Nonconvulsive status epilepticus in rats leads to brain pathology

Avdic, Una; Ahl, Matilda; Chugh, Deepti; Ali, Idrish; Chary, Karthik; Sierra, Alejandra; Ekdahl, Christine T.

doi:10.1111/epi.14070

Cited by 30 publications

(38 citation statements)

References 43 publications

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“…The descriptions did not include the variety of electrographic patterns revealed by our initial analysis of EEG in rats with lateral FPI. Nor did the descriptions of EEG patterns in rats during NCSE induced with hippocampal stimulation 28 or in rats with repeated unprovoked seizures and interictal epileptiform activity with subtle behavioral symptoms induced by ballistic TBI 29 correspond to the EEG patterns observed in our animals. Rather, the electrographic patterns we observed corresponded to those described in human complex partial SE after brain injury.…”

Section: Lateral Fpi Induces Ncsementioning

confidence: 61%

Acute Non-Convulsive Status Epilepticus after Experimental Traumatic Brain Injury in Rats

Andrade

Bañuelos-Cabrera

Lapinlampi

et al. 2019

Journal of Neurotrauma

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Severe traumatic brain injury (TBI) induces seizures or status epilepticus (SE) in 20-30% of patients during the acute phase. We hypothesized that severe TBI induced with lateral fluid-percussion injury (FPI) triggers post-impact SE. Adult Sprague-Dawley male rats were anesthetized with isoflurane and randomized into the sham-operated experimental control or lateral FPI-induced severe TBI groups. Electrodes were implanted right after impact or sham-operation, then videoelectroencephalogram (EEG) monitoring was started. In addition, video-EEG was recorded from naïve rats. During the first 72 h post-TBI, injured rats had seizures that were intermingled with other epileptiform EEG patterns typical to nonconvulsive SE, including occipital intermittent rhythmic delta activity, lateralized or generalized periodic discharges, spike-and-wave complexes, poly-spikes, poly-spike-and-wave complexes, generalized continuous spiking, burst suppression, or suppression. Almost all (98%) of the electrographic seizures were recorded during 0-72 h post-TBI (23.2-17.4 seizures/rat). Mean latency from the impact to the first electrographic seizure was 18.4-15.1 h. Mean seizure duration was 86-57 sec. Analysis of high-resolution videos indicated that only 41% of electrographic seizures associated with behavioral abnormalities, which were typically subtle (Racine scale 1-2). Fifty-nine percent of electrographic seizures did not show any behavioral manifestations. In most of the rats, epileptiform EEG patterns began to decay spontaneously on Days 5-6 after TBI. Interestingly, also a few sham-operated and naïve rats had post-operation seizures, which were not associated with EEG background patterns typical to non-convulsive SE seen in TBI rats. To summarize, our data show that lateral FPI-induced TBI results in non-convulsive SE with subtle behavioral manifestations; this explains why it has remained undiagnosed until now. The lateral FPI model provides a novel platform for assessing the mechanisms of acute symptomatic non-convulsive SE and for testing treatments to prevent post-injury SE in a clinically relevant context.

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Section: Lateral Fpi Induces Ncsementioning

confidence: 61%

Acute Non-Convulsive Status Epilepticus after Experimental Traumatic Brain Injury in Rats

Andrade

Bañuelos-Cabrera

Lapinlampi

et al. 2019

Journal of Neurotrauma

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“…In two studies, contralateral hippocampal alterations were observed when a convulsive status epilepticus was promoted using either high doses of unilaterally injected KA 37 or repeated unilateral hippocampal stimulation. 38 In a recent report, unilateral hippocampal electrical stimulation in rats demonstrated cell loss and changes in the expression of N-cadherin in the hippocampus contralateral to stimulation 39 exclusively in a subgroup of animals that developed seizures 4 weeks after ncSE. Of interest, contralateral neuronal loss was not observed in rats submitted to ncSE that did not develop spontaneous seizures in the chronic phase.…”

Section: Discussionmentioning

confidence: 96%

“…39 We utilized postfixed tissue because it allows longer MR scanning times that improve imaging definition without altering the significance of the recorded signals; apparent diffusion coefficient (ADC) measurements in fixed brains are characterized by lower values compared to in vivo condition. These data confirmed the results of the above-mentioned study on the ncSE model induced by unilateral electrical stimulation of one hippocampus.…”

Section: Discussionmentioning

confidence: 99%

“…These data confirmed the results of the above-mentioned study on the ncSE model induced by unilateral electrical stimulation of one hippocampus. 39 We utilized postfixed tissue because it allows longer MR scanning times that improve imaging definition without altering the significance of the recorded signals; apparent diffusion coefficient (ADC) measurements in fixed brains are characterized by lower values compared to in vivo condition. 46,47 T1-weighted MRI images showed signal changes suggesting BBB disruption only in KA-injected hippocampus, although we cannot exclude minor, undetectable BBB permeability changes on the contralateral side.…”

Section: Discussionmentioning

confidence: 99%

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Epileptiform activity contralateral to unilateral hippocampal sclerosis does not cause the expression of brain damage markers

et al. 2019

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Objective Patients with epilepsy often ask if recurrent seizures harm their brain and aggravate their epileptic condition. This crucial question has not been specifically addressed by dedicated experiments. We analyze here if intense bilateral seizure activity induced by local injection of kainic acid (KA) in the right hippocampus produces brain damage in the left hippocampus. Methods Adult guinea pigs were bilaterally implanted with hippocampal electrodes for continuous video—electroencephalography (EEG) monitoring. Unilateral injection of 1 μg KA in the dorsal CA1 area induced nonconvulsive status epilepticus (ncSE) characterized by bilateral hippocampal seizure discharges. This treatment resulted in selective unilateral sclerosis of the KA‐injected hippocampus. Three days after KA injection, the animals were killed, and the brains were submitted to ex vivo magnetic resonance imaging (MRI) and were processed for immunohistochemical analysis. Results During ncSE, epileptiform activity was recorded for 27.6 ± 19.1 hours in both the KA‐injected and contralateral hippocampi. Enhanced T1‐weighted MR signal due to gadolinium deposition, mean diffusivity reduction, neuronal loss, gliosis, and blood–brain barrier permeability changes was observed exclusively in the KA‐injected hippocampus. Despite the presence of a clear unilateral hippocampal sclerosis at the site of KA injection, no structural alterations were detected by MR and immunostaining analysis performed in the hippocampus contralateral to KA injection 3 days and 2 months after ncSE induction. Fluoro‐Jade and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining at the same time points confirmed the absence of degenerating cells in the hippocampi contralateral to KA injection. Significance We demonstrate that intense epileptiform activity during ncSE does not cause obvious brain damage in the hippocampus contralateral to unilateral hippocampal KA injection. These findings argue against the hypothesis that epileptiform activity per se contributes to focal brain injury in previously undamaged cortical regions.

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“…People with epilepsy or epileptic encephalopathy often develop ongoing NCSE after status epilepticus (SE) with prominent motor activity (convulsive SE) ( 1 – 4 ). Functional outcome and prognosis may be worse in patients with ongoing NCSE due to increased metabolic demand and thus causing secondary brain damage ( 5 – 8 ). Recent studies show mortality of up to 40% in super-refractory SE and increased costs and length of stay associated with refractory course ( 9 ).…”

Section: Introductionmentioning

confidence: 99%

Automated Long-Term EEG Review: Fast and Precise Analysis in Critical Care Patients

et al. 2018

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Background: Ongoing or recurrent seizure activity without prominent motor features is a common burden in neurological critical care patients and people with epilepsy during ICU stays. Continuous EEG (CEEG) is the gold standard for detecting ongoing ictal EEG patterns and monitoring functional brain activity. However CEEG review is very demanding and time consuming. The purpose of the present multirater, EEG expert reviewer study, is to test and assess the clinical feasibility of an automatic EEG pattern detection method (Neurotrend).Methods: Four board certified EEG reviewers used Neurotrend to annotate 76 CEEG datasets à 6 h (in total 456 h of EEG) for rhythmic and periodic EEG patterns (RPP), unequivocal ictal EEG patterns and burst suppression. All reviewers had a predefined time limit of 5 min (± 2 min) per CEEG dataset and were compared to a predefined gold standard (conventional EEG review with unlimited time). Subanalysis of specific features of RPP was conducted as well. We used Gwet's AC1 and AC2 coefficients to calculate interrater agreement (IRA) and multirater agreement (MRA). Also, we determined individual performance measures for unequivocal ictal EEG patterns and burst suppression. Bonferroni-Holmes correction for multiple testing was applied to all statistical tests.Results: Mean review time was 3.3 min (± 1.9 min) per CEEG dataset. We found substantial IRA for unequivocal ictal EEG patterns (0.61–0.79; mean sensitivity 86.8%; mean specificity 82.2%, p < 0.001) and burst suppression (0.68–0.71; mean sensitivity 96.7%; mean specificity 76.9% p < 0.001). Two reviewers showed substantial IRA for RPP (0.68–0.72), whereas the other two showed moderate agreement (0.45–0.54), compared to the gold standard (p < 0.001). MRA showed almost perfect agreement for burst suppression (0.86) and moderate agreement for RPP (0.54) and unequivocal ictal EEG patterns (0.57).Conclusions: We demonstrated the clinical feasibility of an automatic critical care EEG pattern detection method on two levels: (1) reasonable high agreement compared to the gold standard, (2) reasonable short review times compared to previously reported EEG review times with conventional EEG analysis.

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Nonconvulsive status epilepticus in rats leads to brain pathology

Abstract: These findings provide evidence for a significant brain pathology following NCSE in an experimental rodent model.

Cited by 30 publications

References 43 publications

Acute Non-Convulsive Status Epilepticus after Experimental Traumatic Brain Injury in Rats

Acute Non-Convulsive Status Epilepticus after Experimental Traumatic Brain Injury in Rats

Epileptiform activity contralateral to unilateral hippocampal sclerosis does not cause the expression of brain damage markers

Automated Long-Term EEG Review: Fast and Precise Analysis in Critical Care Patients

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