Abstracts

Rationale: Sudden Unexpected Death in Epilepsy (SUDEP) is the major cause of epilepsy-related deaths, accounting for up to 17% of all deaths (Tellez-Zenteno, Ronquillo et al. 2005). The mechanisms underlying SUDEP remain poorly understood but cardiac and respiratory dysregulation during or after a seizure is likely. Inflammation, acute neuronal injury due to hypoxia and acute blood brain barrier (BBB) dysfunction are known to both follow and provoke or perpetuate seizures (Vezzani, Friedman et al. 2013). Our aim was to explore these processes, in brain regions involved in autonomic and cardio-respiratory regulation, in a SUDEP series. Methods: Using immunohistochemistry we investigated expression of markers of inflammation (CD163 and HLA-DR), acute neuronal injury due to hypoxia (HIF-1α) and BBB disruption (IgG and Albumin) in the hippocampus, medulla and amygdala in 45 cases: 13 definite SUDEP, 11 probable SUDEP (Nashef, So et al. 2012), 5 epilepsy without SUDEP controls and 16 non-epileptic sudden death controls. A semi-quantitative analysis of immunoreactivity was scored in six regions of the medulla [including ventro-lateral medulla (cardioregulatory nuclei), dorsal Xth nucleus, solitary tract, pyramids, olives and arcuate nucleus], in the hippocampus [dentate gyrus, CA1 to 4, subiculum and white matter], and in the amygdala [lateral nucleus, basal nucleus, accessory basal nucleus]. Results: There were no differences overall between cases in the distribution of HLA-DR-immunopositive cells within medullary and amygdaloid nuclei in SUDEP compared to controls; CD163 was expressed mainly in perivascular macrophages in all groups. In the subgranular zone in the hippocampus, 89% of definite SUDEP cases showed increased HLA-DR-immunopositive cells and 79% of definite SUDEP cases showed strong immunolabeling with IgG on astroglial cells in CA4. HIF-1α immunolabeling was observed in the cytoplasm of a very small number of neurons and on synaptic processes in all studied brain regions. Conclusions: Our results do not support acute inflammatory mechanisms in the brainstem in SUDEP as a potential contributing factor to the mechanism of death. Our findings do not support either cerebral hypoxia as a factor playing a role in neuronal damage in SUDEP. We noted increased inflammatory reaction and BBB disruption in the hippocampal subgranular zone in SUDEP; whether this is a reflection of pre-mortem seizure activity or mechanistically linked to SUDEP requires further investigation. Acknowledgements: This work was supported by Citizens United for Research in Epilepsy (CURE) research award. Literature: 1. Nashef, L., E. L. So, et al. (2012). "Unifying the definitions of sudden unexpected death in epilepsy." Epilepsia 53(2): 227-233. 2. Tellez-Zenteno, J. F., L. H. Ronquillo, et al. (2005). "Sudden unexpected death in epilepsy: evidence-based analysis of incidence and risk factors." Epilepsy Res 65(1-2): 101-115. 3. Vezzani, A., A. Friedman, et al. (2013). "The role of inflammation in epileptogenesis." Neuropharmacology 69(0): 16-24.