Neurobiology of disease
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Neurobiology of disease · Mar 2019
ReviewThe epilepsy bioinformatics study for anti-epileptogenic therapy (EpiBioS4Rx) clinical biomarker: Study design and protocol.
The Epilepsy Bioinformatics Study for Anti-epileptogenic Therapy (EpiBioS4Rx) is a longitudinal prospective observational study funded by the National Institute of Health (NIH) to discover and validate observational biomarkers of epileptogenesis after traumatic brain injury (TBI). A multidisciplinary approach has been incorporated to investigate acute electrical, neuroanatomical, and blood biomarkers after TBI that may predict the development of post-traumatic epilepsy (PTE). We plan to enroll 300 moderate-severe TBI patients with a frontal and/or temporal lobe hemorrhagic contusion. ⋯ Validation of selected biomarkers that are discovered in planned animal models will be a principal feature of this work. Specific hypotheses regarding the discovery of biomarkers have been set forth in this study. An international cohort of 13 centers spanning 2 continents will be developed to facilitate this study, and for future interventional studies.
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Neurobiology of disease · Mar 2019
ReviewAffective, neurocognitive and psychosocial disorders associated with traumatic brain injury and post-traumatic epilepsy.
Survivors of traumatic brain injury (TBI) often develop chronic neurological, neurocognitive, psychological, and psychosocial deficits that can have a profound impact on an individual's wellbeing and quality of life. TBI is also a common cause of acquired epilepsy, which is itself associated with significant behavioral morbidity. This review considers the clinical and preclinical evidence that post-traumatic epilepsy (PTE) acts as a 'second-hit' insult to worsen chronic behavioral outcomes for brain-injured patients, across the domains of emotional, cognitive, and psychosocial functioning. ⋯ Further, the relationship between PTE and behavioral dysfunction is increasingly recognized to be a bidirectional one, whereby premorbid conditions are a risk factor for PTE. Clinical studies in this arena are often challenged by the confounding effects of anti-seizure medications, while preclinical studies have rarely examined an adequately extended time course to fully capture the time course of epilepsy development after a TBI. To drive the field forward towards improved treatment strategies, it is imperative that both seizures and neurobehavioral outcomes are assessed in parallel after TBI, both in patient populations and preclinical models.
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Epilepsy is one of the most common brain disorders, causing serious disability and premature death worldwide. Approximately 1.2% of the U. S. population has active epilepsy, and 30 to 40% have seizures that do not respond to antiseizure drugs. ⋯ This requires better understanding of neuronal mechanisms underlying the development of epilepsy, and biomarkers of this process that would permit cost-effective drug discovery, and validation in clinical trials, for potential antiepileptogenic compounds. EpiBioS4Rx is an NIH-funded Center without Walls consisting of collaborative investigations in the United States, Europe, and Australia of traumatic brain injury in patients, and a standardized animal model, to identify biomarkers of epileptogenesis and to determine their ability to assess the effectiveness of potential antiepileptogenic agents. Successful completion of this project is expected to result in design of an economically feasible, full-scale clinical trial of at least one antiepileptogenic intervention.
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Neurobiology of disease · Mar 2019
Early seizures and temporal lobe trauma predict post-traumatic epilepsy: A longitudinal study.
Injury severity after traumatic brain injury (TBI) is a well-established risk factor for the development of post-traumatic epilepsy (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. ⋯ Our results indicate that in a cohort of patients with a moderate-severe TBI, 1) lesion location specificity (e.g. the temporal lobe) is related to both a high incidence of early seizures and longitudinal development of 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.
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Neurobiology of disease · Mar 2019
ReviewModelling traumatic brain injury and posttraumatic epilepsy in rodents.
Posttraumatic epilepsy (PTE) is one of the most debilitating and understudied consequences of traumatic brain injury (TBI). It is challenging to study the effects, underlying pathophysiology, biomarkers, and treatment of TBI and PTE purely in human patients for a number of reasons. Rodent models can complement human PTE studies as they allow for the rigorous investigation into the causal relationship between TBI and PTE, the pathophysiological mechanisms of PTE, the validation and implementation of PTE biomarkers, and the assessment of PTE treatments, in a tightly controlled, time- and cost-efficient manner in experimental subjects known to be experiencing epileptogenic processes. This article will review several common rodent models of TBI and/or PTE, including their use in previous studies and discuss their relative strengths, limitations, and avenues for future research to advance our understanding and treatment of PTE.