Abstracts

Rationale: Sudden Unexpected Death in Epilepsy (SUDEP) is a non-traumatic fatal complication in epileptic patients. Cardiorespiratory dysfunction causing SUDEP is postulated to be due to invasion of epileptiform activity into the cardiorespiratory nuclei in the brainstem. In a model of recurring frequent hippocampal-originating generalized seizures, we hypothesized that general anesthesia under isoflurane differentially suppresses brainstem seizures and concomitant respiratory abnormalities at lower doses than required to suppress cerebral seizures

Methods: Adult male Wistar rats (6-15 weeks old, 250-600 gr) were anesthetized with isoflurane (Iso) for surgical operation at 3% (vol/vol of oxygen), and then were maintained at 1.5-2.5%. A bipolar electrode and a cannula-bipolar electrode were implanted into the brainstem nucleus tractus solitarius (NTS) and dorsal hippocampus CA1, respectively. To induce cerebral seizures, 10 μL of 4-aminopyridine (4-AP) at 100 mM was injected into CA1 via a cannula. In order to simultaneously monitor the oxygen saturation (SpO2), heart rate (HR), and breathing rate (BR), we used the MouseOx Pulse Oximeter foot sensor (Starr Life Sciences Corp. Oakmont, PA, USA). All procedures were approved and in accordance with guidelines of Canadian Council on Animal Care

Results: Extracellular recordings of spontaneous neural activities in right CA1 and NTS were captured for 30 mins under 2.5% Iso, following which 4-AP was injected. In CA1, 4-AP triggered aberrant frequency and amplitude changes in the signal, i.e. indicative of seizures. Over the next few minutes, interictal spikes (ISs) became more robust and frequent, as did seizure intensity and duration. In contrast, NTS did not show any significant electrographical irregularity compared to baseline whereas peripheral markers, including HR, BR and SpO2 remained unaltered. After 30 mins, Iso was lowered to 1.5% which resulted in NTS displaying large neural oscillatory activities, namely seizure-like events (SLE), that were simultaneous and concomitant with disruption in BR, independent from hippocampal seizure onset, whereas HR and SpO2 remained unaltered. Although partially immobilized, rats also developed unilateral whiskers and rapid movements of their ears and bilateral exophthalmos. Following 30 mins, Iso was raised back to 2.5% and higher, which partially subsided hippocampal seizures, returned BR to baseline, and suppressed SLEs in the brainstem

Conclusions: Our physiological multi-readout system coupled with intracranial recordings from brainstem and hippocampus demonstrated that (i) seizure invasion into the brainstem disrupts respiratory, but not cardiac activity, making BR a potential peripheral readout for brainstem seizure; (ii) isoflurane differentially suppresses brainstem seizures and respiratory abnormalities more than cerebral seizures. Hence, it is hypothesized that isoflurane can be a good candidate to reduce brainstem seizures, intervene with respiratory disruption, and eventually shed light on SUDEP prevention

Funding: Please list any funding that was received in support of this abstract.: MITACS and Novela Neurotechnologies Inc.