Abstracts

This abstract is a recipient of the Nurse and Advanced Practice Provider Travel Award
This abstract has been invited to present during the Translational Research platform session

Rationale: Surgery for temporal lobe epilepsy (TLE) is a well-recognised therapy for drug-resistant seizures which occur in more than 50% of patients with this form of the condition. Blood-brain barrier (BBB) dysfunction is a common pathological finding observed in resected brain tissue from patients with treatment-resistant epilepsy. While previous studies have shown an association between BBB dysfunction and seizure activity in epilepsy, there are few studies that have documented the recovery of BBB function after seizures have been controlled.

Methods: A retrospective observational histopathological study of twelve surgical specimens removed from patients and stained for claudin-5 protein to look for BBB integrity._x000D_ We prospectively recruited seven cases of patients listed for temporal lobe resections and one new-onset epilepsy case. The seven surgical patients were imaged pre-operatively using a Dynamic contrast-enhanced MRI (DCE- MRI) protocol as an in vivo measure of BBB function using permeability maps. Resected tissue from the seven surgical cases was again stained for claudin 5. In all but one case (a surgical case) seizures were controlled with resection. All seven cases were imaged using the DCE-MRI post-operatively. A regression analysis was performed to look for a significant association between clinical characteristics of all nineteen cases for which there was pathology and quantitative histological findings. Circulating biomarkers were collected before and after imaging in the eight prospective cases. A customisable Lumenix magnetic bead-based multiplex panel allowed for screening of several brain- specific or brain-enriched proteins and inflammatory markers, which has the potential to identify a multifactorial panel of markers, in combination with changes in circulating miRNAs, that are indicative of changes in blood-brain barrier integrity.

Results: All twelve retrospective surgical samples stained for Claudin 5 demonstrated varying levels of BBB disruption. A regression analysis of a range of clinical phenotypical factors revealed only two that correlated significantly with the degree of BBB disruption; lower age of onset of epilepsy and length of epilepsy history. _x000D_ The DCE-MRI demonstrated widespread BBB dysfunction pre-operatively in the seven surgical cases and in the new-onset epilepsy case. Tissue staining for Claudin 5 in all the surgical samples demonstrated a similar pattern of BBB disruption to those in retrospective cohort. Post-operatively DCE-MRI in six of seven cases who were rendered seizure-free post-op demonstrated rescue of BBB function. In the one case with ongoing post- op seizures, DCE-MRI showed persistent BBB dysfunction. A regression analysis of a range of clinical phenotypical factors over all nineteen cases revealed lower age of onset of epilepsy and length of epilepsy history correlated significantly with the degree of BBB disruption._x000D_ Circulating biomarkers (results awaited) _x000D_

Conclusions: BBB dysfunction is a key component of the molecular disruption caused by seizures and in particular in longstanding early-onset chronic epilepsy that is refractory to treatment. Here we demonstrate for the first time the rescue of BBB dysfunction by controlling seizures.

Funding: FutureNeuro-SFI Research Centre for Chronic and Rare Neurological Diseases