News Topics: Post-Traumatic Epilepsy

Research Looks to Halt Stress-Induced Seizures Following Brain Injury

For the over one million Canadians living with traumatic brain injury, the likelihood of developing epilepsy increases significantly because of their injury. When faced with stress or anxiety, that likelihood increases even more dramatically.

While a clinically well-known phenomenon, exactly what is occurring in the brain to cause this relationship has always been unclear.

Now, Western researchers have demonstrated a key factor in this relationship is that an injured brain responds differently to stress hormones. The team was able to show abnormal electrical activity in the brain tied to these stress-induced seizures and, most importantly, they found a way to stop it from occurring.

In a publication for eNeuro, “CRF Mediates Stress-Induced Pathophysiological High-Frequency Oscillations in Traumatic Brain Injury,” the research team used a rodent model of traumatic brain injury. When the animals were subjected to a stressful and anxiety provoking situation, all developed epileptic seizures. In controls with no injury, none developed seizure activity when a stressor was applied.

Epilepsy Research Findings: May 2019

In this month’s research news, treatments, genetic analysis, and preclinical work offer hope to those impacted by hard-to-treat or difficult-to-diagnose forms of epilepsy.

Exciting treatment developments include a positive Phase 3 clinical trial outcomefor the cannabidiol-based drug EPIDIOLEX® for the treatment of seizures associated with tuberous sclerosis complex. In addition, an improved treatment regimen targeting the severe, prolonged seizures that make up status epilepticus has been created.

In promising genetics news, a report from CURE’s own Epilepsy Genetics Initiativeunderscores the value of continued reanalysis of genetic information from people with epilepsy to increase their chances of obtaining a genetic diagnosis for their epilepsy.

Additionally, important preclinical work led by CURE Grantees Dr. Chris Dulla and Dr. Janice Naegele uncovers a potential drug to treat post-traumatic epilepsy and a way to restore the balance of brain activity and reduce seizures in temporal lobe epilepsy, respectively.

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

Treatment Advances

GW Pharmaceuticals Reports Reduction in Seizure Frequency for EPIDIOLEX® (cannabidiol) Oral Solution in Patients with Seizures Associated With Tuberous Sclerosis Complex
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GW Pharmaceuticals and Greenwich Biosciences announced positive top-line results of a Phase 3 clinical trial of EPIDIOLEX® (cannabidiol or CBD) in the treatment of seizures associated with Tuberous Sclerosis Complex (TSC). TSC is a rare and severe form of childhood-onset epilepsy. In this trial, EPIDIOLEX met its primary endpoint, which was a reduction in seizure frequency in the group given EPIDIOLEX compared to the placebo group.

Breakthrough for Children with Serious Epileptic Seizures
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A new treatment regimen of administering levetiracetam and phenytoin one after the other has given emergency medicine doctors a better way to treat severe, prolonged epileptic seizures in children. These treatment modifications will lower the chances of intubation and intensive care, as well as increase the chances of children recovering more quickly.

Diagnostic Advances

The Epilepsy Genetics Initiative: Systematic Reanalysis of Diagnostic Exomes Increases Yield
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Featuring CURE’s Epilepsy Genetics Initiative

Results from CURE’s Epilepsy Genetics Initiative (EGI) show that when the genetic information of a person with epilepsy is systematically reanalyzed, there is an increase in the return of a genetic diagnosis. Eight new diagnoses were made as a result of updated annotations or the discovery of novel epilepsy genes after the initial diagnostic analysis was performed. One novel epilepsy gene was discovered through dual interrogation of research and clinically generated whole-exome sequencing. According to this recently-published report, EGI’s contributions to gene discovery underscore the importance of data sharing and the value of collaborative enterprises.

Research Discoveries

Using a Drug that Mimics the Ketogenic Diet to Help Prevent Epilepsy after Traumatic Brain Injury
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Featuring the work of CURE Grantee Dr. Chris Dulla

Neuroscientists led by CURE Grantee Dr. Chris Dulla at Tufts University School of Medicine prevented the development of epileptic activity in mice after traumatic brain injury by using a drug that mimics the metabolic effects of the ketogenic diet.

Neural Stem Cell Transplantation May Reduce Abnormal Increases in New Cells in the Brains of Mice with Temporal Lobe Epilepsy
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Featuring the work of CURE Grantee Dr. Janice Naegele

According to a new, CURE-funded study featuring the work of grantee Dr. Janice Naegele, the transplantation of inhibitory cells into the brains of mice with temporal lobe epilepsy may reduce the abnormal growth of new neurons in an area of the brain called the hippocampus. This in turn could reduce brain hyperexcitability that leads to seizures.

Stimulating the Epileptic Brain Breaks Up Neural Networks to Prevent Seizures
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Responsive neurostimulation treats epilepsy by detecting seizures and intervening with a jolt of electric current. Over time, most patients find their seizures become fewer and further between. New evidence suggests responsive neurostimulation can remodel the brain to be less susceptible to seizures.

Scientists Discover Trigger Region for Absence Epileptic Seizures
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Scientists have discovered a neurological origin for absence seizures – a type of seizure characterized by very short periods of lost consciousness in which people appear to stare blankly at nothing. Using a mouse model of childhood epilepsy, a group of scientists has shown that absence epilepsy can be triggered by impaired communication between two brain regions: the cortex and the striatum.

Autism-Related Memory and Seizures Improved through Gene Repair in Adults
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Scientists have shown that correcting the protein deficiency caused by a genetic form of autism spectrum disorder in adult mice can improve behavioral and electrophysiological measures of both memory and seizure. The evidence suggests this is true even when the treatment is carried out well past what has traditionally been thought of as the critical window of early brain development.

Drug Used to Treat Multiple Sclerosis May Be Beneficial for Individuals with Epilepsy 
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A drug commonly used to treat multiple sclerosis may, after necessary modifications, one day be used to treat patients with epilepsy, according to research from the laboratory of Dr. Inna Slutsky.

Study Reveals How Glial Cells May Play Key Epilepsy Role
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A study provides potential new targets for treating epilepsy and novel fundamental insights into the relationship between neurons and their glial “helper” cells. This study reports finding a key sequence of molecular events in which the genetic mutation in a fruit fly model of epilepsy leaves neurons vulnerable to becoming hyper-activated by stress, leading to seizures.

Ketogenic Diet May Reduce Sudden Unexpected Deaths in Epilepsy, Mouse Study Suggests
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Sudden unexpected death in epilepsy (SUDEP) occurs more frequently during the early evening and is significantly prevented by prolonged use of the ketogenic diet, research in a mouse model of Dravet syndrome suggests. The reasons why this happens are unclear and should be examined in more depth by future studies, but these findings may be useful to understand why most SUDEP episodes happen at night and how certain diets can benefit people with epilepsy, especially those with Dravet syndrome, researchers say.

Attention, Behavioral Problems Common in New, Recent-Onset Juvenile Myoclonic Epilepsy
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Children with new recent-onset juvenile myoclonic epilepsy are more likely to have difficulty with executive, attention, and verbal faculties than their healthy peers and are also more likely to use a greater number of academic services, researchers found.

Also Notable

Zogenix Receives Refusal to File Letter from FDA for FINTEPLA® New Drug Application
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Zogenix announced that it received a Refusal to File letter from the FDA regarding its New Drug Application (NDA) for FINTEPLA® for the treatment of seizures associated with Dravet syndrome. Upon its preliminary review, the FDA determined that the NDA was not sufficiently complete to permit a substantive review.

Can the Effects of the Ketogenic Diet Help Prevent Epilepsy After Traumatic Brain Injury?

Featuring the work of CURE Grantee Chris Dulla

Neuroscientists led by Chris Dulla at Tufts University School of Medicine prevented the development of epileptic activity in mice after traumatic brain injury by using a drug that mimics the metabolic effects of the ketogenic diet. An advance copy of the study is published today in JCI Insight.

The ketogenic diet was originally developed in the 1920s to treat drug-resistant epilepsy in children. By limiting carbohydrates in the diet, the body is forced to burn fat rather than glucose, the usual source of energy in the body. Although researchers do not know exactly how the therapeutic effects of the diet works, evidence to date suggests the change in metabolism is key.

“While we know the ketogenic diet can control seizures in people with epilepsy, we wanted to learn if it would be able to prevent the development of post-traumatic epilepsy,” says Jenny Koenig, an M.D. and Ph.D. student at Tufts University School of Medicine and the Sackler School of Graduate Biomedical Sciences at Tufts who works in Dulla’s lab.

Post-traumatic epilepsy develops within three years of a traumatic brain injury (TBI) in about 1 out of 10 people. TBIs lead to the dysfunction of the brain’s inhibitory network, including the cells that normally quiet down brain activity. Without inhibition, brain activity increases, causing the behavioral and cognitive challenges seen after injury.

Along with increased activity comes an increased demand for energy production through a process called glycolysis, a system that provides energy to the brain by burning glucose, or sugar. Rather than focus directly on reducing neuronal activity, the research team inhibited glycolysis with a drug called 2-deoxyglucose (2-DG) to mimic the metabolic effects of the ketogenic diet.

By recording brain activity from cells in the injured area with a common electrophysiological technique called whole-cell recording, the researchers determined that excitatory cells were more active in injured tissue, compared to control brain tissue from mice.

How Concussions May Lead to Epilepsy

Featuring the work of CURE PTE Initiative team members Oleksii Shandra and Stefanie Robel

Researchers have identified a cellular response to repeated concussions that may contribute to seizures in mice like those observed following traumatic brain injury in humans. The study, published in JNeurosci, establishes a new animal model that could help improve our understanding of post-traumatic epilepsy.

Stefanie Robel, Oleksii Shandra, and colleagues induced mild traumatic brain injury in mice to mimic blows to the head that result in human concussions. A unique population of astrocytes responded to these injuries and the researchers observed spontaneous recurrent seizures in some mice within one month. These results highlight the role of astrocytes in the development of epilepsy following the most common type of traumatic brain injury in humans.

Virginia Tech Team

Virginia Tech Leads $2.6 Million Study of Brain Trauma, Epilepsy Connection

Featuring the work of CURE Grantee, Dr. Harald Sontheimer

Virginia Tech is launching a $2.6 million study to determine if traumatic brain injuries can cause changes within the brain that lead to epilepsy.

Funded by the nonprofit Citizens United for Research in Epilepsy (CURE) and the U.S. Department of Defense, the three-year study seeks to identify the root causes behind why a person may develop epilepsy after he or she has suffered brain trauma, including sports-related concussion and focal contusion injuries.

Five Virginia Tech groups are heading the study: The School of Neuroscience, part of the College of Science; the Virginia Tech Carilion Research Institute (VTCRI); the Virginia-Maryland College of Veterinary Medicine; and the College of Engineering. All of the research leaders have wide experience in brain injury and neurological disorders.

Announcing the 2018 Post-Traumatic Epilepsy Initiative Grantees

Announcing the grant recipients in CURE’s Post-Traumatic Epilepsy Initiative! Read about this team’s innovative projects below:

Post-traumatic epilepsy (PTE) is a frequent and debilitating complication of traumatic brain injury (TBI). Over 40% of combat troops who suffer severe TBI will develop PTE.

Having secured a $10 million grant from the US Department of Defense, CURE has launched an unprecedented Post-Traumatic Epilepsy Initiative. This initiative is a team science, multi-disciplinary program that will expand the knowledge around the types of injuries that predispose the brain to epilepsy, as well as a develop new models to study epilepsy that results from injury.

Meet CURE’s pioneering Post-Traumatic Epilepsy Initiative team:

Victoria E. Johnson, MBChB, PhD

University of Pennsylvania

Dr. Johnson will characterize the relationship between the detrimental neural changes which can follow TBI and the development of PTE. These changes include chronic leakage of the blood-brain barrier, neuronal degeneration, and gliosis. The research team will utilize tissue from humans following TBI, as well as novel models of TBI.

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Harald Sontheimer, PhD

Virginia Tech

Dr. Sontheimer and his team of collaborators have identified the need for additional animal models of PTE. The team’s hope is that identifying alternative animal models will lead to the discovery of new PTE biomarkers and, eventually, to novel treatments. To identify new animal models, Dr. Sontheimer’s team plans to investigate how TBI leads to PTE in a new mouse model compared to an established one.

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Kevin Staley, MD

Harvard Medical School

Dr. Staley will test if changes in the brain’s neuronal support system after TBI alter the balance of inhibitory and excitatory neurotransmission. His team is also set to explore why PTE following TBI is often difficult to treat. Using highly innovative imaging techniques, Dr. Staley aims to provide new insight into how PTE develops and new methods to identify high-risk patients.

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Kevin Wang, PhD

University of Florida

Dr. Wang has developed a robust rat model of penetrating TBI to understand how this type of injury can lead to PTE. His team will compare rats that develop PTE to those that do not. The goal is to uncover the unique chemical and molecular processes which lead to PTE following a penetrating TBI. These findings could provide new areas of focus and potential biomarkers for developing treatments.

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Clinical Trial: Neuroimaging Biomarker for Seizures (NIBMSZS)

Numerous Veterans and civilians have seizures, which can be epileptic or nonepileptic in nature. Epileptic seizures are caused by abnormal brain cell firing. Nonepileptic seizures appear similar to epileptic seizures, but are associated with traumatic experiences and underlying psychological stressors. Both types of seizure are common and disabling, and many patients with seizures do not have adequate control resulting in loss of quality of life.

This multi-site study will examine patients with epilepsy (ES) following head injury [i.e., post-traumatic epilepsy (PTE)] and post-traumatic psychogenic non-epileptic seizures (PNES), and will compare these patients to those with traumatic brain injury (TBI) who do not have seizures using functional neuroimaging.

In this proposed 3-site study (Providence, RI and Birmingham, AL), which are epilepsy centers with expertise both in epilepsy and PNES, we will enroll 88 patients with video-EEG confirmed PNES and 88 with confirmed post-traumatic epilepsy (PTE) and will obtain functional neuroimaging before and after they receive a behavioral treatment – Cognitive Behavioral Therapy for Seizures. The functional neuroimaging studies in these 176 Veterans will be compared to 88 Veterans with traumatic brain injury without seizures to test the hypothesis that the faulty processing of emotions and stress in patients with PNES/PTE and abnormal brain connectivity have unique signals in patients with seizures compared to Veterans without seizures and that the neuroimaging signatures can be modified using behavioral intervention.

Eligibility Criteria

Ages Eligible for Study: 18 Years to 60 Years (Adult)
Sexes Eligible for Study: All
Accepts Healthy Volunteers: No

Inclusion Criteria:

  • Inclusion criteria for PNES, ES and TBI (w/o PNES or ES) participants:
    • Individuals with history of documented TBI (any severity)
    • Males and Females ages 18-60 years
    • Women of child bearing potential, if currently using appropriate contraception
  • Inclusion criteria of PNES and ES participants:
    • Diagnosed by video/EEG with lone PNES or by EEG with lone ES
    • Patients must have at least 1 PNES or 1 ES during the year prior to enrollment

 

Exclusion Criteria:

  • Exclusion Criteria of PNES, ES and TBI (w/o PNES or ES) participants
    • Current or past year self-injurious behavior
    • Current suicidal intent (BDI suicide question 9 score of >1)
    • Current or past year psychosis
    • Pending litigation or current application for long term disability
    • Active substance or alcohol use disorder (dependence), in past 3 months
    • Serious illness requiring systemic treatment or hospitalization; the participant either completes therapy or is clinically stable on therapy, for at least 30 days prior to study entry
    • Inability to fill out the self-report surveys
    • Women who are or/are attempting to become pregnant during the study
    • Ineligible or unwilling to complete MRI imaging
    • Inability to document TBI
  • Exclusion Criteria for PNES and ES participants
    • Inability or unwillingness to participate in CBT and assigned homework
    • Currently enrolled in cognitive therapy aimed at PNES (Current CBT or other psychotherapy may be administered)
      • Concurrent mixed ES/PNES or equivocal video/EEG findings in discerning between ES and PNES will not be enrolled

Early Seizures and Temporal Lobe Trauma Predict Post-Traumatic Epilepsy: A Longitudinal Study

CONCLUSION: Our results indicate that in a cohort of patients with a moderate-severe Traumatic Brain Injury (TBI), 1) lesion location specificity (e.g. the temporal lobe) is related to both a high incidence of early seizures and longitudinal development of Post-Traumatic Epilpesy (PTE), 2) early seizures, whether convulsive or non-convulsive in nature, are associated with an increased risk for PTE development, and 3) patients who develop PTE have greater chronic temporal lobe atrophy and worse functional outcomes, compared to those who do not develop PTE, despite matched injury severity characteristics. This study provides the foundation for a future prospective study focused on elucidating the mechanisms and risk factors for epileptogenesis.

OBJECTIVE: Injury severity after TBI is a well-established risk factor for the development of PTE. However, whether lesion location influences the susceptibility of seizures and development of PTE longitudinally has yet to be defined. We hypothesized that lesion location, specifically in the temporal lobe, would be associated with an increased incidence of both early seizures and PTE. As secondary analysis measures, we assessed the degree of brain atrophy and functional recovery, and performed a between-group analysis, comparing patients who developed PTE with those who did not develop PTE.

METHODS: We assessed early seizure incidence (n?=?90) and longitudinal development of PTE (n?=?46) in a prospective convenience sample of patients with moderate-severe TBI. Acutely, patients were monitored with prospective cEEG and a high-resolution Magnetic Resonance Imaging (MRI) scan for lesion location classification. Chronically, patients underwent a high-resolution MRI, clinical assessment, and were longitudinally monitored for development of epilepsy for a minimum of 2?years post-injury.

RESULTS: Early seizures, occurring within the first week post-injury, occurred in 26.7% of the patients (n?=?90). Within the cohort of subjects who had evidence of early seizures (n?=?24), 75% had a hemorrhagic temporal lobe injury on admission. For longitudinal analyses (n?=?46), 45.7% of patients developed PTE within a minimum of 2?years post-injury. Within the cohort of subjects who developed PTE (n?=?21), 85.7% had a hemorrhagic temporal lobe injury on admission and 38.1% had early (convulsive or non-convulsive) seizures on cEEG monitoring during their acute ICU stay. In a between-group analysis, patients with PTE (n?=?21) were more likely than patients who did not develop PTE (n?=?25) to have a hemorrhagic temporal lobe injury (p?<?0.001), worse functional recovery (p?=?0.003), and greater temporal lobe atrophy (p?=?0.029).

CURE Discovery: Preventing Post-Traumatic Epilepsy with 2-Deoxy-D-Glucose Treatment

The latest results from a CURE-funded grant represent a promising advance in the quest to prevent post-traumatic epilepsy. Dr. Thomas Sutula from the University of Wisconsin and his team have found that the administration of 2-Deoxy-D-Glucose (2DG) following a traumatic brain injury can significantly reduce the subsequent development of post-traumatic epilepsy in a rodent model.

The finding that 2DG can prevent the development of post-traumatic epilepsy in rats is exciting for several reasons. 2DG is a sugar-like molecule that has been proposed to mimic the ketogenic diet – a diet that is highly effective in the treatment of difficult-to-treat epilepsies. Therefore, like the ketogenic diet, 2DG may also have therapeutic effects for individuals that have already developed epilepsy (in this case, post-traumatic epilepsy). 2DG is also already being used in the treatment of other illnesses, including cancer, and can likely progress rapidly to a clinical trial for post-traumatic epilepsy. Furthermore, with this research, Dr. Sutula and his team have successfully utilized a novel rat model that more readily develops a post traumatic-epilepsy-like syndrome with frequent seizures following traumatic brain injury, providing a great research tool in the quest for treatments and a cure for post-traumatic epilepsy.

Post-traumatic epilepsy is a type of epilepsy that develops following a traumatic brain injury such as a bump or blow to the head. Post-traumatic epilepsy accounts for nearly 20% of all symptomatic epilepsies in the general population, and is one of the most common causes of acquired epilepsy. Post-traumatic epilepsy can be particularly devastating because no known prevention or cure for the disorder currently exists.

Because post-traumatic epilepsy can develop months or even years after an initial traumatic brain injury, there is a critical window of time during which the development of post-traumatic epilepsy might be prevented, if only a preventative measure were in existence. For these reasons, Dr. Sutula’s finding that 2DG significantly reduces the development of post-traumatic epilepsy in his novel breed of rat within this critical window is an important one.

In the future, Dr. Sutula and his team plan on taking strategic steps to push their research forward towards an Investigational New Drug trial to test the effectiveness of this drug in the prevention of post-traumatic epilepsy in humans. In this way, Dr. Sutula hopes that his research will impact the lives of individuals suffering from post-traumatic epilepsy, or those with the potential to develop post-traumatic epilepsy, as soon as possible.

Clinical Trial: Neuroimaging Biomarker for Seizures

Brief Summary: This multi-site study will examine patients with epilepsy (ES) following head injury [i.e., posttraumatic epilepsy (PTE)] and posttraumatic psychogenic Non-epileptic seizures (PNES) and will compare them to patients with traumatic brain injury (TBI) who do not have seizures using functional neuroimaging.

Detailed Description: Numerous Veterans and civilians have seizures, which can be epileptic or nonepileptic in nature. Epileptic seizures are caused by abnormal brain cell firing. Nonepileptic seizures appear similar to epileptic seizures, but are associated with traumatic experiences and underlying psychological stressors. Both types of seizure are common and disabling, and many patients with seizures do not have adequate control resulting in loss of quality of life.

Impact: This grant application for the first study investigating mechanisms of PNES and PTE will provide increased understanding of neural circuitry in PTE and PNES, which can inform PTE and PNES treatments and could change clinical neurologic and psychiatric practice for PTE and PNES.

Anticipated study start date: March 1, 2018
Primary completion date: March 2021
Estimated study completion date: September 2011

Eligibility Criteria

Inclusion Criteria:

Inclusion criteria for PNES, ES and TBI (w/o PNES or ES) participants

  • Individuals with history of documented TBI (any severity).
  • Males and Females ages 18-60 years .
  • Women of child bearing potential, if currently using appropriate contraception.

 

Inclusion criteria of PNES and ES participants

  • Diagnosed by video/EEG with lone PNES or by EEG with lone ES.
  • Patients must have at least 1 PNES or 1 ES during the year prior to enrollment.

 

Exclusion Criteria:

Exclusion Criteria of PNES, ES and TBI (w/o PNES or ES) participants

  • Current or past year self-injurious behavior.
  • Current suicidal intent (BDI suicide question 9 score of >1).
  • Current or past year psychosis.
  • Pending litigation or current application for long term disability.
  • Active substance or alcohol use disorder (dependence), in past 3 months.
  • Serious illness requiring systemic treatment or hospitalization; the participant either completes therapy or is clinically stable on therapy, for at least 30 days prior to study entry.
  • Inability to fill out the self-report surveys.
  • Women who are or/are attempting to become pregnant during the study.
  • Ineligible or unwilling to complete MRI imaging.
  • Inability to document TBI.

 

Exclusion Criteria for PNES and ES participants

  • Inability or unwillingness to participate in CBT and assigned homework.
  • Currently enrolled in cognitive therapy aimed at PNES (Current CBT or other psychotherapy may be administered).
  • Concurrent mixed ES/PNES or equivocal video/EEG findings in discerning between ES and PNES will not be enrolled.