Therapeutic choices in convulsive status epilepticus.

Review

Therapeutic choices in convulsive status epilepticus

Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Tulane University on 01/27/15 For personal use only.

Ivań Sańchez Fernańdez & Tobias Loddenkemper† †

1.

Introduction

2.

Time to treatment in SE

3.

Treatment choices in SE

4.

Conclusion

5.

Expert opinion

Boston Children’ s Hospital, Harvard Medical School, Division of Epilepsy and Clinical Neurophysiology, Department of Neurology, Boston, MA, USA

Introduction: Convulsive status epilepticus (SE) is one of the most frequent and severe neurological emergencies in both adults and children. A timely administration of appropriate antiepileptic drugs (AEDs) can stop seizures early and markedly improve outcome. Areas covered: The main treatment strategies for SE are reviewed with an emphasis on initial treatments. The established first-line treatment consists of benzodiazepines, most frequently intravenous lorazepam. Benzodiazepines that do not require intravenous administration like intranasal midazolam or intramuscular midazolam are becoming more popular because of easier administration in the field. Other benzodiazepines may also be effective. After treatment with benzodiazepines, treatment with fosphenytoin and phenobarbital is usually recommended. Other intravenously available AEDs, such as valproate and levetiracetam, may be as effective and safe as fosphenytoin and phenobarbital, have a faster infusion time and better pharmacokinetic profile. The rationale behind the need for an early treatment of SE is discussed. The real-time delays of AED administration in clinical practice are described. Expert opinion: There is limited evidence to support what the best initial benzodiazepine or the best non-benzodiazepine AED is. Recent and developing multicenter trials are evaluating the best treatment options and will likely modify the recommended treatment choices in SE in the near future. Additionally, more research is needed to understand how different treatment options modify prognosis in SE. Timely implementation of care protocols to minimize treatment delays is crucial. Keywords: benzodiazepines, epilepsy, lorazepam, midazolam, seizures, status epilepticus Expert Opin. Pharmacother. [Early Online]

1.

Introduction

Clinicians from any medical specialty will encounter at least a few cases of convulsive status epilepticus (SE) during their professional lives and will be expected to provide at least initial management to these patients. Convulsive SE is associated with a high burden of morbidity and mortality and an appropriate early treatment is the main factor which can improve outcome and minimize cognitive and medical complications. In this review we summarize the main treatment strategies for convulsive SE with an emphasis on first-line treatments. The importance of an early treatment and a timely switch between antiepileptic drugs (AEDs) with different mechanisms of action is underlined. This review will not discuss non-convulsive SE, and for the purposes of this article we will use SE as a synonym for convulsive SE. SE is one of the most common neurologic emergencies in both adults and children. Incidence of SE is ~ 3.5 -- 12.5/100,000 and follows a ‘U’ distribution in which the highest incidence occurs in children < 10 years (14.3/100,000) and in adults > 50 years (28.4/100,000) [1]. SE-associated mortality is ~ 7 -- 22% in the 10.1517/14656566.2015.997212 © 2015 Informa UK, Ltd. ISSN 1465-6566, e-ISSN 1744-7666 All rights reserved: reproduction in whole or in part not permitted

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I. Sańchez Fernańdez & T. Loddenkemper

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Convulsive status epilepticus (SE) is a life-threatening emergency which requires immediate treatment as appropriate and rapid treatment may improve the outcome and reduce the cognitive and medical sequelae. The currently established first-line treatment for convulsive SE is intravenous lorazepam. Non-intravenous first-line choices such as rectal diazepam, nasal midazolam or intramuscular midazolam have demonstrated similar efficacy and safety and are easier to administer in the field. After failure of one or two doses of benzodiazepines, a rapid therapeutic escalation to non-benzodiazepine antiepileptic drugs (AEDs) is recommended. The most commonly used non-benzodiazepine AEDs are phenytoin (or fosphenytoin) and phenobarbital. The efficacy and safety of other non-benzodiazepine AEDs such as valproate or levetiracetam may be noninferior to phenytoin/fosphenytoin and phenobarbital and these drugs have a faster infusion time and a better pharmacokinetic profile. When SE is resistant to benzodiazepines and nonbenzodiazepine AEDs, continuous infusions of AEDs or anesthetics are usually tried. Midazolam, propofol and pentobarbital are the most commonly used initial infusions. Other therapies like ketamine infusion, immunotherapy, ketogenic diet, epilepsy surgery or hypothermia may be considered in cases of super-refractory SE after failure of previously outlined therapies.

short term (in-hospital or within 30 days of SE) and as high as 43% in the long-term (within 10 years following initial survival 30 days after SE) [2]. Mortality is lowest in children with a short-term mortality of 3 -- 9%, and a long-term mortality of ~ 7%, and highest in the elderly (typically considered > 55 or 65 years) with a short-term mortality of 22 -- 38%, and a long-term mortality of ~ 82% (long-term mortality in the elderly probably includes a significant proportion of deaths unrelated to SE) [2]. More recent series report even a lower short-term mortality rate of 0 -- 3% in children [3-9]. Both children and adults who survive SE present a significant burden of subsequent epilepsy, cognitive and behavioral sequelae [7,10].

Time to treatment in SE

Time in the definition of SE The essential characteristic which differentiates SE from other seizures is duration. SE presents as a prolonged seizure, a seizure that lasts longer than expected. However, the duration threshold which separates an ordinary seizure from SE is a matter of ongoing debate. The classical definition of SE or ‘established’ SE requires that seizures to last for a minimum of 30 min [4]. However, when seizures last > 5 min, they are 2.1

2

Rationale behind the need for a rapid treatment There are three major known factors that determine prognosis in SE: age, etiology and SE duration [6,7,16,17]. Age is a nonmodifiable factor and etiology may or may be modifiable or treatable. In contrast, SE duration can be potentially modified with an appropriate treatment administered in a timely fashion. Current guidelines and protocols for the treatment of SE recommend a rapid administration of AEDs. This recommendation is based on results from basic and clinical research. Animal models of SE have demonstrated that prolonged seizures per se cause brain damage [18]. In addition, several clinical studies have shown that more prolonged seizures are associated with a worse outcome. In a series of 45 episodes of generalized SE in children, the duration of SE was shorter (32 vs 60 min) and the risk of recurrent seizures was lower (58 vs 85%) in the 19 episodes treated with pre-hospital diazepam than in the 26 episodes without pre-hospital treatment [19]. In a study of 182 children with convulsive SE, for each minute delay from seizure onset to arrival at the emergency department there was a 5% cumulative increase in the risk of SE lasting > 60 min [20]. In a series of 157 children with SE, a delay of > 30 min in administering the first AED was associated with worse response to treatment (time from the initiation of the treatment to the end of the clinical seizure activity) [21]. Another study reported 27 children, and firstline (benzodiazepine) and second-line (phenytoin or phenobarbital) medications were effective in terminating SE in 2.2

This box summarizes key points contained in the article.

2.

less likely to spontaneously stop [11,12] and meet the definition of ‘impending’ SE. At present, both duration thresholds coexist in the literature. The 5-min threshold is useful from an operational point of view as it marks the point where seizures will probably not stop unless actively treated. It is currently unknown whether defining SE as seizures that last for 5 or 30 min identifies different patient populations with different electroclinical characteristics. A large series compared 226 patients (91 children and 135 adults) with seizure duration of ‡ 30 min, with 81 patients (31 children and 50 adults) with seizure duration of 10 -- 29 min [13]. Patients in the ‡ 30-min group had a lower probability of resolution without treatment (7 vs 43%) and a higher mortality rate (19 vs 2.6%) [13]. Other characteristics were similar in the two groups [13]. A recent study compared 149 children with seizures of ‡ 30 min with 296 children with seizures of 5 -- 29 min duration [14]. The group of patients with seizures of ‡ 30 min was younger at the time of seizure onset but there were no differences in seizure frequency, seizure types, presence of developmental delay and electroencephalogram abnormalities at baseline [14]. Mortality in this cohort increased with seizure duration [14]. In a larger series of 1062 patients from the same cohort, risk factors for SE were similar when using a 5- or a 30-min threshold [15]. Together, these results suggest that both thresholds identify very similar populations, although mortality is higher in patients with more prolonged seizures.

Expert Opin. Pharmacother. (2014) 16(4)



86% when seizure duration was < 20 min at presentation and only in 15% when seizure duration exceeded 30 min [22]. As in children, in adults, a correlation between longer duration and worse prognosis has also been found in several studies. In a series of 66 adults with generalized tonic-clonic SE, major determinants of death were age, longer duration of SE before initiation of treatment and CNS etiology [23]. Among 253 adults with SE, those with SE duration < 1 h had a lower mortality than patients with SE duration ‡ 1 h (2.7 vs 32% after 1 month of follow up) [24]. Furthermore, a series of 118 episodes of generalized convulsive SE in 111 adults showed that patients who received out-of-hospital treatment had shorter SE duration [25]. Together, these results suggest that an early and appropriate treatment may markedly reduce the duration of SE and likely improve the outcome. Changes of neurotransmitter receptors in the seizing brain

2.3

Changes in neurotransmitter receptors explain the tendency of seizures to become self-sustained and progressively more treatment-resistant with increasing seizure duration. Changes in the subunit composition of AMPA, NMDA and GABA receptors in the seizing brain promote self-sustaining seizures (Table 1) [26]. In addition, when the brain is exposed to prolonged seizures, there is a rapid decrease in the number of functional postsynaptic GABAA receptors [27,28] and an increase in the number of functional postsynaptic NMDA receptors [29]. This loss of inhibition and increase in excitation in the brain synapses promote self-sustaining prolonged seizures (Figure 1). Furthermore, it may explain the loss of efficacy of benzodiazepines over time in animal models of SE [30] and the progressive pharmacoresistance to benzodiazepines with prolonged SE [21,22]. Delays in treatment administration Compared with the vast number of series on efficacy of different AEDs, the topic of delays in AED administration in SE has been studied less frequently. There are only a few studies on the topic of time from seizure onset to treatment administration. In a retrospective multicenter study of 542 episodes of convulsive seizure of ‡ 10-min duration in children, the median (p25 -- p75) time from hospital arrival until administration of a non-benzodiazepine AED was 24 (15 -- 36) min [31]. In a retrospective study of 889 patients (625 adults and 264 children) with SE, ~ 60% of patients received their first AED after 30 min and ~ 25% after 60 min [32]. In a series of 199 children with febrile SE, the median time from seizure onset to administration of the first AED was 30 min [33]. Among 82 adults with SE, the time elapsed since seizure onset to administration of the first medication was 35 min, and the median time from seizure onset to administration of nonbenzodiazepine AED was 180 min [34]. A recent series of 81 children with refractory convulsive SE specifically studied 2.4

delays in the administration of AEDs [35]. The median (p25 -- p75) time elapsed from seizure onset to the administration of the first AED was 28 (6 -- 67) min, to the second AED was 40 (20 -- 85) min and to the third AED was 59 (30 -- 120) min [35].Furthermore, the median (p25 -- p75) time to administration of the first non-benzodiazepine AED was 69 (40 -- 120) min [35] and in the 64 patients with out-of-hospital SE onset, 40 (62.5%) did not receive any AED before hospital arrival [35]. Together, these results suggest delays in SE management. Policies that streamline AED administration in pediatric and adult SE are urgently needed. 3.

Treatment choices in SE

Overview of treatment protocols Most current SE protocols recommend a stepwise approach. The first step in the treatment of SE, as an emergency situation, is to secure the airway, ensure adequate breathing and circulation. Most seizures resolve spontaneously in < 5 min. However, when seizures last ‡ 5 min, they should be considered as impending SE and treatment should be initiated immediately [36-38]. Benzodiazepines are the first-line treatment and intravenous lorazepam is frequently the preferred option. When an intravenous line is not available, intramuscular, rectal, intranasal or buccal medication applications are potential alternatives. The first dose of benzodiazepines can be repeated if seizures have lasted for < 10 min. However, as discussed above, seizures progressively become more refractory to treatment. After 10 min of seizures it is recommended to switch to non-benzodiazepine AEDs. Among those, the most commonly used is intravenous fosphenytoin (or phenytoin). If seizures do not stop, another non-benzodiazepine AED is recommended, with phenobarbital as the preferred option. Other popular non-benzodiazepine AEDs are medications that can also be applied intravenously, such as valproate and levetiracetam. However, once these two appropriate doses of non-benzodiazepine AEDs have been administered and/or seizure duration is longer than 30 -- 60 min, then initiation of continuous infusions/anesthetic therapy is recommended (Figure 2). 3.1

Evidence supporting benzodiazepines as a first-line treatment

3.2

In a double-blind trial, 205 adults with out-of-hospital seizures of at least 5 min duration were randomized to receive either intravenous lorazepam, intravenous diazepam or placebo [39]. SE had been terminated on arrival at the emergency department in more patients treated with lorazepam (59%) or diazepam (43%) (not statistically significant differences in their efficacy) than in patients treated with placebo (21%) [39]. The rates of respiratory or circulatory complications after the study treatment was administered were 11% for lorazepam, 10% for diazepam and 23% for placebo [39]. This landmark study established that treatment with benzodiazepines was more effective and even safer than not treating


3

4 Study design

Rats with tetanus toxin- or flurothyl-induced seizures (compared to control rats)


Patients with tuberous sclerosis complex and epilepsy who underwent epilepsy surgery (compared to patients with epilepsy without

"Increased. #Decreased. Reproduced with permission [26]. *RNA studies. EPI: Refractory epilepsy; ESES: Electrical status epilepticus in sleep; SE: Status epilepticus.

Talos et al. (2008) [82]

Rats with pilocarpine-induced SE (compared to Rajasekaran et al. control rats) (2012) [80] Data from epilepsy surgery performed for refractory epilepsy Individual neurons from dysplastic tissue from Crino et al. (2001) [81] epilepsy surgery (compared to non-dysplastic tissue from epileptic patients and to autopsy specimens from patients who died from nonneurological causes). Temporal neocortex and dorsolateral frontal neocortex

Swann et al. (2007) [79]

Animal models of seizures and SE Rats with pilocarpine-induced SE and subsequent Brooks-Kayal et al. development of spontaneous temporal lobe (1998) [78] seizures (compared to control rats) Hippocampus

Author and year

GluA1 GluA4 GluA2 GluA3

" " # #

GluA1 #*

Heterotopic neurons

Tissue from tubers

GluA1 #* GluA4 "*

GluA2 surface expression #

AMPA

Dysplastic neurons

Flurothyl-induced seizures in hippocampus Flurothyl-induced seizures in neocortex

Tetanus toxin-induced seizures at p10 in hippocampus

1 -- 4 months after SE and with spontaneous temporal lobe seizures

24 h after SE

Substudy features (if applicable)

Table 1. Subunit composition of glutamate and GABA receptors in the seizing brain.


GluN2B " GluN3A "

GluN2A #* GluN2B "* GluN2C "*

GluN2A #

GluN1 # GluN2A # GluN2B # GluN2A #

NMDA

a1 #* a2 #* b1 #* b2 #* a1 #* a2 #* b2 #*

a1 #* a3 "* a4"* a1/non a1 #* b1#* b3"* d"* ""* a1 #* a4"* a1/non a1 #* d"* ""* b1#* b3 "*

GABA


Study design


"Increased. #Decreased. Reproduced with permission [26]. *RNA studies. EPI: Refractory epilepsy; ESES: Electrical status epilepticus in sleep; SE: Status epilepticus.

tuberous sclerosis and to autopsy cases without neurological diseases) Patients with tuberous sclerosis complex and Talos et al. (2012) [83] epilepsy who underwent epilepsy surgery or whose tissues were collected at autopsy and patients with focal cortical dysplasia and epilepsy who underwent epilepsy surgery to resect the epileptogenic tissue (compared to autopsy cases without neurological diseases) Patients with malformations of cortical Finardi et al. (2006) [84] development undergoing epilepsy surgery because of refractory epilepsy (compared to patients with focal epilepsy without underlying malformation and to non-epileptic patients’ brain tissue resected next to a tumor) Data from epilepsy surgery performed for refractory SE Patients with SE and ESES (compared to epilepsy Loddenkemper et al. surgery patients without SE EPI and to autopsy (2014) [85] cases)

Author and year

EPI

ESES

GluN2B " GluN2B/GluN2A " GluN2B/GluNA " SE

GluN2B " GluN3A "

NMDA

GluN2B " GluN1 # GluN2A # GluN2B #

GluA1 " GluA1/GluA2 " GluA1/Glu2 "

GluA1 " GluA2 #

AMPA

Focal cortical dysplasia Periventricular nodular heterotopia

Focal cortical dysplasia IIb

Focal cortical dysplasia IIa

Cortex from epileptic patients without tuberous sclerosis Tubers

Substudy features (if applicable)

Table 1. Subunit composition of glutamate and GABA receptors in the seizing brain (continued).


a2/a1 " a2 "* a2/a1 "*

a2/a1 " a2 "*

a1 # a4/a1 " a4 # a4/a1 # a1 # a4/a1 "

GABA


5


A.

Intracellular vacuole

B.

Intracellular vacuole

Postsynaptic neuron


GABA reception NMDA reception

Presynaptic neuron

Postsynaptic neuron

GABA reception NMDA reception

Presynaptic neuron

Figure 1. Schematic representation of the changes in neurotransmitter receptor concentration at baseline and during prolonged seizures. A. At baseline GABA (inhibitory) neurotransmission predominates over NMDA (excitatory) neurotransmission. B. During seizures, GABA receptors get internalized and NMDA receptors accumulate in the postsynaptic membrane favoring self-sustaining seizures and resistance to antiepileptic drugs with a GABAergic mechanism of onset like benzodiazepines.

5 – 10 min

First AED: Lorazepam 0.05 – 0.1 mg/kg iv (maximum 5 mg) If no iv: Diazepam 0.2 – 0.5 mg/kg/dose PR (maximum 20 mg) Repeat once if necessary

Impending SE

10 – 15 min

15 – 30 min

Second AED: Fosphenytoin 20 mg PE/Kg iv

Third AED: Phenobarbital 20 mg/kg iv Other options: Valproate, levetiracetam

Established SE

30 – 60 min

Continuous infusions/anesthetics: Midazolam pentobarbital Other options: Ketamine, isoflurane, propofol

Refractory SE

Figure 2. The first-line AED is usually a benzodiazepine (most frequently lorazepam). Sometimes it might be useful to try a second dose of benzodiazepines. However, when seizures last ‡ 10 min, the recommended treatment is fosphenytoin and for seizures of > 15- to 30-min duration, a second non-benzodiazepine AED should be administered. The most commonly used is phenobarbital, although other options include valproate or levetiracetam. When seizures last > 30 -- 60 min and the patient has not responded to prior medications, SE can be considered refractory and switch to continuous infusions of AEDs or anesthetic therapies is advised. AED: Antiepileptic drug; i.v.: Intravenous. ; PE: Fosphenytoin equivalents; PR: Per rectum; SE: Status epilepticus.

impending SE [39]. The Veterans Affair Cooperative Study, another large double-blind study, randomized 384 adults to receive four initial treatments for SE -- lorazepam, phenobarbital, phenytoin and diazepam -- followed by phenytoin in 6

order to determine optimal first-line treatment [40]. In this study lorazepam was superior to phenytoin, but in an intention-to-treat analysis there were no differences among the four treatment groups [40].




3.3

Lorazepam as the preferred first-line drug for SE

Based on the results of these studies, intravenous lorazepam became widely regarded as the optimal first-line choice for SE. The results of the Veterans Affair study are frequently extrapolated to children even though there were no children in that study. In pediatrics, the preference of lorazepam as first-line therapy is essentially based on the large North London series of 182 children with SE, in which treatment with intravenous lorazepam was associated with a 3.7 (95% CI: 1.7 -- 7.9) times greater likelihood of seizure cessation than treatment with rectal diazepam [20]. Several studies also show efficacy of benzodiazepines as first-line treatment of SE but the superiority of one benzodiazepine over the others is less clear [41]. In a recent doubleblind study, 273 children with SE were randomized to receive intravenous diazepam (n = 140) or intravenous lorazepam (n = 133) [42]. The primary efficacy outcome was cessation of SE by 10 min without recurrence within 30 min and the primary safety outcome was the need for assisted ventilation [42]. The rate of SE cessation (72% on diazepam and 73% on lorazepam) and the rate of requiring assisted ventilation (16% on diazepam, 18% on lorazepam) were similar [42]. In a series of 48 children with prolonged seizures treated in the emergency department, there were no differences in the rate of seizure control between patients treated with intravenous diazepam (65%) and in patients treated with intravenous lorazepam (65%) [43]. In a series of 76 episodes of pediatric seizures of at least 5 min duration treated with intravenous midazolam bolus doses of 0.1 -- 0.2 mg/kg, seizure control was achieved with the first bolus in 40/76 (53%) patients, with a second bolus in 20/36 (55%) and with a third bolus in 8/16 (50%) [44]. A recent series randomized 893 patients (both children and adults) to receive intramuscular midazolam or intravenous lorazepam as a first-line, out-ofhospital treatment [45]. Seizure resolution at the time of arrival in the emergency department was 73% in the intramuscular midazolam group and was 63% in the intravenous lorazepam group [45]. In a Cochrane review of three studies which included 264 patients, intravenous lorazepam was slightly superior to intravenous diazepam on cessation of seizures and was not different on requirement of ventilatory support or other adverse effects [46,47]. Intravenous clonazepam has been used for controlling SE in 16/24 patients in one series [48] and in all 17 patients in a different study [49]. In summary, intravenous lorazepam, intravenous midazolam, intramuscular midazolam and intravenous diazepam have demonstrated similar efficacy, with lorazepam being slightly superior in some studies and with intramuscular midazolam being noninferior to intravenous lorazepam [45]. Need for other routes of administration Intravenous lorazepam is associated with a major disadvantage: the need to obtain an intravenous line and the lack of easily accessible alternative route. Most episodes of SE start 3.4

out of the hospital and obtaining an intravenous line in an actively convulsing patient can be particularly challenging. Therefore, other non-intravenous first-line treatments are being increasingly considered. A meta-analysis concluded that non-intravenous midazolam was at least as safe and effective as intravenous or non-intravenous diazepam in children and young adults [50]. A series of 28 children with severe epilepsy at a residential school who presented with seizures of at least 5 min duration were randomized to receive buccal midazolam or rectal diazepam [51]. In this series, buccal midazolam was shown to be at least as effective (75% seizure control) as rectal diazepam (59%) with no clinically important adverse events in any of the groups [51]. A prospective randomized study of 92 children compared intranasal midazolam (0.2 mg/kg with a maximum of 10 mg) with rectal diazepam (0.3 -- 0.5 mg/kg with a maximum of 20 mg) as home treatment of acute seizures [52]. The median time from medication administration to seizure cessation was 3 min in the intranasal midazolam group and 4.3 min in the rectal diazepam group [52]. There were no marked differences in the rate of complications between the two groups [52]. In a prospective study, 24 children with motor seizures of at least 10 min duration were randomized to receive intramuscular midazolam or intravenous diazepam [53]. Patients in the midazolam group received medication sooner (mean: 3.3 vs 7.8 min) and had more rapid cessation of their seizures (mean: 7.8 vs 11.2 min) than patients randomized to diazepam [53]. A recent landmark, double-blind, noninferiority trial randomized 893 patients (both children and adults) to receive intramuscular midazolam or intravenous lorazepam as a first-line, out-of-hospital treatment [45]. The primary outcome was absence of seizures at the time of arrival in the emergency department without the need for rescue therapy [45]. As discussed above, seizure resolution at the time of arrival in the emergency department was similar in the intramuscular midazolam group and in the intravenous lorazepam group [45]. There were no significant differences in the need for endotracheal intubation (14% in both groups) or the proportion of seizure recurrence (11% in both groups) [45]. In this study, the time saved using the intramuscular route (1.2 min in the intramuscular midazolam group and 4.8 min in the intravenous lorazepam group) appears to at least offset the delay in the drug onset of action (3.3 min in the intramuscular midazolam group and 1.6 min in the intravenous lorazepam group) [45]. In summary, there are non-intravenous alternatives to lorazepam which have similar efficacy and are easier and faster to administer.

Non-benzodiazepine AEDs After benzodiazepines have failed to control SE and/or SE has lasted for 10 min, a switch to non-benzodiazepine AED is recommended. Although there are several options available, evidence supporting one AED versus the others is weak. There are few studies which have specifically addressed the efficacy of second-line AEDs in SE and their methodology and end 3.5


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points vary widely. Most of the evidence comes from observational and retrospective studies. Currently, phenytoin (or fosphenytoin) is the recommended first option as non-benzodiazepine AED and phenobarbital is the most commonly used second option when phenytoin (or fosphenytoin) fails to control SE [36-38]. These choices are essentially based on the fact that these drugs have been available for much longer than any new AED [36-38]. Therefore, they are time-tested and there is abundant literature on their efficacy. In the North London series of 182 pediatric patients with convulsive SE, treatment with intravenous phenytoin as a second-line therapy was associated with a nine times greater likelihood of seizure cessation as compared to treatment with rectal paraldehyde [20]. However, when phenytoin is compared to newer drugs, there is no clear advantage of phenytoin. A retrospective series of 167 adults with SE compared phenytoin, valproate and levetiracetam as secondline drugs (after failure of benzodiazepines as first-line drugs) [54]. Valproate failed to control SE in 25% of patients in whom it was prescribed, phenytoin in 41% and levetiracetam in 48% [54]. After adjustment for SE severity, this study showed that valproate was more effective than levetiracetam (odds ratio comparing levetiracetam failure with valproate failure: 2.69, 95% CI: 1.19 -- 6.08), whereas there was no difference in the efficacy of phenytoin compared to valproate or phenytoin compared to levetiracetam [54]. A series of generalized convulsive seizures that lasted > 5 min, which did not respond to a bolus of intravenous diazepam, were randomly assigned to either phenobarbital or valproate [55]. Although differences were not statistically significant, there was a tendency toward a higher rate of seizure cessation with valproate than with phenobarbital (90 vs 77%) with fewer associated clinically significant adverse events (24 vs 74%) [55]. A study of 68 patients (children and adults) with SE randomly assigned valproate or phenytoin as initial therapy [56]. Seizures were aborted in 66% in the valproate group and in 42% in the phenytoin group [56]. As a second choice in refractory patients, valproate was effective in 79% and phenytoin was effective in 25% [56]. There were no marked differences in side effects between the two groups [56]. A recent meta-analysis evaluated the efficacy of phenytoin, phenobarbital, valproate, levetiracetam and lacosamide to stop SE after benzodiazepine failure [57]. For phenytoin, eight studies reporting 294 SE episodes were analyzed with a mean efficacy of 50% (95% CI: 43 -- 66%) [57]. For phenobarbital, two studies reporting 42 SE episodes were analyzed with a mean efficacy of 74% (95% CI: 58 -- 85%) [57]. For valproate, eight studies reporting 250 SE episodes were analyzed with a mean efficacy of 76% (95% CI: 64 -- 85%) [57]. For levetiracetam, eight studies reporting 204 SE episodes were analyzed with a mean efficacy of 69% (95% CI: 56 -- 79%) [57]. There was insufficient detail in patients treated with lacosamide to perform a meta-analysis [57], although this drug shows some promising results [58,59]. In summary, observational studies show that new drugs like valproate or levetiracetam have a 8

similar, if not superior, efficacy than phenytoin (fosphenytoin) and phenobarbital. Apart from efficacy, relatively new drugs such as valproate and levetiracetam have potential practical advantages: in general, they can be administered faster than phenytoin (or fosphenytoin), have a better pharmacokinetic profile and have a lower risk of hypotension and respiratory depression [60]. It should be emphasized that although valproate is a generally safe drug in adults and children, it disrupts organic acid metabolism and can lead to serious toxicity in children with underlying metabolic disorders (often undiagnosed at the time of presentation with SE) and in children < 2 years of age [61]. The Established SE Treatment Trial (ESETT), a large international collaboration, is developing a randomized controlled trial to definitively establish whether valproate and/or levetiracetam are superior to phenytoin as second-line treatment for SE [60]. Refractory SE When SE persists despite the administration of appropriate doses of benzodiazepines, and one or two doses of nonbenzodiazepine AEDs, continuous infusions of AEDs or anesthetic therapies are recommended [36]. If the patient is not already on mechanical ventilation, this should be instituted before initiating treatment with continuous infusions. In addition, vasopressor agents may be required because of hypotension and cardiopulmonary depression. The most commonly used continuous infusions are midazolam, propofol (with the caveat of worsening underlying metabolic conditions) and pentobarbital with insufficient evidence to recommend any one in particular over the others [62-64]. Other options may also include ketamine or inhalation anesthetics, among others. Midazolam infusion (0.2 mg/kg loading dose followed by 0.2 -- 0.6 mg/kg/h) is relatively safe, causes less hypotension than pentobarbital infusion and is frequently used as the initial continuous drip [65]. Tachyphylaxis often develops within 24 -- 48 h, so the perfusion dose should be increased to maintain a constant pharmacological action [65]. In a series of patients with refractory SE, continuous infusion of midazolam (mean infusion rate: 2 µg/kg/min) controlled seizures in 19 of 20 (95%) children after a mean interval of 0.9 h after the initiation of the infusion [66]. In another series of children with refractory SE, a continuous infusion of midazolam (mean infusion rate: 3.1 µg/kg/min) controlled seizures in 26 of 27 (96%) cases within 65 min of the initiation of the midazolam infusion. Pentobarbital infusion (5 mg/kg loading dose followed by 1 -- 5 mg/kg/h) has a long half-life making both uptitration and weaning challenging. In a retrospective series of children with refractory SE treated with pentobarbital infusion (mean loading dose of 5.4 mg/kg followed by an initial infusion of 1.1 mg/kg/h and maximum infusion of 4.8 mg/kg/h), 10 of 30 (33%) achieved sustained burst suppression without relapse during therapy [67]. Of the patients who experienced seizure relapse, 12 of 20 (60%) eventually re-achieved burst 3.6



Table 2. Treatment alternatives for refractory and super-refractory SE. Comments Thiopental [69,86]

Metabolized to pentobarbital

Ketamine [87,88]

Mechanism of action particularly well suited to treat refractory and super-refractory SE (NMDA receptor antagonist) High complication rate; needs closed system (gas recovery)

Inhaled anesthetics [89]


Adverse events

Ketogenic diet [90-92]

Relatively safe (no respiratory and cardiocirculatory instability); slow onset of action; requires skilled dietician

Lidocaine [93,94]

Minor respiratory depression compared with other drugs

Hypothermia [95]

Only transitory control (cannot be a prolonged therapy)

Resective surgery [96-99]

Long-term treatment of seizures; not all patients are eligible

Hypotension, respiratory depression, cardiac depression High intracranial pressure, hypotension, hallucinations Hypotension, infection, paralytic ileus Gastroesophageal reflux, constipation, acidosis, hypertriglyceridemia Cardiocirculatory instability, possible induction of seizures Hypotension, cardiovascular instability, impaired coagulation (bleeding risks) Surgical risks

SE: Status epilepticus.

suppression [67]. The rate of adverse effects in this series was particularly high with hypotension requiring inotropes in 93% of patients, infection in 66%, metabolic acidosis in 10% and pancreatitis in 10% [67]. Propofol infusion (2 mg/kg loading dose followed by 2 -- 5 mg/kg/h) has a short half-life. Its main disadvantage is its potential to cause propofol infusion syndrome, a potentially fatal complication most often seen in critically ill children undergoing long-term propofol infusion at high doses. Propofol infusion syndrome mechanism is based on the propofol-mediated impairment of free fatty acid utilization and mitochondrial activity [68]. An imbalance between energy demand and utilization is a key pathogenetic mechanism which may lead to cardiac and peripheral muscle necrosis [68]. The main clinical features of propofol infusion syndrome are cardiocirculatory collapse with lactic acidosis, hypertriglyceridemia and rhabdomyolysis [68]. As this syndrome is frequently lethal, propofol infusions with doses of at least 5 mg/kg/h are not recommended for > 48 h, especially in children [68]. In a series of children with refractory SE, propofol infusion controlled 14 of 22 (64%) episodes [69]. Propofol infusion had to be stopped on four occasions: one patient had rhabdomyolysis and three patients developed hypertriglyceridemia which normalized after stopping propofol [69]. Super-refractory SE When SE does not respond to the abovementioned medications, it is considered super-refractory. A more precise definition is ‘status epilepticus that continues for 24 hours or more after the onset of anesthesia, including those cases in which the status epilepticus recurs on the reduction or withdrawal of anesthesia’ [70]. When patients have super-refractory SE, 3.7

several therapeutic approaches should be tried sequentially although evidence on their efficacy is generally limited to case reports or small case series (Table 2) [70]. Autoimmune SE and immune therapies The possibility of autoimmune encephalitis should be considered, especially when SE is refractory or super refractory. Autoimmune encephalitis is a rare etiology of SE, but it is potentially treatable and requires specific therapies. Patients of any age who develop rapidly progressing symptoms including a combination of seizures or SE, behavioral changes and encephalopathy with no other explanation for them should be evaluated in serum and cerebrospinal fluid for autoantibodies [71,72]. The suspicion or confirmation of autoimmune encephalitis should raise the possibility of treatment with immunotherapy such as steroids, intravenous immunoglobulins or plasma exchange, although the response is variable [73,74] and not all cases of inflammatory SE may be amenable to immunotherapy [75]. 3.8

4.

Conclusion

Current SE treatment protocols emphasize the need for a timely administration of AEDs in a stepwise approach [36-38]. There is reasonably good evidence supporting the efficacy of benzodiazepines as initial SE treatment. Although intravenous lorazepam is widely regarded as the best initial treatment, other benzodiazepines with non-intravenous route of administration have demonstrated similar efficacy and advantages on the route of administration [45,51,52]. Once SE has not responded to benzodiazepines, there is a wide variety of non-benzodiazepine AED alternatives. Although phenytoin (fosphenytoin) and phenobarbital are time-tested alternatives,


9


newer AEDs such as valproate or levetiracetam are being increasingly considered as they may be at least noninferior [57]. Treatment for refractory SE is based on continuous infusions of midazolam, propofol and/or pentobarbital. Once SE becomes super refractory, different therapeutic options with limited supporting evidence may be tried sequentially [70]. There are delays in AED administration in the treatment of SE [34,35].


5.

Expert opinion

The field of SE treatment is experiencing significant and exciting developments in the past few years. The established sequence of treatment with intravenous lorazepam, intravenous phenytoin (fosphenytoin) and intravenous phenobarbital is being challenged by recent studies. SE is a life-threatening emergency that requires immediate treatment. As most episodes of SE start out of the hospital, there is a need for drugs which are effective at stopping SE and fast and easy to administer. Rectal diazepam is a timetested drug widely used to stop SE in young children. However, its absorption through the rectal mucosa is unpredictable, and administration in older patients may be perceived as stigmatizing and socially embarrassing. More straightforward routes of delivery are being tested. Intramuscular midazolam has demonstrated noninferiority compared to intravenous lorazepam and is being widely used by different emergency medical services. Intranasal and buccal midazolam are gaining popularity and small series have demonstrated that their efficacy and safety is comparable to other benzodiazepines [76]. Limitations of intranasal and buccal midazolam include unpredictable absorption through the buccal and nasal mucosa and not being approved and commercially available in many countries. In the near future, it is likely that intramuscular midazolam auto-injectors and intranasal and buccal midazolam will be widely used by families and emergency medical services. Large multicenter consortia are being developed to redefine the best treatment options in SE. The ESETT will evaluate whether valproate and levetiracetam are better than intravenous phenytoin (fosphenytoin) for treatment of benzodiazepine-resistant SE [60]. This international collaboration is developing a blinded comparative randomized clinical trial with a goal of 1500 patients from at least 50 centers [60]. It is likely that in the near future valproate and levetiracetam will become initial options after benzodiazepine failure. The Pediatric SE Research Group (pSERG) is a multicenter network within the US that tries to develop an evidencebased approach for the management of pediatric SE [77].

10

The data obtained from this prospective collection of current clinical practice can inform future decisions about care and treatment trials both in the out-of-hospital setting, emergency department and intensive care unit [77]. In an initial phase, this consortium is analyzing data on treatment choices and healthcare delivery for SE in large reference pediatric hospitals [77]. During a later phase, this consortium will perform randomized clinical trials to evaluate the best therapeutic options in pediatric SE. Results from this consortium include the description of significant delays in AED administration in pediatric SE [35]. In the future, pSERG will further research on causes of treatment delay and will develop recommendations for policy changes that optimize the timing of AED administration based on comparative effectiveness data. In order to optimize timing of AED administration, it can be useful in considering shifting from the classic stepwise approach to a treatment protocol in which several drugs are administered simultaneously. Further research is needed on the best treatment options for refractory and super-refractory SE. Because of the rarity of these conditions, this research may only advance in large multicenter consortia. The ultimate goal of research in this field is to stop SE as soon as possible so that complications and sequelae are minimal and outcome is optimized.

Declaration of interest I Sańchez Fernańdez is funded by a grant for the study of Ivań Sańchez Fernańdez is funded by a grant for the study of Epileptic Encephalopathies from “Fundacion Alfonso Martıń Escudero” and the HHV6 Foundation. Tobias Loddenkemper serves on the Laboratory Accreditation Board for Long Term (Epilepsy and Intensive Care Unit) Monitoring, on the Council of the American Clinical Neurophysiology Society, on the American Board of Clinical Neurophysiology, as an Associate Editor for Seizure, as Contributing Editor for Epilepsy Currents, and as an Associate Editor for Wyllie’s Treatment of Epilepsy 6th edition. He is part of pending patent applications to detect seizures and to diagnose epilepsy. He receives research support from the American Epilepsy Society, the Epilepsy Foundation of America, the Epilepsy Therapy Project, PCORI, the Pediatric Epilepsy Research Foundation, Cure, Danny-Did Foundation, HHV-6 Foundation, Lundbeck, Eisai, and Upsher-Smith. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.



Bibliography Papers of special note have been highlighted as either of interest () or of considerable interest () to readers. 1.

2.


3.

4.

5.

6.

7.

Dham BS, Hunter K, Rincon F. The epidemiology of status epilepticus in the United States. Neurocrit Care 2014;20:476-83 Chin RF, Neville BG, Scott RC. A systematic review of the epidemiology of status epilepticus. Eur J Neurol 2004;11:800-10 Chin RF, Neville BG, Peckham C, et al. Incidence, cause, and short-term outcome of convulsive status epilepticus in childhood: prospective population-based study. Lancet 2006;368:222-9 DeLorenzo RJ, Hauser WA, Towne AR, et al. A prospective, population-based epidemiologic study of status epilepticus in Richmond, Virginia. Neurology 1996;46:1029-35 Loddenkemper T, Syed TU, Ramgopal S, et al. Risk factors associated with death in in-hospital pediatric convulsive status epilepticus. PLoS One 2012;7:e47474 Maytal J, Shinnar S, Moshe SL, Alvarez LA. Low morbidity and mortality of status epilepticus in children. Pediatrics 1989;83:323-31 Raspall-Chaure M, Chin RF, Neville BG, Scott RC. Outcome of paediatric convulsive status epilepticus: a systematic review. Lancet Neurol 2006;5:769-79

8.

Singh RK, Stephens S, Berl MM, et al. Prospective study of new-onset seizures presenting as status epilepticus in childhood. Neurology 2010;74:636-42

9.

Wu YW, Shek DW, Garcia PA, et al. Incidence and mortality of generalized convulsive status epilepticus in California. Neurology 2002;58:1070-6

10.

11.

12.

Shinnar S, Berg AT, Moshe SL, Shinnar R. How long do new-onset seizures in children last? Ann Neurol 2001;49:659-64

24.

Towne AR, Pellock JM, Ko D, DeLorenzo RJ. Determinants of mortality in status epilepticus. Epilepsia 1994;35:27-34

13.

DeLorenzo RJ, Garnett LK, Towne AR, et al. Comparison of status epilepticus with prolonged seizure episodes lasting from 10 to 29 minutes. Epilepsia 1999;40:164-9

25.

Aranda A, Foucart G, Ducasse JL, et al. Generalized convulsive status epilepticus management in adults: a cohort study with evaluation of professional practice. Epilepsia 2010;51:2159-67

14.

Sańchez Fernańdez I, Vendrame M, Kapur K, et al. Comparison of pediatric patients with status epilepticus lasting 529min versus >/=30min. Epilepsy Behav 2014;37C:1-6

26.

Sańchez Fernańdez I, Loddenkemper T. Subunit composition of neurotransmitter receptors in the immature and in the epileptic brain. BioMed Res Int 2014;2014:301950

15.

Sańchez Fernańdez I, Klehm J, An S, et al. Comparison of risk factors for pediatric convulsive status epilepticus when defined as seizures >/=5min versus seizures >/=30min. Seizure 2014;23:692-8

27.

Goodkin HP, Yeh JL, Kapur J. Status epilepticus increases the intracellular accumulation of GABAA receptors. J Neurosci 2005;25:5511-20

28.

Naylor DE, Liu H, Wasterlain CG. Trafficking of GABA(A) receptors, loss of inhibition, and a mechanism for pharmacoresistance in status epilepticus. J Neurosci 2005;25:7724-33

29.

Naylor DE, Liu H, Niquet J, Wasterlain CG. Rapid surface accumulation of NMDA receptors increases glutamatergic excitation during status epilepticus. Neurobiol Dis 2013;54:225-38

30.

Mazarati AM, Baldwin RA, Sankar R, Wasterlain CG. Time-dependent decrease in the effectiveness of antiepileptic drugs during the course of self-sustaining status epilepticus. Brain Res 1998;814:179-85

31.

Lewena S, Pennington V, Acworth J, et al. Emergency management of pediatric convulsive status epilepticus: a multicenter study of 542 patients. Pediatr Emerg Care 2009;25:83-7

32.

Pellock JM, Marmarou A, DeLorenzo R. Time to treatment in prolonged seizure episodes. Epilepsy Behav 2004;5:192-6

33.

Seinfeld S, Shinnar S, Sun S, FEBSTAT study team. Emergency management of febrile status epilepticus: results of the FEBSTAT study. Epilepsia 2014;55:388-95

34.

Ka¨mppi L, Mustonen H, Soinila S. Analysis of the delay components in the treatment of status epilepticus. Neurocrit Care 2013;19:10-18

35.

Loddenkemper T, Abend NS, Agadi S, et al. Management of pediatric refractory convulsive status epilepticus in clinical practice. Pediatric Status Epilepticus

16.

Logroscino G, Hesdorffer DC, Cascino GD, et al. Long-term mortality after a first episode of status epilepticus. Neurology 2002;58:537-41

17.

Sutter R, Kaplan PW, Ruegg S. Outcome predictors for status epilepticus -- what really counts. Nat Rev Neurol 2013;9:525-34

18.

Lothman E. The biochemical basis and pathophysiology of status epilepticus. Neurology 1990;40:13-23

19.

20.

.

Alldredge BK, Wall DB, Ferriero DM. Effect of prehospital treatment on the outcome of status epilepticus in children. Pediatr Neurol 1995;12:213-16 Chin RF, Neville BG, Peckham C, et al. Treatment of community-onset, childhood convulsive status epilepticus: a prospective, population-based study. Lancet Neurol 2008;7:696-703 Large series of children with SE in London, UK.

21.

Rossetti AO, Hurwitz S, Logroscino G, Bromfield EB. Prognosis of status epilepticus: role of aetiology, age, and consciousness impairment at presentation. J Neurol Neurosurg Psychiatry 2006;77:611-15

Eriksson K, Metsaranta P, Huhtala H, et al. Treatment delay and the risk of prolonged status epilepticus. Neurology 2005;65:1316-18

22.

Jenssen S, Gracely EJ, Sperling MR. How long do most seizures last? A systematic comparison of seizures recorded in the epilepsy monitoring unit. Epilepsia 2006;47:1499-503

Lewena S, Young S. When benzodiazepines fail: how effective is second line therapy for status epilepticus in children? Emerg Med Australas 2006;18:45-50

23.

Sagduyu A, Tarlaci S, Sirin H. Generalized tonic-clonic status epilepticus: causes, treatment, complications and predictors of case fatality. J Neurol 1998;245:640-6


11


Research Group (pSERG). In: American Epilepsy Society Meeting; 2013 36.

37.


38.

39.

.

40.

.

41.

42.

Brophy GM, Bell R, Claassen J, Neurocritical Care Society Status Epilepticus Guideline Writing Committee. Guidelines for the evaluation and management of status epilepticus. Neurocrit Care 2012;17:3-23 Loddenkemper T, Goodkin HP. Treatment of pediatric status epilepticus. Curr Treat Options Neurol 2011;13:560-73 Wilkes R, Tasker RC. Pediatric intensive care treatment of uncontrolled status epilepticus. Crit Car Clin 2013;29:239-57 Alldredge BK, Gelb AM, Isaacs SM, et al. A comparison of lorazepam, diazepam, and placebo for the treatment of out-of-hospital status epilepticus. N Engl J Med 2001;345:631-7 Randomized controlled trial which demonstrated that benzodiazepines were better than placebo as initial treatment for status epilepticus (SE) in adults. Treiman DM, Meyers PD, Walton NY, et al. A comparison of four treatments for generalized convulsive status epilepticus. Veterans Affairs Status Epilepticus Cooperative Study Group. N Engl J Med 1998;339:792-8 Randomized controlled trial which established lorazepam as the preferred option for convulsive SE. Glauser TA. Designing practical evidence-based treatment plans for children with prolonged seizures and status epilepticus. J Child Neurol 2007;22:38S-46S Chamberlain JM, Okada P, Holsti M, Pediatric Emergency Care Applied Research Network. Lorazepam vs diazepam for pediatric status epilepticus: a randomized clinical trial. JAMA 2014;311:1652-60

43.

Qureshi A, Wassmer E, Davies P, et al. Comparative audit of intravenous lorazepam and diazepam in the emergency treatment of convulsive status epilepticus in children. Seizure 2002;11:141-4

44.

Papavasiliou AS, Kotsalis C, Paraskevoulakos E, et al. Intravenous midazolam in convulsive status epilepticus in children with pharmacoresistant epilepsy. Epilepsy Behav 2009;14:661-4

12

45.

.

46.

Silbergleit R, Durkalski V, Lowenstein D, NETT Investigators. Intramuscular versus intravenous therapy for prehospital status epilepticus. N Engl J Med 2012;366:591-600 Randomized controlled trial which demonstrated that intramuscular midazolam is at least noninferior to intravenous lorazepam in the initial treatment of SE. Prasad K, Al-Roomi K, Krishnan PR, Sequeira R. Anticonvulsant therapy for status epilepticus. Cochrane Database Syst Rev 2005(4):CD003723

55.

Malamiri RA, Ghaempanah M, Khosroshahi N, et al. Efficacy and safety of intravenous sodium valproate versus phenobarbital in controlling convulsive status epilepticus and acute prolonged convulsive seizures in children: a randomised trial. Eur J Paediatr Neurol 2012;16:536-41

56.

Misra UK, Kalita J, Patel R. Sodium valproate vs phenytoin in status epilepticus: a pilot study. Neurology 2006;67:340-2

57.

Yasiry Z, Shorvon SD. The relative effectiveness of five antiepileptic drugs in treatment of benzodiazepine-resistant convulsive status epilepticus: a metaanalysis of published studies. Seizure 2014;23:167-74

47.

Prasad M, Krishnan PR, Sequeira R, Al-Roomi K. Anticonvulsant therapy for status epilepticus. Cochrane Database Syst Rev 2014;9:CD003723

48.

Singh AN, Le Morvan P. Treatment of status epilepticus with intravenous clonazepam. Prog Neuropsychopharmacol Biol Psychiatry 1982;6:539-42

58.

Grosso S, Zamponi N, Bartocci A, et al. Lacosamide in children with refractory status epilepticus. A multicenter Italian experience. Eur J Paediatr Neurol 2014;18:604-8

49.

Congdon PJ, Forsythe WI. Intravenous clonazepam in the treatment of status epilepticus in children. Epilepsia 1980;21:97-102

59.

Santamarina E, Toledo M, Sueiras M, et al. Usefulness of intravenous lacosamide in status epilepticus. J Neurol 2013;260:3122-8

50.

McMullan J, Sasson C, Pancioli A, Silbergleit R. Midazolam versus diazepam for the treatment of status epilepticus in children and young adults: a meta-analysis. Acad Emerg Med 2010;17:575-82

60.

Cock HR, Group E. Established status epilepticus treatment trial (ESETT). Epilepsia 2011;52(Suppl 8):50-2

61.

Price KE, Pearce RE, Garg UC, et al. Effects of valproic acid on organic acid metabolism in children: a metabolic profiling study. Clin Pharmacol Ther 2011;89:867-74

62.

Claassen J, Hirsch LJ, Emerson RG, Mayer SA. Treatment of refractory status epilepticus with pentobarbital, propofol, or midazolam: a systematic review. Epilepsia 2002;43:146-53

63.

Pugin D, Foreman B, De Marchis GM, et al. Is pentobarbital safe and efficacious in the treatment of super-refractory status epilepticus: a cohort study. Crit Care 2014;18:R103

64.

Riviello JJ Jr, Claassen J, LaRoche SM, Neurocritical Care Society Status Epilepticus Guideline Writing Committee. Treatment of status epilepticus: an international survey of experts. Neurocrit Care 2013;18:193-200

65.

Rossetti AO, Lowenstein DH. Management of refractory status epilepticus in adults: still more questions

51.

52.

53.

54.

Scott RC, Besag FM, Neville BG. Buccal midazolam and rectal diazepam for treatment of prolonged seizures in childhood and adolescence: a randomised trial. Lancet 1999;353:623-6 Holsti M, Dudley N, Schunk J, et al. Intranasal midazolam vs rectal diazepam for the home treatment of acute seizures in pediatric patients with epilepsy. Arch Pediatr Adolesc Med 2010;164:747-53 Chamberlain JM, Altieri MA, Futterman C, et al. A prospective, randomized study comparing intramuscular midazolam with intravenous diazepam for the treatment of seizures in children. Pediatr Emerg Care 1997;13:92-4 Alvarez V, Januel JM, Burnand B, Rossetti AO. Second-line status epilepticus treatment: comparison of phenytoin, valproate, and levetiracetam. Epilepsia 2011;52:1292-6



..

66.


67.

68.

69.

70.

71.

72.

73.

74.

75.

76.

than answers. Lancet Neurol 2011;10:922-30 Review on the management of refractory SE in adults.

77.

Koul RL, Raj Aithala G, Chacko A, et al. Continuous midazolam infusion as treatment of status epilepticus. Arch Dis Child 1997;76:445-8 Barberio M, Reiter PD, Kaufman J, et al. Continuous infusion pentobarbital for refractory status epilepticus in children. J Child Neurol 2012;27:721-6

78.

Vasile B, Rasulo F, Candiani A, Latronico N. The pathophysiology of propofol infusion syndrome: a simple name for a complex syndrome. Intensive Care Med 2003;29:1417-25

79.

van Gestel JP, Blusse van Oud-Alblas HJ, Malingre M, et al. Propofol and thiopental for refractory status epilepticus in children. Neurology 2005;65:591-2 Ferlisi M, Shorvon S. The outcome of therapies in refractory and superrefractory convulsive status epilepticus and recommendations for therapy. Brain 2012;135:2314-28 Davis R, Dalmau J. Autoimmunity, seizures, and status epilepticus. Epilepsia 2013;54(Suppl 6):46-9 Holzer FJ, Seeck M, Korff CM. Autoimmunity and inflammation in status epilepticus: from concepts to therapies. Expert Rev Neurother 2014;14:1181-202 Petit-Pedrol M, Armangue T, Peng X, et al. Encephalitis with refractory seizures, status epilepticus, and antibodies to the GABAA receptor: a case series, characterisation of the antigen, and analysis of the effects of antibodies. Lancet Neurol 2014;13:276-86 Suleiman J, Brilot F, Lang B, et al. Autoimmune epilepsy in children: case series and proposed guidelines for identification. Epilepsia 2013;54:1036-45 van Baalen A, Hausler M, Plecko-Startinig B, et al. Febrile infection-related epilepsy syndrome without detectable autoantibodies and response to immunotherapy: a case series and discussion of epileptogenesis in FIRES. Neuropediatrics 2012;43:209-16 Humphries LK, Eiland LS. Treatment of acute seizures: is intranasal midazolam a

a retrospective multicenter study. Epilepsia 2013;54:1498-503

viable option? J Pediatr Pharmacol Ther 2013;18:79-87

80.

81.

82.

Sańchez Fernańdez I, Abend NS, Agadi S, Pediatric Status Epilepticus Research Group. Gaps and opportunities in refractory status epilepticus research in children: a multi-center approach by the Pediatric Status Epilepticus Research Group (pSERG). Seizure 2014;23:87-97 Brooks-Kayal AR, Shumate MD, Jin H, et al. Selective changes in single cell GABA(A) receptor subunit expression and function in temporal lobe epilepsy. Nat Med 1998;4:1166-72 Swann JW, Le JT, Lee CL. Recurrent seizures and the molecular maturation of hippocampal and neocortical glutamatergic synapses. Dev Neurosci 2007;29:168-78 Rajasekaran K, Todorovic M, Kapur J. Calcium-permeable AMPA receptors are expressed in a rodent model of status epilepticus. Ann Neurol 2012;72:91-102 Crino PB, Duhaime AC, Baltuch G, White R. Differential expression of glutamate and GABA-A receptor subunit mRNA in cortical dysplasia. Neurology 2001;56:906-13 Talos DM, Kwiatkowski DJ, Cordero K, et al. Cell-specific alterations of glutamate receptor expression in tuberous sclerosis complex cortical tubers. Ann Neurol 2008;63:454-65

83.

Talos DM, Sun H, Kosaras B, et al. Altered inhibition in tuberous sclerosis and type IIb cortical dysplasia. Ann Neurol 2012;71:539-51

84.

Finardi A, Gardoni F, Bassanini S, et al. NMDA receptor composition differs among anatomically diverse malformations of cortical development. J Neuropathol Exp Neurol 2006;65:883-93

85.

Loddenkemper T, Talos DM, Cleary RT, et al. Subunit composition of glutamate and gamma-aminobutyric acid receptors in status epilepticus. Epilepsy Res 2014;108(4):605-15

86.

Parviainen I, Uusaro A, Kalviainen R, et al. High-dose thiopental in the treatment of refractory status epilepticus in intensive care unit. Neurology 2002;59:1249-51

87.

Gaspard N, Foreman B, Judd LM, et al. Intravenous ketamine for the treatment of refractory status epilepticus:


88.

Rosati A, L’Erario M, Ilvento L, et al. Efficacy and safety of ketamine in refractory status epilepticus in children. Neurology 2012;79:2355-8

89.

Mirsattari SM, Sharpe MD, Young GB. Treatment of refractory status epilepticus with inhalational anesthetic agents isoflurane and desflurane. Arch Neurol 2004;61:1254-9

90.

Nabbout R, Mazzuca M, Hubert P, et al. Efficacy of ketogenic diet in severe refractory status epilepticus initiating fever induced refractory epileptic encephalopathy in school age children (FIRES). Epilepsia 2010;51:2033-7

91.

Nam SH, Lee BL, Lee CG, et al. The role of ketogenic diet in the treatment of refractory status epilepticus. Epilepsia 2011;52:e181-4

92.

Thakur KT, Probasco JC, Hocker SE, et al. Ketogenic diet for adults in superrefractory status epilepticus. Neurology 2014;82:665-70

93.

Hamano S, Sugiyama N, Yamashita S, et al. Intravenous lidocaine for status epilepticus during childhood. Dev Med Child Neurol 2006;48:220-2

94.

Walker IA, Slovis CM. Lidocaine in the treatment of status epilepticus. Acad Emerg Med 1997;4:918-22

95.

Corry JJ, Dhar R, Murphy T, Diringer MN. Hypothermia for refractory status epilepticus. Neurocrit Care 2008;9:189-97

96.

Alexopoulos A, Lachhwani DK, Gupta A, et al. Resective surgery to treat refractory status epilepticus in children with focal epileptogenesis. Neurology 2005;64:567-70

97.

Lhatoo SD, Alexopoulos AV. The surgical treatment of status epilepticus. Epilepsia 2007;48(Suppl 8):61-5

98.

Ma X, Liporace J, O’Connor MJ, Sperling MR. Neurosurgical treatment of medically intractable status epilepticus. Epilepsy Res 2001;46:33-8

99.

Ng YT, Kerrigan JF, Rekate HL. Neurosurgical treatment of status epilepticus. J Neurosurg 2006;105:378-81

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Affiliation Ivań Sańchez Fernańdez1,2 MD & Tobias Loddenkemper†3 MD † Author for correspondence 1 Epilepsy Fellow, Boston Children’s Hospital, Harvard Medical School, Division of Epilepsy and Clinical Neurophysiology, Department of Neurology, Fegan 9, 300 Longwood Avenue, Boston, MA 02115, USA 2 Universidad de Barcelona, Hospital Sant Joan de Deu, Department of Child Neurology, Barcelona, Spain 3 Associate Professor of Neurology, Boston Children’s Hospital, Harvard Medical School, Division of Epilepsy and Clinical Neurophysiology, Department of Neurology, Fegan 9, 300 Longwood Avenue, Boston, MA 02115, USA Tel: +617 355 2443; Fax: +617 730 0463; E-mail: [email protected]. edu

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Convulsive disorders: status epilepticus.

Hypothermia for Convulsive Status Epilepticus.

Non-convulsive status epilepticus in the elderly.

Cefepime- Induced Non-Convulsive Status Epilepticus (NCSE).

Non convulsive status epilepticus masquerading as stroke.

Treatment of Generalized Convulsive Status Epilepticus in Pediatric Patients.

Grand Rounds: An Update on Convulsive Status Epilepticus.

Non-convulsive status epilepticus and non-convulsive seizures in neurological ICU patients.

A multicentre randomised controlled trial of levetiracetam versus phenytoin for convulsive status epilepticus in children (protocol): Convulsive Status Epilepticus Paediatric Trial (ConSEPT) - a PREDICT study.

Therapeutic Hypothermia for Refractory Status Epilepticus.

Ketamine in refractory convulsive status epilepticus in children avoids endotracheal intubation.

Anti-NMDA Receptor Antibody Encephalitis Presenting with Unilateral Non-convulsive Status Epilepticus in a Male Patient.

Prediction of functional outcome in patients with convulsive status epilepticus: the END-IT score.

Ictal epileptic headache revealing non convulsive status epilepticus in a case of eyelid myoclonia with absences.

Cefepime-Induced Non-Convulsive Status Epilepticus in a Patient with Normal Renal Function.

A protocol for the inhospital emergency drug management of convulsive status epilepticus in adults.

Prevalence and factors associated with convulsive status epilepticus in Africans with epilepsy.

Ictal and interictal EEG patterns in patients with nonconvulsive and subtle convulsive status epilepticus.

Convulsive status epilepticus and health-related quality of life in children with epilepsy.

Long-term survival and outcome in children admitted to kilifi district hospital with convulsive status epilepticus.

Treatment of refractory generalized convulsive status epilepticus with enteral topiramate in resource limited settings.

Refractory Convulsive Status Epilepticus in Children: Etiology, Associated Risk Factors and Outcome.

The aetiology of convulsive status epilepticus: a study of 258 cases in Western China.

Orphenadrine-induced convulsive status epilepticus in rats responds to the NMDA antagonist dizocilpine.