Neuroprotective effects of deep hypothermia in refractory status epilepticus

Abstract

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.

Hypothermia as an adjuvant treatment in paediatric refractory or super‐refractory status epilepticus

“…Liu et al 24 Intraictal treatment Decreases duration Decrease 28 37-42 Maeda et al 31 Intraictal treatment Increases latency Not available 30 37 Hrncic et al 32 Intraictal treatment 100% efficacy Yes 30 37 Kowski et al 28 Intraictal treatment Relative efficacy Yes 30 a 37 Wang et al 30 Chronic epilepsy Decreases frequency Not available 30 37 Niquet et al 39 Refractory status epilepticus…”

Treatment of Seizures and Postanoxic Status Epilepticus

“…Animal studies have suggested that hypothermia may have anticonvulsant effects. [32][33][34] Several case series in humans have shown the benefits of systemic hypothermia when status epilepticus is refractory to multiple anesthetic agents, [35][36][37][38] and focal cortical hypothermia has been shown to decrease epileptiform discharges. 35,39,40 These findings may account for more frequent seizures as patients reach normal body temperature.…”

Die Therapie und Prognose des refraktären und super-refraktären Status epilepticus

“…Durch eine verringerte Permeabilität der Bluthirnschranke tritt ein antiödematöser Effekt ein, zudem wirkt die Hypothermie anti-inflammatorisch. Aufgrund dieser Mechanismen wird der Hypothermie nicht nur ein antikonvulsiver, sondern auch ein neuroprotektiver Effekt zugeschrieben [42,43]. Erst kürzlich wurde der Einfluss der Hypothermie in der Statusbehandlung auf das Outcome nach 90 Tagen in der randomisierten, multizentrischen HYBERNATUS-Studie systematisch untersucht.…”