CURE Discovery: Temporal Lobe Epilepsy and Memory Impairment

Key Points

Picture of the researcher

  • CURE Taking Flight grantee, Dr. Tristan Shuman and his team, in collaboration with two other research groups, used a mouse model of temporal lobe epilepsy (TLE) to examine how chronic epilepsy leads to cognitive and memory deficits.
  • The team developed innovative research tools, including a wireless miniature microscope that can “see” into the brain and analyze the exact firing patterns brain cells use to communicate with each other.
  • The team found that disrupting these firing patterns plays an important role in the development of memory deficits. Restoring these firing patterns may someday provide relief from the memory deficits and cognitive delays that accompany TLE.

Deep Dive

Temporal lobe epilepsy (TLE), which occurs in the temporal lobe of the brain, is the most common type of focal epilepsy.1,2 Unfortunately, people with TLE also often experience disabling cognitive and memory impairments.1 With support from a CURE Taking Flight award, Dr. Tristan Shuman and his team may have discovered a possible cause for these debilitating symptoms. His team at the Icahn School of Medicine at Mount Sinai in New York collaborated with Dr. Peyman Golshani’s laboratory at the University of California, Los Angeles. Together, they examined how two small areas of the brain that play key roles in memory and learning share information between each other to explore possible origins of the cognitive and memory deficits that develop in people with chronic epilepsy.

HippocampusThe temporal lobe of the brain contains a region called the hippocampus which plays a vital role in regulating learning, memory, and spatial navigation.3 Dr. Shuman and his team focused on two subregions of the hippocampus important in spatial navigation: the dentate gyrus (DG) and the CA1. Spatial information from other areas in the brain enters through the DG and leaves through the CA1.3 Dr. Shuman aimed to understand if disrupting this input/output circuit contributed to the cognitive and memory deficits observed in mice with TLE.

To study the interactions between the neurons in the DG and CA1, Dr. Shuman and colleagues first developed novel tools which enabled them to make their initial findings. They determined that in mice with chronic epilepsy, electrical impulses moving between neurons in the DG and CA1 were disrupted, indicating that these two regions were not able to process spatial information.

Hippocampus

The researchers then examined how each individual neuron fired as the mice ran along a track. To accomplish this, the mice were fitted with a wireless, mouse-sized mini microscope, created by Dr. Shuman and his collaborators, that can “see” into the brain and record the activity of hundreds of neurons. They discovered that in the brains of mice with epilepsy, the number of place cells, a specific type of CA1 neuron that gathers and relays information about the position of objects in space, was reduced when compared to normal mice. In normal mice, these place cells were stable and active in the same location every day that the animals ran on the track. However, in the mice with TLE, the place cells changed their firing patterns every few minutes, indicating that the mice could not remember their location.

To further his research, Dr. Shuman collaborated with Dr. Panayiota Poirazi at the Foundation for Research and Technology Hellas in Greece to confirm his findings using a computer model. Using this approach, the team confirmed that by changing the timing of electrical inputs into the hippocampus, they could disrupt processing of spatial information.

Understanding how individual neuronal circuits are disturbed in epilepsy is a first step in creating future therapies to target disrupted firing patterns in people with epilepsy. By continuing to explore this promising avenue of research, scientists may one day be able to design therapeutic interventions that restore neuronal firing patterns, reducing seizures and improving cognitive function for people with chronic epilepsy.

Literature Cited

1Bell, B. et al. The neurobiology of cognitive disorders in temporal lobe epilepsy. Nat. Rev. Neurol. 2011; 7(3): 154-164.
2 Téllez-Zenteno, J.F. & Hernández-Ronquillo, L. A review of the epidemiology of temporal lobe epilepsy. Epilepsy Res. Treat. 2012; 2012: 630853.
3 Saniya, K. et al. Neuroanatomical changes in brain structures related to cognition in epilepsy: an update. J. Nat. Sci. Biol. Med. 2017; 8(2): 139-143.

Probable Reasons for the Underutilization of Neurosurgery for Drug Resistant Epilepsy (DRE): A Literature Review

Abstract, published in Epilepsia

Patients with drug-resistant epilepsy (DRE) rarely achieve seizure freedom with medical therapy alone. Despite being safe and effective for select patients with DRE, epilepsy surgery remains heavily underutilized. Multiple studies have indicated that the overall rates of surgery in patients with DRE have stagnated in recent years and may be decreasing, even when hospitalizations for epilepsy-related problems are on the rise. Ultimately, many patients with DRE who might otherwise benefit from surgery continue to have intractable seizures, lacking access to the full spectrum of available treatment options.

In this article, researchers review the various factors accounting for the persistent underutilization of epilepsy surgery and uncover several key themes, including the persistent knowledge gap among physicians in identifying potential surgical candidates, lack of coordinated patient care, patient misconceptions of surgery, and socioeconomic disparities impeding access to care. Moreover, factors such as the cost and complexity of the preoperative evaluation, a lack of federal resource allocation for the research of surgical therapies for epilepsy, and difficulties recruiting patients to clinical trials all contribute to this multifaceted dilemma.

Temporal Lobe Surgery and Memory: Lessons, Risks, and Opportunities

Careful study of the clinical outcomes of temporal lobe epilepsy (TLE) surgery has greatly advanced our knowledge of the neuroanatomy of human memory. After early cases resulted in profound amnesia, the critical role of the hippocampus and associated medial temporal lobe (MTL) structures to declarative memory became evident. Surgical approaches quickly changed to become unilateral and later, to be more precise, potentially reducing cognitive morbidity.

Neuropsychological studies following unilateral temporal lobe resection (TLR) have challenged early models, which simplified the lateralization of verbal and visual memory function. Diagnostic tests, including intracarotid sodium amobarbital procedure (WADA), structural magnetic resonance imaging (MRI), and functional neuroimaging (functional MRI (fMRI), positron emission tomography (PET), and single-photon emission computed tomography (SPECT)), can more accurately lateralize and localize epileptogenic cortex and predict memory outcomes from surgery. Longitudinal studies have shown that memory may even improve in seizure-free patients.

From 70 years of experience with epilepsy surgery, science now has a richer understanding of the clinical, neuroimaging, and surgical predictors of memory decline-and improvement-after TLR.

Epilepsy Research Findings: November 2019

Among the interesting research published this past month are advances in epilepsy genetics that may help predict who is at risk for developing epilepsy and a novel gene therapy concept for treating temporal lobe epilepsy. Research has also furthered our understanding of how epilepsy may impact cognition – even when seizures are controlled by medication.

In this update, we also feature the results of the “Seize the Truth about Epilepsy Perceptions” survey. This national survey of adult epilepsy patients, caregivers, and healthcare professionals explores the physical, social, emotional, and financial consequences associated with epilepsy.

Summaries of these research discoveries and news highlights are below.

Research Discoveries & News

  • Epilepsy Genetics: Risk scores are being used to investigate the genetic risk of epilepsy in a large sample of people with and without epilepsy. The international team led by the Cleveland Clinic is using this model to work towards a more personalized method of epilepsy diagnosis and treatment. Learn more
  • Epilepsy Gene Therapy: A new gene therapy concept has been developed for the treatment of temporal lobe epilepsy. In a “proof-of-concept” study, the researchers demonstrated that strategically delivering a specific gene to the place in the brain where seizures start can suppress them on demand in animal models. Learn more
  • Understanding Epilepsy: A new, national survey of adult epilepsy patients, caregivers, and healthcare professionals (HCPs) revealed a wide range of challenges in the management of the condition. The findings range from significant disconnects that occur in conversations among patients, caregivers, and HCPs to revelations about the far-reaching impact of epilepsy. Learn more
  • Epilepsy and Cognition: A study by Stanford University School of Medicine investigators may help explain why even people benefiting from medications for their epilepsy often continue to experience bouts of difficulty thinking, perceiving, and remembering clearly. The cause is a pathological buzz of electrical brain activity, called a high-frequency oscillation, that interferes with the brain’s normal activity. Learn more
  • Seizures in Newborns: Utilizing a mouse model of hypoxic-ischemic seizures has shed light on why seizures in newborns may lead to behavioral issues and learning disabilities much later, according to a study from University of Virginia Children’s Hospital. This research suggests that the brain’s learning and memory centers are among the regions most affected by seizures caused by inadequate oxygen and blood flow. Learn more

Introducing the CURE Epilepsy Research Mobile App for research updates in the palm of your hand! Download today. iOS | Android

Gene Therapy for Epilepsy Shows Promise in Animal Models

A new gene therapy concept has been developed for the treatment of temporal lobe epilepsy. The researchers demonstrated that this strategy is capable of suppressing seizures at their site of origin on demand in animal models.

The study was conducted at Charité – Universitätsmedizin Berlin, Germany and the Medical University of Innsbruck, Austria. The method is now being optimised for clinical trials.

The technique involves the selective delivery of a specific gene to nerve cells within the area of the brain where the epileptic seizures originate.

The gene is delivered via an adeno-associated virus (AAV), which then provides the cells with the information they need to synthesise dynorphins: naturally produces peptides that modulate neural activity.

Professor Christoph Schwarzer, one of the lead researchers, said: “High-frequency stimulation of the nerve cells, such as that seen at the beginning of a seizure, results in the release of stored dynorphins. Dynorphin dampens signal transduction and as a result, the epileptic seizure doesn’t spread… As the cells will only release this substance when needed, this type of gene therapy is referred to as ‘release-on-demand’.”

Using an animal model, the researchers were able to show that this gene therapy is capable of suppressing epileptic seizures for several months.

Moreover, no side effects were observed, which the researchers suggest is due to the site-specific release of dynorphin and its short duration of action.

An Interneuron

Epilepsy: Function of ‘Brake Cells’ Disrupted

In some forms of epilepsy, the function of certain “brake cells” in the brain is presumed to be disrupted. This may be one of the reasons why the electrical malfunction is able to spread from the point of origin across large parts of the brain. A current study by the University of Bonn, in which researchers from Lisbon were also involved, points in this direction. The results will be published shortly in the renowned Journal of Neuroscience, but are already available online.

For their study, the researchers investigated rats suffering from temporal lobe epilepsy. This is the most common form of the disease in humans. Unfortunately, it barely responds to the currently available medicines. “This makes it all the more important to determine exactly how it arises,” stresses Dr. Leonie Pothmann, who completed her doctorate on the subject at the Institute of Experimental Epileptology at the University of Bonn.

The data that has just been published may help scientists with this endeavor, because they indicate that a certain cell type does not function properly in patients. The affected cells are a class of so-called inhibitory interneurons, which are cells that can attenuate the excitation of brain areas. “We investigated interneurons in the hippocampus, an area of the temporal lobe known as the focus of epileptic seizures,” explains Pothmann.

Pyramidal cells play an important role in the transmission of excitation in the hippocampus. They generate voltage pulses in response to an electrical stimulus. These stimulate, among other things, interneurons, which in turn inhibit the pyramidal cells. This feedback loop acts as a kind of brake: It prevents the voltage pulses from propagating unhindered. An epileptic seizure would thus be nipped in the bud before it is able to spread to other parts of the brain.

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
Learn More

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 
Learn More

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
Learn More

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
Learn More

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
Learn More

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
Learn More

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
Learn More

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
Learn More

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
Learn More

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 
Learn More

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
Learn More

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
Learn More

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
Learn More

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
Learn More

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.