences related to their child’s sleep habits and management, the impact of sleep difficulties on the child and their family, and available support. According to the study, epilepsy exacerbated the struggle to initiate sleep (settling and falling asleep), maintenance of sleep (experiencing night or early morning wakings), duration of sleep, daytime sleepiness, and sleep anxiety. Study authors noted that mothers were aware of the links between sleep and seizures yet felt that they lacked guidance about how to address or improve their child’s sleep, including from their healthcare teams. The authors also stated that the finding emphasizes the need to ensure adequate help is available to support healthy sleep in children with epilepsy.

Learn More

 

New Understanding of the Cause of Post-Traumatic Epilepsy (PTE)

A research team has uncovered information about changes that occur in the brain following a traumatic brain injury (TBI) that could help advance future preventative treatments for PTE, a type of epilepsy caused by a TBI. The findings show that activation of a subset of neurons within an area of the brain called the hippocampus plays a key role in the changes that occur during the development of PTE. For this study, the team looked at neurons called dentate granule cells, which continuously regenerate in areas of the brain that are crucial for learning and memory and are also commonly impacted by epilepsy. The team found that when the dentate granule cells were activated, the activity of other brain cells involved in epilepsy was inhibited. They also found that the cells that were formed just prior to a were much more likely to activate this circuit than those generated at other points in time. The team noted that being able to get to a point of understanding the changes that occur in the development of epilepsy may lead to the ability to prevent or reverse epilepsy.

Learn More

 

Links Between Parental Factors, Emotional, and Behavioral Issues Found in Pediatric Epilepsy

Adolescents with epilepsy commonly experience emotional and behavioral problems, which vary depending on demographic, clinical, and parental factors, according to a new study. The parental factors included how parents perceived that others treated their child. The study included 289 adolescents aged between 11 and 18 years. The study found 18.3% of adolescents with epilepsy had at least one emotional or behavioral problem in the clinical range. Additionally, consistent with findings of prior studies, this study showed one in four parents of adolescents with epilepsy perceived that other people felt uncomfortable with their child, treated their child as inferior, or preferred to avoid their child because of their epilepsy. Due to these findings, the study’s authors emphasized it is crucial to identify and properly manage these problems early to decrease comorbid psychopathology in adolescents with epilepsy.

Learn More

 

Use of Newer Antiseizure Medications for Epilepsy Differs by Race, Ethnicity

Racial and ethnic minority groups are less likely to be taking newer-generation antiseizure medications for their epilepsy, an analysis of Medicaid data showed. Compared with white patients, Black, Hispanic, and Native Hawaiian/Pacific Islander patients had lower odds of being on newer antiseizure medications, the study found. Of note, taking a second-generation antiseizure medication was associated with better treatment adherence, and those seeing a neurologist had higher odds of being on newer antiseizure medications. The study authors stated that being on a newer, second and third-generation antiseizure medication may represent an important marker of quality of care for people with epilepsy and that differences appear to reflect racial and ethnic inequities in epilepsy care.

Learn More

New Research Reveals Clues About the Development of Epilepsy 

Article published by Medical Xpress

Traumatic brain injury is a leading cause of epilepsy, a chronic neurological disorder characterized by recurrent seizures that affects around 50 million people. A research team led by Bret Smith, professor and head of the Department of Biomedical Sciences, discovered specific neuronal processes that could help advance future preventative treatments for post-traumatic epilepsy. 

The findings, published in The Journal of Neuroscience, show that activation of a subset of hippocampal neurons plays a key role in the changes that occur during the development of post-traumatic epilepsy and may be restorative. 

“We know that trauma induces a cascade of events that can cause epilepsy,” says Smith. “We want to understand exactly what is occurring, and what the endpoints are, and then work backwards to try and stop epilepsy from developing after a brain injury.”

Neuroscience research in Smith’s lab focuses on two distinct programs; one is aimed at identifying neural changes related to the development of epilepsy, which the team has created leading models in the field to study, and the other examines how the brain is influenced by and contributes to hyperglycemia in diabetes.

For this study, Smith’s team looked at neurons called dentate granule cells, which continuously regenerate in areas of the brain that are crucial for learning and memory and are also commonly impacted by epilepsy. The team was surprised to find that when they were activated, the activity of other brain cells involved in epilepsy were inhibited. And that the cells that were formed just prior to a traumatic brain injury were much more likely to activate this circuit than those generated at other points in time.

CURE Epilepsy Grantee Announcement Fall 2022

CURE Epilepsy is honored to announce our newest CURE Epilepsy grantees. Our research grants are awarded for cutting-edge, novel research projects that seek to accelerate treatments, improve outcomes, and get us to cures so that we can live in a world free of seizures. This year’s grantees’ research will focus on a wide range of epilepsies – sudden unexpected death in epilepsy (SUDEP), sleep and epilepsy, genetic causes of epilepsy, Lafora disease, post-traumatic epilepsy, pediatric epilepsy, and focal epilepsy.

TAKING FLIGHT AWARD GRANTEES – $100,000 for one year 

This award seeks to promote the careers of early-career epilepsy investigators to allow them to develop a research focus independent of their mentor(s).

Jeffrey Calhoun, PhD
Northwestern University – Chicago, Illinois

With this grant, funded by the Joseph Gomoll Foundation, Dr. Calhoun’s research will work to develop a new method to assess the functionality of variants of the SCN1A gene.
Learn More

William Tobin, PhD
The University of Vermont and State Agriculture  – Burlington, Vermont

With a grant co-funded by the KCNT1 Epilepsy Foundation, Dr. Tobin will test strategies to optimize cutting-edge gene therapy methods for the gene KCNT1.
Learn More

Gerben van Hameren, PhD
Dalhousie University– Nova Scotia, Canada

Dr. van Hameren will study a possible way to prevent the development of post-traumatic epilepsy.
Learn More

_________________

CURE EPILEPSY AWARD GRANTEES – $250,000 over two years  

This award reflects CURE Epilepsy’s continued focus on scientific advances that have the potential to truly transform the lives of those affected by epilepsy, with prevention and disease modification as critical goals.

Gordon Buchanan, MD, PhD
University of Iowa Medicine – Iowa City, Iowa

For this grant, generously funded by The Joanna Sophia Foundation, Dr. Buchanan’s group will examine whether a signaling molecule called serotonin drives a time-of-day vulnerability to SUDEP (Sudden Unexpected Death in Epilepsy).
Learn More

Annaelle Devergnas, PhD
Emory University – Atlanta, Georgia

The hypothesis for Dr. Devergnas’ project is that frontal seizures disrupt the normal function of the brain structure called the pedunculopontine nucleus (PPN), leading to changes in sleep, and that manipulating PPN activity might restore normal sleep activity.
Learn More

Juliet Knowles, MD, PhD
Stanford School of Medicine – Palo Alto, California

For this project, Dr. Knowles and her team will study the therapeutic potential for targeting myelin plasticity in Lennox-Gastaut syndrome.
Learn More

_________________

CATALYST AWARD GRANTEES – $250,000 over two years 

The CURE Epilepsy Catalyst Award stimulates and accelerates the development of new, transformative therapies for epilepsy, moving promising preclinical and/or clinical research closer to clinical application.

James Pauly, PhD, Greg Gerhardt, PhD, and Matthew Gentry, PhD
University of Kentucky – Lexington, Kentucky

In collaboration with Enable Therapeutics, Drs. PaulyGerhardt, and Gentry developed a potential drug called VAL-1221 that can penetrate brain cells and degrade the aberrant sugar aggregates therein that cause LaFora disease. Having obtained promising initial results, this project will test the safety and brain distribution of this novel therapy.
Learn More

John Gledhill, PhD
Cognizance Biomarkers, LLC  – Philadelphia, Pennsylvania

Dr. Gledhill and the team at Cognizance will build upon their preliminary research showing that people with treatment-resistant epilepsy have differences in inflammation-associated proteins in the blood compared with those who do respond to treatment. For this project, the team proposes to extend their observations by assessing additional blood samples from treatment-resistant and treatment-responsive people with epilepsy and developing an algorithm to predict response to initial anti-seizure medications.
Learn More

Incidence and Risk Factors of Posttraumatic Epilepsy Following Pediatric Traumatic Brain Injury: A Systematic Review and Meta-Analysis

Abstract found on Wiley Online Library

Posttraumatic epilepsy (PTE) is a well-known chronic complication following traumatic brain injury (TBI). Despite some evidence that age at the time of injury may influence the likelihood of PTE, the incidence of PTE in pediatric populations remains unclear. We, therefore, conducted a systematic review to determine the overall reported incidence of PTE, and explore potential risk factors associated with PTE after pediatric TBI. A comprehensive literature search of the PubMed, Embase, and Web of Science databases was conducted, including randomized controlled trials and cohort studies assessing the incidence of PTE in TBI pediatric patients. We excluded studies with a sample size of <10 patients and those in which a pediatric cohort was not clearly discernable. The review was conducted in accordance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. We found that the overall incidence of PTE following pediatric TBI was 10% (95% confidence interval [CI] = 5.9%–15%). Subgroup analysis of a small number of studies demonstrated that the occurrence of early seizures (cumulative incidence ratio [CIR] = 7.28, 95% CI = 1.09–48.4, p =?.040), severe TBI (CIR = 1.81, 95% CI = 1.23–2.67, p <?.001), and intracranial hemorrhage (CIR = 1.60, 95% CI = 1.06–2.40, p =?.024) increased the risk of PTE in this population. Other factors, including male sex and neurosurgical intervention, were nonsignificantly associated with a higher incidence of PTE. In conclusion, PTE is a significant chronic complication following childhood TBI, similar to in the adult population. Further standardized investigation into clinical risk factors and management guidelines is warranted.

Modification of Post-Traumatic Epilepsy by Fecal Microbiota Transfer

Abstract found on PubMed

It has been well established that traumatic brain injury (TBI) modifies the composition of gut microbiome. Epilepsy, which represents one of the common sequelae of TBI, has been associated with dysbiosis. Earlier study showed that the risk of post-traumatic epilepsy (PTE) after lateral fluid percussion injury (LFPI) in rats can be stratified based on pre-existing (i.e., pre-TBI) gut microbiome profile. In the present study, we examined whether fecal microbiota transfer (FMT) from naïve rats with different prospective histories of PTE would affect the trajectory of PTE in recipients. Fecal samples were collected from naïve adult male Sprague-Dawley rats, followed by LFPI. Seven months later, upon four weeks of vide-EEG monitoring (vEEG), the rats were categorized as those with and without PTE. Recipients were subjected to LFPI, followed by FMT from donors with and without impending PTE. Control groups included auto-FMT and no-FMT subjects. Seven month after LFPI, recipients underwent four-week vEEG to detect spontaneous seizures. After completing vEEG, rats of all groups underwent kindling of basolateral amygdala. Fecal microbiota transfer from donors with impending PTE exerted mild-to-moderate pro-epileptic effects in recipients, evident as marginal increase in multiple spontaneous seizure incidence, and facilitation of kindling. Analysis of fecal samples in selected recipients and their respective donors confirmed that FMT modified microbiota in recipients along the donors’ lines, albeit without full microbiome conversion. The findings provide further evidence that gut microbiome may actively modulate the susceptibility to epilepsy.

Neuroscientists Create Maps of the Brain After Traumatic Brain Injury

Article found on Science Daily

Every year in the United States, nearly two million Americans sustain a traumatic brain injury (TBI). Survivors can live with lifelong physical, cognitive and emotional disabilities. Currently, there are no treatments.

One of the biggest challenges for neuroscientists has been to fully understand how a TBI alters the cross-talk between different cells and brain regions.

In the new study, researchers improved upon a process called iDISCO, which uses solvents to make biological samples transparent. The process leaves behind a fully intact brain that can be illuminated with lasers and imaged in 3D with specialized microscopes.

The researchers focused on connections to inhibitory neurons, because these neurons are extremely vulnerable to dying after a brain injury. The team first looked at the hippocampus, a brain region responsible for learning and memory. Then, they investigated the prefrontal cortex, a brain region that works together with hippocampus. In both cases, the imaging showed that inhibitory neurons gain many more connections from neighboring nerve cells after TBI, but they become disconnected from the rest of the brain.

To get a closer look at the damaged brain connections, the research team devised a technique for reversing the clearing procedure and probing the brain with traditional anatomical approaches.

The findings surprisingly showed that the long projections of distant nerve cells were still present in the damaged brain, but they no longer formed connections with inhibitory neurons.

The researchers then wanted to determine if it was possible for inhibitory neurons to be reconnected with distant brain regions. To find out, the research team transplanted new interneurons into the damaged hippocampus and mapped their connections, based on the team’s earlier research demonstrating interneuron transplantation can improve memory and stop seizures in mice with TBI.

The new neurons received appropriate connections from all over the brain. While this may mean it could be possible to entice the injured brain to repair these lost connections on its own, the researcher said learning how transplanted interneurons integrate into damaged brain circuits is essential for any future attempt to use these cells for brain repair.

“Our study is a very important addition to our understanding of how inhibitory progenitors can one day be used therapeutically for the treatment of TBI, epilepsy or other brain disorders,” said the researcher.

Hippocampal Position and Orientation as Prognostic Biomarkers for Post-Traumatic Epileptogenesis – an Experimental Study in Rat Lateral Fluid-Percussion Model

Abstract found on Wiley Online Library

Objective: To identify prognostic biomarkers for post-traumatic epileptogenesis derived from parameters related to the hippocampal position and orientation.

Methods: Data was derived from two pre-clinical magnetic resonance imaging (MRI) follow-up studies: EPITARGET (156 rats) and EpiBioS4Rx (UEF Cohort 43 rats). Epileptogenesis was induced with lateral fluid-percussion induced traumatic brain injury (TBI) in adult male Spraque-Dawley rats. In the EPITARGET cohort, ??2T2?-weighted MRI was performed at 2 d, 7 d and 21 d and in the EpiBioS4Rx cohort at 2 d, 9 d, 30 d, and 5 months post-TBI. Both hippocampi were segmented using convolutional neural networks. The extracted segmentation mask was used for a geometric construction, extracting 39 parameters that described the position and orientation of the left and right hippocampus. In each cohort, we assessed the parameters as prognostic biomarkers for post-traumatic epilepsy (PTE) both individually, using repeated measure ANOVA, as well as in combination using random forest classifiers.

Results: The extracted parameters were highly effective in discriminating between sham-operated and TBI rats in both the EPITARGET and EpiBioS4Rx cohorts at all timepoints (t) (balanced accuracy > 0.9). The most discriminating parameter was the inclination of the hippocampus ipsilateral to the lesion at ?=2t=2 d and the volumes at ??7t?7 d after TBI. Furthermore, in the EpiBioS4Rx cohort, we could effectively discriminate epileptogenic vs. non-epileptogenic animals with a longer MRI follow-up, at ?=150t=150 d (AUC 0.78, balanced accuracy 0.80, p=0.0050), based on the orientation of both hippocampi. We found that the ipsilateral hippocampus rotated outward on the horizontal plane, while the contralateral hippocampus rotated away from the vertical direction.

Significance: We demonstrate that assessment of TBI-induced hippocampal deformation by clinically translatable MRI methodologies detects subjects with prior TBI as well as those at high-risk of PTE, paving the way towards subject stratification for antiepileptogenesis studies.

CURE Epilepsy Discovery: Preventing Post-Traumatic Epilepsy May be Possible by Inhibiting Two Inflammation-Based Signaling Pathways

Key Points:

  • For his CURE Epilepsy “Prevention of Acquired Epilepsies” grant, Dr. Xiaoming Jin and his team sought to understand the role of two related signaling pathways called TLR4 and RAGE, in the development of post-traumatic epilepsy (PTE) following brain injury in mice [1-3].
  • The team found that inhibiting either of these two inflammatory pathways soon after injury decreased seizure susceptibility as well as frequency.
  • In addition, inhibiting these pathways changed the levels of three types of brain cells, improving neuron survival and reducing brain tissue scarring.
  • These results suggest that inhibiting either of these inflammatory pathways may impede the development of PTE. 

 


Deep Dive:

Post-traumatic epilepsy (PTE) is one of the most devasting consequences of a traumatic brain injury (TBI). Depending on the severity of the injury, anywhere from 5% to 53% of people with TBI may develop PTE [1,4,5], and, unfortunately, PTE is often resistant to currently available antiseizure medications. Importantly, there is often a span of time between the injury and the onset of epilepsy, known as the “latent period,” during which treatments could be initiated to either reduce the chance of or completely prevent PTE [1,6].

One potential cause of PTE is inflammation in the brain. In hopes of preventing PTE or decreasing the  probability of it developing, researchers are working to understand the role of inflammation in the brain as a means to prevent PTE. The inflammatory process is regulated by “parent” proteins that, when activated, bind to target receptors to subsequently activate downstream signaling pathways. One of these “parent” proteins is known as HMGB1, and two of its receptor partner systems are TLR4 and RAGE [7]. All three of these proteins have been implicated in development of seizures, a process called epileptogenesis [8,9]. With funding from CURE Epilepsy, Dr. Jin and his team at the Stark Neurosciences Institute of the Indiana University School of Medicine sought to determine if these proteins also played a role in PTE and whether inhibiting these pathways could represent an approach for reducing the likelihood of epileptogenesis and PTE following TBI [10].

To test their hypothesis, the researchers first confirmed that the expression of HMGB1, RAGE, and TLR4 increased in three types of brain cells (neurons [“regular” nerve cells], astrocytes, and microglia) in their PTE mouse model [3,10] soon after injury. After completing this initial experiment, the team evaluated the ability of inhibitors of TLR4 or RAGE to lower seizure susceptibility and frequency in their PTE mice.  

For TLR4, they used the drug TAK242 (also known as resatorvid), a substance that has previously been employed by other researchers to prevent epileptogenesis in a different rodent model of PTE [11]. For RAGE, the researchers used an antibody (mAb) specifically designed in the laboratory to bind to the RAGE protein (RAGE mAb) and inhibit its signaling pathway. The team found that when either substance (TAK242 or RAGE mAb) was administered to mice one week after injury, the treated PTE mice were less prone to having tonic-clonic seizures and remained seizure-free for a longer period of time [10]. 

To provide additional evidence for the role of RAGE signaling in PTE, the researchers used mice in which RAGE had been genetically deleted (“RAGE knockout mice”). Data revealed that the RAGE knockout mice exhibited a higher threshold of seizure susceptibility and a longer period of seizure freedom after a TBI than their control counterparts.

The fact that similar results were obtained from two different, but complementary, types of experiments (pharmacological and genetic) provide corroboration for the critical roles that RAGE and TLR4 play in the onset of PTE. 

Once Dr. Jin’s team demonstrated that inhibiting TLR4 or RAGE seemed to have therapeutic value, they sought to understand what would happen at the cellular level when these two pathways were pharmacologically inhibited in their PTE model. Mice that were treated with either TAK242 or RAGE mAb one week after injury lost fewer neurons compared to those that were not treated with one of the two substances. Along with neurons, the team examined astrocytes and microglia. These cells mediate a process known as gliosis, a type of nonspecific scarring of brain tissue generated in response to brain damage that can lead to drug-resistant seizures [12]. Analogous to the results with neurons, there was much less gliosis in treated versus untreated PTE mice.  

Research to assess what happens in the brain after TBI is crucial to discovering possible therapeutic options to prevent epilepsy from developing. Data from Dr. Jin’s lab further validate the roles of HMGB1, its receptors TLR4 and RAGE, and their downstream inflammatory pathways in the PTE process itself, including cellular level changes, and how blocking either of these pathways may one day prevent PTE.

 

Literature Cited:

  1. Golub, V.M. & Reddy, D.S. Post-traumatic epilepsy and comorbidities: advanced models, molecular mechanisms, biomarkers, and novel therapeutic interventions. Pharmacol. Rev. 2022; 74(2): 387-438.
  2. Pitkänen, A. & McIntosh, T.K. Animal models of post-traumatic epilepsy. J. Neurotrauma 2006; 23(2): 241-261.
  3. Ping, X. & Jin, X. Chronic posttraumatic epilepsy following neocortical undercut lesion in mice. PLoS One 2016; 11(6): e0158231.
  4. Frey, L.C. Epidemiology of posttraumatic epilepsy: a critical review. Epilepsia 2003; 44(s10):11-17.
  5. Lowenstein, D.H. Epilepsy after head injury: an overview. Epilepsia 2009; 50(Suppl. 2): 4-9.
  6. Dulla, C.G. & Pitkänen, A. Novel approaches to prevent epileptogenesis after traumatic brain injury. Neurotherapeutics 2021; 18(3): 1582-1601.
  7. Yang, H. et al. Targeting inflammation driven by HMGB1. Front. Immunol. 2020; 11: 484.
  8. Friedman, A. and Dingledine, R. Molecular cascades that mediate the influence of inflammation on epilepsy. Epilepsia 2011; 52(Suppl 3): 33-39.
  9. Maroso, M. et al. Toll-like receptor 4 and high-mobility group box-1 are involved in ictogenesis and can be targeted to reduce seizures. Nat. Med. 2010; 16(4): 413-419.
  10. Ping, X. et al. Blocking receptor for advanced glycation end products (RAGE) or toll-like receptor 4 (TLR4) prevents posttraumatic epileptogenesis in mice. Epilepsia 2021; 62(12): 3105-3116.
  11. Zhang, D. et al. TLR4 inhibitor resatorvid provides neuroprotection in experimental traumatic brain injury: implication in the treatment of human brain injury. Neurochem. Int. 2014; 75: 11-18.
  12. Losi, G., Cammarota, M. & Carmignoto, G. The role of astroglia in the epileptic brain. Front. Pharmacol. 2012; 3(132): 1-13.

Epilepsy Research News: April 2022

This month in Epilepsy Research News, we highlight an interesting study of 39 products containing cannabidiol (CBD), such as beverages and oils, which found that the majority were inaccurately labeled. Next, we share the announcement of the first FDA-approved drug, Ztalmy®, to treat seizures for CDLK5 deficiency disorder (CDD), a rare epilepsy caused by mutations in the CDKL5 gene, in children two years of age and older.

In pediatrics news, we share a study that found that pediatric patients with drug-resistant epilepsy that received vagus nerve stimulation and antiseizure medications (ASMs), had lower hospital costs compared to those using ASM alone. Additionally, another study found that assessing the number of days that children are minimally impacted by seizures may be a more appropriate method of evaluating severe childhood epilepsies than measuring seizure frequency alone when determining a patient’s quality of life.

Switching gears, we report on the development of a system that uses specialized sound waves to release medication into specific areas of the brain to stop seizure activity. Finally, a group of researchers reports the development of an animal model of post-traumatic epilepsy (PTE) that has spontaneous seizures after traumatic brain injury as well as behavioral disturbances which can occur in people with PTE.

Summaries of the above mentioned information follow below.

Inaccuracy of Non-Prescription Cannabidiol (CBD) Product Labeling: An analysis of 39 products containing CBD (a non-intoxicating substance found in the cannabis sativa plant) finds that most of these products were inaccurately labeled, and in fact, may contain measurable amounts of THC (an intoxicating substance found in cannabis sativa). The study analyzed the contents of CBD-infused beverages, oils, and other products, including chocolate bars, honey, coconut oil, transdermal patches, and more. Of these products, only 15.4 percent were accurately labeled. Unreliable labeling raises concerns about potential exposure to unwanted substances like THC and inconsistent exposure to CBD if used for medicinal purposes. Learn more

FDA Approves Ztalmy® (Ganaxolone) for CDLK5 Deficiency Disorder (CDD): The FDA has approved a new therapy to treat seizures for CDD, a rare epilepsy caused by mutations in the CDKL5 gene. The drug, Ztalmy (ganaxolone), manufactured by Marinus Pharmaceuticals, is now approved to treat seizures associated with CDD in patients 2 years of age and older. This medication is the first FDA-approved treatment specifically for CDD. It is expected to be available for patients in July 2022. Learn more

Vagus Nerve Stimulation (VNS) Lowers Costs of Care for Children with Uncontrolled Epilepsy: A new study examined a population of pediatric patients with drug-resistant epilepsy and found that the patients who received VNS, when used with antiseizure medications (ASM), had lower hospital costs compared to the use of ASMs alone. Vagus nerve stimulators are implantable devices that send mild electrical pulses to the brain by stimulating the vagus nerve.  The researchers note that these results are important because they show lower costs to the health care system following VNS surgery. Learn more

Measuring Quality of Life in Children with Epilepsy: Researchers have found that assessing the days children are minimally impacted by seizures may be a more appropriate method of evaluating severe childhood epilepsies than measuring seizure frequency alone when determining quality of life. The researchers worked with patient advocacy organizations and developed a questionnaire that was distributed to primary caregivers of children with developmental and epileptic encephalopathies (DEEs), a group of severe epilepsies that often have a genetic basis. The researchers found that quality of life scores were strongly associated with the number of days minimally disrupted by seizures rather than seizure frequency alone, an often-used measure of quality of life. These results suggest the need to re-evaluate how disease severity is measured in DEEs. Learn more

Development of Drug Delivery System to Control Seizures: Researchers have developed a system that uses specialized sound waves to release medication into specific areas of the brain to stop seizure activity. So far, the researchers have tested the system in a laboratory setting but envision creating a device that could be triggered by a person when they have an aura before the onset of a seizure, or automatically by a system that detects seizure activity beginning in the brain, activating the release of the drug to stop the seizure from developing. Though the researchers note that further studies are necessary to determine the utility and safety of the technology in humans, they state that this novel new way of delivering drugs could be an effective solution, and a life-changer for some patients with epilepsy. Learn more

Development of an Animal Model of Post-Traumatic Epilepsy (PTE): A team of researchers have created a novel animal model that has spontaneous recurrent seizures after brain injury, similar to the spontaneous recurrent seizures that occur in humans who develop epilepsy following a traumatic brain injury, a type of epilepsy called PTE. In addition to changes in brain activity, the team also found changes in the animals’ behavior and degeneration of neurons in the brain. The team states that this model provides a vital tool to further understand PTE and can be used to test medical treatments to prevent seizures and other neuropsychiatric conditions in military personnel. Learn more