Abstracts

Rationale: Non-convulsive status epilepticus (NCSE), a condition with often subtle signs, is likely underdiagnosed. The aggressivity of its treatment is also controversial. Unlike its convulsive counterpart, NCSE is not well-studied in animals, and its effects on the developing brain remain largely elusive. To better gauge the urgency of its diagnostic workup, and the level of aggressivity of its treatment, it is essential to gain insight into its potential harmful consequences. We therefore investigated potential limbic NCSE-induced behavioral deficits and hippocampal injury in peri-adolescent rats.


Methods: Seizures were induced in P40 Sprague Dawley rats by injecting 6.25 ng of kainic acid (NCSE group, n=14) or volume-matched saline (controls, n=18) into the basolateral amygdala under continuous epidural cortical electroencephalography (EEG). Following one month of EEG recordings, rats were subjected (P73-91) to the open field and forced swim tests (FST), Morris water maze (MWM), and modified two-way active avoidance (MAAV). Rats were sacrificed at P91 to histologically assess hippocampal injury with NeuN (neuronal nuclei) staining, levels of GFAP (glial fibrillary acidic protein), and synaptophysin (Syp).


Results: All rats in the NCSE group experienced electrographic seizure activity accompanied by unresponsiveness to tapping on the cage by the experimenters with intermittent head nodding, and orofacial automatisms (latency: 15.93 ± 4.70 min, duration: 68.35 ± 17.97 min). There were no seizure recurrences in the rest of the long-term recordings. None of the controls experienced seizures. Compared to controls, NCSE rats had significantly lower immobility in the FST, impaired place learning in the MWM, and lower rates of context-cued shock avoidance in the MAAV (p< 0.05). There were no differences in other tests. The NCSE and control groups had comparable hippocampal neuronal densities and GFAP levels, but NCSE rats had significantly lower hilar Syp levels.


Conclusions: One episode of limbic NCSE during peri-adolescence results in later life hippocampal synaptic dysfunction and contextual learning deficits. Our novel findings suggest that a higher index of suspicion and a more urgent treatment approach may be needed to prevent NCSE-induced brain injury. Ongoing work in our laboratory investigates the potential effects of seizure burden on such detrimental long-term consequences.


Funding: This research project was funded by the American University of Beirut (MPP 320150 to MO), and Indiana University School of Medicine to MO.