Deep hypothermia for the treatment of refractory status epilepticus

Niquet, Jérôme; Baldwin, Roger A.; Gezalian, Michael; Wasterlain, Claude G.

doi:10.1016/j.yebeh.2015.06.028

Cited by 27 publications

(21 citation statements)

References 64 publications

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“…EEG power in normothermic animals decreased from pretreatment SE, probably in part due to midazolam, but remained significantly above baseline for 4.1 ± 1.1 h (mean ± SEM; n = 9) after midazolam injection, indicating continuation of SE. In hypothermic animals, cooling brought power down to baseline level in 23.8 ± 3.9 min (mean ± SEM; n = 5) and significantly lowered EEG power compared to normothermia at 30 min and beyond as described in a preliminary report . In these animals, EEG power decreased below prepilocarpine baseline, and remained close to baseline values for the remaining of the 24 h, suggesting that SE had been terminated and did not return.…”

Section: Resultsmentioning

confidence: 51%

Neuroprotective effects of deep hypothermia in refractory status epilepticus

Niquet

Gezalian

Baldwin

et al. 2015

Ann Clin Transl Neurol

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ObjectivePharmacoresistance develops quickly during repetitive seizures, and refractory status epilepticus (RSE) remains a therapeutic challenge. The outcome of RSE is poor, with high mortality and morbidity. New treatments are needed. Deep hypothermia (20°C) is used clinically during reconstructive cardiac surgery and neurosurgery, and has proved safe and effective in those indications. We tested the hypothesis that deep hypothermia reduces RSE and its long‐term consequences.MethodsWe used a model of SE induced by lithium and pilocarpine and refractory to midazolam. Several EEG measures were recorded in both hypothermic (n = 17) and normothermic (n = 20) animals. Neuronal injury (by Fluoro‐Jade B), cell‐mediated inflammation, and breakdown of the blood–brain barrier (BBB) (by immunohistochemistry) were studied 48 h following SE onset.ResultsNormothermic rats in RSE seized for 4.1 ± 1.1 h, and at 48 h they displayed extensive neuronal injury in many brain regions, including hippocampus, dentate gyrus, amygdala, entorhinal and pyriform cortices, thalamus, caudate/putamen, and the frontoparietal neocortex. Deep hypothermia (20°C) of 30 min duration terminated RSE within 12 min of initiation of hypothermia, reduced EEG power and seizure activity upon rewarming, and eliminated SE‐induced neuronal injury in most animals. Normothermic rats showed widespread breakdown of the BBB, and extensive macrophage infiltration in areas of neuronal injury, which were completely absent in animals treated with hypothermia.InterpretationThese results suggest that deep hypothermia may open a new therapeutic avenue for the treatment of RSE and for the prevention of its long‐term consequences.

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Section: Resultsmentioning

confidence: 51%

Neuroprotective effects of deep hypothermia in refractory status epilepticus

Niquet

Gezalian

Baldwin

et al. 2015

Ann Clin Transl Neurol

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“…Therefore, we used both C57BL/6J mice and Gfap‐Gfp transgenic mice on a C57BL/6NCr background to investigate the appropriate experimental conditions. A literature search indicated that systemic pilocarpine administration induces hypothermia in mice (Friedman & Jaffe, ; Glick & Marsanico, ), and that hypothermia prevents the development of epileptic seizures (Kowski, Kanaan, Schmitt, & Holtkamp, ; Niquet, Baldwin, Gezalian, & Wasterlain, ). We also found that although in some studies on the pilocarpine model, mice were kept in an incubator set at 30–32°C (Cho et al, ; Walter, Murphy, Pun, Spieles‐engemann, & Danzer, ), they did not clearly mention the effect of the incubator on mouse body temperature, SE induction, survival, and mortality.…”

Section: Resultsmentioning

confidence: 99%

“…To overcome these problems, we improved the procedure for inducing epileptic seizures in C57BL/6J and C57BL/6NCr mice, by use of a heated platform. This improved procedure is based on the following two facts: 1) the systemic administration of pilocarpine to mice results in a profound decrease in body temperature (Friedman & Jaffe, ), and 2) hypothermia in mice has an anticonvulsant effect (Kowski et al, ; Niquet et al, ). In fact, we found a sharp drop in body temperature after pilocarpine injection in mice, as well as a low rate of incidence of seizures.…”

Section: Discussionmentioning

confidence: 99%

The polarity and properties of radial glia‐like neural stem cells are altered by seizures with status epilepticus: Study using an improved mouse pilocarpine model of epilepsy

et al. 2019

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In the adult mouse hippocampus, new neurons are produced by radial glia‐like (RGL) neural stem cells in the subgranular zone, which extend their apical processes toward the molecular layer, and express the astrocyte marker glial fibrillary acidic protein, but not the astrocyte marker S100β. In rodent models of epilepsy, adult hippocampal neurogenesis was reported to be increased after acute and mild seizures, but to be decreased by chronic and severe epilepsy. In the present study, we investigated how the severity of seizures affects neurogenesis and RGL neural stem cells in acute stages of epilepsy, using an improved mouse pilocarpine model in which pilocarpine‐induced hypothermia was prevented by maintaining body temperature, resulting in a high incidence rate of epileptic seizures and low rate of mortality. In mice that experienced seizures without status epilepticus (SE), the number of proliferating progenitors and immature neurons were significantly increased, whereas no changes were observed in RGL cells. In mice that experienced seizures with SE, the number of proliferating progenitors and immature neurons were unchanged, but the number of RGL cells with an apical process was significantly reduced. Furthermore, the processes of the majority of RGL cells extended inversely toward the hilus, and about half of the aberrant RGL cells expressed S100β. These results suggest that seizures with SE lead to changes in the polarity and properties of RGL neural stem cells, which may direct them toward astrocyte differentiation, resulting in the reduction of neural stem cells producing new granule cells. This also suggests the possibility that cell polarity of RGL stem cells is important for maintaining the stemness of adult neural stem cells.

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“…Animal studies have demonstrated that therapeutic hypothermia has neuroprotective and antiepileptic properties. In a rat model of SE, deep hypothermia (20 °C) of 30 min duration terminated RSE within 12 min of initiation of hypothermia and eliminated SE-induced neuronal injury in most animals [79]. A case series of five children with RSE who were treated with mild hypothermia (32-35 °C) demonstrated reduction in seizure burden during and after hypothermia treatment without relapse after hypothermia [80].…”

Section: Therapeutic Hypothermia and Other Non-pharmacologic Therapiesmentioning

confidence: 99%

Pharmacotherapy for Pediatric Convulsive Status Epilepticus

2019

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Convulsive status epilepticus (CSE) is one of the most common pediatric neurological emergencies. Ongoing seizure activity is a dynamic process and may be associated with progressive impairment of gamma-aminobutyric acid (GABA)-mediated inhibition due to rapid internalization of GABA A receptors. Further hyperexcitability may be caused by AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) and NMDA (N-methyl-d-aspartic acid) receptors moving from subsynaptic sites to the synaptic membrane. Receptor trafficking during prolonged seizures may contribute to difficulties treating seizures of longer duration and may provide some of the pathophysiological underpinnings of established and refractory SE (RSE). Simultaneously, a practice change toward more rapid initiation of first-line benzodiazepine (BZD) treatment and faster escalation to second-line non-BZD treatment for established SE is in progress. Early administration of the recommended BZD dose is suggested. For second-line treatment, non-BZD anti-seizure medications (ASMs) include valproate, fosphenytoin, or levetiracetam, among others, and at this point there is no clear evidence that any one of these options is better than the others. If seizures continue after second-line ASMs, RSE is manifested. RSE treatment consists of bolus doses and titration of continuous infusions under continuous electro-encephalography (EEG) guidance until electrographic seizure cessation or burst-suppression. Ultimately, etiological workup and related treatment of CSE, including broad spectrum immunotherapies as clinically indicated, is crucial. A potential therapeutic approach for future studies may entail consideration of interventions that may accelerate diagnosis and treatment of SE, as well as rational and early polytherapy based on synergism between ASMs by utilizing medications targeting different mechanisms of epileptogenesis and epileptogenicity.

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Deep hypothermia for the treatment of refractory status epilepticus

Cited by 27 publications

References 64 publications

Neuroprotective effects of deep hypothermia in refractory status epilepticus

Neuroprotective effects of deep hypothermia in refractory status epilepticus

The polarity and properties of radial glia‐like neural stem cells are altered by seizures with status epilepticus: Study using an improved mouse pilocarpine model of epilepsy

Pharmacotherapy for Pediatric Convulsive Status Epilepticus

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