News Topics: Acquired Epilepsies

CURE Epilepsy Discovery: Strides Made in the Understanding of Acquired Epilepsies by CURE Epilepsy Grantees

Key Points:

  • An acquired epilepsy can occur as a result of brain infection, tumor, or injury leading to spontaneous seizures.
  • Little is known about the mechanisms underlying epileptogenesis, the process by which the brain starts generating seizures following an insult or injury.
  • CURE Epilepsy grantee Dr. Annamaria Vezzani at the Mario Negri Institute for Pharmacological Research in Milan has made strides understanding the process of neuroinflammation as it relates to epileptogenesis in acquired epilepsy.
  • Her work on a molecule known as High Mobility Group Box 1 (HMGB1) gives clues as to a potential blood-based biomarker of epileptogenesis and pharmacoresistance (failure to respond to at least two anti-seizure medications (ASMs)).
  • Vezzani’s mentee and continued colleague, Dr. Teresa Ravizza, has also been funded by CURE Epilepsy and continues to drive research to understand the biological mechanisms of acquired epilepsy.

 

Deep Dive

Epilepsy (also referred to as a “seizure disorder”) is a group of conditions characterized by recurrent seizures. Epilepsy can be the result of many different underlying causes including through “acquired” physical injury, infection, brain tumor, or stroke.[1] In acquired epilepsy, spontaneous seizures start after the injury or insult to the brain has occurred. The process by which the brain starts generating seizures after a brain injury or insult is called epileptogenesis. Currently, there is no way to predict who will experience epileptogenesis, and there are no treatments that can prevent or halt epileptogenesis. If there was a way to know that epileptogenesis is taking place or predict who is at risk for it, it might be possible to gain valuable insights into treating and even preventing seizures.

CURE Epilepsy has awarded numerous grants to investigators examining diverse aspects of acquired epilepsies. A few examples of discoveries funded by CURE Epilepsy include Dr. Bruce Gluckman and Dr. Steven Schiff’s development of preclinical models to predict acquired epilepsy following a brain infection, Dr. Gerben van Hameren’s work looking at a particular part of the cell called the mitochondria as a target for post-traumatic epilepsy (PTE), and Dr. Asla Pitkanen’s work that aims to study changes in gene expression in brain tissue in a preclinical model of traumatic brain injury (TBI).

A subset of acquired epilepsies is called PTE, which develops in the months or years following a TBI.[2] TBI may be caused by blows to the head, blasts, penetrating head injuries, accidental falls, sports-related injuries, or motor vehicle accidents. It is currently not possible to predict who will develop PTE after a TBI.[3] Dr. Annamaria Vezzani, head of the Laboratory of Epilepsy and Therapeutic Strategies, Department of Acute Brain Injury at the Mario Negri Institute for Pharmacological Research in Milan, has been an important part of CURE Epilepsy’s efforts to understand acquired epilepsies for decades as an early (2002) and repeat (2015) grantee, and more recently, as part of the PTE Initiative. Dr. Vezzani’s work centers on the role of inflammation in epilepsy. Her work looks at neuroinflammation (i.e., the inflammatory response that is sustained by cells in the brain after insult or injury) and has shown that neuroinflammation can play an important role in the generation of seizures.[4] Through a study funded by CURE Epilepsy, Dr. Vezzani first studied a specific signaling pathway in the brain called interleukin-1 (IL-1) type 1 receptor/Toll-like receptor (IL-1R/TLR4). Her experiments in experimental animals showed that IL-1beta and an inflammatory molecule known as High Mobility Group Box 1 (HMGB1) are released from specific brain cells known as “glia” during seizures.[5] The levels of HMGB1 increased in the brain and the blood before animals developed epilepsy, and this increase in HMGB1 levels was maintained during the development of epilepsy.[6,7] These results gave her precise biological mechanisms that could be targeted to stop seizures.

In addition to showing that HMGB1 is closely involved with seizures, Dr. Vezzani’s work also showed that during an injury or seizures, HMGB1 moves from the nucleus to the cytoplasm of a cell, and this form of HMGB1 can also be measured in blood.[5,8,9,10] More specifically, Dr. Vezzani showed that there is a form of HMGB1 (the disulfide isoform of HMGB1) that contributes to seizures [11]; this finding may inform development of targeted therapeutic strategies. What makes this discovery on HMGB1 particularly exciting for the epilepsy community is its numerous applications: this work could lead to the development of novel drugs to target and halt epileptogenesis, and could also be a way to stop seizures once they have started. As a biomarker, increased levels of HMGB1 could be a sign that epilepsy is about to develop.[10,11] Dr. Vezzani’s work also found that a combination of anti-oxidant drugs that are already used in medical practice is capable of preventing the increase in HMGB1 and delaying the onset of seizures, as well as reducing seizure burden and the memory impairments that are seen in epilepsy.[7]

The role of HMGB1 has also been studied in people with epilepsy. Patients with epilepsy whose seizures were not adequately controlled by ASMs were found to have higher levels of HMGB1 when compared to those who responded to ASMs, and people who did not have epilepsy. Therefore, this work is evidence that HMGB1 can distinguish, with a high level of accuracy, those who respond to ASMs versus those who do not. This adds to the evidence that suggests that HMGB1 can be used as a biomarker for predicting how someone will respond to ASMs.[12] Dr. Vezzani’s more recent CURE Epilepsy-funded work looks at HMGB1 as a target and a mechanistic biomarker of epileptogenesis. HMGB1 is also being studied in people who have experienced TBI as a part of CURE Epilepsy’s PTE Initiative, which funded a diverse group of researchers, including Dr. Vezzani, to develop experimental models to study PTE and discover prediction methods to enable early intervention and eventual prevention.

In addition to her impact and contribution to epilepsy research, Dr. Vezzani is also passionate about mentorship and has guided many mentees who are now established epilepsy researchers in their own right. One of her mentees, Dr. Teresa Ravizza, also at the Mario Negri Institute for Pharmacological Research, received a Taking Flight Award from CURE Epilepsy in 2011. As part of her project, Dr. Ravizza focused on specific cells in the brain known as “astrocytes” and the role of these cells in acquired epilepsies.[13] She also looked at the mechanisms that may contribute to the breakdown of the blood-brain barrier, a network of cells that keep harmful substances from reaching the brain, as previous studies had shown that activation of inflammatory astrocytes along with a breakdown in the blood-brain barrier leads to the generation and sustaining of seizures.[14] Dr. Ravizza’s work hypothesized that the development of epileptogenesis followed by spontaneous seizures is dependent on the extent, duration, and location of blood-brain barrier breakdown. By using a host of techniques, including visualizing the brain by magnetic resonance imaging (MRI), studying the electrical activity of brain circuits, and looking at the behavior of animals, Dr. Ravizza examined whether blood-brain barrier breakdown and glia activation may predict the development of spontaneous seizures and cognitive deficits. Preliminary data support this hypothesis, suggesting that information obtained from these experiments may one day help predict the trajectory of seizures and serve as an effective therapeutic strategy for acquired epilepsies.

Drs. Vezzani and Ravizza continue their work to study neuroinflammation and the underlying mechanisms that may contribute to epileptogenesis. Their work is instrumental not only to understand why and how the brain generates and sustains seizures, but also to discover biomarkers that could predict if someone will have seizures, or how they may respond to a drug. The ultimate hope is that this work with CURE Epilepsy will lead to the ability to prevent or cure acquired epilepsies.

 

 

Literature Cited:

  1. Epilepsy. Available at: https://www.who.int/en/news-room/fact-sheets/detail/epilepsy. Accessed May 2.
  2. Verellen RM, Cavazos JE. Post-traumatic epilepsy: an overview. Therapy. 2010;7:527-531.
  3. Annegers JF, Coan SP. The risks of epilepsy after traumatic brain injury Seizure. 2000 Oct;9:453-457.
  4. Vezzani A, Aronica E, Mazarati A, Pittman QJ. Epilepsy and brain inflammation Exp Neurol. 2013 Jun;244:11-21.
  5. Maroso M, Balosso S, Ravizza T, Liu J, Bianchi ME, Vezzani A. Interleukin-1 type 1 receptor/Toll-like receptor signalling in epilepsy: the importance of IL-1beta and high-mobility group box 1 J Intern Med. 2011 Oct;270:319-326.
  6. Walker LE, Frigerio F, Ravizza T, Ricci E, Tse K, Jenkins RE, et al. Molecular isoforms of high-mobility group box 1 are mechanistic biomarkers for epilepsy J Clin Invest. 2017 Jun 1;127:2118-2132.
  7. Terrone G, Pauletti A, Pascente R, Vezzani A. Preventing epileptogenesis: A realistic goal? Pharmacol Res. 2016 Aug;110:96-100.
  8. Iori V, Maroso M, Rizzi M, Iyer AM, Vertemara R, Carli M, et al. Receptor for Advanced Glycation Endproducts is upregulated in temporal lobe epilepsy and contributes to experimental seizures Neurobiol Dis. 2013 Oct;58:102-114.
  9. Choi J, Min HJ, Shin JS. Increased levels of HMGB1 and pro-inflammatory cytokines in children with febrile seizures J Neuroinflammation. 2011 Oct 11;8:135.
  10. Pauletti A, Terrone G, Shekh-Ahmad T, Salamone A, Ravizza T, Rizzi M, et al. Targeting oxidative stress improves disease outcomes in a rat model of acquired epilepsy Brain. 2019 Jul 1;142:e39.
  11. Ravizza T, Terrone G, Salamone A, Frigerio F, Balosso S, Antoine DJ, et al. High Mobility Group Box 1 is a novel pathogenic factor and a mechanistic biomarker for epilepsy Brain Behav Immun. 2018 Aug;72:14-21.
  12. Walker LE, Sills GJ, Jorgensen A, Alapirtti T, Peltola J, Brodie MJ, et al. High-mobility group box 1 as a predictive biomarker for drug-resistant epilepsy: A proof-of-concept study Epilepsia. 2022 Jan;63:e1-e6.
  13. Vezzani A, Ravizza T, Bedner P, Aronica E, Steinhäuser C, Boison D. Astrocytes in the initiation and progression of epilepsy Nat Rev Neurol. 2022 Dec;18:707-722.
  14. Vila Verde D, de Curtis M, Librizzi L. Seizure-Induced Acute Glial Activation in the in vitro Isolated Guinea Pig Brain Front Neurol. 2021;12:607603.

Epilepsy Research News: May 2023

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

 

Epilepsy with Eyelid Myoclonia (EEM)

A newly published article, written by a steering committee convened by CURE Epilepsy, provides a comprehensive review of the characteristics of EEM, also known as Jeavons syndrome. EEM is a type of epilepsy?that occurs in childhood, with seizures often continuing into adulthood. It is more common in females and its hallmark traits consist of eyelid myoclonia (brief jerks of the eyelids) with or without absence seizures, eye closure-induced seizures, and photosensitivity. Individuals with EEM are often misdiagnosed and anti-seizure medication resistance is common, highlighting the need for further studies to understand more about this epilepsy and possible interventions to treat it.  

Learn More

 

A Computer Model of Epilepsy Brain Used in Clinical Trial for Epilepsy Surgery

Scientists in France are looking at how a computer model of the brain can improve the localization of the seizure zone before epilepsy surgery. The models are created using the Virtual Epileptic Patient (VEP), which employs brain scans and brainwave-recording data from individuals with epilepsy to build a personalized model to improve the understanding of where their seizures originate. The study authors said that VEP showed a 60% precision in identifying the epileptogenic zones in 53 patients with drug-resistant focal epilepsy. VEP is being evaluated in an ongoing clinical trial called EPINOV. If the trial results are promising, this computer model may become a new, personalized tool used in epilepsy surgical evaluations to improve surgical outcomes.  

Learn More

 

Worsened Perinatal Outcomes in Women with Epilepsy

Recently published findings showed that women with epilepsy have worse perinatal outcomes compared with women without epilepsy, including a 5-fold increase in the odds of maternal death. Combining the results of 76 already-published papers, investigators found that relative to women without epilepsy, those with epilepsy had increased odds of gestational hypertension, preeclampsia, intrauterine growth restriction, miscarriage, preterm birth, induced labor, stillbirth, cesarean delivery, and maternal death. “When counseling pregnant women with epilepsy and those of childbearing age, clinicians should consider these findings,” a lead investigator concluded. “In addition, clinicians and women with epilepsy should bear in mind the increased odds of negative adverse maternal and neonatal outcomes.”  

Learn More

 

Early-Life Meningitis Associated with Risk of Developing Epilepsy in Later Childhood

Infants exposed to invasive Group B Streptococcus (iGBS) meningitis during their first three months of life could have a greater risk of developing epilepsy in later childhood compared to infants who were not exposed, according to a recent study. Investigators evaluated the cumulative risk (CR) of an infant diagnosed with iGBS sepsis or meningitis during the first three months of age developing epilepsy. Examining a group of 1,432 children with iGBS and 14,211 without iGBS, the team found that the overall CR of developing epilepsy into later childhood was 3.6% among children with iGBS disease, whereas the CR of later-adulthood epilepsy was 2.3% in the group without iGBS. The study authors noted that the data have implications for affected individuals and underline the need for better long-term follow-up and care. 

Learn More

Patients With Late-Onset Psychogenic Non-Epileptic Seizures (PNES): How Do They Compare to Those With Younger Onset?

Abstract, originally published in Seizure

Objective: To determine whether patients who experienced their first psychogenic non-epileptic seizure (PNES) at 50 years or older differed from those who developed PNES at a younger age, in terms of demographic, social/clinical as well as psychological measures.

Background: The typical age for PNES onset is roughly between 20 and 40 years of age. Only a handful of studies have examined samples with PNES onset at an older age and therefore information about these individuals is limited.

Methods: This is a retrospective study of 75 consecutive individuals who developed (video EEG-confirmed diagnosis) PNES before age 50 years and 55 consecutive individuals who developed PNES at 50 years or more. Patients were examined on demographics (age, education, working and relationship status), clinical (seizure frequency, trauma type: sexual, multiple trauma, and health-related traumatic experiences), and self-report measures(Coping Inventory for Stressful Situations, Toronto Alexithymia Scale, and the Quality of Life Inventory in Epilepsy-31).

Results: Patients who had experienced sexual trauma were likelier to develop PNES at an earlier age. Those who experienced “health problems pre-PNES onset” were likelier to develop PNES at an older age. On psychological measures, it was noted that after adjusting for the covariate effects, those with elevations in Avoidance (CISS) were likelier to develop PNES at an earlier age. and those with elevations in QOLIE31 cognitive complaints were likelier to be in the older cohort.

Conclusions: No matter at what age PNES presented, patients reported markedly high rates of exposure to psychological trauma (single and multiple), similarly elevated unemployment rates and low quality of life. The groups with different age of onset differed in the type of trauma experienced prior to the development of PNES. In addition, the younger onset group demonstrated a significantly higher use of avoidance as a stress-coping strategy.

Effects of Double-Dose Statin Therapy for the Prevention of Post-Stroke Epilepsy: A Prospective Clinical Study

Abstract, originally published in Seizure

Background: To determine treatment effects on the incidence of post-stroke epilepsy (PSE) using different doses of statin, a prospective hospital-based cohort study was designed to explore whether a double-dose statin treatment can better prevent the occurrence of PSE.

Methods: A total of 1152 patients with newly diagnosed ischemic stroke admitted to our hospital from March to August 2017 were selected, 1033 of whom were followed-up. Patients were divided into two treatment groups:(1) standard-dose (20 mg atorvastatin or 10 mg rosuvastatin, daily oral; 788 patients); and (2) double-dose (40 mg atorvastatin or 20 mg rosuvastatin, daily oral; 245 patients). At 18 months follow-up was conducted to compare the incidence of PSE between groups.

Results: In general, in the standard-dose group we observed two cases of early seizure (ES) (0.25%), 22 cases of late seizure (LS) (2.79%) and 20 cases of PSE (2.54%). In the double-dose group, one patient had ES (0.41%), two patients had LS (0.82%), and one patient had PSE (0.41%). The incidence of PSE was significantly lower in the double-dose group as compared to the standard-dose group. There was a higher proportion of PSE in patients younger than 65 years and in males. Three patients had ES; one presented with focal aware seizure (FAS), and two had focal to bilateral tonic-clonic seizure (FBTCS). Among the 21 patients with PSE, there were two cases of FAS, five cases of focal impaired awareness seizure (FIAS), five cases of FBTCS, and nine cases of GTCS, suggesting that partial seizure is the most common type of PSE. Cerebral cortex was involved in 85.75% of cases with PSE, and multiple lobes were involved in 61.9% of cases with PSE.

Conclusion: Increasing the dose of statin treatment during the acute phase of ischemic stroke reduces the incidence of post-stroke epilepsy. Further research is needed to understand the mechanisms underlying the potential preventative effects of statins against post-stroke epilepsy.

Determinants of Caregiver Burden in Male Patients with Epilepsy Following Penetrating Traumatic Brain Injury

Abstract, originally published in Epilepsy & Behavior

Purpose: We determined burden of caring for patients with post-traumatic epilepsy (PTE) following penetrating traumatic brain injury (TBI) and identified factors predicting higher burden.

Method: We assessed 331 caregiver-veteran dyads in Phase 2 (136 PTE, 136 non-PTE, and 59 HC dyads), 133 in Phase 4 (47 PTE, 56 non-PTE, and 30 HC dyads) – 30 years later, and 46 dyads in the follow-up study (18 PTE, 19 non-PTE, and 9 HC). Caregiver’s burden was measured by Zarit Burden Index and a questionnaire. Veterans completed demographic, mental and physical well-being, quality-of-life, and medical-related information. Caregivers provided information about burden and their assessments of cognitive decline and neuropsychiatric status of the veterans.

Results: PTE caregivers perceived significantly more burden than comparison groups at all phases. Bivariate analyses revealed that caregiver distress due to the veteran’s neuropsychiatric state including cognitive decline, apathy, and disinhibition and the veteran’s characteristics including older age at epilepsy onset and role limitation due to physical problems were associated with higher burden. Finally, we revealed disinhibition distress, and role imitation due to physical problems as the predictors in a model of caregiver burden.

Conclusion: Elevated PTE caregiver burden is persistent across the life span suggesting that caregivers could benefit from counseling and targeted psychosocial interventions to reduce their burden.

Preventing Seizures After Brain Injury Could Stave Off Dementia

Summary, originally published by the University of Alberta

Blocking seizures after a head injury could slow or prevent the onset of dementia, according to new research by University of Alberta biologists.

“Traumatic brain injury is a major risk factor for dementia, but the reason this is the case has remained mysterious,” said Ted Allison, co-author and professor in the Department of Biological Sciences in the Faculty of Science. “Through this research, we have discovered one important way they are linked—namely, post-injury seizures.”

“Our data suggest that, at least in animal models, blocking these seizures also could have a benefit later in life by slowing or preventing the onset of dementia,” he explained. “A prophylactic treatment to prevent dementia is an exciting possibility, though there is much work to be done to develop our concept.”

Late-Onset Epilepsy Tied to a Threefold Increased Dementia Risk

Literature review, originally published on Neurology Reviews

Late-onset epilepsy is linked to a substantial increased risk of subsequent dementia. Results of a retrospective analysis show that patients who develop epilepsy at age 67 or older have a threefold increased risk of subsequent dementia versus their counterparts without epilepsy.

“This is an exciting area, as we are finding that just as the risk of seizures is increased in neurodegenerative diseases, the risk of dementia is increased after late-onset epilepsy and seizures,” study investigator Emily L. Johnson, MD, assistant professor of neurology at Johns Hopkins University, Baltimore, said in an interview. “Several other cohort studies are finding similar results, including the Veterans’ Health Study and the Framingham Study,” she added.

The researchers found that of 9,033 study participants, 671 had late-onset epilepsy. The late-onset epilepsy group was older at baseline (56.5 vs. 55.1 years) and more likely to have hypertension (38.9% vs. 33.3%), diabetes (16.1% vs. 9.6%), and two alleles of APOE4 genotype (3.9% vs. 2.5%), compared with those without the disorder.

In all, 1,687 participants developed dementia during follow-up. The rate of incident dementia was 41.6% in participants with late-onset epilepsy and 16.8% in participants without late-onset epilepsy. The adjusted hazard ratio of subsequent dementia in participants with late-onset epilepsy versus those without the disorder was 3.05 (95% confidence interval, 2.65-3.51).

New CURE-Funded Research Projects to Drive Science Forward

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

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

Catalyst Award Grantee
$250,000 for two years

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

Detlev Boison, PhDDetlev Boison, PhD
Rutgers University

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

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

Learn More

Taking Flight Award Grantee
$100,000 for one year

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

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

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

Learn More

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

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

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

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

Learn More

Two doctors, a man and a woman, in blue scrubs look at a brain scan.

CURE Discovery: Inhibition of an Important Brain Enzyme Attenuates the Development of Epilepsy

In his CURE-funded research, Dr. Detlev Boison and his team found that an adenosine kinase inhibitor called 5-ITU increases adenosine levels in the brain, protecting it from seizures.

Key Points

Dr. Detlev Boison

  • CURE Grantee Dr. Detlev Boison and his team discovered that short-term use of a substance called 5-ITU prevents epilepsy from developing in mouse models of acquired epilepsy.
  • 5-ITU inhibits a brain enzyme called adenosine kinase (ADK) that regulates a substance called adenosine (ADO), which, in turn, plays a critical role in preventing epilepsy following an injury to the brain.
  • Dr. Boison’s groundbreaking work supports the development of improved, more selective treatments which aim to cure underlying causes of epilepsy, rather than merely control seizures.

Deep Dive

A graphic which illustrates the relationship between adenosine and adenosine kisase.One of the most common ways of developing epilepsy is through “acquired” means, such as a severe concussion, brain infection, fever-induced seizure, or stroke. A naturally occurring substance in the brain, called adenosine (ADO), plays a protective role by decreasing excessive neuronal activity1,2 and protecting the DNA in nerve cells from changes that contribute to the development of epilepsy.3 ADO levels in the brain are regulated by an enzyme called adenosine kinase (ADK) and, unfortunately, brain injuries often trigger a series of events that elevate levels of ADK. In his CURE-funded research, Dr. Detlev Boison and his team found that an ADK inhibitor called 5-ITU increases ADO levels in the brain and protects it from seizures.

To make this discovery, the team evaluated if short-term treatment of 5-ITU following an injury to the brain could halt the development of epilepsy over the long-term.4 To do so, they used a mouse model of acquired epilepsy that reliably develops seizures two weeks after an injury. The team first had to determine the appropriate time points to administer 5-ITU following a head injury. Over a two-week period, the team monitored the progression of brain tissue damage in their mouse model, along with ADK levels and changes in EEG, analyzing samples at different days post-injury compared to controls. The team found that by the third day, ADK levels had started to increase and continued to increase over the two-week time period, accompanied by a loss of neurons in an area of the brain called the hippocampus and changes in EEG patterns by the fourteenth day post-injury.

Reasoning that 5-ITU should first be administered when ADK levels initially rise, the team gave their mouse model the substance for a limited time – for only five days starting on day 3 post-injury – and continued to monitor the mice closely. After six weeks, the team found that the 5-ITU-treated mice had little brain tissue damage, significantly decreased ADK levels, and fewer seizures compared to the control group. Importantly, these changes were sustained even after nine weeks.

Discovering that short-term inhibition of ADK leads to a long-lasting antiepileptogenic effect makes this a promising therapy, especially since it could avoid any potential toxicities and intolerable side effects from long-term use of ADK inhibitors. Such a treatment would represent a true cure for epilepsy. Dr. Boison’s groundbreaking research supports the development of improved, more selective compounds which can one day be tested in clinical trials and, hopefully, approved for clinical use.

Dr. Boison’s Research Continues

For more than 20 years CURE has been on an unrelenting mission to end epilepsy. We have funded more than 240 grants in 15 countries to better understand the causes of epilepsy, uncover new therapies, and cure epilepsy once and for all. Now it is time to take those research findings one step further.

We are thrilled to expand our current research approach with the CURE Catalyst award, and to name Dr. Boison the first grantee under this new mechanism. This grant funds translational research, where findings from basic research studies are “translated” into the next phase of research to prepare potential new treatments for clinical trials. You can learn about the continuation of Dr. Boison’s work here.

1 Fedele, D.E. et al. Engineering embryonic stem cell derived glia for adenosine delivery. Neurosci. Lett. 2004; 370(2-3) 160-165.
2 Guttinger, M. et al. Suppression of kindled seizures by paracrine adenosine release from stem cell-derived brain implants. Epilepsia 2005 46(8): 1162-1169.
3 Williams-Karnesky, R.L. et al. Epigenetic changes induced by adenosine augmentation therapy prevent epilpetogenesis. J. Clin. Invest. 2013; 123(8): 3552-3563
4 Sandau, U.S. et al. Transient use of a systemic adenosine kinase inhibitor attenuates epilepsy development in mice. Epilepsia 2019; 60: 615-625.

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

Epilepsy Research Findings: April 2020

Research findings reported over the past month include advances in our understanding of an area of the brain that may contribute to Sudden Unexpected Death in Epilepsy (SUDEP) in children, as well as intriguing discoveries about autoantibody-induced epilepsy. In addition, scientists are turning to plants to identify novel anti-seizure drugs (ASDs) for novel anti-seizure medications. Finally, we spotlight a development for a model of the NeuroPace responsive neurostimulator (RNS®), which will broaden its availability as a treatment option, and strike a precautionary note about the effectiveness of multiple epilepsy surgeries.

Summaries of these research discoveries and news highlights are below.

Research Discoveries & News

  • SUDEP in Children: A specific area of the brain called the amygdala may play a role in causing children to stop breathing during a seizure. The findings could have important implications for predicting, treating, and/or preventing SUDEP in children. Learn More
  • Immune System and Epilepsy: In some people with epilepsy, an autoantibody (an antibody that attacks a person’s own body instead of a disease-causing agent) appears to “sneak” into neurons in an area of the brain called the hippocampus, leading to inflammation and then seizures. This study also suggests that it may be possible to prevent these types of seizures with immunosuppressant drugs. Learn More
  • Novel Anti-Seizure Drugs (ASDs): Extracts made from magnolia bark, a plant used in traditional Chinese medicine as an anti-seizure remedy, reduced seizures in both zebrafish and mouse models of epilepsy, according to a recent study. The researchers state the isolated compound, magnolol, may serve as a starting point for the development of improved treatments for drug-resistant epilepsy. Learn More
  • RNS Device: The NeuroPace RNS system, model RNS-320, received FDA approval for use with magnetic resonance imaging (MRI) machines. This approval means that epilepsy patients who require MRI monitoring can now be offered this model of the RNS as a treatment option as appropriate. Learn More
  • Neurosurgery: For patients with drug-resistant epilepsy who undergo multiple neurosurgeries, the likelihood of long-term seizure control decreases with each attempt, according to this study. Learn More