The goal of Dr. Cloyd’s research is to develop an intravenous form of topiramate (TPM) as a new therapy to protect newborns from seizures and brain cell injuries. Although phenobarbital and phenytoin have been the standard treatment in these cases, their safety has been questioned as recent studies have shown that both drugs cause increased cell death in brains of newborn laboratory animals and are associated with long-term developmental problems in children.¹ Topiramate has emerged as a potential alternative to older medications, as it has been proven to be safe and effective for treatment of seizures in older children; has neuroprotective properties; and relative to phenobarbital and phenytoin, it has a lower potential for causing cell death in the brain. Dr. Cloyd has made progress with developing the IV form of TPM. As of this publication, he has manufactured more than 200 doses of IV TPM and completed 12 months of studies demonstrating its stability. Next steps include an additional study in 12 healthy volunteers to further characterize the safety and the absorption, distribution, and metabolism of IV TPM, which must be done in adults before children. Dr. Cloyd has applied to the FDA and has secured a pharmaceutical company to bring the new drug form to the market. Results from this pilot study will help determine the design of subsequent studies, including controlled clinical trials the efficacy and safety of IV TPM for neonatal seizures.

Reference: ¹Glier C, Dzietko M, Bittigau P, Jarosz B, Korobowicz E, Ikonomidou C. Therapeutic doses of topiramate are not toxic to the developing rat brain. Exp Neurol. Jun 2004; 187(2):403-409.

Publications for this research:
Clark A, Cloyd J, Leppik I, White J, Brundage J, Kriel R. Pharmacokinetics and safety of intravenous topiramate in adult patients. Abstract 2.206, American Epilepsy Society 2009.

Mondick J, Zuppa A, Pirzadeh A, Pastuszko P, Faught R, Cloyd J, Clark A, Gastonguay M, Clancy R. A modeling and simulation approach to characterizing the effects of cardiopulmonary bypass and deep hypothermic cardiac arrest on topiramate pharmacokinetics. Abstract 3.127, American Epilepsy Society 2009.

For many years, the use of intracranial EEG (IEEG) has frustrated epileptologists looking for separate, resectable areas of the brain during evaluation for epilepsy surgery. Similarly, efforts to apply direct stimulation in the brain to stop seizures after they are sufficiently detected with standard equipment have met with only partial success. Dr. Worrell and colleagues believe that enhancing the resolution of IEEG can improve the effects of epilepsy surgery and responsive brain stimulation to control seizures. With funding from the Epilepsy Research Foundation, they were able to develop a sophisticated platform for obtaining multi-scale EEG recordings from the human brain, and perform experiments necessary to collect data that supports their hypothesis. They also developed a software procedure for detection of seizure activity in the brain not easily detected with standard EEG. The preliminary data from this study helped Dr. Worrell secure funding from NIH to complete analysis of this new system and compare their findings with surgical outcome in patients undergoing evaluation for epilepsy surgery. This research brings Dr. Worrell closer to the goal of pinpointing human epileptic networks in the brain to improve the outcome of epilepsy surgery and brain stimulation to stop seizures.

Publication for this research:
Van Gompel JJ, Stead SM, Giannini C, Meyer FB, Marsh WR, Fountain T, So E, Cohen-Gadol A, Lee KH, Worrell GA. Phase I trial: safety and feasibility of intracranial electroencephalography using hybrid subdural electrodes containing macro- and microelectrode arrays. Neurosurg Focus. 2008 Sep; 25(3):E23.

Report on Mood Disorders Research

Dr. Wagner has published findings from her research that was funded by the Epilepsy Foundation’s Targeted Research Initiative for Mood Disorders. In the first publication, the findings show the importance of interventions that assist youth in identifying epilepsyrelated aspects of functioning over which they can realistically exercise control and challenging negative thoughts about situations they cannot control.

Wagner JL, Smith G., Ferguson P, Horton S., & Wilson E (2009). A hopelessness model of depressive symptoms in youth with epilepsy. Journal of Pediatric Psychology, 34, 89-96.

In the second publication, Dr. Wagner reports on the portion of the study that evaluated seizure severity in youth and caregiver self-report measures of the emotional and social variables that occur in epilepsy. Seizure severity has been investigated using multiple tools over the years, and its defining features continue to be debated. Severity ratings are necessary for medical, psychological and epidemiologic investigations. The results indicate that a longer recovery time from the last seizure and a longer duration of seizure influence how severe a caregiver judges seizures. The usual elements such as type of epilepsy, frequency of seizures, and most recent seizure were not significantly related to severity rating. Behavior ratings were also not related to severity rating. Clinicians often rely heavily on caregiver information during clinic visits to help inform treatment decisions; therefore, a standard way to measure seizure severity from the caregivers’ perception is key in providing care. Rather than assuming what makes a seizure severe to a parent, Dr. Wagner’s work shows that more research should be conducted on what elements contribute to severity, as judged by both the parent and youth.

Wagner JL, Smith G, Ferguson P & Wannamaker B (2009). Caregiver Perceptions of Seizure Severity in Pediatric Epilepsy. Epilepsia, 50, 2102-2109.