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Seizure-Associated Spreading Depolarization, Autonomic Dysfunction, and Epileptogenesis in a Murine Model of Post-Cerebral Malaria Epilepsy
Restricted (Penn State Only)
Engineering Science and Mechanics
Master of Science
Date of Defense:
April 03, 2017
Bruce J. Gluckman, Thesis Advisor
Patrick J. Drew, Committee Member
Steven J. Schiff, Committee Member
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%. Worldwide, this corresponds to initiation of approximately 300,000 new cases of potentially preventable epilepsy per year. We investigated murine models of CM for evidence of post-malarial epilepsy by combining four mouse strains and two Plasmodium berghei (Pb) parasites (NK65 and ANKA): Swiss-Webster SW-PbNK65, SW-PbANKA, C57BL/6-PbANKA, and CBA-PbANKA. Cohorts of three-week old littermates were inoculated with infected erythrocytes. We rescued animals with Artesunate when they demonstrated signs of advanced CM. Controls were inoculated with uninfected erythrocytes. We developed a chronic recording system for long-term monitoring of brain and heart dynamics with DC sensitivity. 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. In all model combinations studied, recurrent spontaneous seizures were observed in a large fraction (50-90%) of the animals that survived to recording. Seizures were typically accompanied by clear spreading depolarization (SD) signatures in the DC components of the recordings. Post-implant mortality were observed in some model mixtures. In these cases, death was accompanied by typically a single seizure-like event followed either by immediate death or a severe decrement in health. We recorded many seizure-related deaths including 5/13 SW-PbANKA and 8/20 SW-PbNK65. All epileptic mice showed significant changes in cardiac activity associated with seizures. Aside peri-ictal tachycardia and bradycardia, we observed incidents of sinus pause both peri-ictally and late during epileptogenesis. This condition was preceded by appearance of interictal discharges. Further investigation of brain-heart dynamics during epileptogenesis indicated a causal relationship between interictal discharges (IID) and long RR intervals which progressed into IID-induced loss of cardiac rhythmicity 2-days prior to the first seizure. Our findings suggest that repeated epileptic discharges cause or exacerbate serious cardiac pathologies and point to an autonomic nervous system disorder that later reinforces the epileptic state. As the conditions worsen and overt seizures occur, postictal episodes of spreading depolarization modulate the network’s threshold to further hyperexcitability via effects on the autonomic regulatory nuclei. We have developed models of post-malarial epilepsy (PoME). In long-term chronic recordings, we observe complex interactions between epileptic-like activity and cardiac regulation during epileptogenesis and further seizures, heart arrhythmias, spreading depolarization, and death. This model, which is induced from infection not genetic mutation, therefore provides a unique platform for the study of the mechanisms of epileptogenesis and investigation of complex interactions between seizures, spreading depolarization, cardiac and respiratory dysfunction, and sudden death (SUDEP).
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