Abstracts

Rationale: It is well established – though relatively unknown – that cerebral malaria (CM) leads to epilepsy. For the nearly 500,000 children who survive CM per year in sub-Saharan Africa, the estimated epilepsy rate after two-years is approximately 16% which means 80,000 new cases of potentially preventable childhood epilepsy per year locally and many times that worldwide.We have demonstrated in a combination of mouse-strain and Plasmodium-berghei (Pb) parasite that when rescued from CM, 75% of mice develop epilepsy (ssentongo 2017).  Latencies to first convulsive seizure ranged from 30-140 days, and a number of SUDEP and other seizure related deaths were observed. As in humans, seizures were accompanied by significant cardiac arrhythmias. Furthermore, smaller epileptic discharges prior to the first convulsive seizure were accompanied by distinct cardiac arrhythmia. We investigated the brain-heart interactions during epileptogenesis to determine the causality of such interaction and its application as a potential biomarker of epileptogenesis. Methods: We investigated four murine models of post-cerebral malaria epilepsy by combining mouse strains (Swiss Webster (SW), C57BL/6, CBA) and two Plasmodium-berghei (Pb) parasites (NK65 and ANKA): SW-PbNK65, SW-PbANKA, C57BL/6-PbANKA, and CBA-PbANKA. Cohorts of three-week old littermates were inoculated with infected erythrocytes, then rescued with Artesunate when they demonstrated signs of advanced CM.  Animals were implanted with EEG, EMG, and ECG electrodes 14 or more days post treatment, and video-EEG monitored continuously for 1-8 months per animal. Results: All epileptic mice with ECG recordings showed significant changes in cardiac activity associated with seizures. In 80% of the seizures, a transient pre-ictal episode of tachycardia occurred followed by ictal and late-ictal bradycardia. Abnormally long RR intervals resembling AV blocks and sinus pause incidents were also observed peri-ictally.We detect a significant causal relationship between brain discharges and long RR intervals during epileptogenesis. The severity of such events increases over time and peaks prior to the onset of the first seizure.  In parallel, the severity of the detected discharges evolves from marginally detectable to distinctly epileptiform events. No significant incident of discharge induced cardiac arrhythmia was observed in controls. Conclusions: Our findings suggest that epileptiform discharges influence autonomic regulation early during epileptogenesis. Repeated instances of discharge-induced cardiac dysregulations can cause or exacerbate serious cardiac pathologies. Therefore, detection of such causal relationship between epileptiform discharges and autonomic misbalance provides a marker of epileptogenesis and potentially a window to intervene early during the process, as well as the possibility to prevent development of overt epileptic states and/or related cardiac comorbidity. Funding: Multidisciplinary grant from Citizen’s United for Research in Epilepsy (CURE).