Neuroscientists Discover a New Drug Candidate for Treating Epilepsy

Article published by Medical Xpress

Temporal lobe epilepsy (TLE) is one of the most common types of epilepsy worldwide. Although symptomatic medications are available, one-third of TLE patients remain unresponsive to current treatment, so new drug targets are critically needed. A research team co-led by a City University of Hong Kong (CityU) neuroscientist has recently identified and developed a new drug candidate with the potential for effectively treating TLE by suppressing neuroinflammation.

A research team co-led by Dr. Geoffrey Lau Chun-yue, Assistant Professor in the CityU Department of Neuroscience, identified a new, small organic molecule called D4, whose effects the team investigated in treating TLE using a mouse model. The findings suggest that D4 strongly suppresses TLE-induced neuroinflammation, curbs TLE seizures, and increases the animal’s survival rate.

“These are very exciting and encouraging results for translational research in epilepsy,” said Dr. Lau. “We have found a very promising new drug candidate for treating epilepsy that works through a new mechanism—blocking connexin hemichannels. Our findings also highlight the important involvement of neuroinflammation in neurological disorders such as epilepsy.”

First-Line Levetiracetam (Keppra ®) Versus Enzyme-Inducing Antiseizure Medication in Glioma Patients with Epilepsy

Abstract found on Wiley Online Library

Objective: This study aimed to directly compare the effectiveness of first-line monotherapy levetiracetam (LEV) versus enzyme-inducing antiseizure medications (EIASMs) in glioma patients.

Methods: In this nationwide retrospective observational cohort study grade 2-4 glioma patients were included, with a maximum duration of follow-up of 36 months. Primary outcome was ASM treatment failure for any reason and secondary outcomes were treatment failure due to uncontrolled seizures and due to adverse effects. For estimation of the association between ASM treatment and ASM treatment failure, multivariable cause-specific cox proportional hazard models were estimated, adjusting for potential confounders.

Results: In the original cohort a total of 808 brain tumour patients with epilepsy were included, of which 109 glioma patients were prescribed first-line LEV and 183 glioma patients first-line EIASMs. The EIASMs group had a significantly higher risk of treatment failure for any reason compared to LEV (adjusted hazard ratio [aHR]=1.82 [95%CI=1.20-2.75], p=0.005). Treatment failure due to uncontrolled seizures did not differ significantly between EIASMs and LEV (aHR=1.32 [95%CI=0.78-2.25], p=0.300), but treatment failure due to adverse effects differed significantly (aHR=4.87 [95%CI=1.89-12.55], p=0.001).

Significance: In this study it was demonstrated that levetiracetam (LEV) had a significantly better effectiveness (i.e. less often ASM treatment failure for any reason or due to adverse effects) compared to enzyme-inducing anti-seizure medications (EIASMs), supporting the current neuro-oncology guideline recommendations to avoid EIASMs in glioma patients.

Parents’ Opinions About Epilepsy Surgery in Children with Epilepsy

Abstract found on PubMed

Objective: This survey aimed to investigate the opinions of the parents of children with epilepsy with regard to the application of epilepsy surgery for their children.

Methods: We surveyed all the parents of children with epilepsy referred to our neurology clinic (Shiraz University of Medical Sciences) in April-July 2022. We collected their opinions about epilepsy surgery based on a predesigned questionnaire. The inclusion criteria included parents of all children with epilepsy (1 to 16 years of age, with at least one-year history of epilepsy, and with at least one drug used in the past 12 months).

Results: In total, 472 people participated in the study; 277 participants (58.7%) were willing to have epilepsy surgery for their child; the most common reason was to be able to discontinue the drugs. Sex (male), age (younger), and education (college) of the parents had significant associations with the parental willingness to have surgery for their children. The patient’s drug regimen (polytherapy) and history of ictal injury (in the child) also had significant associations with the parental willingness to have surgery for the children.

Conclusion: Most parents of children with epilepsy are willing to have epilepsy surgery for their children if their physician presents epilepsy surgery to them as an established, safe, and effective treatment option. Patient and parental-related factors should be considered when designing educational materials and programs for preoperative counseling for the parents of children with drug-resistant seizures.

Epilepsy Research News: November 2022

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

Development of Seizures in an Animal Model of West Syndrome

A new publication that features the work of former CURE Epilepsy grantee Dr. John Swann describes the development of an animal model of West syndrome. West syndrome is characterized by infantile spasms (a type of seizure that begins in infancy) and is often accompanied by developmental delay, and hypsarrhythmia or an irregular pattern of brain waves seen on an electroencephalographic (EEG) recording. The study’s authors state that this work is the first to show the progressive development of infantile spasms on EEG, providing an animal model that might allow for an in-depth study of the role of spasm development on decreasing cognitive abilities. The authors also state that this model may be helpful in understanding why early treatment is essential for improved neurodevelopmental outcomes in children with West syndrome.

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Psychogenic Nonepileptic Seizures (PNES) Show Structural Abnormalities in Brain Scans

PNES, also known as functional seizures, have long been thought to be caused by psychological factors such as anxiety and post-traumatic stress disorder. However, a new study finds that PNES is associated with structural changes in the brain that can be seen using MRI. A team of researchers analyzed more than 650 clinical-grade MRIs, comparing images from patients with PNES to those who did not experience seizures and could have other mental health conditions, such as depression and anxiety. The results of the study revealed that patients with PNES had thinning in an area of the brain called the superior temporal cortex, which affects a person’s cognitive awareness and control of one’s actions, and thickness in an area of the brain called the left occipital cortex, responsible for the processing of visual and other sensory information. These changes were not present in people who had depression, anxiety, or obsessive-compulsive disorder. The researchers hope that by understanding changes in the brain associated with PNES, therapies can be developed to counter these changes and treat PNES.

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Creation of Data Standardization Tools for Preclinical Epilepsy Research

The International League Against Epilepsy/American Epilepsy Society Joint Translational Task Force has published a set of “tools” to improve data standardization and transparency in preclinical epilepsy research. These “tools” are known as common data elements (CDEs) which describe the important variables to be considered in the collection and reporting of epilepsy research, and case report forms (CRFs) which contain these CDEs. This work is published in a two-part series that focuses on tools to improve the standardization of omics research. Contributors to the work include numerous CURE Epilepsy advisors, grantees, and staff.

Part 1

Part 2

Epilepsy: Gene Therapy Technique Targeting Overactive Brain Cells Shows Promise in Treating Drug-Resistant Form of the Condition

Article published by The Conversation

Since epileptic seizures are caused by excessive activity of brain cells (neurons) in specific parts of the brain, being able to target these neurons and turn them off could very well prevent seizures from happening.

Using an innovative new gene therapy approach the authors developed, the authors report that they were able to show in cell and animal models that it is possible to specifically target the neurons that cause epileptic seizures. This subsequently prevented them from becoming overactive and causing seizures in the future.

This discovery not only has major implications for treating drug-resistant epilepsy, but there’s a chance it may also be used to treat other neurological conditions caused by overactive neurons, including Parkinson’s disease and migraines.

This research is published in Science.

Beyond Seizure-Freedom: Dissecting Long-Term Seizure Control after Surgical Resection for Drug Resistant Epilepsy

Abstract found on PubMed

Objective: To better understand the long-term palliative and disease-modifying effects of surgical resection beyond seizure-freedom, including frequency reduction and both late recurrence and remission, in patients with drug-resistant epilepsy.

Methods: Retrospective database-driven cohort study of all patients with > 9 years follow-up at a single high-volume epilepsy center. We included patients who underwent lobectomy, multilobar resection, or lesionectomies for drug-resistant epilepsy; we excluded patients who underwent hemispherectomies. Our main outcomes were: 1. Reduction in frequency of disabling seizures (at 6 months, each year up to 9 years postoperatively, and at last follow-up). 2. Achievement of seizure remission (>6 months, >1 year, and longest duration). 3. Seizure freedom at last follow-up.

Results: We included 251 patients; 234 (93.2%) achieved 6 months, and 232 (92.4%) experienced 1 year of seizure freedom. Of these, the average period of seizure freedom was 10.3 years. 182 (72.5%) patients were seizure-free at last follow-up (defined as > 1 year without seizures), with a median 11.9 years since remission. For patients not completely seizure-free, the mean seizure frequency reduction at each timepoint was 76.2%, and ranged from 66.6% to 85.0%. Patients decreased their number of antiseizure medications on average by 0.58, and 53 (21.2%) patients were on no antiseizure medication at last follow-up. Nearly half (47.1%) of those seizure-free at last follow-up were not seizure-free immediately postoperatively.

Significance: Patients who continue to have seizures after resection often have considerable reductions in seizure frequency, and many are able to achieve seizure freedom in a delayed manner.

Changes Impact QOL Within the Context of Seizure Outcome

Abstract found on PubMed

Purpose: Neurosurgery is an effective treatment option for pharmacoresistant epilepsy. Although post-surgical seizure freedom is considered the primary goal of epilepsy surgery, other factors that impact Quality of Life (QOL) are also important to consider, including post-surgical cognitive changes. This study aimed to examine the impact of post-surgical cognitive changes on QOL in the context of seizure outcomes.

Methods: Participants were 196 adults with focal epilepsy who underwent either frontal (n = 27) or temporal (n = 169) lobe resection. Each participant completed pre- and post-surgical neuropsychological evaluations, and cognitive composites were constructed for the following domains: language, attention/processing speed, memory, executive function, and visuospatial skill. The Quality of Life in Epilepsy (QOLIE-10) questionnaire was used to assess QOL. Seizure outcome was determined by seizure status six months post-surgery.

Results: Eighty-one percent of patients were seizure-free post-surgery and generally reported improved QOL. While a significant portion of patient’s demonstrated declines in language and verbal memory following surgery, only a decline in verbal memory was associated with worse QOL; however, this relationship was no longer significant after controlling for seizure outcome. Instead, reduced post-surgical QOL was primarily observed in those who experienced both seizure recurrence and a decline in executive function. Notably, depression was a significant covariate in all of the models.

Conclusions: The findings from this study improve our ability to counsel patients about the trade-off between cognitive decline and seizure remittance in the greater context of overall QOL. Reassuringly, it appears that QOL is improved regardless of cognitive changes when patients have good seizure outcomes. However, for those that experience a “double hit” (i.e., cognitive decline without seizure remission), post-surgical QOL may be reduced. Changes in depression also appear to play a crucial role in QOL outcomes.

Researcher Combines AI and Microelectronics to Create Neural Implants that Fight Brain Disorders

Article published by MedicalXpress

Neural implants can help treat brain disorders such as Parkinson’s disease and epilepsy by directly modulating abnormal activities—and the University of Toronto’s Xilin Liu is working with microelectronics and artificial intelligence to make this emerging technology both safer and smarter.

“Neurons talk to each other in part via electrical signals, and a therapeutic neural implant produces electrical stimulation—like a pacemaker for the brain,” says Liu, an assistant professor in the Faculty of Applied Science & Engineering. “In cases of tremors or seizures, the stimulation attempts to restore the neurons to a normal condition.

“It’s as if the stimulus turns the neural networks off and on—almost like restarting a computer, though it’s definitely not that simple. Scientists don’t fully understand how it works yet.”

Liu’s team integrates neural implants into miniature silicon chips via the same process for fabricating chips used in today’s computers and smartphones. This technology, referred to as CMOS for complementary metal-oxide semiconductor, allows them to reduce the device’s physical dimensions and power consumption, thus minimizing the risks associated with the implant’s initial surgical procedure and long-term use.

Medical Treatment in Infants and Young Children with Epilepsy: Off-Label Use of Antiseizure Medications Survey Report of ILAE Task Force Medical Therapies in Children

Abstract found on Wiley Online Library

Objective: Antiseizure medications (ASMs) remain the mainstay of epilepsy treatment. These ASMs have mainly been tested in trials in adults with epilepsy, which subsequently led to the market authorization (MA). For treatment of –especially young– children with epilepsy, several ASMs do not have a MA and guidelines are lacking, subsequently leading to “off-label” use of ASMs. Even though “off-label” ASM prescriptions for children could lead to more adverse events, it can be clinically appropriate and rational if the benefits outweigh the risks. This could be the case if “on-label” ASM, in mono- or polytherapy, fail to achieve adequate seizure control.

Methods: The Medical Therapies Task Force of the International League Against Epilepsy (ILAE) Commission for Pediatrics performed a survey to study the current treatment practices in six classic, early life epilepsy scenarios. Our aim was not only to study first- and second-line treatment preferences, but also to illustrate the use of “off-label” drugs in childhood epilepsies.

Results: Our results reveal that several ASMs (e.g. topiramate, oxcarbazepine, benzodiazepines) are prescribed “off-label” in distinct scenarios of young children with epilepsy. In addition, recent scientific guidelines were not always adopted by several survey respondents, suggesting a potential knowledge gap.

Significance: We report the relatively common use of “off-label” prescriptions that underlines the need for targeted and appropriately designed clinical trials, including younger patients, which will also result in the ability to generate evidence-based guidelines.

Epilepsy Research News: October 2022

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

Pregnant Women with Epilepsy Have More Depression and Anxiety Symptoms

A recent study that tracked pregnant women with epilepsy, pregnant women who did not have epilepsy, and women with epilepsy who were not pregnant, found pregnant women with epilepsy were more likely to have symptoms of depression and anxiety during pregnancy compared to the other two groups. Following the birth of their child, the cohort of women with epilepsy who were formerly pregnant were more likely to have symptoms of depression than either of the other groups. According to the study’s author, the results underscore the importance of regularly screening pregnant women with epilepsy for any signs of depression or anxiety and providing effective treatment.
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Women With Epilepsy Have Poorer Sleep Quality During Pregnancy

A recent study compared pregnant women with epilepsy to pregnant women without epilepsy and women with epilepsy who were not pregnant and found that pregnant women with epilepsy had worse sleep during pregnancy and postpartum than non-pregnant women with epilepsy during comparable periods. The study authors highlight that understanding the interaction between epilepsy, pregnancy, and sleep provides opportunities to improve sleep in pregnant women with epilepsy and provides the opportunity to reduce sleep-related health risks in pregnant women with epilepsy.
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Creation of a Data Platform to Combine Data from Clinical and Preclinical Models of Post Subarachnoid Hemorrhage Epilepsy

Subarachnoid hemorrhage can lead to many complications including epilepsy. A report, featuring the work of CURE Epilepsy Post-Traumatic Epilepsy (PTE) Initiative grantee Dr. Jeffrey Loeb and his laboratory, describes the creation of a web-based data platform to help researchers and clinicians understand the large number of variables related to a subarachnoid hemorrhage injury and subsequent development of epilepsy. The team hopes that this program will improve research and clinical practice for subarachnoid hemorrhage and other brain injuries.
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Bariatric Surgery Recipients May Have an Elevated Risk of Epilepsy

People who have had bariatric surgery may have an increased risk of developing epilepsy, according to a new study. Researchers examined health records from Ontario, Canada to identify people who had bariatric surgery during a six-year period. After excluding people with a history of seizures, epilepsy, psychiatric disorders, or drug or alcohol abuse, there were 16,958 people remaining who had bariatric surgery. This group was compared to 622,514 people with obesity who did not have bariatric surgery. People who had bariatric surgery had a 45% increased risk of developing epilepsy compared to people who did not have bariatric surgery. People who had a stroke after their bariatric surgery were 14 times more likely to develop epilepsy than those who did not have a stroke. The researchers stated that when considering bariatric surgery, people should talk to their doctors about the benefits and risks.
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Newly Discovered Peptide Could Prevent Seizures

A new peptide referred to as A1R-CT shows promise as an anticonvulsant in an animal model and could be explored as a treatment to prevent seizures in both epilepsy and Alzheimer’s disease. A1R-CT disrupts the signaling in the brain between the molecule neurabin and the adenosine 1 receptor (A1R). It has previously been established that when A1R is activated by adenosine, it mediates an anticonvulsant response. This response, however, can be blocked by neurabin. Using an Alzheimer’s disease mouse model with spontaneous seizures, researchers found that nasal delivery of the A1R-CT peptide reduced seizure-like activity, likely by preventing neurabin from blocking the anti-convulsant effects of A1R activation. The team’s next steps will be to optimize the peptide so it can function optimally and, perhaps one day, be used as a rescue treatment for people suffering from chronic seizures.
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