Research Reveals Underappreciated Role of Brainstem in Epilepsy

New research from Vanderbilt suggests that repeated seizures reduce brainstem connectivity, a possible contributor to unexplained neurocognitive problems in epilepsy patients.

The brainstem has been rarely studied in epilepsy because seizures typically originate in the temporal lobe or other areas of the cortex. Noting that people with temporal lobe epilepsy often lose consciousness even though the temporal lobe does not control wakefulness, Dario Englot, MD, PhD, surgical director of epilepsy at Vanderbilt University Medical Center, said he decided to focus on the region that does control wakefulness — the brainstem. He hypothesized that connectivity disruptions with the brainstem resulting from a history of seizures might play a role in diminished cognitive functions that are not related to the temporal lobe.

The research, published online May 30 in Neurology, is the first to investigate how epilepsy affects the ascending reticular activating system (ARAS) — circuitry that is responsible for regulating wakefulness — within the brainstem. Functional magnetic resonance imaging revealed that ARAS disruptions occurred, with decreases in circuitry being quantitatively associated with disease severity.

“Seizures do not start in areas deep below the surface of the brain called subcortical nuclei,” said Englot, the study’s lead author and assistant professor of Neurological Surgery, Radiology and Radiological Sciences and Biomedical Engineering. “So these areas are not often studied in epilepsy. But we think that problems develop in some deep subcortical circuits that may contribute to some of the unexplained global brain problems in temporal lobe epilepsy, including progressive neurocognitive problems and problems with arousal that can’t be explained by problems in the temporal lobe.”

Study: Increased Cardiac Stiffness is Associated with Autonomic Dysfunction in Patients with Temporal Lobe Epilepsy

Autonomic dysfunction is linked to sudden death regardless of the presence of structural heart disease. The pathway from autonomic dysfunction to sudden death is not fully understood, but myocardial sympathetic stimulation leading to arrhythmia and/or cardiac fibrosis might play a role. Our goal was to evaluate cardiac stiffness by echocardiography and its association with clinical, structural, and autonomic variables in people with epilepsy (PWE) compared to healthy controls.

A 12-lead electrocardiogram, treadmill testing, and transthoracic echocardiography from 30 patients with temporal lobe epilepsy (TLE) without any known cardiovascular disorders were compared to 30 individuals without epilepsy matched by sex, age, and body mass index. Distribution of cardiovascular risk factors was similar in both groups. PWE had a higher left ventricle stiffness, left ventricle filling pressure, and greater left atrial volume as well as markers of autonomic dysfunction such as impaired chronotropic index and percentage achieved of predicted peak heart rate at effort. In multiple regressions, autonomic dysfunction explained 52% of stiffness and carbamazepine treatment and polytherapy with antiepileptic drugs (AEDs) explained, additionally, 6% each.

Stiffness is increased in young patients with TLE and is related to autonomic dysfunction and to a lesser extent, carbamazepine use and polytherapy with AEDs.

Study: Phenotypic Spectrum in Families with Mesial Temporal Lobe Epilepsy Probands

Purpose: The traditional perception of mesial temporal lobe epilepsy (MTLE) as a predominantly acquired disorder is challenged due to emerging evidence of familial aggregation. In this study, we ascertained the extent of familial occurrence of epilepsy in MTLE patients, as well as phenotypic heterogeneity in affected relatives.

Methods: We identified and reevaluated patients with MTLE, treated at Epilepsy Department for a period of two years. All eligible putatively affected relatives were asked to participate in the study. In addition to comprehensive epilepsy interview, they underwent EEG and MRI studies.

Results: 52 patients with MTLE were included; nine of them (17%) had at least one family member with epilepsy. Subsequently, we analyzed nine probands with MTLE and a total of 15 relatives with seizures. Among affected relatives, spectrums of clinical manifestations were observed. Typical MTL seizures were described in five individuals, while other types of focal or generalized tonic-clonic seizures were reported in other ten relatives. A total of seven individuals had febrile seizures. Hippocampal sclerosis was found in three probands and none of the relatives. Two of affected family members had a traumatic brain injury in addition to febrile seizures, prior to the occurrence of their epilepsy.

Conclusion: We demonstrate that familiar occurrence of epilepsy and subsequently putative genetic background, accounts for a substantial proportion MTLE patients. In addition, we foreground the remarkable intra- and interfamilial phenotypic heterogeneity than usually described, displaying the complexity of the genotype-phenotype correlations.

Presurgical imaging may predict whether epilepsy surgery will work

According to, “A Hierarchical Bayesian Model for the Identification of PET Markers Associated to the Prediction of Surgical Outcome after Anterior Temporal Lobe Resection,” a study in Frontiers in Neuroscience [1]:

[Researchers] have identified a subgroup of temporal lobe epilepsy patients at high risk for post-surgical seizure recurrence after anterior temporal lobe resection.

[The study] developed an integrative Bayesian predictive modeling framework that identifies individual pathological brain states based on the selection of fluoro-deoxyglucose positron emission tomography (PET) imaging biomarkers and evaluated the association of those states with a clinical outcome.

[The study] shows that the proposed method achieves high cross-validated accuracy in predicting post-surgical seizure recurrence.

CURE Conversations: Esther Krook-Magnuson, PhD

Get to know our researchers! CURE Conversations features interviews with our scientists and discusses the focus of their work as well as recent breakthroughs in the field of epilepsy research. These investigators are the people behind the scenes who work diligently in the labs to unravel the mysteries of epilepsy, studying the science that will one day lead to cures for the epilepsies.

Assistant Professor, Department of Neuroscience, University of Minnesota

Can you share some details about what you do?
I am working to understand the specific roles of the different types of brain cells, how they work together to form functional groups or networks, and how those networks in turn interact. Using a mouse model of temporal lobe epilepsy, I seek to understand how these interactions can give rise to seizures, and how the system can be manipulated to stop or inhibit seizures.

What motivated you to become interested in this area of research?
To be honest, I avoided epilepsy research for a long time, because I was frustrated by what seemed to an outsider to be a laundry list of changes seen with epilepsy, without any clear understanding of causation and thus having limited potential to make a positive impact. However, in part due to new tools, the field is changing. My initial project with epilepsy was one I believed in; something I thought someone needed to do. And now I feel equipped to use these tools to answer some important questions.

What is your current research focus?
I am currently using a tool called optogenetics—which allows unprecedented specificity of intervention—to understand seizure circuitry and identify potential new targets for intervention and to look at the outcomes of such selective intervention strategies. I use optogenetics in what is called an “on-demand” or “responsive” fashion to modulate specific aspects of the brain circuitry selectively at the time of seizures.

Can you share some of the latest findings?
Recently, I found that modulating a brain region not typically associated with temporal lobe epilepsy can have profound and unique inhibitory effects on temporal lobe seizures. I have also found that, by identifying key components in the seizure network, it is possible to reduce the degree of intervention (to directly target fewer cells) without greatly sacrificing the efficacy of the intervention.

What is the ultimate goal for the research and how will it impact patients with epilepsy?
The goal is to understand epilepsy circuitry and identify ways to stop or prevent seizures while interfering as little as possible. The ultimate goal is to have a strategy that stops seizures without producing negative side effects—intervention where it is needed, when it is needed, and no more.

What accomplishment—personal or professional—are you most proud of?
While I am extremely proud of our research, I am most proud of my wonderful family. I was raised in an amazing, large family, and now I have a terrific and supportive husband and two children I couldn’t be prouder of. My children aren’t really an “accomplishment,” but I am very proud of them. I am also extremely lucky that they are healthy, and that is something I wish for all parents.

CURE Conversations: Janice R. Naegele, PhD

Get to know our researchers! CURE Conversations features interviews with our scientists and discusses the focus of their work as well as recent breakthroughs in the field of epilepsy research. These investigators are the people behind the scenes who work diligently in the labs to unravel the mysteries of epilepsy, studying the science that will one day lead to cures for the epilepsies.

Can you share some details about what you do?
I am a Professor of Biology, Neuroscience and Behavior at Wesleyan University, where I have been on the faculty for 23 years. In addition to teaching courses in neuroscience and developmental neurobiology, I especially enjoy working closely with students in my research laboratory. My research group includes undergraduates, Masters, and PhD students, and my lab manager/research technician. In addition to research and teaching, I direct the Wesleyan Center for Faculty Career Development. As part of this job, I mentor and help to train junior faculty and have a strong commitment to promoting inclusion of women and minorities in science and mathematics. I am also involved in advocacy work on behalf of the American Epilepsy Society, and I serve on the Board of Trustees of the Lennox-Lombroso Trust.

What motivated you to become interested in this area of research?
I have a long-standing interest in neuronal regeneration and neural plasticity. My lab has worked for many years on GABAergic interneurons and their roles in neural development and epilepsy. Our research focusing on stem cell therapies for temporal lobe epilepsy developed as a result of conversations with clinicians working with patients with severe intractable seizures and scientific discussions with stem cell biologists. My father-in-law, the late Dr. Cesare Lombroso, had a tremendous impact on my decision to shift my laboratory’s research focus from neural development to translational models of epilepsy and the development of therapies.

What is your current research focus?
In my lab, we are broadly interested in understanding the mechanisms of epileptogenesis and in developing stem cell transplantation approaches for stimulating repair of hippocampal circuits in mouse model of temporal lobe epilepsy. A sustained seizure may trigger GABAergic interneuron cell death in the hippocampus and related limbic circuits, and increase the rate of adult granule cell neurogenesis, axonal sprouting and other plastic changes.

These neuroplastic changes contribute to hyperexcitability, spontaneous seizures, and can lead to cognitive impairments. Our research focuses on preventing the degeneration of GABAergic interneurons after seizures and on developing cell-based therapies to replace these neurons to cure temporal lobe epilepsy. We are testing the ability of mouse and human embryonic stem cell-derived GABAergic neurons and fetal GABAergic cells to integrate and form synapses with adult-born granule neurons after the stem cells are transplanted into the hippocampus of adult mice with TLE.

Our studies monitoring seizures behaviorally and with electroencephalography have shown that GABAergic progenitors suppress seizures and integrate into mature hippocampal neural circuits. We are studying how the transplanted neural stem cells integrate synaptically and whether they improve disease outcomes.

Can you share some of the latest findings?
In rodent epilepsy models, transplants of a certain cell type that inhibit brain activity provide short-term seizure suppression. Few studies have examined the cellular mechanisms or the long-term effects of these transplants on seizure suppression. In this study, we examined seizure frequency and duration for over 100 days following cell transplant. Compared with controls, mice with temporal lobe epilepsy that had transplants showed significant attenuation of spontaneous seizures, beginning by about 3-4 weeks after transplantation.

To determine whether the gradual disease modifying effects of the transplants were due to increased inhibition of a certain type of cell, we measured several physiological properties of the cells. Our data suggest that greater inhibition is responsible for attenuating spontaneous seizures. Furthermore, strong seizure suppression was associated with the formation of new inhibitory networks in certain areas of the brain near the transplant. These results indicate that transplanted inhibitory cells mediate long-term spontaneous seizure suppression by forming new inhibitory networks with the hyperexcitable cells thought to contribute to seizure generation.

What is the ultimate goal for the research and how will it impact patients with epilepsy?
The goal of our research is to develop and optimize cell-based therapies for treating patients with severe temporal lobe epilepsy and other forms of intractable seizures. Before moving into the clinic, it is essential that we understand the mechanisms for integration of transplanted cells, whether these transplanted cells can survive for long periods, how they wire up with cells in the host brain, and whether they have adverse consequences or beneficial effects on cognition, in addition to suppressing seizures.

What accomplishment—personal or professional—are you most proud of?
I am extremely proud of my former trainees and students, many of whom have gone on to careers in basic neuroscience research or clinical medicine. Many of them are currently working in basic neuroscience research or exploring frontiers in translational neuroscience to understand the causes of epilepsy and other neurological conditions.

CURE Conversations: Dr. Jim McNamara

Get to know our researchers! CURE Conversations features interviews with our scientists and discusses the focus of their work as well as recent breakthroughs in the field of epilepsy research. These investigators are the people behind the scenes who work diligently in the labs to unravel the mysteries of epilepsy, studying the science that will one day lead to cures for the epilepsies.

M.D., University of Michigan, 1968
A.B., Marquette University, 1964

Duke School of Medicine Professor of Neurosciences
Departments of Neurobiology and Neurology
Director, Center for Translational Neuroscience
Duke University School of Medicine

Work in Dr. McNamara’s laboratory seeks to elucidate the mechanisms of epileptogenesis, the process by which a normal brain becomes epileptic. Understanding the mechanisms of epileptogenesis in molecular terms may provide novel targets for pharmacologic interventions for prevention of epilepsy.

Earlier this year, CURE announced a partnership with the Howard Hughes Medical Institute’s Research Fellows Program to provide support for up to three medical students to conduct mentored research on epilepsy. One of the Fellows CURE is supporting is Ethan Ludmir, a second year medical student at Duke University School of Medicine. He will be working in Dr. McNamara’s lab, studying cellular and molecular mechanisms underlying development of temporal lobe epilepsy. In 2007, CURE awarded Dr. McNamara a Traumatic Brain Injury (TBI) grant. He eventually shifted his focus to temporal lobe epilepsy, and recently had a major breakthrough.

After completing his residency training in neurology, postdoctoral training in biochemistry, and two years of military service practicing neurology, Dr. James McNamara was offered a faculty position combining clinical work in epilepsy with a preclinical research program in epilepsy. Ever since, he’s been dedicated to researching the molecular mechanisms underlying development of temporal lobe epilepsy. This work culminated in an exciting recent discovery, the identification of a molecular mechanism by which an episode of prolonged seizures in a mouse results in temporal lobe epilepsy and associated anxiety-like behavior.

Dr. McNamara was kind enough to speak with CURE about this exciting discovery.

How did you become interested in epileptogenesis?
I’m a neurologist and interested in developing novel treatments for neurological diseases by understanding mechanisms of the diseases. I wanted to align my research program with my clinical interests and was offered a position at Duke to run an epilepsy program in 1975.This led me to focus my research interests on epilepsy and, in particular, on a problem aligned with my training in biochemistry. This led me to seek the biochemical or molecular mechanism by which temporal lobe epilepsy develops. This was a dream opportunity for me because I could combine care of patients with the same disorder that I investigated in the laboratory. Insights into the disease at the bedside guided and informed my laboratory studies. Likewise, insights from the laboratory studies helped me better understand and treat patients with epilepsy. I am privileged to have been able to pursue this career.

So it’s a cycle—between the lab and the physicians’ office?
Exactly—it’s a mutually reinforcing cycle. I am blessed to have been able to do this.

How would you describe this discovery to someone unfamiliar with the science behind epilepsy?
This requires a bit of an explanation. First of all, the temporal lobes of the brain are important for memory formation. Temporal lobe seizures disrupt the function of the temporal lobe transiently, so it is not surprising that individuals experiencing such a seizure have no memory of the event and the individual is unaware of her or his surroundings during the seizure. The unpredictable occurrence of temporal lobe seizures limits the patient’s ability to drive and to do many jobs.

Temporal lobe epilepsy is one of the most common forms of epilepsy, accounting for approximately 40% of patients. What causes temporal lobe epilepsy? One cause of the most severe cases appears to be an episode of prolonged seizures early in life, the episode frequently triggered by a fever. Inducing an episode of prolonged seizures in a normal mouse is followed by recovery and the emergence of severe temporal lobe epilepsy days to weeks later. We wanted to understand how the prolonged seizure transformed a mouse brain from normal to epileptic because this would provide a clue to what is going on in humans. We recently discovered that the prolonged seizure triggers excessive activation of a receptor called TrkB and that this excessive activation is required for induction of late onset epilepsy.

We are excited about this discovery for three reasons. Our work demonstrates that it is possible to prevent emergence of epilepsy even if we initiate treatment with an inhibitor of TrkB after the episode of prolonged seizures; this is important because treatments started after the prolonged seizure in a human may also be effective. We also found that inhibiting TrkB for just two weeks was sufficient to prevent the animal from becoming epileptic when studied weeks to months later; this is important because treatment of humans for a relatively period following the prolonged seizures may be effective, the brief period limiting unwanted effects of the drug. Finally, our work identifies a specific receptor, TrkB, that is critical and raises hope that drugs to inhibit TrkB can be developed and tested for preventive treatment.

Your discovery raises the possibility of preventive treatment for the most common form of human epilepsy. Are there preventive treatments for other common diseases of the brain? If not, why not?
This is an excellent question. Apart from treating high blood pressure and elevated lipids for prevention of stroke, there are no preventive treatments for any common disease of the human brain. For example, we have no treatments to prevent development of Alzheimer’s or Parkinson’s disease, schizophrenia, manic-depressive disease, multiple sclerosis, etc. The lack of preventive treatments reflects the complexity of the challenge. Availability of an informative animal model of these common diseases is enormously helpful but, even if available, there are literally hundreds of thousands of possibilities. Enormous advances in basic science in the fields of molecular biology, imaging, chemistry, and many others are paving the way for attacking these difficult problems. I am optimistic that scientists will make great progress with these challenges during the next decade and this progress will greatly reduce the burden of disease of the nervous system and other organs as well.

Are genetics involved? For example, if a parent has one prolonged seizure in their lifetime, does it affect the chances that their child will develop epilepsy? Is this something that will be studied?
Longitudinal studies of children who have prolonged seizures reveals that roughly 40% of them go on to develop epilepsy later in life. Why is it that 40% develop epilepsy and the remaining 60% do not? I suspect that one factor that accounts for these differences is genetic susceptibility.

What are the next steps? What is involved in developing a drug?
The next step is to develop a drug that potently and selectively inhibits TrkB. I think that such a drug may benefit multiple disorders of the nervous system, including epilepsy. Developing such a drug requires substantial expertise, resources, time and energy. We and others are working hard on this important challenge. Success with this effort holds promise for preventing epilepsy that arises after episodes of prolonged seizures.