Microglia Proliferation Plays Distinct Roles in Acquired Epilepsy Depending on Disease Stages

Featuring the work of CURE Epilepsy PTE Initiative Members Dr. Annamaria Vezzani, Dr. Teresa Ravizza and Rossella Di Sapia

Abstract, originally published in Epilepsia

Objective: Microgliosis occurs in animal models of acquired epilepsy and in patients. It includes cell proliferation that is associated with seizure frequency and decreased neuronal cells in human epilepsy. The role of microglia proliferation in the development of acquired epilepsy is unknown; thus, we examined its contribution to spontaneous seizure, neurodegeneration, and cognitive deficits in different disease phases.

Methods: We used a model of acquired epilepsy triggered by intra-amygdala kainic acid in C57BL6N adult male mice. Mice were electroencephalographically (EEG) monitored (24/7) during status epilepticus and in early and chronic disease. Microglia proliferation was blocked by GW2580, a selective CSF1 receptor inhibitor, supplemented in the diet for 21 days from status epilepticus onset. Then, mice were returned to placebo diet until experiment completion. Control mice were exposed to status epilepticus and fed with placebo diet. Experimental mice were tested in the novel object recognition test (NORT) and in Barnes maze, and compared to control and sham mice. At the end of the behavioral test, mice were killed for brain histopathological analysis. Additionally, seizure baseline was monitored in chronic epileptic mice, then mice were fed for 14 days with GW2580 or placebo diet under 24/7 EEG recording.

Results: GW2580 prevented microglia proliferation in mice undergoing epilepsy, whereas it did not affect microglia or basal excitatory neurotransmission in the hippocampus of naive mice. Mice with occluded microglia proliferation during early disease development underwent status epilepticus and subsequent epilepsy similar to placebo diet mice, and were similarly impaired in NORT, with improvement in Barnes maze. GW2580-treated mice displayed neuroprotection in the hippocampus. In contrast, blockade of microglia proliferation in chronic epileptic mice resulted in spontaneous seizure reduction versus placebo mice.

Significance: Microglia proliferation during early disease contributes to neurodegeneration, whereas in late chronic disease it contributes to seizures. Timely pharmacological interference with microglia proliferation may offer a potential target for improving disease outcomes.

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

Study Compares Drug Treatment for Epilepsies Caused by Two Infectious Agents

Seizures are often caused by infectious agents that have invaded the brain and formed cysts, visible as circular lesions on medical imaging scans. These lesions cause victims to develop epilepsy. Two common infectious agents are a tapeworm, which causes neurocysticercosis, and a bacterium, which causes tuberculosis. Although antiepileptic drugs are used to treat both types of epilepsy, the duration of this treatment is still debated.

To resolve the debate, the incidence of seizure recurrence in patients with neurocysticerosis versus tuberculosis were compared. Results revealed that those with neurocystericosis are much more prone to seizures than are those with tuberculosis. Indeed, antiepileptic drugs can be tapered off in those with tuberculosis after 18 months with a low risk of recurrence.