Temporal Lobe Epilepsy

New Materials Could Lead to Implantable Treatments for Epilepsy

Article published by PhysOrg

The prospect of a cure for a type of epilepsy could be one step closer following breakthrough research on materials that may help new types of probes be safely implanted in the brain.

Bioengineering researchers from the University of Glasgow have investigated new dissolvable coatings which could help safely guide flexible implants into brains to help regulate temporal lobe epilepsy.

The development of the material, outlined in an early-view paper in the journal Advanced NanoBiomed Research, is part of a collaboration that aims to tackle epilepsy by treating and regenerating damaged brain tissue.

The €8m Hybrid Enhanced Regenerative Medicine Systems project—HERMES—was launched in 2019. It brings together 12 partners from seven EU countries to find new ways to heal brain disorders using transplants that combine biological and artificial components.

Neural probes capable of deep brain stimulation have been used to help treat people living with Parkinson’s disease and other conditions like obsessive-compulsive disorder. They are a promising future treatment for temporal lobe epilepsy, which can be resistant to drugs.

Currently, deep brain stimulation probes, which are made from silicon, often cause scarring around their implantation site because of a mismatch between the stiffness of the artificial materials and the soft tissue of the brain.

One solution could be a new generation of flexible probes made from new bendable materials which offer a better match with the softness of brain tissue. Flexible implants could also widen the possibilities of where the implants could be placed in the brain, opening up treatments for more conditions.

However, the increased flexibility of the materials can increase the risk of the probes bending or breaking when introduced into brain tissue—a key problem that needs to be solved before the HERMES team and others can use them effectively as implants.

In the paper, the Glasgow team and colleagues in Italy outline how they explored the potential of four different biological materials as coatings for future HERMES implants. The materials act as temporary stiffeners, which could allow flexible probes to reach their target in the brain without bending, before dissolving once the surgery is complete.

Epilepsy Research News: June 2023

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

CURE Epilepsy’s Team Science Post-Traumatic Epilepsy (PTE) Initiative: Approach and Advances

CURE Epilepsy’s PTE Initiative united six preclinical and clinical research teams to form a consortium focused on improving ways to study PTE in a laboratory setting, understanding changes in the brain that occur after a traumatic brain injury (TBI) that lead to PTE, and uncovering risk factors associated with the development of PTE. PTE is a debilitating type of epilepsy that can develop in the months or even years following a TBI. Currently, there is no way to predict who will develop PTE or any way to prevent it. A recently published paper from the PTE Initiative describes scientific advances from CURE Epilepsy’s PTE Initiative, as well as its methods, implementation, and emphasis on team science and collaboration. Work on the PTE Initiative is ongoing, with the ultimate goal of understanding who is at risk for PTE, and laying the groundwork for the development of ways to prevent it from occurring. This work was supported by the Office of the Assistant Secretary of Defense for Health Affairs, through the Psychological Health and Traumatic Brain Injury Research Program under Award No. W81XWH-15-2-0069.

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Genetic Mutations Contributing to Adult Epilepsy

A recent study sheds new light on the role of changes in DNA known as somatic mutations in patients who develop mesial temporal lobe epilepsy (MTLE). Unlike inherited DNA mutations, which are passed down from a person’s parents, somatic mutations occur after a person is conceived. To examine the role of somatic mutations, researchers analyzed DNA from brain tissue samples collected from 105 patients with drug-resistant MTLE as well as 30 people who did not have epilepsy. The team pinpointed 11 somatic mutations that were enriched in the hippocampus (the region of the brain where seizures typically originate in MTLE) of 11 patients with drug-resistant MTLE. All but one of the 11 mutations were connected to a specific genetic pathway known as the RAS/MAPK pathway. The researchers noted that certain anti-cancer drugs target this pathway, opening a new avenue of therapeutic possibilities for MTLE patients that are resistant to antiseizure medications. In addition to suggesting a potential path to treatment, the findings could also be used to help inform treatment decisions for patients who harbor these somatic mutations.

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Improving Seizure Freedom After Epilepsy Surgery

A network of connections in the brain could be the key to improving frontal lobe epilepsy surgery, according to new research. This research suggests that disconnecting certain pathways in the frontal lobe could lead to longer-lasting seizure freedom after brain surgery. These pathways link the frontal lobe to brain structures deep in the brain, including areas called the thalamus and striatum. The researchers analyzed the cases of 47 people who underwent surgery for drug-resistant frontal lobe epilepsy and found that disconnection of these pathways was associated with seizure freedom after three and five years. The research found that this surgery also did not have negative effects on language or executive functions like planning, self-control, and focus. However, other functions, such as mood and emotions, still need to be studied. These findings provide hope that disconnection could lead to improved outcomes and long-term seizure freedom in people with frontal lobe epilepsy.

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Predictors of Epilepsy in Children with Complex Febrile Seizures

Four predictors of future epilepsy in children with complex febrile seizures (CFS) have been identified in a recently published study. These include experiencing more than three febrile seizures in 24 hours, a certain type of brain activity seen on a post-CFS electroencephalogram (EEG), a family history of seizures not associated with fever, and CFS onset at age three or later. The researchers retrospectively examined 621 children and found that having all four risk factors raised the risk of developing epilepsy to over 75%. The researchers noted that early identification of children who will develop epilepsy after a CFS is essential to future management and counseling for parents and caregivers.

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Research Finds Ability to Predict Seizures in Temporal Lobe Epilepsy, 30+ Mins Ahead

Article published by The Mirage

Seizures can be predicted more than 30 minutes before onset in patients with temporal lobe epilepsy, opening the door to a therapy using electrodes that could be activated to prevent seizures from happening, according to new research from UTHealth Houston.

The study, led by Sandipan Pati, MD, associate professor in the Department of Neurology with McGovern Medical School at UTHealth Houston, was recently published in NEJM Evidence, a publication of the New England Journal of Medicine.

“The ability to predict seizures before they occur is a major step forward in the field of epilepsy research,” said Pati, senior author of the study and a member of the Texas Institute for Restorative Neurotechnologies at UTHealth Houston Neurosciences. “These findings are significant because they suggest that we may be able to develop more effective therapies for epilepsy, which could greatly improve the quality of life for patients who suffer from this condition.”

Surgery is a common treatment for many patients with epilepsy. But when seizures affect larger areas of the brain, removing part of the brain surgically is not an option. Neuromodulation therapy could offer an alternative solution for patients with these seizures, Pati said.

Past studies of continuous electroencephalography (EEG) – the measurement and recording of electrical activity in different parts of the brain – have suggested that seizures in people with focal-onset epilepsies tend to occur during periods of heightened risk, represented by pathologic brain activities known as “pro-ictal states.” The EEG-based detection of pro-ictal states is critical to the success of adaptive neuromodulation, with the early detection of seizures allowing electrodes to be applied therapeutically to the brain’s seizure onset zone and thalamus.

To distinguish these pro-ictal states, Pati’s team studied a prospective, consecutive series of 15 patients with temporal lobe epilepsy who underwent limbic thalamic recordings in addition to routine intracranial EEG for seizure localization. In total, they analyzed 1,800 patient hours of continuous EEG.

Epilepsy Research News: December 2022

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

Increased Seizures After COVID Compared to the Flu

Researchers have found that the risk of seizures or epilepsy following a COVID infection is significantly higher than after being infected with the flu. The team looked at the health records of people who had been infected with COVID and matched them (so that they were similar in characteristics such as age, sex, and medical conditions) with a group of people who had been infected with the flu. The team then compared the incidence of epilepsy and seizures between the two groups over a six-month period following the initial infection. The rate of new cases of epilepsy or seizures was 0.94% in the people who had COVID, compared with 0.6% in those who had the flu. The team indicated that while the overall risk of seizures was very low, people who had COVID were 55% more likely to develop epilepsy or seizures over the next six months than people who had the flu.

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New Statistical Tool to Understand Seizures

A new study seeks to understand how some people’s seizures change over time in what is known as a seizure ‘cycle’ and understand how certain triggers might increase or decrease seizure risk, perhaps giving people with epilepsy a better idea of how and why their seizures happen, and to better recognize the early warning signs. The study found that aging itself, as well as common triggers, may be contributing factors to how the medical condition affects those prone to seizures. The researchers studied the seizure diaries of more than 1,000 patients ages 2 months to 80 years and developed a new statistical model to explicitly capture the effect of factors that may drive transitions in seizure risk, looking at factors like antiseizure medications, illness, and menstrual cycles. In examining the way seizure cycles vary in people with epilepsy, the researchers found that individuals in older age groups had shorter “calm” stretches between seizures, while younger age groups had longer stretches. This work paves the way for future studies to further examine seizure cycles.

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Identification of a Possible Molecule to Treat Temporal Lobe Epilepsy (TLE)

Researchers have recently identified and developed a small molecule called D4 with the potential to treat TLE by suppressing neuroinflammation. The findings suggest that D4 strongly suppresses TLE-induced neuroinflammation, curbs TLE seizures, and increases survival rate in an animal model of TLE. D4 works by blocking “hemichannels” in the brain, which are channels that act as pathways for neuroinflammatory molecules. The researchers note that their findings bring forward a possible new pathway for drug development for epilepsy and also highlight the involvement of neuroinflammation in epilepsy.

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Pinpointing Brain Areas Involved in GLUT1 Deficiency Syndrome Seizures

A small group of brain cells linked to a circuit in the brain is responsible for setting off whole-brain seizures in a rare form of epilepsy affected by blood sugar levels, a new study suggests. This rare genetic disorder is known as GLUT1 deficiency syndrome. Researchers used a combination of electroencephalography (EEG) as well as brain imaging in humans to show that the seizures started from brain areas called the thalamus and somatosensory cortex. When blood sugar levels dipped, abnormal electrical activity in the circuit formed by these areas spread throughout the brain. The researchers also used an animal model of GLUT1 deficiency syndrome to further investigate this circuit and pinpoint the cell types important in causing an imbalance in inhibitory brain activity compared to excitatory brain activity (which can lead to seizures). The researchers suggested these results could point to a mechanism for seizures in GLUT1 deficiency syndrome that might be targeted as a potential treatment for seizures related to GLUT1 Deficiency syndrome.

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Stereoelectroencephalography-Based Research on the Value of Drug-Resistant Temporal Lobe Epilepsy Auras: A Retrospective Single-Center Study

Abstract found on PubMed

Purpose: To explore the localization value of drug-resistant temporal lobe epilepsy (TLE) aura for preoperative evaluation, based on stereoelectroencephalography (SEEG), and its prognostic value on the surgical outcome.

Methods: The data of patients with drug-resistant TLE who had SEEG electrodes implanted during preoperative evaluation at the First Affiliated Hospital of the University of Science and Technology of China (Hefei, China) were retrospectively analyzed. The patients were divided into aura-positive and aura-negative groups according to the presence of aura in seizures. To explore the clinical features of aura, we evaluated the localizing and prognostic values of aura for the outcome of anterior temporal lobectomy based on SEEG.

Results: Among forty patients, twenty-seven patients were in the aura-positive group and ten (25.0%) patients had multiple auras. The most common TLE aura was abdominal aura [thirteen (34.2%) patients]. The postoperative seizure frequency was significantly reduced in the preoperative aura-positive patients compared to the preoperative aura-negative patients (P = 0.011). Patients with abdominal (P = 0.029) and single (P = 0.036) auras had better surgical prognoses than aura-negative patients. In the preoperative evaluation, aura-positive patients had a better surgical outcome if the laterality of positron emission tomography-computed tomography (PET-CT) hypometabolism was concordant with the epileptogenic focus identified with SEEG (P = 0.031). A good postoperative epileptic outcome in aura-positive patients was observed among those with hippocampal sclerotic medial temporal lobe epilepsy (P = 0.025).

Conclusion: Epileptic aura is valuable for the localization of the epileptogenic focus. Abdominal aura and single aura were good predictors of better surgical outcomes. Among patients with a preoperative diagnosis of hippocampal sclerosis or with laterality of PET-CT hypometabolism concordant with the epileptogenic focus identified using SEEG, those with aura are likely to benefit from surgery.

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.”

Changes in Heart Rate During the Peri-Ictal Period in Focal Epilepsy

Abstract found on PubMed

Objective: We explored changes in heart rate during the peri-ictal period in patients with focal epilepsy, and differences in heart rate changes according to epileptic site and side were assessed.

Methods: A total of 198 epileptic seizures in 102 patients with focal epilepsy, who had a definite epileptogenic focus and had undergone surgical treatment, were assessed from 2014 to 2019. Heart rate was measured manually during the peri-ictal period. Change in heart rate and the time it occurred were assessed and compared between different epileptic sites and sides.

Results: Heart rate increased in 177 (89.4%) of 198 seizures. In 82 (44.8%) of 183 seizures, the change in heart rate occurred before seizure onset. The median period of heart rate change was seven seconds (interquartile range: 3–11 seconds) in seizures with heart rate change before seizure onset. The number of seizures with heart rate increase before seizure onset was significantly greater for medial temporal lobe epilepsy compared to lateral temporal lobe epilepsy (p=0.019) and extratemporal lobe epilepsy (p=0.002).

Significance: A change in heart rate prior to seizure onset is more likely to occur in patients with medial temporal lobe epilepsy, compared to those with lateral temporal lobe epilepsy and extratemporal lobe epilepsy. Patients with medial temporal lobe epilepsy may likely benefit from seizure warning and detection devices.

FSU Team Makes Discovery Advancing Epilepsy Research

Article published by Florida State University News

A team of Florida State University College of Medicine researchers has found a link between a specific protein in the brain and increased vulnerability to neurodegeneration for individuals with temporal lobe epilepsy (TLE).

Their findings are published in the Journal of Neurophysiology.

TLE is the most common form of epilepsy in adults and is often resistant to medication. Professor of Biomedical Sciences Sanjay Kumar, who led the study, said the team used a novel technique that made it possible to study small amounts of tissue from hard-to-reach regions within the brain. Kumar, FSU researcher Stephen Beesley and former doctoral student Thomas Sullenberger focused on a chemical messenger called glutamate and one of its receptors, N-methyl-D-aspartate (NMDA).

Glutamate plays a major role in learning and memory, and it must be present in the right concentration at the right time for the brain to function properly. It is also the body’s most abundant amino acid, a building block of protein.

The team discovered that although two proteins commonly associated with NMDA — GluN1 and GluN2 — were evenly distributed in a critical hippocampal region of the brain, a third one — GluN3 — was distributed on a gradient. A pattern of neuron loss in the hippocampal and para-hippocampal regions of the brain is a hallmark feature of TLE.

Because GluN3 makes neurons more susceptible to calcium-induced cellular damage, the discovery helps researchers narrow the focus to identify exactly where neurons are dying and in how large an area.

Kumar has applied to patent the novel technique, known as area-specific tissue analysis (ASTA), that he developed. ASTA’s added precision created an improved method of testing for both the presence and volume of specific proteins linked to TLE.

Deep Learning Resting State fMRI Lateralization of Temporal Lobe Epilepsy

Abstract found on Wiley Online Library

Objective: Localization of focal epilepsy is critical for surgical treatment of refractory seizures. There remains a great need for non-invasive techniques to localize seizures for surgical decision-making. We investigate the use of deep learning using resting state functional MRI (RS-fMRI) to identify the hemisphere of seizure onset in temporal lobe epilepsy (TLE) patients.

Methods: 2132 healthy controls and 32 pre-operative TLE patients were studied. All participants underwent structural MRI and RS-fMRI. Healthy control data was used to generate training samples for a 3D convolutional neural network (3DCNN). RS-fMRI was synthetically altered in randomly lateralized regions in the healthy control participants. The model was then trained to classify the hemisphere containing synthetic noise. Finally, the model was tested on TLE patients to assess its performance for detecting biological seizure-onset zones, and gradient-weighted class activation mapping (Grad-CAM) identified the strongest predictive regions.

Results: The 3DCNN classified healthy control hemispheres known to contain synthetic noise with 96% accuracy, and TLE hemispheres clinically identified to be seizure onset zones with 90.6% accuracy. Grad-CAM identified a range of temporal, frontal, parietal, and subcortical regions that were strong anatomical predictors of the seizure onset zone, while the resting state networks which colocalized with Grad-CAM results included default mode, medial temporal, and dorsal attention networks. Lastly, in an analysis of a subset of patients with post-surgical outcomes, the 3DCNN leveraged a more focal set of regions to achieve classification in patients with Engel class > 1 compared to Engel class 1.

Significance: Non-invasive techniques capable of localizing the seizure-onset zone could improve pre-surgical planning in patients with intractable epilepsy. We have demonstrated the ability of deep learning to identify the correct hemisphere of the seizure onset zone in TLE patients using RS-fMRI with high accuracy. This approach represents a novel technique of seizure lateralization that could improve preoperative surgical planning.

Seizure Latency and Epilepsy Localization as Predictors of Recurrence Following Epilepsy Surgery

Abstract found in Wiley Online Library

Summary

Objective: The primary purpose is to determine if the time between epilepsy surgery and first seizure recurrence can estimate the timing of the next seizure event for temporal and extratemporal epilepsy. A secondary endpoint aimed to compare temporal and extratemporal epilepsy surgery and examine which subgroup has a higher hazard of subsequent seizure recurrence.

Methods: Data was used from a retrospective database at Thomas Jefferson University Hospital. Records were stratified into temporal (N = 943) and extratemporal (N = 125) surgeries. Analyses were done using SAS and utilized Cox-Proportional hazards models while controlling for demographics and clinical factors. The primary predictor of time between surgery and first recurrence was treated as a nominal variable binned into six segments, while secondary endpoints used a categorical predictor of epilepsy location while controlling for seizure latency.

Results: Generally, as seizure latency following surgery increased, the time between first seizure and second seizure increased. These results were statistical meaningful in the temporal set (Wald Chi Square: 40.4715, df = 5, p<0.0001). Outcomes could also be interpreted based on predictor group, for instance, if seizure one occurred between one to two months following surgery in the temporal set, the median number of days until the next seizure was 35.5 days (95% CIs: 21 – 89 days). Secondary analysis showed that temporal lobe epilepsy had a lower hazard of a second seizure than extratemporal lobe epilepsy (89.2% reduction in hazard; 95% CIs: 0.015 – 0.795).

Significance: This analysis provides a framework to use initial seizure latency to predict the median number of days until the next seizure event, while stratifying based on epilepsy location and controlling for multiple variables. It also suggests that the hazard of seizure recurrence in temporal lobe epilepsy is lower than extratemporal lobe epilepsy.