Seizure activity and brain damage in a model of focal non‐convulsive status epilepticus

Abstract

Aims: Focal non-convulsive status epilepticus (FncSE) is a common emergency condition that may present as the first epileptic manifestation. In recent years, it has become increasingly clear that de novo FncSE should be promptly treated to improve post-status outcome. Whether seizure activity occurring during the course of the FncSE contributes to ensuing brain damage has not been demonstrated unequivocally and is here addressed. Methods: We used continuous video-EEG monitoring to characterise an acute experimental FncSE model induced by unilateral intrahippocampal injection of kainic acid (KA) in guinea pigs. Immunohistochemistry and mRNA expression analysis were utilised to detect and quantify brain injury, 3-days and 1-month after FncSE. Results: Seizure activity occurring during the course of FncSE involved both hippocampi equally. Neuronal loss, blood-brain barrier permeability changes, gliosis and up-regulation of inflammation, activity-induced and astrocyte-specific genes were observed in the KAinjected hippocampus. Diazepam treatment reduced FncSE duration and KA-induced neuropathological damage. In the contralateral hippocampus, transient and possibly reversible gliosis with increase of aquaporin-4 and Kir4.1 genes were observed 3 days post-KA. No tissue injury and gene expression changes were found 1-month after FncSE. Conclusions: In our model, focal seizures occurring during FncSE worsen ipsilateral KAinduced tissue damage. FncSE only transiently activated glia in regions remote from KA-injection, suggesting that seizure activity during FncSE without local pathogenic cofactors does not promote long-lasting detrimental changes in the brain. These findings demonstrate that in our experimental model, brain damage remains circumscribed to the area where the primary cause (KA) of the FncSE acts. Our study emphasises the need to use antiepileptic drugs to contain local damage induced by focal seizures that occur during FncSE.

Peripheral blood mononuclear cell activation sustains seizure activity

“…44 Both proinflammatory cytokines and chemokines released by a-PBMCs and hALB extravasation promote resident microglia activation, 45 which in turn are expected to activate astrocytes and exacerbate reactive pathways. 10 In our experiments, microgliosis was evident when either ConA-activated hPBMCs or a-hPBMC supernatant only (both associated with LPS and hALB infusion) were perfused into the in vitro guinea pig brain. Glial cells have a plethora of housekeeping functions such as sensing and responding to alterations in energy supply, neuronal activity, extracellular ion concentrations, osmolarity, among many other processes.…”

“…We observed that microglial cells responded promptly to these immunological triggers through a significant change in their morphological phenotype toward a more activated state demonstrated by their amoeboid shape 44 . Both proinflammatory cytokines and chemokines released by a‐PBMCs and hALB extravasation promote resident microglia activation, 45 which in turn are expected to activate astrocytes and exacerbate reactive pathways 10 . In our experiments, microgliosis was evident when either ConA‐activated hPBMCs or a‐hPBMC supernatant only (both associated with LPS and hALB infusion) were perfused into the in vitro guinea pig brain.…”

“…Although CNS‐resident cells such as microglia and astrocytes are key modulators of neuroinflammation, the interaction between adaptive immune cells and intraluminal endothelial molecules triggers the release of diffusible inflammatory mediators into brain parenchyma (cytokines, chemokines) that are known to activate glial cells and increase neuronal excitability, along with serum albumin extravasation 4,9,10 . In addition, extensive clinical and experimental evidence suggests that inflammatory processes play a role in the generation and recurrence of epileptic seizures 11 …”

“…6 Although CNS-resident cells such as microglia and astrocytes are key modulators of neuroinflammation, the interaction between adaptive immune cells and intraluminal endothelial molecules triggers the release of diffusible inflammatory mediators into brain parenchyma (cytokines, chemokines) that are known to activate glial cells and increase neuronal excitability, along with serum albumin extravasation. 4,9,10 In addition, extensive clinical and experimental evidence suggests that inflammatory processes play a role in the generation and recurrence of epileptic seizures. 11 In this study we aimed to investigate the specific role of peripheral blood mononuclear cells (PBMCs) in initiating brain inflammation and BBB damage, either autonomously or in cooperation with blood-borne molecules and microglial cells, to induce seizure-like events (SLEs).…”

A Preliminary Report: The Hippocampus and Surrounding Temporal Cortex of Patients With Schizophrenia Have Impaired Blood-Brain Barrier

“…Since this is critical information necessary for comparing BBB function among the Ctrl and subjects with SZ, we have developed a semi-quantitative protocol using the Cavalieri estimator stereological function in Stereo Investigator software (MBF Bioscience, VT, United States). Similar to previous studies, our semi-quantitative protocol relies on the immunoreactivity demonstrated by the extravasated IgGs with neurons and neuropil ( Librizzi et al, 2021 ; Vila Verde et al, 2021 ). The Cavalieri estimator method is a proven unbiased stereological method used to calculate areas in tissue sections, and we have adopted it to estimate IgG leaked area fraction or the extent of BBB leak ( Cohen, 1992 ; No authors, 2021 ).…”