Seizure activity and brain damage: a tale of two hippocampi

Objective: Focal non-convulsive status epilepticus (ncSE) is a relatively common emergency condition that in most cases presents itself as first epileptic manifestation. In recent years it became increasingly clear that de novo focal ncSE should be promptly treated to improve post-status outcome. Whether the presence of seizures during this condition contributes to ensuing brain damage is not unequivocally demonstrated and is here addressed. Methods: We used continuous video-EEG monitoring to characterize an acute experimental focal ncSE model induced by unilateral intrahippocampal injection of kainic acid (KA) in guinea pigs. Immunohistochemistry, morphological reconstruction and mRNA expression analysis were used as markers to detect and quantify brain injury at 3 days and 1 month post focal ncSE. To distinguish between the effects of seizure activity vs excitotoxic properties of KA, another cohort of animals was generated and i.p. injected with diazepam. Results: Seizure activity during focal ncSE involved both hippocampi and neuronal loss was limited to the KA-injected hippocampus. Diazepam treatment reduced both ncSE duration and local KA-induced neuropathological damage. Transient and possibly reversible astro and microgliosis associated with upregulation of astrocytic-specific aquaporin-4 and Kir4.1 genes was observed mainly in the hippocampus contralateral to KA injection. Ipsilaterally, permanent gliosis was present and neuronal loss as well as blood-brain barrier dysfunction were not averted. Interpretation: Seizures at the site of injection of KA worsen tissue damage. We also show that focal ncSE induces a transient and possibly reversible activation of astro and microglia in regions remote from KA injection, suggesting that seizure activity without a local pathogenic co-factor does not promote detrimental changes in the brain. These findings demonstrate that focal damage remains circumscribed to the lesional region during focal ncSE and that the propagation of seizure activity to regions remote from the primary site of injection did not seem to exert a harmful effect, in this model. Lastly, our study emphasizes the need of antiepileptic treatment to contain the local epileptic focus during focal ncSE.