Abstracts

Rationale: Sudden unexpected death in epilepsy (SUDEP) is mechanistically complex with various known risk factors. One possible cause is seizure-related respiratory dysfunction. The medulla contains respiratory regulatory nuclei, including the pre-Botzinger complex (pre-BötC) in the ventrolateral medulla (VLM), the solitary tract and the medullary raphe nuclei (MR). Previous work from our group has shown pathological alteration in the pre-BötC and modulatory serotonergic and galanergic networks. The region of the VLM also contains catecholaminergic neurones which also directly project to the pre-BötC and are known to regulate breathing under hypoxic conditions. Methods: In 47 post mortem cases from four patient groups [SUDEP (15), Dravet syndrome (7), epilepsy controls (7) and non-epilepsy controls (18)] fixed sections of medulla from obex 1-12 mm were examined. Serial sections at 200 micron intervals were immunolabelled for tyrosine hydroxylase (TH). The slides were digitised and regions of interest outlined, including the pre-BötC, solitary tract and MR using Definiens image analysis. TH-positive neurons were counted in these regions as well as the overall labelling index for each region (neurons and processes) and compared between groups. Results: TH immunoreactivity was mainly localised to the cell body, proximal processes of large neurons as well as axon bundles in the regions studied. There was no statistically significant difference in the density of TH-positive neurons or labelling index between the four groups. When SUDEP cases were stratified into definite and possible/probable SUDEP, there were still no significant differences from control groups.  There were significantly more TH-positive neurons in the pre-BötC and solitary tract region than the MR (p<0.001). In all cases there was an inverse correlation between TH labelling index in the VLM and mid obex level (p = 0.04). There was no correlation with TH measurements and age of seizure onset, age at death or seizure duration. Conclusions: In this series we found no conclusive evidence for alteration of medullary TH-positive neurons in SUDEP to implicate dysfunction of catecholaminergic systems in disease mechanism. Localisation of TH neurons to the medullary raphe has not previously been reported.  Funding: NIH grant (Centre for SUDEP Research) 5U01NS090415