Request for Funding

Medical Student Research Fellowship for Summer 2004

Mentor: Ramon Diaz-Arrastia, MD, PhD
Department: Neurology
Room number: J3.126
Mail Code: 9036
Phone number: 214-648-6409
E-mail: Ramon.Diaz-Arrastia@UTSouthwestern.edu

Two Projects

Project I title: Continuous video-EEG monitoring in traumatic brain injury.

Human subjects IRB approved project number (where applicable): Pending (Applied for 1/2004)

Animal subjects IRB approved project number (where applicable):

Project Type (patient-based research, animal-based research, or basic research; this characterization is only to permit a general classification for grouping similar types of projects) Patient-oriented research

Brief Description of Project:

Traumatic brain injury (TBI) is a major cause of mortality and morbidity, particularly among persons below the age of 45. Convulsive seizures occur during the acute period in 4-10% of patients with severe TBI, and it is likely that these behaviorally evident seizures represent only a small fraction of all epileptic phenomena. Nonconvulsive seizures, which have either no or very subtle behavioral manifestations and can be reliably diagnosed only by EEG monitoring, are substantially more common and occur in 20-35% of patients with severe TBI. The occurrence of nonconvulsive seizures is a poor prognostic sign, but it is unclear whether they a simply a reflection of an extensive insult or whether they contribute to ongoing secondary injury. Further, it is unknown whether treatment with high dose antiepileptic drugs is effective in controlling nonconvulsive seizures or in improving the neurologic outcome. Finally, such treatments, which usually include high dose benzodiazepines, phenobarbital, and occasionally even anesthetic doses of pentobarbital, carry a small but appreciable risk.
The goal of this project is to determine the feasibility efficacy of continuous video-EEG (CVEEG) monitoring and aggressive treatment of nonconvulsive seizures in patients with severe TBI. Eligible patients will be those with TBI, GCS < 12, or any unexplained deterioration in sensorium within 72 hours of admission. Enrolled patients will be monitored continuously with video and digital EEG (CVEEG monitoring), that will be continuously reviewed by trained EEG technologists with the help of computerized seizure-detection algorithms and backup from a board certified neurophysiologist. We anticipate that approximately 1 patient per week will be monitored, for a duration of 48 hours.

Endpoint 1. Association of nonconvulsive seizures with poor outcome. Within the group randomized to invasive monitoring, is the occurrence of nonconvulsive seizures a poor prognostic sign, independent of factors such as age, severity of initial injury, or occurrence of other recognized secondary complications? Is outcome worse in patients whose nonconvulsive seizures were refractory to high dose antiepileptic drugs, compared to those whose seizures were successfully controlled?
Endpoint 2. Feasibility of real-time diagnosis of nonconvulsive seizures. Prior studies using continuous EEG monitoring have identified nonconvulsive seizures through review of EEG records done hours before, and typically there is a delay of many hours before the diagnosis is established and treatment is instituted. In this study measures will be taken to attain diagnosis and treatment of nonconvulsive seizures within 30 minutes of onset, which has not been achieved in standard clinical practice. Determination of the feasibility and efficacy of these measures is an important goal of this study.

Role of the Research Fellow:

The fellow will be primarily involved in identifying eligible patients, arranging for video-EEG monitoring to be performed, and with the assistance of a clinical neurophysiologist (Drs. Van Ness, Agostini, or Diaz-Arrastia), monitoring the EEG for nonconvulsive seizures. Duties will also include prospectively collecting clinical information relating to the severity of the initial traumatic injury, following the patients daily during their acute hospitalization, and obtaining outcome data at 6 months, using a structured interview. This will be accomplished by having the fellow attend daily morning rounds with the neurosurgical service at Parkland Memorial Hospital, identify patients who are meet eligibility criteria for the study, and coordinate with the clinical neurophysiology department to perform video-EEG monitoring. Afternoons will be spent obtaining outcome information via telephone interviews. Opportunities to learn about EEG interpretation of patients in coma will also be available.

Project II title: Genetic Factors in Outcome after Traumatic Brain Injury

Human subjects IRB approved project number (where applicable): IRB # 0399-123
Animal subjects IRB approved project number (where applicable): Not applicable

Project Type Patient-oriented research

Brief Description of Project:

Traumatic brain injury (TBI) is a major cause of mortality and morbidity, particularly among persons below the age of 45. In the US, approximately 55,000 deaths each year are attributed to TBI, and an additional 50,000 individuals each year suffer long-term physical and psychological problems that limit their independence and ability to work. Factors such as severity of injury, age, and complications during the acute hospitalization only partly account for outcome, and it is likely that inherited genetic factors predispose certain individuals to have a poor functional outcome after brain trauma. Recent progress in the Human Genome Project has identified common polymorphisms in a number of genes that have been proposed, on the basis of human and animal studies, to regulate the response of neural tissue to injury. Our hypothesis is that inheritance of certain alleles of these polymorphic candidate genes is predictive of poor neurologic recovery after TBI. Understanding which genes may predispose to poor outcome after TBI will be useful in developing tailored therapy to limit damage or improve functional recovery after TBI. This proposal has two specific aims: (1) To characterize and collect DNA from a population of patients who suffered TBI, as well as prospectively collect information on the severity of injury and functional outcome six months after injury. In order to obtain a sufficiently large sample, patients with TBI will be recruited from two busy brain injury centers: Parkland Memorial Hospital/Univ. of Texas Southwestern (Dallas site), and Harborview Hospital Center/Univ. of Washington (Seattle site). Our goal is to collect DNA from 750 subjects with TBI, anticipating that 50% of them will have a poor outcome, as measured the University of Washington Functional Status Examination. (2) To determine, using a case-cohort approach, whether inheritance of certain polymorphic alleles is associated with poor outcome after TBI. We will study a total of seven polymorphisms in candidate genes. These polymorphisms were chosen based on their linkage to other neurologic diseases that are believed to share pathophysiologic features with TBI, and biologic plausibility of a role in the reaction of neural tissue to trauma. These include APOE4, IL-1A*2, IL-1B*2, IL-1RN*2, TNF2, A2M*2, and GSTM3*B. These studies, if successful, will provide genetic evidence for the role of specific genes in the response of neural tissue after traumatic injury. This approach may identify novel targets for therapeutic intervention aimed at limiting secondary injury and improving functional outcome.

Role of the Research Fellow:

The fellow will be primarily involved in prospectively collecting clinical information relating to the severity of the initial traumatic injury, following the patients daily during their acute hospitalization, and obtaining outcome data at 6 months, using a structured interview. This will be accomplished by having the fellow attend daily morning rounds with the neurosurgical service at Parkland Memorial Hospital, identify patients who are meet eligibility criteria for the study, obtain informed consent from patients or family members, and collect intake information. Afternoons will be spent obtaining outcome information via telephone interviews. Opportunities for performing genotype analysis using the polymerase chain reaction also exist.

Previous Research Activities or Publications with Medical Students:

Four medical students have done Summer research in Dr. Diaz-Arrastia's laboratory over the past 8 years.

Previous Research Activities or Publications with Medical Students:

Four medical students have done Summer research in Dr. Diaz-Arrastia's laboratory over the past 8 years.

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