Seizures are episodes of abnormally synchronous activity generated by cortical brain regions. Depending on a number of factors, they sometimes begin in one brain region and spread or generalize secondarily throughout much larger areas of the cortex. This extensive cortical involvement is responsible for the motor convulsions and loss of consciousness during the seizure episode. Seizures also spread into deep brain structures where the abnormal activity can ultimately impact the autonomic regulation of systemic physiology (e.g. heart rhythm), respiration, and even immune system function.
Sudden unexpected death in epilepsy (SUDEP) is the term used for unexplained death in an epileptic patient. Usually, there is evidence of a seizure occurring near the time of death. The existing evidence for seizure spread into the autonomic nervous system suggests ways in which severe seizure activity might lead to death, but the detailed mechanism(s) remain mysterious.
In brain slice studies, we can explore the brain regions capable of seizure generation and the details of seizure spread. We concentrate on a subset of the limbic cortices, the hippocampal and parahippocampal areas, because these are the sites for seizure foci in patients with temporal lobe epilepsy. With a variety of single cell and population electrophysiological methods, pharmacological manipulations, and anatomical techniques we have characterized relevant aspects of the intrinsic connectivity and inter-regional connectivity that influence seizure generation and spread.
Systemic studies are performed in various intact animal preparations where seizure activity and its spread through hypothalamus, medulla, and autonomic peripheral nerves can be studied in detail. Our urethane/kainate model is a unique and powerful tool for studying all aspects of seizure spread to the periphery, and has allowed us to generate a clear hypothetical model for sudden death in epilepsy.
Sakamoto, K., Saito, T., Orman, R., Koizumi, K., Lazar, J., Salciccioli, L., and Stewart, M. (2008). Autonomic consequences of kainic acid-induced limbic cortical seizures in rats: peripheral autonomic nerve activity, acute cardiovascular changes, and death. Epilepsia 49, 982-996.
Orman, R., Von Gizycki, H., Lytton, W. W., and Stewart, M. (2008). Local axon collaterals of area CA1 support spread of epileptiform discharges with CA1, but propagation is unidirectional. Hippocampus 18, 1021-1033.
Hotta, H., Lazar, J., Orman, R., Koizumi, K., Shiba, K., Kamran, H., and Stewart, M. (2009). Vagus nerve stimulation-induced bradyarrhythmias in rats. Auton. Neurosci. 151, 98-105.
Stewart, M. (2009). Autonomic consequences of seizures, including sudden unexpected death in epilepsy. In Encyclopedia of Basic Epilepsy Research (P. A. Schwartzkroin, ed.), Elsevier, pp. 1289-1294.
Hotta, H., Watanabe, N., Orman, R., and Stewart, M. (2010). Efferent and afferent vagal actions on cortical blood flow and kainic acid-induced seizure activity in urethane anesthetized rats. Auton. Neurosci. 156, 144-148.
Silverberg, J., Ginsburg, D., Orman, R., Amassian, V., Durkin, H.G., and Stewart, M. (2010). Lymphocyte infiltration of neocortex and hippocampus after a single brief seizure in mice. Brain Behav. Immun. 24, 263-272.
Stewart, M. (2011). The urethane/kainate seizure model as a tool to explore physiology and death associated with seizures. In Sudden Death in Epilepsy: Forensic and Clinical Issues (C. M. Lathers, P. L. Schraeder, M. W. Bungo, and J. E. Leetsma, eds.), Taylor & Francis Group, Boca Raton, pp. 627-644.
Rena Orman, Ph.D., Research Assistant Professor
Isaac Naggar, M.D./Ph.D. Student
Co-director, Program in Nanomedicine (a joint program with the College of Nanoscale Science and Engineering, Albany, NY)
Co-director, Program in Developmental Neuroscience (a joint program with the Institute for Basic Research, Staten Island, NY)