SMC Finds Method to Eliminate Certain Complications During Temporal Lobe Epilepsy Surgery

Researchers at Samsung Medical Center (SMC) have discovered that intraoperative motor-evoked potential (MEP) monitoring can eliminate the risk of postoperative motor deficits during temporal lobe epilepsy (TLE) surgery, the hospital said Friday.

Temporal lobe epilepsy surgery is an essential treatment for patients with refractory epilepsy, offering the opportunity to maximize seizure freedom as well as prevent untimely death. Although the temporal lobectomy is far from the motor nerve system, the operation can cause complications such as hemiplegia in 1 to 3 percent of patients who undergo surgery.

The SMC team, led by Professor Seo Dae-won, aimed to analyze whether MEP was effective in preventing complications.

The team compared postoperative neurological deficits in patients who underwent TLE surgery with or without transcranial MEPs combined with somatosensory evoked potential (SSEP) monitoring between January 1995 and June 2018.

The team performed the transcranial motor stimulation using subdermal electrodes and recorded the MEP responses in the four extremity muscles. Professor Seo made a decrease of more than 50 percent in the MEP or the SSEP amplitudes compared with baseline a warning criterion.

As a result, in the TLE surgery group without MEP monitoring, postoperative permanent motor deficits newly developed in seven of 613 patients, while no permanent motor deficit occurred in 279 patients who received transcranial MEP and SSEP monitoring.

Epilepsy Research Findings: June 2019

This month’s round-up of epilepsy news features an announcement about a new antiepileptic rescue medication, NAYZILAM®. This therapy is the first FDA-approved nasal treatment option for people with epilepsy who experience episodes of frequent seizure activity.

We also highlight many research advances, from the discovery of a compound found in fruit and honey which can inhibit seizures to the development of a new drug to treat Dravet syndrome. Research in the cannabidiol (CBD) space has also advanced, with the creation of a synthetic form of CBD which may be easier to purify and does not need to be cultivated from hemp plants.

In more sobering news, reports over the past month show that one-third of epilepsy cases go without appropriate treatment for up to three years following diagnosis. In addition, people with psychogenic nonepileptic seizures (PNES) as well as epileptic seizures may be at a higher risk for sudden unexpected death in epilepsy (SUDEP)during the years immediately following diagnosis with PNES.

Summaries of all highlighted studies follow below. I’ve organized the findings into three categories: Treatment Advances, Research Discoveries, and Also Notable.

Treatment Advances

FDA Approves NAYZILAM® Nasal Spray to Treat Intermittent, Stereotypic Episodes of Frequent Seizure Activity in People Living with Epilepsy in the US
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The FDA has approved a New Drug Application for UCB’s newest antiepileptic drug NAYZILAM® (midazolam) nasal spray. This therapy is a benzodiazepine indicated for the acute treatment of intermittent, stereotypic episodes of frequent seizure activity (i.e., seizure clusters, acute repetitive seizures) distinct from a patient’s usual seizure pattern in individuals with epilepsy who are 12 years of age and older.

Study Advances More Effective Laser Ablation and Standard Epilepsy Surgery 
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In the largest study of its kind to date, researchers across 11 centers analyzed data on a relatively new minimally invasive alternative surgery for epilepsy. These researchers discovered changes that could make the procedure more effective in both laser ablation and standard surgery.

Research Discoveries

Brain Network Activity can Improve in Epilepsy Patients after Surgery
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Successful epilepsy surgery can improve brain connectivity similar to patterns seen in people without epilepsy, according to a new study published in the journal Neurosurgery. The study of 15 people with temporal lobe epilepsy is the first to show improvements in brain networks after surgery compared to a group of healthy subjects.

New Drug Could Help Treat Neonatal Seizures
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A new drug that inhibits neonatal seizures in rodent models could open new avenues for epilepsy treatment in human newborns. Researchers have found that gluconate—a small organic compound found in fruit and honey—acts as an anticonvulsant, inhibiting seizures by targeting the activity of channels that control the flow of chloride ions in and out of neonatal neurons.

Research Looks to Halt Stress-Induced Seizures Following Brain Injury
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The likelihood of developing epilepsy increases significantly with a traumatic brain injury. Stress and anxiety increase that likelihood even more dramatically. Researchers have been able to demonstrate that an injured brain responds differently to stress hormones than a healthy brain. The research team showed abnormal electrical activity in the brain tied to these stress-induced seizures and, most importantly, found a way to stop this activity from occurring.

Synthetic Version of Cannabidiol (CBD) Treats Seizures in Rats
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A synthetic, non-intoxicating analogue of CBD was found to be effective for treating seizures in rats. Researchers note the synthetic CBD alternative is easier to purify than a plant extract, eliminates the need to use agricultural land for hemp cultivation, and could avoid legal complications associated with cannabis-related products.

AZD7325 Has Seizure-Protective Effect in Mouse Model of Dravet Syndrome, Study Says
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Treatment with AZD7325, a compound that stimulates an inhibitory receptor in the brain, has a seizure-protective effect in a mouse model of Dravet syndrome. This treatment significantly increased the temperature threshold animals could withstand without experiencing any seizures during a hyperthermia-induced seizure test.

Children’s Brains Reorganize after Epilepsy Surgery to Retain Visual Perception
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Children can keep their full ability to process and understand visual information after brain surgery for severe epilepsy, according to a study funded by the National Eye Institute, part of the National Institutes of Health. This new report from a study of children who underwent epilepsy surgery and suggests that the lasting effects on visual perception can be minimal, even among children who lost tissue in the brain’s visual centers.

One-Third of Epilepsy Cases Go Untreated up to 3 Years After Diagnosis
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A small yet substantial subset of patients with newly diagnosed epilepsy go without appropriate treatment approximately 3 years after diagnosis. This gap in treatment may be increasing the risk for medical events and hospitalization in these patients.

Study Suggests ‘High Risk Period’ for SUDEP for People with Psychogenic Nonepileptic Seizures in Addition to Epileptic Seizures 
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Findings of a recently published study suggest that patients with comorbid epileptic seizures (ES) and Psychogenic Nonepileptic Seizures (PNES) can die from SUDEP and that there may be a high?risk period after the diagnosis of PNES is made. The authors state such patients should be closely monitored and provided with coordinated care of both their epilepsy and psychiatric disorder(s).

Also Notable

Fralin Biomedical Research Institute Neuroscientist Awarded Grant to Study Epilepsy
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Featuring CURE Grantee Dr. Sharon Swanger

Dr. Sharon Swanger of the Fralin Biomedical Research Institute was recently awarded a $1.7 million grant through the National Institute of Neurological Disorders and Stroke to study the role of glutamate receptors in the thalamus – an area of the brain involved in seizure generation. “If we can figure out how each [receptor] subtype functions and modulate select subtypes, then maybe we can target therapies to the circuit where the disease originated while leaving healthy circuits intact,” said Dr. Swanger.

Tool Helps GPs Predict Risk of Seizures in Pregnancy
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Doctors, midwives, and others can use a new risk calculator to identify those pregnant women at high-risk of seizures and to plan early referral for specialist input. The specialist could determine the need for close monitoring in pregnancy, labor, and after birth, and assess antiepileptic drug management, according to new research in PLOS Medicine. The study authors added that the model’s performance is unlikely to vary with the antiepilepsy drug dose management strategy – and that it could save maternal and infant lives.

Development of Epilepsy Prediction Device to Improve Independence for People with Epilepsy
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The University of Sydney’s Faculty of Engineering and Information Technologies is developing a system, NeuroSyd, which aims at real-time monitoring and processing of brain-signals while driving in a group of people living with epilepsy. NeuroSyd will be developed to deliver an early warning of the likelihood of an epileptic seizure.

Pfizer’s Lyrica at Doses 5mg and 10mg Fails Phase 3 Trial in Epilepsy
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Pfizer’s Lyrica has failed to meet its primary endpoint in a phase 3 trial in primary generalized tonic-clonic (PGTC) seizures. The study evaluated two doses of the drug – 5 mg and 10 mg – over a period of 12 weeks. Treatment with the drug did not result in a statistically significant reduction in seizure frequency versus placebo. Another phase 3 trial in May 2018 was successful, showing that a 14 mg dose of Lyrica resulted in a statistically significant reduction in seizure frequency versus placebo.

Brain Network Activity Can Improve in Epilepsy Patients After Surgery

Successful epilepsy surgery can improve brain connectivity similar to patterns seen in people without epilepsy, according to a new study published in the journal Neurosurgery.

The Vanderbilt University Medical Center (VUMC) study of 15 people with temporal lobe epilepsy is the first to show improvements in brain networks after surgery compared to a group of healthy subjects.

Brain networks involved in the study are important for keeping the brain awake and alert, according to senior author Dario Englot, MD, PhD, surgical director of VUMC’s Epilepsy Program.

“It’s important to realize that, over time, seizures lead to brain network problems which may be related to cognitive deficits seen in patients with epilepsy,” said Englot. “Our new results show some brain network activity can improve with surgery if you stop the seizures.”

Neural Stem Cell Transplantation May Reduce Abnormal Increases in New Cells in the Brains of Mice with Temporal Lobe Epilepsy

Featuring the work of former CURE Grantee Dr. Janice Naegele

Adult neurogenesis, a process whereby new neurons are added to the brain, is thought to be confined in mammals to just a few regions, including the hippocampus, a structure important for learning. Whether this process occurs in the adult human brain is controversial, but in most other mammals that have been studied, adult neurogenesis in the hippocampus appears to be essential for forming memories.

Producing new neurons in the adult hippocampus is regulated by the environment, mood, exercise, diet, and disease. In some forms of epilepsy, the production of new cells in the hippocampus, called granule cells, becomes highly abnormal and the altered neurogenesis is thought to increase over-excitation and exacerbate seizures.

In the Naegele laboratory at Wesleyan, researchers are studying whether neural stem cell transplantation can reduce this abnormal adult neurogenesis in mice that have temporal lobe epilepsy. The research is spearheaded by Janice Naegele, the Alan M. Dachs Professor of Science; professor of biology; and professor, neuroscience and behavior.

“Our prior studies in mice with epilepsy showed that transplanting inhibitory neurons from the embryonic mouse brain into the adult mouse hippocampus reorganized neural circuits in the hippocampus and reduced seizures,” Naegele said. “In our most recent study, we asked whether transplanted inhibitory neurons formed functional synaptic connections with adult-born hippocampal neurons generated after the onset of epilepsy.”

The results of that study were published March 27 in eNeuro, an open-access journal of the Society for Neuroscience. The paper is titled “Restrained Dendritic Growth of Adult-born Granule Cells Innervated by Transplanted Fetal GABAergic Interneurons in Mice with Temporal Lobe Epilepsy.

€8 Million Research Project Aims to Develop New Cure for Epilepsy

A new European research project which aims to heal epilepsy by regenerating brain tissue and ‘training’ neurons is getting underway.

The five-year, €8m Hybrid Enhanced Regenerative Medicine Systems project – HERMES, brings together 12 partners from seven EU countries to heal brain disorders using transplants which combine biological and artificial components.

HERMES researchers will study temporal lobe epilepsy, the most common form of epilepsy, which can be resistant to current pharmacological therapies. Temporal lobe epilepsy affects areas of the brain that are involved in learning, memory and emotions, such as the hippocampus.

HERMES will aim to rebuild the part of the hippocampus damaged by this form of epilepsy. Researchers will generate hippocampal tissue in the laboratory and develop a neuromorphic neuroprosthesis – an electronic device that mimics the normal function of the brain’s neurons.

The two components – one biological and the other artificial – will be implanted in the damaged brain area in an animal model with the aim of rebuilding the damaged hippocampus. The neuromorphic neuroprosthesis will be equipped with artificial intelligence to guide the implanted tissue towards the correct integration within the brain.

The device will then serve as a “trainer” for the tissue recreated in the laboratory and will be discontinued upon complete regeneration and functional recovery of the brain area. The new paradigm introduced by HERMES is called enhanced regenerative medicine.

Seizure Control by Low-Intensity Ultrasound in Mice with Temporal Lobe Epilepsy

BACKGROUND: Temporal lobe epilepsy (TLE) is the most common form of focal epilepsy. Recent studies have demonstrated that ultrasound stimulation can inhibit spontaneous recurrent seizures and improve behavioral outcomes for rodents with TLE. However, the exact underlying mechanism for inhibition of TLE via ultrasound stimulation remains unknown.

METHODS: In this study, low-intensity pulsed ultrasound stimulation (LIPUS) and low-intensity continuous ultrasound stimulation (LICUS) and concurrent local field potentials (LFPs) in the CA3 field of the hippocampus were recorded in the kainite-induced mouse model of TLE. The power spectrum and the phase-amplitude coupling in the LFPs were quantitatively analyzed.

RESULTS: This study found three significant changes in LFPs after ultrasound stimulation: (i) the intensity of the power spectrum in the low frequency (<10 Hz) was significantly decreased (p < 0.01); (ii) the phase amplitude coupling strength between slow (delta-, theta-, and alpha-frequency bands) and fast (gamma frequency bands) neural oscillations were weakened (p < 0.01); (iii) the interval between seizures was significantly increased (p < 0.01).

CONCLUSIONS: These results indicate that the seizures of temporal lobe epilepsy can be effectively inhibited by ultrasound stimulation, and this effect is independent of ultrasound type (pulsed or continuous).

Using Connectomics to Gain Insight into Epilepsy

Abnormalities in structural brain networks and how brain regions communicate may underlie a variety of disorders, including epilepsy, which is one focus of a two-part Special Issue on the Brain Connectome in Brain Connectivity, a peer-reviewed journal from Mary Ann Liebert, Inc., publishers.

This second special issue includes the article entitled “Effective Connectivity within the Default Mode Network in Left Temporal Lobe Epilepsy: Findings from the Epilepsy Connectome Project,” –with results reported from the Epilepsy Connectome Project–contributed by Mary Meyerand, Jeffrey Binder and colleagues from University of Wisconsin-Madison, Medical College of Wisconsin (Milwaukee), and Froedtert Hospital (Milwaukee). Individuals with epilepsy can have memory impairment. Therefore, the researchers studied the default mode network that is a collection of brain regions involved in memory function. The results showed a difference in these memory-related connections between healthy individuals and individuals with epilepsy. The researchers identified an excitatory connection association with inhibition of formation of the left hippocampal region in patients with temporal lobe epilepsy.

The Special Issues were led by Guest Editors Brent Munsell, PhD, College of Charleston (SC), Guorong Wu, PhD, University of North Carolina at Chapel Hill, Leonardo Bonilha, MD, PhD, Medical University of South Carolina (Charleston), and Paul Laurienti, MD, PhD, Wake Forest School of Medicine (Winston-Salem, NC).

Researchers ID Factors Predictive of Naming Decline After Epilepsy Surgery

Paper- and online-based externally validated nomograms are effective in predicting naming decline after temporal lobe surgery in patients with epilepsy, according to study results published in Neurology. Factors predictive of postsurgical naming decline in this patient population included side of surgery, age at epilepsy onset, age at surgery, sex, and education, and preoperative naming score.

A total of 719 patients with epilepsy who underwent temporal lobe epilepsy surgery at the Cleveland Clinic were included in the study. In addition, the investigators enrolled an external validation cohort of 138 patients who also underwent temporal lobe surgery at Columbia University Medical Center, Emory University School of Medicine, or University of Washington School of Medicine.

Groundbreaking Stem Cell Brain Implant Helps Fight Epilepsy in Rats

Severe epilepsy is very difficult to treat, but an experimental approach involving implanted stem cells in the brain represents a groundbreaking way to potentially stop seizures for good.

Carried out by researchers at Texas A&M University, the technique has yet to be tried on human subjects, but has proven highly successful on rats. Rats given the implants suffered 70 percent fewer seizures than those without. That figure could drop further with additional research.

The investigation is the first study of its kind. It demonstrated that grafting certain cells derived from human-induced pluripotent stem cells into the brain can help alleviate seizures, as well as improve brain function. The work targets temporal lobe epilepsy (TLE), the most common type of epilepsy in which seizures originate from the brain’s hippocampus. TLE is a non-genetic form of epilepsy, often resulting from an incident such as a traumatic head injury, brain infections, or fever-related seizures during childhood.

Experiences of Self-Conscious Emotions in Temporal Lobe Epilepsy

Self-conscious emotions (SCEs) with a negative valence (such as shame and guilt) or a positive valence (such as pride) are moral emotions that emerge from self-reflection and self-evaluation processes in social contexts. In some neurologic and psychiatric disorders, experiences of SCEs are dysregulated.

Relative to controls, patients with TLE were more likely to experience negative-valence SCEs to a higher extent and positive SCEs to a lesser extent. The patients who experienced negative-valence SCEs to a higher extent (rather than to a lesser extent) had a higher frequency of seizures, more severe anxiety and depressive symptoms, and a greater prevalence of anxiety and depressive disorders. Furthermore, patients who experienced positive-valence SCEs to a lesser extent (rather than to a higher extent) displayed a higher level of anxiety. Lastly, differences in experiences of SCEs by patients with TLE were associated with a lower quality of life.

In conclusion, experiences of SCEs can be dysregulated in patients with TLE. This dysregulation is linked to the patients’ clinical and psychological symptoms and quality of life. In this context, SCEs might be a target of interest in the management of epilepsy.