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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Synergistic Effects of the Neuropeptide Galanin Analog 810-2 with the Antiseizure Medication Levetiracetam (Keppra ®) in Rodent Seizure Models

Abstract found on PubMed 

Objective: The use of many antiseizure medications (ASMs) is limited due to pharmacoresistance and dose-limiting side effects, suggesting an unmet need for novel therapeutic approaches. The neuropeptide galanin reduces seizures in several preclinical seizure and seizure models but its clinical utility is limited due to rapid metabolism and poor blood-brain barrier penetration. The lead galanin analog 810-2 is systemically bioavailable and reduces seizures when administered alone. Further development of this analog, with the potential for use as an add-on therapy in patients with epilepsy, requires a better understanding of the use of this analog in combination with approved ASMs. We sought to evaluate 810-2 in combination with commonly used ASMs in rodent models of seizures.

Methods: The mouse 6 Hz seizure assay was used to test efficacy of 810-2 in combination with either levetiracetam (LEV), valproic acid (VPA), or lacosamide (LCM) using 1:1 dose ratios in isobolographic studies. Further characterization was performed for the combination of 810-2 and LEV in the mouse corneal kindling and rat 6 Hz assays.

Results: While the combination of 810-2 with VPA and LCM yielded additive interactions, the combination of 810-2 with LEV demonstrated a synergistic interaction in the mouse 6 Hz assay. Supra-additive effects were also observed in the mouse corneal kindling and rat 6 Hz assays for this combination.

Significance: The combination of the neuropeptide galanin analog 810-2 with levetiracetam suggests the potential for this galanin analog to be further developed as an add-on therapy for patients with epilepsy, particularly when co-administered with levatiracetam.

Study to Use Tracking Technology to Predict Epileptic Seizure Patterns

Article published by Mid-Tech Innovation News

A new study will use long term seizure tracking technology to monitor and potentially predict patterns in epileptic seizures using continuous data collection of brain activity in people with drug-resistant epilepsy.

The Real World Testing and Cost-effectiveness Analysis of Subcutaneous EEG (REAL-ASE) trial, which is being led by the Institute of Psychiatry, Psychology & Neuroscience (IoPPN) at King’s College London and funded by the NIHR, hopes to establish if the use of a small implant that records brain activity can improve outcomes for treatment and care.

While seizures can occur in predictable patterns, it is difficult to accurately track how often seizures occur as it relies on the person affected manually documenting their attacks in a diary. As seizures can have an amnesic effect, and can happen while a person is asleep, accurately recording these events is often not possible.

Subcutaneous implanted EEG is a new technology. Conventional EEG technology either requires the person to be admitted to hospital or be tested at home, using EEG electrodes glued to their scalp, which can be undertaken for only a few days. NHS waiting lists for these tests can vary from months to years. Subcutaneous implanted EEG, the technology being trialed in this study, enables researchers to continuously record EEG in an unobtrusive way, for up to 15 months, while the person lives their life completely normally.

The trial will recruit 33 people with drug resistant epilepsy and implant a miniaturised electroencephalogram (EEG) device just under their scalp during a minimally invasive, twenty-minute procedure that is performed under local anaesthetic. Researchers will then monitor each person’s brainwaves over six months. By tracking the brainwaves, researchers can count the person’s seizures, which enables them to provide reliable information to clinicians, as an alternative to seizure diaries.

Long Term Outcomes After New-Onset Refractory Status Epilepticus (NORSE): Treatment with Vagus Nerve Stimulation

Abstract found on Wiley Online Library

New-onset refractory status epilepticus (NORSE) is associated with high mortality, therapy resistant epilepsy (TRE) and poor cognitive and functional outcomes. Some patients develop multifocal TRE, for whom surgery with a curative intention, is not an option. In these patients, Vagus Nerve Stimulation (VNS) is performed as a palliative treatment. We report the long-term outcomes regarding seizure frequency, functional and cognitive outcome, and effectiveness of VNS in two patients with TRE as a consequence of NORSE. In the first patient with cryptogenic new-onset refractory status epilepticus, vagus nerve stimulation implantation occurred during the acute stage, probably contributing to the cessation of her status epilepticus. However, in the long-term follow-up, the patient persisted with daily multifocal seizures. In the second patient, VNS implantation was delayed to manage his epilepsy when the NORSE, ultimately due to autoimmune encephalitis, had resolved. During long-term follow-up, no reduction in seizure frequency was achieved. The current evidence supporting the use of vagus nerve stimulation in patients with therapy resistant epilepsy after new-onset refractory status epilepticus warrants further investigation.

Successful Treatment of Adult Dravet Syndrome Patients with Cenobamate (XCOPRI ®)

Abstract found on Wiley Online Library

Dravet syndrome (DS) is a rare drug resistant severe developmental and epileptic encephalopathy caused by pathogenic variants in the ? subunit of the voltage-gated sodium channel gene SCN1A. Hyperexcitability in DS results from loss of function in inhibitory interneurons. Thus, sodium channel blockers are usually contraindicated in DS patients as they may lead to disease aggravation. Cenobamate (CNB) is a novel anti-seizure-medication (ASM) with promising rates of seizure freedom in patients with focal-onset drug resistant epilepsy. CNB blocks persistent sodium currents by promoting the inactive states of sodium channels. In a multi-center study, we analyzed retrospectively the effect of an add-on therapy of CNB in adult patients with DS. We report four adult patients with DS in whom the use of CNB resulted in a significant seizure reduction of more than 80%, with a follow-up of up to 542?days. CNB was the first drug in these patients that resulted in a long-lasting and significant seizure reduction. No severe adverse events occurred. We highlight cenobamate as an antiseizure medication that may lead to a clinically meaningful reduction of seizure frequency in adult patients with Dravet syndrome. It is, however, unclear if all patients with DS benefit, requiring further investigation and functional experiments.