YEBEH-04438; No of Pages 5

Epilepsy & Behavior xxx (2015) xxx–xxx

Contents lists available at ScienceDirect

Epilepsy & Behavior

journal homepage: www.elsevier.com/locate/yebeh

Deep hypothermia for the treatment of refractory status epilepticus

Jerome Niquet a,b,⁎, Roger Baldwin b, Michael Gezalian b, Claude G. Wasterlain a,b,c
a
Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
b
Epilepsy Research Laboratory (151), Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, CA, USA
c
Brain Research Institute, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA

a r t i c l e i n f o a b s t r a c t

Article history: In a rat model of status epilepticus (SE) induced by lithium and pilocarpine and refractory to midazolam, deep
Revised 11 June 2015 hypothermia (20 °C for 30 min) reduced EEG power over 50-fold, stopped SE within 12 min, and reduced EEG
Accepted 13 June 2015 spikes by 87%. Hypothermia deserves further investigation as a treatment of last resort for refractory SE.
Available online xxxx
This article is part of a Special Issue entitled “Status Epilepticus”.
Keywords:
Published by Elsevier Inc.
Status epilepticus
Hypothermia
EEG power

1. Introduction than anticonvulsant drugs, may be able to stop the pharmacoresistant

seizures of RSE/SRSE.
Refractory and super-refractory status epilepticus (RSE, SRSE) are an Hypothermia activates many anticonvulsant and neuroprotective
increasingly common therapeutic challenge in our intensive care units mechanisms. It reduces the cerebral metabolic rate by 6–7% per degree
(ICUs), at enormous financial and human costs. This increase may be Celsius, so that at 20 °C, the human cerebral oxygen consumption was
due in part to greater availability of EEG monitoring, to increased recog- measured at one-fifth of normothermic values [5]. It alters the function
nition of “subtle” SE, to improvements in ICU care, and to the aging of of ion pumps [6,7], intrinsic membrane properties, and voltage-gated
the population, since SE and RSE are common in the elderly. Drugs fail ion channels [8–10]. It slows the release of excitatory neurotransmitters
to stop SE in 31–53% of cases [1–3]. In the VA Cooperative Study, 47% [11,12] and modifies gene expression [13].
of patients with SE had RSE [3]. New methods for treating RSE and These actions reduce excitatory drive and would be expected to
SRSE are clearly needed. inhibit seizure activity. They also activate several neuroprotective
During SE, pharmacoresistance develops progressively. All currently mechanisms: reduction of the cerebral demand for oxygen and glucose
available drugs display this phenomenon in experimental SE, with the [14]; preservation of ATP, energy stores, and tissue pH; reduction of the
possible exception of NMDA antagonists in some models [4]. In humans, release of excitotoxic amino acids [15] and of calcium influx into
early treatment of SE is much more effective than late treatment, neurons [16,17]; inhibition of early gene expression and stress
suggesting that pharmacoresistance may be present as well. In the VA response; induction of the expression of heat shock and other stress
Cooperative Study [3], four treatments were randomly rotated. The proteins [18,19]; and inhibition of early molecular cascades involved
first treatment (regardless of which one of the 4 was selected) was in neuronal apoptosis.
successful in 53% of patients. The third treatment given was successful Mild to moderate hypothermia has been shown to reduce seizure
in 2% of patients. Time-dependent pharmacoresistance is the most activity in experimental animals and in humans [20,21], although
likely explanation for these results. We need alternative treatments seizures frequently recur upon rewarming. Maeda et al. [22] induced
for RSE/SRSE and a way to overcome pharmacoresistance. Here, we sug- SE with intraamygdalar kainic acid injection and found that mild hypo-
gest that hypothermia, which acts by completely different mechanisms thermia (30 °C) reduced seizure frequency and severity. Schmitt et al.
[23] used mild hypothermia (≥29 °C) to treat SE induced by perforant
path stimulation. Hypothermia alone reduced motor but not EEG
seizures. The combination of mild hypothermia with low-dose
⁎ Corresponding author at: Epilepsy Research Laboratory, Veterans Affairs Greater Los
Angeles Healthcare System, 11301 Wilshire Boulevard, Building 114, Room 139, West
diazepam reduced all measures of seizure activity, but seizures returned
Los Angeles, CA 90073, USA. Tel.: +1 310 478 3711x41974; fax: +1 310 268 4856. upon rewarming. Liu et al. [24] induced SE with kainate in rats kept
E-mail address: [email protected] (J. Niquet). hypothermic for 4 h and in normothermic controls. Seizure reduction

http://dx.doi.org/10.1016/j.yebeh.2015.06.028
1525-5050/Published by Elsevier Inc.

Please cite this article as: Niquet J, et al, Deep hypothermia for the treatment of refractory status epilepticus, Epilepsy Behav (2015), http://
dx.doi.org/10.1016/j.yebeh.2015.06.028
2 J. Niquet et al. / Epilepsy & Behavior xxx (2015) xxx–xxx

was much greater during hypothermia at 23 °C than at 28 °C, suggesting cannot rule out a midazolam contribution to the behavioral or EEG re-
that the depth of hypothermia increases its efficacy [25]. sponse to treatment.
Anecdotal reports of successful treatment of clinical SE with hypo- All animals received scopolamine (2 mg/kg) at the same time as
thermia have been published [21,26]. Recooling stopped seizure activity midazolam. One of the problems of chemical models of SE is the
which developed upon rewarming in an infant treated for hypoxic– difficulty of obtaining clean results because of the presence of a convul-
ischemic encephalopathy [27]. Cold saline perfusion suppressed sant in the animal. A specific treatment might stop the seizures, but the
interictal spike foci during electrocorticography [20] and was used to convulsant could immediately restart them if it is not neutralized.
stop seizures triggered by intraoperative cortical stimulation. Morrissett et al. [58] were the first to show that an amount of atropine
The neuroprotective role of hypothermia has been well-documented or scopolamine which blocked SE as pretreatment was unable to stop
in focal hypoxia–ischemia, in traumatic brain injury (TBI), and in global SE after seizures became established. The seizures had become indepen-
cerebral ischemia. It has also been seen with seizure-associated neuronal dent of their original trigger (probably because of receptor trafficking).
injury [28], seizure-associated leaks in the blood–brain barrier (BBB) We took advantage of this feature to block the effects of pilocarpine
[29], and other conditions [30]. without altering the course of SE. In preliminary experiments,
In neonatal hypoxic–ischemic encephalopathy, hypothermia im- we studied the amount of antimuscarinic agent which stops 100% of
proves developmental and radiological outcome [31–33]. Bernard et al. seizures when given as pretreatment but blocks 0% of seizures when
[34] and the Hypothermia after Cardiac Arrest Study Group [35] showed given after seizure onset. Scopolamine 2 mg/kg reached that goal.
benefits of hypothermia after cardiac arrest due to ventricular fibrillation. Cooling was then started with whole body ice packs. Rectal temper-
In focal ischemia, many animal models showed improved outcome after ature closely approximated “brain surface” temperature. When rectal
hypothermia [36], but adverse effects of deep hypothermia have been temperature reached 20 °C, it was held for 30 min at that temperature
reported [37]. Hypothermia reverses many ischemia-induced changes ± 1 °C, then ice packs were replaced by a warming blanket with
in gene expression and alters the expression of genes involved in protein circulating 37 °C water, until rectal temperature reached 36 °C. Mean
synthesis, in cell cycle and cell division, and in apoptotic pathways [38]. cooling time from 37 °C to 20 °C was 39.5 min. Mean rewarming time
Hypothermia protects from TBI-induced neuronal injury [39–41] from 20 °C to 36 °C was 61.5 min. In “cool cap” animals, only the head
and changes in gene expression [42]. It reduces BBB disruption and and neck of the animals were packed with ice.
cell-mediated inflammation [43,44]. Hypothermia decreases TBI- Acute seizures were monitored by video/EEG for 24 h. The video/
induced inflammatory cytokines, cell-mediated immune responses, EEGs were analyzed using our standard methods for quantifying many
and activation of immune transcription factors [45,46]. Mild hypother- components of seizure severity [59,60]. Relative EEG power was the
mia after TBI mitigated the TBI-associated reduction in pentylenetetra- ratio of EEG power at the time of measurement to EEG power before
zol seizure threshold 12 weeks later [47]. seizure induction in the same rat. It increased approximately 100-fold
Recent developments in ICU technology have reduced the complica- during early SE, then declined as a function of time, treatment, and
tions of hypothermia. Mild hypothermia has become routine treatment temperature.
for neonatal hypoxic–ischemic encephalopathy [48,49], for TBI [50], and Analysis of variance was used for statistical testing if the data were
for postcardiac arrest encephalopathy [34] and may have potential for normally distributed with similar variance; otherwise, either data
stroke [51]. Deep hypothermia is routinely used to protect the brain or transform to improve normality or nonparametric tests such as the
spinal cord when circulatory arrest is needed in cardiac surgery [52], Kruskal–Wallis test were used. P values were considered significant
vascular surgery [53], and neurosurgery [54]. Most of the complications at the 0.05 level. Post hoc tests consisted of Scheffe's or Tukey's in
reported after deep hypothermia are the result of induced circulatory the case of ANOVA and Dunn's in the case of Kruskal–Wallis. The
arrest, not the result of hypothermia itself [55,56], although the poten- Graph-Pad/Prism statistical package was used for these tests.
tial for adverse effects, especially for very deep hypothermia, is signifi-
cant [57]. 3. Results
Our results suggest that deep hypothermia is quite effective in stop-
ping seizures in this experimental model of RSE and may deserve Pilocarpine injection was followed by an increase in EEG power and
further study. in behavioral activity, then by the appearance of EEG spikes, followed by
individual EEG seizures with behavioral arrest, twitching of face and
2. Materials and methods vibrissae, or clonic forelimb activity. The EEG seizures (Fig. 1A) merged
rapidly into nearly continuous polyspikes, while behavioral seizures in-
Status epilepticus was induced with lithium (3 mEq/kg ip 16 h prior) creased in frequency, severity, and duration but remained intermittent.
and pilocarpine (60 mg/kg ip) + methylscopolamine (1 mg/kg ip) in The injection of midazolam (41 ± 19 min after pilocarpine) was follow-
adult male Wistar rats (200–250 g) previously implanted with skull ed by a mild decrease in EEG power in both groups, but SE was not
screw electrodes. Control animals were given an equal volume of saline interrupted until animals became hypothermic. Hypothermia stopped
ip. Only lithium/pilocarpine-treated rats displaying behavioral/EEG seizures after approximately 25 min of SE (1483 ± 291 s), or 12 min
manifestations of seizures were used. Electroencephalography was re- (761 ± 243 s, n = 5) after initiation of hypothermia (Fig. 1A and E),
corded from skull-implanted electrodes. “Brain surface” temperature while SE continued for 17.9 ± 4.6 h after initiation of cooling in paired
was recorded from a probe preimplanted near the surface of the parietal normothermic animals (n = 5, p b 0.0001). The average brain and rectal
cortex. When full-blown SE was established (12 min after the 2nd stage temperatures at the time of seizure termination was 31 ± 0.6 °C (Fig. 1C
≥3 seizure), midazolam (3 mg/kg ip) was injected. The second stage ≥3 and E). In hypothermic animals, EEG power decreased with cooling
seizure is a discrete and easily recognizable event. The time between the (Fig. 1B), and by the time they reached 20 °C, relative power in hypo-
second stage 3 or higher seizure and the onset of continuous polyspikes thermic animals was 3% of that of the normothermic group measured
is both short and reproducible (1.28 ± 1.1 min, n = 16). Choosing the at the same time (p b 0.01). It was below prepilocarpine baseline and
second stage 3 seizure as our time anchor and recording 12 min of showed no seizure or residual paroxysmal activity. It remained below
EEG before treating guarantees that all our rats are in full-blown SE preseizure baseline through rewarming and in most animals, stayed
when treatment begins. In this study, we initiated cooling right after close to baseline values for the remaining of the 24 h, although some
completing the midazolam injection. In later experiments (not reported late spikes and sharp wave activity did return. Manual review of EEGs
here), we introduced an additional 15 min delay between midazolam confirmed the absence of seizures after rewarming in most rats. In one
and the initiation of hypothermia, in order to eliminate animals which animal, 12 late seizures were observed 8.2–11.9 h after the initiation
respond to midazolam from the study, but in the current study, we of rewarming. Many of these seizures were brief (mean duration:

Please cite this article as: Niquet J, et al, Deep hypothermia for the treatment of refractory status epilepticus, Epilepsy Behav (2015), http://
dx.doi.org/10.1016/j.yebeh.2015.06.028
 J. Niquet et al. / Epilepsy & Behavior xxx (2015) xxx–xxx 3

Fig. 1. Deep cooling durably reduces relative EEG power. (A) The upper panel shows the compressed 4-hour EEG of a normothermic (red) and a hypothermic rat (blue, 20 °C for 30 min)
with brain and rectal temperature. Both rats received midazolam 3 mg/kg ip (arrow), and cooling was initiated 2 min later. The lower panel shows the magnified 4-second EEG traces
marked by vertical lines (a–d) (vertical bar = 0.75 mV, horizontal bar = 1 s). (B) Relative EEG power (EEG power / baseline EEG power) in normothermic (red bars) and hypothermic
rats (blue bars, temperature in degrees Celsius) at the same time points. Relative EEG power was reduced by hypothermia in a dose-dependent fashion. The 20 °C point and the slope
were significantly different from normothermics (*p b 0.01). (C) “Brain surface” temperature during cooling and rewarming. (D) Brain temperature as a function of electrode depth
with the “cool cap” method. Steep temperature gradients suggest that deep structures such as the hippocampus may remain warmer than the cortical surface. (E) The left y-axis of
this graph shows the ratio of EEG power at each time point to initial EEG power at baseline, before pilocarpine injection. Note the logarithmic scale. Every time point beyond 30 min showed
a significant difference between normothermic and hypothermic rats (**p b 0.01, *p b 0.05). The right y-axis shows the rectal and brain temperature scales. Note that the temperature of a
probe positioned at the surface of the parietal cortex was close to the rectal temperature. (For interpretation of the references to color in this figure legend, the reader is referred to the web
version of this article.)

45 ± 6 s), and SE did not recur. In normothermic rats, EEG power de- Most measures of the severity of SE were reduced in the hypother-
creased from pretreatment SE (probably in part due to midazolam) mic group compared to their normothermic counterparts. The number
but remained significantly above baseline for many hours, reflecting of EEG spikes per 24 h, including those which occurred before the initi-
continuation of SE (Fig. 1E). In most normothermic rats, semiperiodic ation of cooling, was 7440 ± 1999 in the normothermic group (N) and
spike bursts which slowly decreased in amplitude over time were sepa- 1004 ± 296 in the hypothermic group (H) (p b 0.01). The time it took
rated by stretches of low voltage background activity which increased for EEG power to decline to twice prepilocarpine values was 4.97 ±
progressively in duration (Fig. 1A), and this pattern often continued 1.89 h after pilocarpine injection in the normothermic group against
for the whole 24 h of recording. 0.8 ± 0.13 h in the hypothermic group (p b 0.05). Hjorth function

Please cite this article as: Niquet J, et al, Deep hypothermia for the treatment of refractory status epilepticus, Epilepsy Behav (2015), http://
dx.doi.org/10.1016/j.yebeh.2015.06.028
4 J. Niquet et al. / Epilepsy & Behavior xxx (2015) xxx–xxx

integral [61] for the first 6 h after pilocarpine injection was 9879 ± 1939 stops self-sustaining SE. It enables us to study self-sustaining SE without
in normothermics versus 3990 ± 618 in hypothermics (p = 0.01). the confusing presence of a chemical convulsant on board [60,66].

4. Discussion 5. Conclusion

These results suggest that deep hypothermia is a powerful tool for This present study shows that deep hypothermia (20 °C for 30 min)
seizure termination in this animal model and deserves further evalua- is an efficient treatment to stop RSE. Hypothermia is very neuroprotec-
tion as a potential treatment of last resort for RSE. In the current tive in animal models of ischemic or traumatic brain injury [67], and our
study, hypothermia reduced EEG power over 100-fold and reduced preliminary data (not shown) indicate a strong reduction of neuronal
the duration of SE from a mean of 17.9 h (median: 24 h) to a mean of injury in RSE as well. Further studies of the risk/benefit ratio of hypo-
0.2 h (median: 0.16 h). It terminated RSE in all animals. Seizures stopped thermia in RSE and SRSE seem to be worth undertaking.
well before reaching our target temperature (range: 29–33 °C) and
returned in only one rat, many hours after the completion of
Acknowledgments
rewarming. Our experiments were designed to mimic the clinical situa-
tion where hypothermia is likely to be used only after drug treatment.
This study was supported by VHA Research Service (CW) and NINDS
We induced SE with lithium and pilocarpine and treated with midazo-
(grant UO1 NS074926, CW).
lam when SE was well established. Midazolam reduced EEG power
We confirm that we have read the Journal's position on issues in-
and seizure severity but did not stop SE in normothermic animals. In
volved in ethical publication and affirm that this report is consistent
this study, hypothermia was applied just after midazolam injection.
with those guidelines.
Pilot experiments showed that the temperature of a probe positioned
on the surface of the parietal cortex was close to rectal temperature,
Disclosure of conflicts of interest
so the latter was used in most experiments. Temperature was brought
down and maintained near 20 °C for the relatively short period of None of the authors has any conflict of interest to disclose.
30 min. Warming was then initiated by wrapping the rats in an electri-
cal heating pad. Mean cooling time (39.5 min) was shorter than mean
rewarming time (61.5 min). All animals tolerated hypothermia well. References
Deep hypothermia (13–20 °C) is used in vascular and cardiac surger- [1] Holtkamp M, Othman J, Buchheim K, Meierkord H. Predictors and prognosis of
ies and neurosurgery, with good results for periods of circulatory arrest refractory status epilepticus treated in a neurological intensive care unit. J Neurol
Neurosurg Psychiatry 2005;76:534–9.
of 25–50 min [62], and the equipment and expertise needed are
[2] Mayer SA, Claassen J, Lokin J, Mendelsohn F, Dennis LJ, Fitzsimmons BF. Refractory
available in most large surgical centers. Its potential for treating RSE status epilepticus: frequency, risk factors, and impact on outcome. Arch Neurol
has never been evaluated, although results in experimental SE were 2002;59:205–10.
encouraging [23,25]. Our results suggest that cooling to 20 °C can be [3] Treiman DM, Meyers PD, Walton NY, Collins JF, Colling C, Rowan AJ, et al. A compar-
ison of four treatments for generalized convulsive status epilepticus. Veterans Affairs
very effective in stopping seizures. While surgical applications use Status Epilepticus Cooperative Study Group. N Engl J Med 1998;339:792–8.
hypothermia as a method to allow circulatory arrest during repair of [4] Mazarati AM, Wasterlain CG. N-methyl-D-aspartate receptor antagonists abolish the
aortic or cerebral aneurysms or congenital heart disease [63,64], its maintenance phase of self-sustaining status epilepticus in rat. Neurosci Lett 1999;
265:187–90.
use as a treatment for RSE would be free of the complications of circula- [5] McCullough JN, Zhang N, Reich DL, Juvonen TS, Klein JJ, Spielvogel D, et al. Cerebral
tory arrest. It would add a nonpharmacological option to our treatment metabolic suppression during hypothermic circulatory arrest in humans. Ann Thorac
regimens for RSE as well as for cholinergic seizures induced by nerve Surg 1999;67:1895–9 [discussion 1919–21].
[6] Aihara H, Okada Y, Tamaki N. The effects of cooling and rewarming on the neuronal
agents or organophosphate insecticides and deserves further study. activity of pyramidal neurons in guinea pig hippocampal slices. Brain Res 2001;893:
Computer-generated seizure counts were reviewed manually, to 36–45.
eliminate frequent duplicate counts, but underestimate seizure activity [7] Volgushev M, Vidyasagar TR, Chistiakova M, Yousef T, Eysel UT. Membrane
properties and spike generation in rat visual cortical cells during reversible cooling.
since the computer counts long periods of high-amplitude polyspikes J Physiol 2000;522(Pt 1):59–76.
(frequently seen in the early phase of SE) as single seizures and does [8] Schiff SJ, Somjen GG. The effects of temperature on synaptic transmission in
not count as seizures the long periods of semiperiodic bursts on a low- hippocampal tissue slices. Brain Res 1985;345:279–84.
[9] Thompson SM, Masukawa LM, Prince DA. Temperature dependence of intrinsic
amplitude background which is seen in most normothermic animals
membrane properties and synaptic potentials in hippocampal CA1 neurons
in the late phase of SE. Preliminary experiments using “Cool Cap” hypo- in vitro. J Neurosci 1985;5:817–24.
thermia were disappointing. The depression of seizure activity by head [10] Shen KF, Schwartzkroin PA. Effects of temperature alterations on population and
cooling was transient, and in these adult rats, “cool cap” hypothermia cellular activities in hippocampal slices from mature and immature rabbit. Brain
Res 1988;475:305–16.
did not block seizures from returning upon rewarming. In “cool cap” [11] Volgushev M, Kudryashov I, Chistiakova M, Mukovski M, Niesmann J, Eysel UT.
animals, we found steep temperature gradients between the parietal Probability of transmitter release at neocortical synapses at different temperatures.
cortex and deep brain, as shown in Fig. 1D. At a depth of 5 mm from J Neurophysiol 2004;92:212–20.
[12] Yang XF, Ouyang Y, Kennedy BR, Rothman SM. Cooling blocks rat hippocampal
the cortical surface, brain temperature was over 8 °C warmer than cor- neurotransmission by a presynaptic mechanism: observations using 2-photon
tex temperature. This result is not surprising since the adult brain tissue microscopy. J Physiol 2005;567:215–24.
has a high fat content and would be expected to be an excellent thermal [13] Fuller BJ. Gene expression in response to low temperatures in mammalian cells: a
review of current ideas. Cryo Letters 2003;24:95–102.
insulator, and steep temperature gradients after local cooling have [14] Soukup J, Zauner A, Doppenberg EM, Menzel M, Gilman C, Young HF, et al. The
been observed in the mature primate brain [65]. This could result in importance of brain temperature in patients after severe head injury: relationship
inadequate cooling of key brain regions, such as the ventral hippocam- to intracranial pressure, cerebral perfusion pressure, cerebral blood flow, and out-
come. J Neurotrauma 2002;19:559–71.
pus, where seizure activity could persist during cortical cooling and [15] Busto R, Globus MY, Dietrich WD, Martinez E, Valdes I, Ginsberg MD. Effect of mild
from which it could spread (and restart SE) upon rewarming. hypothermia on ischemia-induced release of neurotransmitters and free fatty
The rationale for injecting scopolamine in all animals at the time of acids in rat brain. Stroke 1989;20:904–10.
[16] Nilsson P, Laursen H, Hillered L, Hansen AJ. Calcium movements in traumatic brain
treatment was that two components are involved in chemically induced
injury: the role of glutamate receptor-operated ion channels. J Cereb Blood Flow
SE: the initial pilocarpine stimulation of muscarinic receptors, and a Metab 1996;16:262–70.
later component of self-sustaining seizures which are independent of [17] Colbourne F, Grooms SY, Zukin RS, Buchan AM, Bennett MV. Hypothermia rescues
the original trigger. Since the dose of scopolamine used here blocks all hippocampal CA1 neurons and attenuates down-regulation of the AMPA receptor
GluR2 subunit after forebrain ischemia. Proc Natl Acad Sci U S A 2003;100:2906–10.
seizure activity when used as pretreatment, it should be sufficient to [18] Liu L, Yenari MA. Therapeutic hypothermia: neuroprotective mechanisms. Front
prevent residual pilocarpine from restarting the seizures if a treatment Biosci 2007;12:816–25.

Please cite this article as: Niquet J, et al, Deep hypothermia for the treatment of refractory status epilepticus, Epilepsy Behav (2015), http://
dx.doi.org/10.1016/j.yebeh.2015.06.028
 J. Niquet et al. / Epilepsy & Behavior xxx (2015) xxx–xxx 5

[19] Yenari MA, Han HS. Influence of hypothermia on post-ischemic inflammation: role [45] Truettner JS, Suzuki T, Dietrich WD. The effect of therapeutic hypothermia on the
of nuclear factor kappa B (NFkappaB). Neurochem Int 2006;49:164–9. expression of inflammatory response genes following moderate traumatic brain
[20] Sartorius CJ, Berger MS. Rapid termination of intraoperative stimulation-evoked injury in the rat. Brain Res Mol Brain Res 2005;138:124–34.
seizures with application of cold Ringer's lactate to the cortex. Technical note. [46] Tomura S, de Rivero Vaccari JP, Keane RW, Bramlett HM, Dietrich WD. Effects of
J Neurosurg 1998;88:349–51. therapeutic hypothermia on inflammasome signaling after traumatic brain injury.
[21] Karkar KM, Garcia PA, Bateman LM, Smyth MD, Barbaro NM, Berger M. Focal cooling J Cereb Blood Flow Metab 2012;32:1939–47.
suppresses spontaneous epileptiform activity without changing the cortical motor [47] Atkins CM, Truettner JS, Lotocki G, Sanchez-Molano J, Kang Y, Alonso OF, et al. Post-
threshold. Epilepsia 2002;43:932–5. traumatic seizure susceptibility is attenuated by hypothermia therapy. Eur J
[22] Maeda T, Hashizume K, Tanaka T. Effect of hypothermia on kainic acid-induced Neurosci 2010;32:1912–20.
limbic seizures: an electroencephalographic and 14C-deoxyglucose autoradiographic [48] Azzopardi D, Strohm B, Edwards AD, Halliday H, Juszczak E, Levene M, et al.
study. Brain Res 1999;818:228–35. Treatment of asphyxiated newborns with moderate hypothermia in routine clinical
[23] Schmitt FC, Buchheim K, Meierkord H, Holtkamp M. Anticonvulsant properties of practice: how cooling is managed in the UK outside a clinical trial. Arch Dis Child
hypothermia in experimental status epilepticus. Neurobiol Dis 2006;23:689–96. Fetal Neonatal Ed 2009;94:F260–4.
[24] Liu Z, Gatt A, Mikati M, Holmes GL. Effect of temperature on kainic acid-induced [49] Shankaran S, Pappas A, McDonald SA, Vohr BR, Hintz SR, Yolton K, et al. Childhood
seizures. Brain Res 1993;631:51–8. outcomes after hypothermia for neonatal encephalopathy. N Engl J Med 2012;366:
[25] Kowski AB, Kanaan H, Schmitt FC, Holtkamp M. Deep hypothermia terminates status 2085–92.
epilepticus—an experimental study. Brain Res 2012;1446:119–26. [50] Kamps M, Bisschops LA, van der Hoeven JG, Hoedemaekers CW. Hypothermia does
[26] Orlowski JP, Erenberg G, Lueders H, Cruse RP. Hypothermia and barbiturate coma for not increase the risk of infection: a case control study. Crit Care 2011;15:R48.
refractory status epilepticus. Crit Care Med 1984;12:367–72. [51] De Georgia MA, Krieger DW, Abou-Chebl A, Devlin TG, Jauss M, Davis SM, et al.
[27] Kendall GS, Mathieson S, Meek J, Rennie JM. Recooling for rebound seizures after Cooling for Acute Ischemic Brain Damage (COOL AID): a feasibility trial of
rewarming in neonatal encephalopathy. Pediatrics 2012;130:e451–5. endovascular cooling. Neurology 2004;63:312–7.
[28] Lundgren J, Smith ML, Blennow G, Siesjo BK. Hyperthermia aggravates and [52] Gega A, Rizzo JA, Johnson MH, Tranquilli M, Farkas EA, Elefteriades JA. Straight deep
hypothermia ameliorates epileptic brain damage. Exp Brain Res 1994;99:43–55. hypothermic arrest: experience in 394 patients supports its effectiveness as a sole
[29] Oztas B, Kaya M. The effect of profound hypothermia on blood–brain barrier means of brain preservation. Ann Thorac Surg 2007;84:759–66 [discussion 766–7].
permeability during pentylenetetrazol-induced seizures. Epilepsy Res 1994;19: [53] Rubens FD, Nathan H. Lessons learned on the path to a healthier brain: dispelling the
221–7. myths and challenging the hypotheses. Perfusion 2007;22:153–60.
[30] Elmas I, Kucuk M, Kalayci RB, Cevik A, Kaya M. Effects of profound hypothermia on [54] Todd MM, Hindman BJ, Clarke WR, Torner JC. Mild intraoperative hypothermia dur-
the blood–brain barrier permeability in acute and chronically ethanol treated rats. ing surgery for intracranial aneurysm. N Engl J Med 2005;352:135–45.
Forensic Sci Int 2001;119:212–6. [55] Fleck TM, Czerny M, Hutschala D, Koinig H, Wolner E, Grabenwoger M. The
[31] Eicher DJ, Wagner CL, Katikaneni LP, Hulsey TC, Bass WT, Kaufman DA, et al. Moder- incidence of transient neurologic dysfunction after ascending aortic replacement
ate hypothermia in neonatal encephalopathy: efficacy outcomes. Pediatr Neurol with circulatory arrest. Ann Thorac Surg 2003;76:1198–202.
2005;32:11–7. [56] Parissis H, Hamid U, Soo A, Al-Alao B. Brief review on systematic hypothermia for the
[32] Gluckman PD, Wyatt JS, Azzopardi D, Ballard R, Edwards AD, Ferriero DM, et al. protection of central nervous system during aortic arch surgery: a double-sword
Selective head cooling with mild systemic hypothermia after neonatal tool? J Cardiothorac Surg 2011;6:153.
encephalopathy: multicentre randomised trial. Lancet 2005;365:663–70. [57] Bickler PE, Warren DE, Clark JP, Gabatto P, Gregersen M, Brosnan H. Anesthetic
[33] Shankaran S, Laptook AR, Ehrenkranz RA, Tyson JE, McDonald SA, Donovan EF, et al. protection of neurons injured by hypothermia and rewarming: roles of intracellular
Whole-body hypothermia for neonates with hypoxic–ischemic encephalopathy. N Ca2+ and excitotoxicity. Anesthesiology 2012;117:280–92.
Engl J Med 2005;353:1574–84. [58] Morrisett RA, Jope RS, Snead III OC. Effects of drugs on the initiation and
[34] Bernard SA, Gray TW, Buist MD, Jones BM, Silvester W, Gutteridge G, et al. Treatment maintenance of status epilepticus induced by administration of pilocarpine to
of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. N lithium-pretreated rats. Exp Neurol 1987;97:193–200.
Engl J Med 2002;346:557–63. [59] Mazarati AM, Baldwin RA, Sankar R, Wasterlain CG. Time-dependent decrease in the
[35] Hypothermia after Cardiac Arrest Study G. Mild therapeutic hypothermia to improve effectiveness of antiepileptic drugs during the course of self-sustaining status
the neurologic outcome after cardiac arrest. N Engl J Med 2002;346:549–56. epilepticus. Brain Res 1998;814:179–85.
[36] Polderman KH. Induced hypothermia and fever control for prevention and [60] Suchomelova L, Baldwin RA, Kubova H, Thompson KW, Sankar R, Wasterlain CG.
treatment of neurological injuries. Lancet 2008;371:1955–69. Treatment of experimental status epilepticus in immature rats: dissociation
[37] Weinrauch V, Safar P, Tisherman S, Kuboyama K, Radovsky A. Beneficial effect of between anticonvulsant and antiepileptogenic effects. Pediatr Res 2006;59:237–43.
mild hypothermia and detrimental effect of deep hypothermia after cardiac arrest [61] Hjorth B. Principles for transformation of scalp EEG from potential field into source
in dogs. Stroke 1992;23:1454–62. distribution. J Clin Neurophysiol 1991;8:391–6.
[38] Nagel S, Papadakis M, Pfleger K, Grond-Ginsbach C, Buchan AM, Wagner S. [62] Prêtre R. Deep hypothermic circulatory arrest. In: Cohn L, Edmunds L, editors. Cardi-
Microarray analysis of the global gene expression profile following hypothermia ac surgery in the adult. New York: McGraw-Hill; 2003. p. 401–12.
and transient focal cerebral ischemia. Neuroscience 2012;208:109–22. [63] Bellinger DC, Newburger JW, Wypij D, Kuban KC, duPlesssis AJ, Rappaport LA. Behav-
[39] Fay T. Observations on generalized refrigeration in cases of severe cerebral trauma. iour at eight years in children with surgically corrected transposition: the Boston
Assoc Res Nerv Ment Dis Proc 1945;24:611–9. Circulatory Arrest Trial. Cardiol Young 2009;19:86–97.
[40] Marion DW, Penrod LE, Kelsey SF, Obrist WD, Kochanek PM, Palmer AM, et al. [64] Wypij D, Newburger JW, Rappaport LA, duPlessis AJ, Jonas RA, Wernovsky G, et al.
Treatment of traumatic brain injury with moderate hypothermia. N Engl J Med The effect of duration of deep hypothermic circulatory arrest in infant heart surgery
1997;336:540–6. on late neurodevelopment: the Boston Circulatory Arrest Trial. J Thorac Cardiovasc
[41] Dietrich WD, Bramlett HM. The evidence for hypothermia as a neuroprotectant in Surg 2003;126:1397–403.
traumatic brain injury. Neurotherapeutics 2010;7:43–50. [65] King C, Robinson T, Dixon CE, Rao GR, Larnard D, Nemoto CE. Brain temperature
[42] Truettner JS, Alonso OF, Bramlett HM, Dietrich WD. Therapeutic hypothermia alters profiles during epidural cooling with the ChillerPad in a monkey model of traumatic
microRNA responses to traumatic brain injury in rats. J Cereb Blood Flow Metab brain injury. J Neurotrauma 2010;27:1895–903.
2011;31:1897–907. [66] Brandt C, Tollner K, Klee R, Broer S, Loscher W. Effective termination of status epilep-
[43] Lotocki G, de Rivero Vaccari JP, Perez ER, Sanchez-Molano J, Furones-Alonso O, ticus by rational polypharmacy in the lithium–pilocarpine model in rats: window of
Bramlett HM, et al. Alterations in blood–brain barrier permeability to large and opportunity to prevent epilepsy and prediction of epilepsy by biomarkers. Neurobiol
small molecules and leukocyte accumulation after traumatic brain injury: effects Dis 2015;75:78–90.
of post-traumatic hypothermia. J Neurotrauma 2009;26:1123–34. [67] Darwazeh R, Yan Y. Mild hypothermia as a treatment for central nervous system
[44] Oda Y, Gao G, Wei EP, Povlishock JT. Combinational therapy using hypothermia and injuries: positive or negative effects. Neural Regen Res 2013;8:2677–86.
the immunophilin ligand FK506 to target altered pial arteriolar reactivity, axonal
damage, and blood–brain barrier dysfunction after traumatic brain injury in rat.
J Cereb Blood Flow Metab 2011;31:1143–54.

Please cite this article as: Niquet J, et al, Deep hypothermia for the treatment of refractory status epilepticus, Epilepsy Behav (2015), http://
All in-text references underlined in blue are linked to publications on ResearchGate, letting you access and read them immediately.
dx.doi.org/10.1016/j.yebeh.2015.06.028