Abstracts

Rationale: Sudden unexpected death in epilepsy (SUDEP) is the most common cause of premature death among young people with epilepsy, and likely results from a centrally-mediated failure to recover from severe generalised tonic-clonic seizure (GTCS)-induced autonomic / respiratory dysfunction. Frequency of GTCS is the most important risk factor associated with SUDEP; experiencing more than three GTCS per year carries the largest SUDEP risk-increase (1). Volumetric gray matter investigations (2,3) show changes to important autonomic brain regions in patients at greater risk of SUDEP; however, functional whole-brain network-based alterations associated with increased SUDEP risk are undescribed. The aim was to investigate a network-based property of functional connectivity (FC), local efficiency, a measure of information exchange, in patients at high- and low- risk of SUDEP to shed light on whole-brain FC biomarkers of elevated SUDEP risk. Methods: We used the criterion of more than 3 GTCS/year to define a group of n=12 high-risk temporal lobe epilepsy (TLE) patients among a cohort of n=37 unilateral TLE cases, providing n=25 control (low-risk) cases. Resting-state functional magnetic resonance Imaging (fMRI) time-courses from 246 brain regions (210 cortical and 36 sub-cortical) were extracted using the Brainnetome atlas - a probabilistic atlas based on multi-modal imaging-derived anatomical and connectional (functional and structural) subdivisions (4). After constructing graphs for each subject, a proportional threshold was applied sparing the highest 10% of connections in each subject’s network. Local efficiency (Eloc) was then computed on the resulting unweighted binary graphs (5).  Analysis of covariance (ANCOVA) was employed to test Eloc differences between high and low-risk patients, controlling for age, gender, GTCS frequency, lateralisation of epilepsy, presence of hippocampal sclerosis, and duration of epilepsy (Bonferroni correction, p < 0.05). Results: Significant reductions and increases in Eloc emerged amongst several cortical (Fig. 1.) and sub-cortical (Fig. 2.) brain sites in the high- vs low-risk TLE group. Regions showing significantly increased Eloc (p < 0.05) were inferior parietal lobule and entorhinal cortex. Regions with significantly reduced Eloc (p < 0.05) involved frontal, temporal, occipital, cingulate, thalamic, and basal ganglia structures. Conclusions: High-risk TLE patients exhibit altered FC among several cortical and subcortical structures linked with cognitive, motor, sensory, and autonomic functions, likely reflecting effects of ongoing and frequent GTCS in the high-risk group. Thalamic, basal ganglia, hippocampal, and cingulate alterations are of concern, given their significant autonomic regulatory roles. Dysfunction among these vital cortical and sub-cortical regions may predispose central autonomic and respiratory systems to a failure-to-recover following extreme challenges, such as GTCS. Funding: This work was undertaken at UCLH/UCL who receives a proportion of funding from the Department of Health’s NIHR Biomedical Research Centres funding scheme. This work was funded by the NIH – National Institute of Neurological Disorders and Stroke U01-NS090407-01 (The Center for SUDEP Research). Functional MRI data acquired through Medical Research Council funding (grant number G0301067). SBV is funded by the National Institute for Health Research University College London Hospitals Biomedical Research Centre (NIHR BRC UCLH/UCL High Impact Initiative). We are grateful to the Wolfson Foundation and the Epilepsy Society for supporting the Epilepsy Society MRI scanner.