Microbot Development Could Help Treat Seizures

Article published by The Hippocratic Post

University of Glasgow researchers are part of a new project which is setting out to develop tiny injectable robots capable of predicting and mitigating epileptic seizures.

The project, called CROSSBRAIN, is led by Tor Vergata University of Rome in Italy and is funded by the European Innovation Council.

Over the course of the next four years, the CROSSBRAIN collaborators will develop implantable ‘microbots’, about a tenth of a millimetre in size, made from advanced nanomaterials with specially-tailored physical properties.

Once implanted in the brain, they will be controlled by a small, wearable central control unit capable of monitoring electrical activity to detect the onset of a seizure and modulate its effect through targeted neurostimulation.

The microbots will be able to deliver genetic material on command, enabling cell- and microcircuit-level neuromodulation in rodent brains during the later stages of the project’s development.

Professor Hadi Heidari, of the University of Glasgow’s James Watt School of Engineering, is leading the UK contribution to CROSSBRAIN. Professor Heidari’s Microelectronics Lab conducts pioneering research on integrated micro and nanoelectronics design for medical and industrial applications. In this project, the Microelectronics Lab will help to design and develop the microbots’ wireless power and data management and delivery systems.

The CROSSBRAIN team will develop a cutting-edge FBAR magnetoelectric antenna at the world-class cleanroom facilities of the University’s James Watt Nanofabrication Centre.

Professor Heidari said: “We’re pleased to be part of this ambitious project, which has the potential to pave the way for transformative treatments for pathological brain conditions like epilepsy.

Adjunctive Cenobamate (XCOPRI ®) in Highly Active and Ultra-Refractory Focal Epilepsy: A ‘Real-World’ Retrospective Study

Abstract found on Wiley Online Library

Objective: Recent clinical trials showed that cenobamate substantially improves seizure control in focal-onset drug-resistant epilepsy. However, little is known about cenobamate’s performance in highly active (?20 seizures/month) and ultra-refractory focal epilepsy (?6 failed epilepsy treatments, including anti-seizure medications [ASM], epilepsy surgery and vagus nerve stimulation). Here, we studied cenobamate’s efficacy and tolerability in a ‘real-world’ severe DRE cohort.

Methods: We conducted a single-centre retrospective analysis of consecutive adults treated with cenobamate between October 2020 and September 2022. All patients received cenobamate through an Early Access Program. Cenobamate retention, seizure outcomes, treatment-emergent adverse events, and adjustments to concomitant ASMs were analysed.

Results: Fifty-seven patients received cenobamate for at least three months (median duration, 11 months). The median cenobamate dose was 250mg/day (range 75-350mg). Baseline demographics were consistent with highly active (median seizure frequency, 60/month) and ultra-refractory epilepsy (median previously failed ASMs, nine). Most (87.8%) had prior epilepsy surgery and/or vagus nerve stimulation. Six patients stopped cenobamate due to lack of efficacy and/or adverse events. One patient died from factors unrelated to cenobamate. Among patients who continued cenobamate, three achieved seizure freedom (5.3% of cohort), 24 had a 75-99% reduction in seizures (42.1% of cohort), and 16 had a 50-74% reduction (28.1% of cohort). Cenobamate led to abolition of focal to bilateral tonic-clonic seizures in 55.6% (20/36) of patients. Among treatment responders, 67.4% (29/43) were treated with cenobamate doses of ?250mg/day. Three-quarters of patients reported at least one side-effect, most commonly fatigue and somnolence. Adverse events most commonly emerged at cenobamate doses of ?250mg/day. Side-effects were partially manageable by reducing the overall ASM burden, most often clobazam, eslicarbazepine and perampanel.

Significance: Patients with highly active and ultra-refractory focal epilepsy experienced meaningful seizure outcomes on cenobamate. Emergence of adverse events at doses above 250mg/day may limit the potential for further improvements in seizure control at higher cenobamate doses.

Differential Diagnosis of Familial Adult Myoclonic Epilepsy

Abstract found on Wiley Online Library

Familial adult myoclonic epilepsy (FAME) is an under-recognized disorder characterized by cortical myoclonus, generalized tonic-clonic seizures and additional clinical symptoms, which vary depending on the FAME subtype. FAME is caused by pentanucleotide repeat expansions of intronic TTTCA and TTTTA in different genes. FAME should be distinguished from a range of differential diagnoses. The phenotypic features of FAME, including generalized tonic-clonic and myoclonic seizures, are also seen in other epilepsy syndromes, such as juvenile myoclonic epilepsy, with a resultant risk of misdiagnosis and lack of identification of the underlying cause. Cortical myoclonus may mimic essential tremor or drug-induced tremor. In younger individuals, the differential diagnosis includes progressive myoclonus epilepsies (PMEs), such as Unverricht-Lundborg disease; whereas, in adulthood, late-onset variants of PMEs, such as sialidoses, myoclonus epilepsy, and ataxia due to potassium channel pathogenic variants should be considered. PMEs may also be suggested by cognitive impairment, cerebellar signs, or psychiatric disorders. The EEG may show similarities to other idiopathic generalized epilepsies or PMEs, with generalized spike-wave activity. Signs of cortical hyperexcitability may be seen, such as an increased amplitude of somatosensory evoked potentials or enhanced cortical reflex to sensory stimuli, together with the neurophysiological pattern of the movement disorder.

Recognition of familial adult myoclonic epilepsy (FAME) will inform prognostic and genetic counseling, and diagnosis of the insidious progression which may occur in older individuals who show mild cognitive deterioration. Distinguishing FAME from other disorders in individuals or families with this constellation of symptoms is essential to allow identification of the underlying aetiology.

Epilepsy Research News: February 2023

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

Combining Diet with Drugs to Reduce Seizures

Following a modified Atkins diet that is high in fat and low in carbohydrates in addition to taking antiseizure medication(s) may reduce seizures in people with tough-to-treat epilepsy, according to a recently published study. The study involved 160 adults and adolescents who had epilepsy for more than 10 years on average and had at least 27 seizures per month, despite trying an average of four antiseizure medications at the maximum tolerated dose. After six months, researchers found that 26% of people who used drug therapy and followed the modified Atkins diet had more than a 50% reduction in seizures, compared to only 3% of the people who had drug therapy alone. Four people in the diet group were seizure free by the end of the study, while no one in the medication-only group was seizure free. A limitation of the study is that seizures were self-reported or reported by caregivers, so some seizures may not have been reported. Despite this important consideration, “for people with drug-resistant epilepsy, or those who have been unable to find effective treatment to reduce seizures, it’s encouraging to see that there are lifestyle changes that can be combined with standard drug therapy to reduce the number of seizures,” stated a study author.

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Parents Need Guidance Managing Sleep Issues in Children with Epilepsy

According to a new qualitative study that included interviews with nine mothers, sleep and epilepsy have a complex and bidirectional relationship. The aim of the study was to capture parental perceptions and experiences related to their child’s sleep habits and management, the impact of sleep difficulties on the child and their family, and available support. According to the study, epilepsy exacerbated the struggle to initiate sleep (settling and falling asleep), maintenance of sleep (experiencing night or early morning wakings), duration of sleep, daytime sleepiness, and sleep anxiety. Study authors noted that mothers were aware of the links between sleep and seizures yet felt that they lacked guidance about how to address or improve their child’s sleep, including from their healthcare teams. The authors also stated that the finding emphasizes the need to ensure adequate help is available to support healthy sleep in children with epilepsy.

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New Understanding of the Cause of Post-Traumatic Epilepsy (PTE)

A research team has uncovered information about changes that occur in the brain following a traumatic brain injury (TBI) that could help advance future preventative treatments for PTE, a type of epilepsy caused by a TBI. The findings show that activation of a subset of neurons within an area of the brain called the hippocampus plays a key role in the changes that occur during the development of PTE. For this study, the 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 found that when the dentate granule cells were activated, the activity of other brain cells involved in epilepsy was inhibited. They also found that the cells that were formed just prior to a were much more likely to activate this circuit than those generated at other points in time. The team noted that being able to get to a point of understanding the changes that occur in the development of epilepsy may lead to the ability to prevent or reverse epilepsy.

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Links Between Parental Factors, Emotional, and Behavioral Issues Found in Pediatric Epilepsy

Adolescents with epilepsy commonly experience emotional and behavioral problems, which vary depending on demographic, clinical, and parental factors, according to a new study. The parental factors included how parents perceived that others treated their child. The study included 289 adolescents aged between 11 and 18 years. The study found 18.3% of adolescents with epilepsy had at least one emotional or behavioral problem in the clinical range. Additionally, consistent with findings of prior studies, this study showed one in four parents of adolescents with epilepsy perceived that other people felt uncomfortable with their child, treated their child as inferior, or preferred to avoid their child because of their epilepsy. Due to these findings, the study’s authors emphasized it is crucial to identify and properly manage these problems early to decrease comorbid psychopathology in adolescents with epilepsy.

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Use of Newer Antiseizure Medications for Epilepsy Differs by Race, Ethnicity

Racial and ethnic minority groups are less likely to be taking newer-generation antiseizure medications for their epilepsy, an analysis of Medicaid data showed. Compared with white patients, Black, Hispanic, and Native Hawaiian/Pacific Islander patients had lower odds of being on newer antiseizure medications, the study found. Of note, taking a second-generation antiseizure medication was associated with better treatment adherence, and those seeing a neurologist had higher odds of being on newer antiseizure medications. The study authors stated that being on a newer, second and third-generation antiseizure medication may represent an important marker of quality of care for people with epilepsy and that differences appear to reflect racial and ethnic inequities in epilepsy care.

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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.