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).

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.

Amendment Passes Senate to Continue DOD Medical Research Funding

WASHINGTON, D.C.— Two provisions in the National Defense Authorization Act threatened to affect important medical research funded by the Department of Defense (DOD). Thanks to the efforts of Senator Dick Durbin (D-IL) and the voices of advocates like CURE through the Research, Not Red Tape initiative, an amendment passed in the Senate in early June to protect this funding so it can continue to support breakthrough research for active service members, military families, and veterans.

This is especially important as it applies to the new, multidisciplinary, team science initiative CURE is developing in collaboration with the DOD to advance the understanding of epilepsy as a result of traumatic brain injuries, the signature wound of the wars in Iraq and Afghanistan.

CURE To Expand Work With Veterans’ Epilepsy Thanks To Department Of Defense Grant

Chicago, IL- Citizens United for Research in Epilepsy today announced that it will create a new research program and focus with a grant of approximately 10 million dollars over 5 years to go toward epilepsy research in veterans with traumatic brain injury. The grant was awarded by the Department of Defense, Psychological Health and Traumatic Brain Injury Research Program, award number W81XWH-15-2-0069.

The grant will support a team approach to researching the prevention and treatment of Post-Traumatic Epilepsy (PTE). The incidence of epilepsy in active service members increased by an alarming 52 percent from 2006 to 2010.Approximately 8 percent of those afflicted have been diagnosed with traumatic brain injury (TBI) , making it the most common predisposing condition. Twenty-four percent of military-related epilepsy is associated with prior TBI.

“Our veterans deserve much better after serving our country,” said Susan Axelrod, founding chair of CURE.  “In the wars in Iraq and Afghanistan the “signature wound” was traumatic brain injury. Those who suffer severe TBI face up to a 50 percent chance of developing Post-Traumatic Epilepsy (PTE), with the symptoms of epilepsy (seizures) manifesting themselves immediately or even up to fifteen years post-injury.   At CURE we are committed to exploring the complex underlying mechanisms of post-traumatic epilepsy and ways to treat it more effectively and one day even prevent it entirely.”

“CURE applauds the U.S. Department of Defense for dedicating this significant amount of resources to epilepsy research,” said Robin Harding, Chief Executive Officer. “We are grateful to those who back our effort to find a cure for this disease through research and by increasing awareness of epilepsy’s prevalence and devastating consequences for patients and their families.  Investing in research is the cornerstone of discovery and an ultimate cure.”

“The next great breakthrough is not going to come from a single researcher working in isolation,” said Julie Milder, PhD, Associate Research Director at CURE and Program Officer for the DOD grant. “We strongly believe in the power of collaboration and its ability to move science forward faster.  We are incredibly grateful for this opportunity to move team science into the area of post-traumatic epilepsy– one that is desperate for greater understanding.”

Next steps for the program include convening a meeting of key opinion leaders in epilepsy, traumatic brain injury and veterans’ health to determine opportunities of biggest impact over the next five years. The outcomes of the meeting will serve as the basis for the development of a targeted team science research program which will be announced through a request for applications in late spring.