Perampanel (FYCOMPA®) as Precision Therapy in Rare Genetic Epilepsies

Abstract found on

Objective: Perampanel, an antiseizure drug with AMPA-receptor antagonist properties, may have a targeted effect in genetic epilepsies with overwhelming glutamate receptor activation. Special interest holds epilepsies with loss of GABA inhibition (e.g. SCN1A), overactive excitatory neurons (e.g. SCN2A, SCN8A ), and variants in glutamate receptors (e.g. GRIN2A). We aimed to collect data from a large rare genetic epilepsy cohort treated with perampanel, to detect possible subgroups with high efficacy.

Methods: A multicenter project based on the framework of NETRE (Network for Therapy in Rare Epilepsies), a web of pediatric neurologists treating rare epilepsies. Retrospective data from patients with genetic epilepsies treated with perampanel was collected. Outcome measures were responder rate (50% seizure reduction), and percentage of seizure reduction after 3 months of treatment. Subgroups of etiologies with high efficacy were identified.

Results: 137 patients, with 79 different etiologies, aged 2 months-61?years (mean 15.48±9.9) were enrolled. The mean dosage was 6.45±2.47 mg, and treatment period was 2.0±1.78?years (1.5 months-8?years). 62 patients (44.9%) were treated for >2?years. 98 patients (71%) were responders, and 93 (67.4%) chose to continue therapy. The mean reduction in seizure frequency was 56.61±34.36%. 60 patients (43.5%) sustained over 75% reduction in seizure frequency, including 38 (27.5%) with >?90% reduction in seizure frequency. The following genes showed high treatment efficacy: SCN1A, GNAO1, PIGA, PCDH19, SYNGAP1, POLG1, POLG2, NEU1. 11/17 (64.7%) of patients with SCN1A, 35.3% of which had over 90% seizure reduction. Other etiologies remarkable for over 90% reduction in seizures were GNAO1 and PIGA. 14 patients had a CSWS EEG pattern and in 6 subjects perampanel reduced epileptiform activity.

Significance: Perampanel demonstrated high safety and efficacy in patients with rare genetic epilepsies, especially in SCN1A, GNAO1, PIGA, PCDH19, SYNGAP1, CDKL5, NEU1 and POLG, suggesting a targeted effect related to glutamate transmission.

Virtual Tool for Treating Epilepsy

Article published by

Researchers from the Human Brain Project (HBP) have developed advanced brain modelling methods that could help doctors more reliably identify where epileptic seizures start in the brain and consequently improve surgical prognoses. Achieved with support from the EU-funded HBP SGA3 project, this personalised brain modelling approach is described in a research article published in ‘Science Translational Medicine’. In about one third of people with epilepsy, medicines are mostly or even completely ineffective in controlling seizures. For this group of patients, surgical removal of the epileptogenic zone – the part of the brain where the seizures originate – is the only potentially effective treatment. However, despite the increasing use of invasive explorations in the last two decades, prognoses have improved only modestly. Currently, surgery has a 60 % success rate.

To construct and simulate personalised brain network models, the research team used an open-source platform called The Virtual Brain (TVB), a simulation service available through the EBRAINS digital research infrastructure powered by the EU co-funded HBP. TVB was developed by HBP scientist Dr Viktor Jirsa of HBP SGA3 project partner Aix-Marseille University, France, together with collaborators. The technology makes it possible to simulate how abnormal activity spreads in a patient’s brain during an epileptic seizure. This helps clinicians to more reliably detect the target areas for surgery. As reported in a news item posted on the HBP website, each patient’s computational models are created using “individually measured anatomy, structural connectivity and brain dynamics data.” The personalised simulations essentially provide a virtual epileptic patient (VEP) tailored to each real patient. According to the news item, the approach has been tested in a number of retrospective studies, with the most recent paper published in the journal Epilepsia.

Personalized Brain Modeling Technique May Lead to Breakthroughs in Clinical Epilepsy Trial

Article published by Medical Xpress

Researchers of the Human Brain Project (HBP) have published a new study in Science Translational Medicine presenting advanced brain modeling methods for epilepsy clinical care. The article, which is featured on this week’s cover of the journal, describes the methodology used in the EPINOV clinical trial (Improving Epilepsy surgery management and progNOsis using Virtual brain technology).

The personalized brain modeling approach has been developed over several years in the HBP, and is supported by the digital research infrastructure EBRAINS.

To create personalized brain models, the researchers use a simulation technology called The Virtual Brain (TVB), which HBP scientist Viktor Jirsa has developed together with collaborators. For each patient, the computational models are created from individually measured anatomy, structural connectivity and brain dynamics data.

For epilepsy, the approach is currently being tested in a large-scale clinical trial to provide a computational, predictive tool in surgery preparation

Even though for many patients, epileptic seizures can be controlled by drugs, almost one-third of patients do not respond to medication. For this group, surgical removal of the epileptogenic zone, the brain area from which the seizure originates and propagates, presents the only treatment option. Currently, the procedure has a 60% success rate.

The TVB technology enables clinicians to simulate the spread of abnormal activity during epileptic seizures in a patient’s brain, helping them to identify the target areas better. The simulations are personalized for each patient, effectively providing a virtual epileptic patient (VEP) tailored to each individual real one. The approach has been tested in several retrospective studies, the latest one published this year in Epilepsia. The clinical trial is expected to run until 2025.

Vagal Nerve Stimulation May Benefit Patients With Medically Intractable Epilepsy

Article published by AJMC

A new review suggests that vagal nerve stimulation (VNS) can offer palliative benefit for patients with epilepsy that is refractory to medical management and not amenable to resective surgery.

This review of randomized controlled trials (RCTs) and prospective nonrandomized studies was published in Journal of Central Nervous System Disease. The final review included 6 total trials.

The authors identified 3 adult trials and 1 pediatric trial in their comprehensive literature search. Across these 4 RCTs, high-frequency VNS stimulation—defined as frequency greater than 20 Hz—consistently achieved a greater seizure frequency reduction, ranging between 23.4% and 33.1%, compared with low-frequency VNS—defined as 1 Hz—which ranged between 0.6% and 15.2%.

The authors also identified 2 RCTs that looked at whether the parameters of VNS influenced seizure control. According to the results from these 2 trials, VNS achieved seizure control comparable to that reported by the first 4 RCTs, with a reduction in seizure frequency ranging between 22% and 43%, irrespective of the parameters utilized for VNS.

“While the reduction in seizure frequency did not reach significance in every RCT, the studies that reported insignificant differences were also those with fewer patients, suggesting that inadequate sample size contributed to the variation in the reported outcome,” the authors said.

Additionally, VNS-associated morbidities were found to be consistently higher in adults who underwent high-frequency VNS, while these differences were not observed in the pediatric population.

New Research Reveals Clues About the Development of Epilepsy

Article published by Medical Xpress

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

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

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

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

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

New Insight into Brain Inflammation Inspires New Hope for Epilepsy Treatment

Article published by The Scientist

Doctors treat epilepsy with anticonvulsants to control seizures, but some patients do not respond to these first-line therapies. For patients with drug-refractory epilepsy (DRE), whose seizures persist after treatment with two or more anticonvulsants, clinicians must surgically remove part of the brain tissue to cure the disease.

When first-line medicines fall short, scientists examine the molecular mechanisms of a disease to understand why and to develop alternatives. At Duke-NUS Medical School and KK Women’s and Children’s Hospital, clinicians and researchers teamed up to investigate how inappropriate proinflammatory mechanisms contribute to DRE pathogenesis. This work builds on evidence from animal models and resected brains of human patients that associated inflammation with epilepsy. Derrick Chan, a clinician scientist at KK Women’s and Children’s Hospital believes this research is an extension of his clinical work. “[T]his direction became really important, because we were looking for a less invasive way to try to help all the children with drug resistant epilepsy,” he said.

Chan and his team partnered with the immunology research group of fellow physician scientist, Salvatore Albani. In a study published in Nature Neuroscience, Chan and Albani described their efforts to understand the immunologic factors that contribute to DRE pathology. They examined the holistic involvement of the immune system in epileptic tissue that clinicians surgically removed from patients. The researchers used a single-cell sequencing technique called cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq), which gathers information on RNA and surface proteins in single cells They uncovered a proinflammatory microenvironment in DRE lesions that resembles brain autoimmune diseases, such as multiple sclerosis (MS).

The researchers identified cell types and their functions in DRE lesions at single-cell resolution and differentiated resident brain and neurovascular cells from infiltrating immune cells. They found that the DRE microenvironment includes activated microglia and other proinflammatory immune cells, and they captured cellular interactions with additional molecular analyses. “We had not expected these interactions between microglia and other immune cells, and then how these microglia become kind of a pivot to attract all of the immune cells by starting this proinflammatory milieu inside the brain,” explained Pavanish Kumar, the first author of the study.

Patients With Epilepsy May Benefit from Muscle Relaxation Exercises, Study Finds

Article published by AJMC

A study on the effects of progressive muscle relaxation (PMR) exercises in patients with epilepsy found a significant decrease in depressive symptoms, improved sleep, and improved quality of life.

“Progressive muscle relaxation exercise enables individuals to feel the difference between tension and relaxedness and teaches individuals to relax on their own,” wrote the authors of this study. “It also provides relaxation and peace while reducing physical and emotional tension.”

This randomized controlled intervention study was published in Seizure – European Journal of Epilepsy.

The study included a total of 70 participants diagnosed with epilepsy. The participants were divided into control and intervention groups between November 1, 2022, and April 15, 2022. The patients in the intervention group underwent 12 PMR exercise sessions, 3 days a week, for 4 weeks.

PMR exercises are mind-body practices that create relaxation through regular and voluntary relaxation of large muscles, with many benefits such as improving mental and physical states of stress, pain, and fatigue.

Risk of Sudden Unexpected Death in Epilepsy (SUDEP) with Lamotrigine (Lamictal ®) and Other Sodium Channel Modulating Antiseizure Medications

Abstract found on Wiley Online Library

Objective: In vitro data prompted U.S Food and Drug Administration warnings that lamotrigine, a common sodium channel modulating anti-seizure medication (NaM-ASM), could increase risk of sudden death in patients with structural or ischaemic cardiac disease, however its implications for Sudden Unexpected Death in Epilepsy (SUDEP) are unclear.

Methods: This retrospective, nested case-control study identified 101 sudden unexpected death in epilepsy (SUDEP) cases and 199 living epilepsy controls from Epilepsy Monitoring Units (EMUs) in Australia and the USA. Differences in proportions of lamotrigine and NaM-ASM use were compared between cases and controls at time of admission, and survival analyses from time of admission up to 16?years were conducted. Multivariable logistic regression and survival analyses compared each ASM subgroup adjusting for SUDEP risk factors.

Results: Proportions of cases and controls prescribed lamotrigine (p=0.166), one NaM-ASM (p=0.80) or ?2NaM-ASMs (p=0.447) at EMU admission were not significantly different. Patients taking lamotrigine (adjusted hazard ratio [aHR]=0.56; p=0.054), one NaM-ASM (aHR=0.8; p=0.588) or ?2 NaM-ASMs (aHR=0.49; p=0.139) at EMU admission were not at increased SUDEP risk up to 16?years following admission. Active tonic-clonic seizures at EMU admission associated with >2-fold SUDEP risk, irrespective of lamotrigine (aHR=2.24; p=0.031) or NaM-ASM use (aHR=2.25; p=0.029). Sensitivity analyses accounting for incomplete ASM data at follow-up suggest undetected changes to ASM use are unlikely to alter our results.

Significance: This study provides additional evidence that lamotrigine and other sodium channel-modulating anti-seizure medications are unlikely to be associated with an increased long-term risk of SUDEP, up to 16?years post epilepsy monitoring unit admission.

Is the Antiparasitic Drug Ivermectin a Suitable Candidate for the Treatment of Epilepsy?

Abstract found on PubMed

There are only a few drugs that can seriously lay claim to the title of “wonder drug” and ivermectin, the world’s first endectocide and forerunner of a completely new class of antiparasitic agents, is among them. Ivermectin, a mixture of two macrolytic lactone derivatives (avermectin B_1a and B_1b in a ratio of 80:20), exerts its highly potent antiparasitic effect by activating the glutamate-gated chloride channel that is absent in vertebrate species. However, in mammals, ivermectin activates several other Cys-loop receptors, including the inhibitory GABA_A and glycine receptors and the excitatory nicotinic acetylcholine receptor of brain neurons. Based on these effects on vertebrate receptors, ivermectin has recently been proposed to constitute a multifaceted wonder drug for various novel neurological indications, including alcohol use disorders, motor neuron diseases, and epilepsy. This review critically discusses the preclinical and clinical evidence of anti-seizure effects of ivermectin and provides several arguments why ivermectin is not a suitable candidate drug for the treatment of epilepsy. First, ivermectin penetrates the mammalian brain poorly, so it does not exert any pharmacological effects via mammalian ligand-gated ion channels in the brain unless it is used in high, potentially toxic doses or the blood-brain barrier is functionally impaired. Second, ivermectin is not selective but activates numerous inhibitory and excitatory receptors. Third, the preclinical evidence for anti-seizure effects of ivermectin is equivocal and, at least in part, ED₅₀ s in seizure models are in the range of the LD₅₀ . Fourth, the only robust clinical evidence of anti-seizure effects stems from the treatment of patients with onchocerciasis in which the reduction of seizures is due to a reduction in microfilariae densities but not a direct anti-seizure effect of ivermectin. We hope that this critical analysis of available data will avert that the unjustified hype associated with the recent use of ivermectin to control COVID-19 recurs also in neurological diseases such as epilepsy.

Epilepsy Research News: January 2023

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

Genetic Testing for Epilepsy Improves Patient Outcomes

Genetic testing in patients with epilepsy can inform treatment and lead to better outcomes in many cases, according to a new study. The study, led and funded by the genetic testing company Invitae, included patients referred for genetic testing between 2016 and 2020 whose testing revealed a positive molecular diagnosis. The investigators asked the patient’s healthcare providers how the results of the genetic test impacted the patient’s treatment plan and outcomes. Of the 418 children and adults with epilepsy who were included in the study, nearly half saw changes in their treatment plans such as a change in medication or referral to a specialist, after genetic testing revealed new information about their condition. The study also found that of 167 patients with follow-up information available, treatment changes were associated with improved patient outcomes including a reduction or elimination of seizures. The authors concluded that results support the use of genetic testing to guide the clinical management of epilepsy to improve patient outcomes. Learn more about genetic testing for epilepsy here.

Learn More

New Tools to Map Seizures and Improve Epilepsy Treatment

A new “tool” – a statistical model – has been developed to help doctors find precisely where seizures originate in the brain to increase the possibility of treating that specific region. Localizing where seizures begin is usually a costly and time-consuming process that can often require days to weeks of invasive monitoring. In this study, researchers aimed to shorten the time it takes to locate the seizure onset zone by studying patients’ brains, both when they weren’t having seizures and when their brains were stimulated with quick electrical pulses, to quickly create maps predicting where seizures begin. In the 65 patients studied, the model predicted the location of the onset of seizures and the ultimate success of surgical intervention with 79% accuracy. The researchers noted that this tool might be used to help clinicians identify the area where seizures begin in a less time-consuming process.

Learn More

Gene Therapy for Epilepsy

A recently published study shows that a potential new treatment can prevent seizures in mice by clearing the accumulation of a protein in the brain known as the tau protein. Researchers at Macquarie University recently found that accumulation of tau protein can lead to neurons becoming hyperexcited. Hyperexcited neurons that fire continuously can result in seizures and cognitive decline. In the newly published study, the researchers developed a gene therapy that uses a brain enzyme known as p38y to prevent this accumulation. When treated with the new gene therapy, mice with uncontrolled epilepsy had a better chance of survival in addition to reduced seizure susceptibility. The researchers note that their next step is to conduct a more detailed study in the laboratory, in hopes of eventually preparing the treatment for a possible clinical trial.

Learn More

World Health Organization (WHO) Focuses on Improving the Lives of People with Epilepsy

A technical brief published by the World Health Organization (WHO) called Improving the Lives of People with Epilepsy sets out the actions required to deliver an integrated approach to epilepsy care and treatment with the goal of meeting the multifaceted needs of people with epilepsy. In summary, the brief highlights the importance of:

Integrated services across the life-course, particularly at the primary care level
Access to anti-seizure medicines
Resources and training for the health and social services workforce
Anti-stigma and discriminatory legislation and practices; promoting and respecting the human rights and full social inclusion of people with epilepsy, their families and caregivers.

Learn More

Memory Impairment in Those with Epilepsy

People with chronic epilepsy often experience impaired memory. Researchers have now found a mechanism using a mouse model of epilepsy that could explain this impairment. Porous channels called ion channels within the brain allow electrically charged particles (ions) to flow into neurons, allowing neurons to communicate with each other. However, the researchers found changes in sodium ion channels within neurons of the hippocampus – an area of the brain important in learning and memory – that could lead to changes in the activity of these neurons and affect their normal function. When the researchers administered substances to restore the normal function of these channels, the firing properties of the neurons normalized, and the animals were better able to remember places they had visited. The study provides insight into the processes involved in memory retrieval. In addition, it provides support for the idea that the development of new drugs may improve the memory of epilepsy patients.

Learn More