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Division of Epilepsy and Clinical Neurophysiology, Department of Neurology, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USAFacultad de Medicina, Universidad Austral de Chile, Valdivia, Chile
Division of Epilepsy and Clinical Neurophysiology, Department of Neurology, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USADepartment of Child Neurology, Hospital Sant Joan de Déu, Universidad de Barcelona, Spain
Prolonged seizures are associated with worse neurological outcomes.
•
As seizures continue, cellular changes may occur which drive treatment resistance.
•
Better data regarding medication optimization and novel therapies are needed.
•
Delayed treatment and use of incorrectly dosed medication are currently prevalent.
•
The time to treatment gap can be addressed with quality improvement methodologies.
Abstract
Objective
Describe basic science, animal models and clinical data related to timing of treatment in status epilepticus (SE).
Methods
We summarized the results of 15 studies that reported time to treatment in SE, and reviewed basic and clinical literature.
Results
SE is a life-threatening and time-sensitive emergency that requires immediate treatment. Current guidelines recommend escalation of anti-seizure medications (ASM) within specified time frames. Prolonged seizures may lead to changes in the composition and location of gamma-aminobutyric acid A receptors (GABAAR) and N-Methyl-d-aspartic acid receptors (NMDAR), leading to loss of inhibition and increased excitation. These biochemical changes are apparent in specific animal models having progressive resistance to benzodiazepines (BZD) with longer seizures.
Later treatments lead to decreased response to BZD, longer seizures, greater need of continuous infusions, potential brain injury and increased in-hospital mortality. Despite mounting evidence that early treatment of SE is more effective and safer, treatment and ASM escalation is often delayed compared to protocols. Literature review of 2212 patients with SE showed an average time to treatment of 42.4 min and time to hospital arrival of 56 min. Also, only 51.8% of patients received treatment by emergency medical services and 12.8% by their families, including patients with a previous diagnosis of epilepsy or with prior SE.
Conclusions
Morbidity and mortality may be avoided with rapid, effective treatment of SE. Treatment application and escalation remains delayed especially in outpatient settings, potentially leading to suboptimal outcomes. Implementation techniques and quality improvement methodologies may provide avenues for improving outcomes in SE.
Status epilepticus (SE) is one of the most common neurological emergencies in childhood and is a major cause of morbidity, mortality and economic burden [
]. Additionally, the economic burden of SE for the U.S. health care system is approximately $4 billion per year, which is higher than most other comparable emergencies (e.g. acute myocardial infarction) [
Several guidelines have been developed to improve SE management, albeit on imperfect evidence. Current SE treatment guidelines recommend a stepwise anti-seizure medication (ASM) treatment with up to 2 doses of benzodiazepines (BZD) within the first 5 to 10 min of SE onset, followed by non-BZD ASM after 10 min [
Evidence-based guideline: treatment of convulsive status epilepticus in children and adults: report of the guideline committee of the american epilepsy society.
]. An American Academy of Neurology (AAN) quality measure recommends third-line ASM should be administered within 60 min of in-hospital seizure or emergency department arrival [
]. However, these recommendations are largely based on expert opinion, lack high-quality evidence, and substantial variation exists between guidelines.
This review aims to describe basic science and clinical data underlining the importance of timing in the treatment of SE and highlights methods of improving outcomes in SE.
2. Methods
2.1 Literature search strategy
We searched the PubMed database up to January 2018 for studies in the English language with a variable combination of the following terms: “status epilepticus”, “time”, “time- to-treatment”, “anticonvulsants”, “benzodiazepines”, “reaction time”, “delay”, “epidemiology”, “emergency medical services”, “treatment delay”, “drug therapy”, “treatment failure”, “therapy”, and “therapeutics”. Subsequently, we added relevant studies not identified by our search from the reference lists of initially identified studies. Lastly, we selected studies that reported the time to initial treatment in patients with SE, or other relevant timings, such as time to emergency medical services (EMS) or hospital arrival.
2.2 Statistical analysis
Our primary outcome was the time to treatment in SE. We also analyzed drug choices and secondary outcomes, such as the presence of prehospital treatment. We used descriptive statistics available in the original manuscripts to summarize results, and calculated proportions and averages by weighting the number of patients reported by each study. As SE was defined differently depending on the study, we provide the definitions used by the authors in Table 1.
Table 1Summary of studies on time to treatment in SE.
31.7 (19 pts PHT), 59.7 (26 pts no PHT). Average 47.8
–
–
15
38–45
Retrospective
Total
–
–
–
26.0 (1770 pts)
52.4% (1062/2026)
862.9 (1871 pts), 122.8 (1340 CSE pst only)
0-50400 (all pts), 0–31995 (CSE only)
55.7% (825/1480)
–
2212–2393
–
Legend:aA median was reported instead of mean. bAn IQR was reported instead of a range.
Summary of studies on time to treatment in SE. Total percentages or averages were weighted by the number of patients reported by each study. All timings are in minutes.
SE: status epilepticus. RSE: refractory status epilepticus. N: number. LZP: lorazepam group. CSE: convulsive status epilepticus. NCSE: non-convulsive status epilepticus. RCT: randomized controlled trial. Pts: patients. ASM: anti-seizure medication. PHT: pre-hospital treatment.
*The study from Alldredge et al. (2001) was a randomized control trial with 3 treatment groups (lorazepam, clonazepam and placebo)
. To be able to compare this trial’s timing with other studies we only utilized information from the lorazepam group, which had largest patient numbers.
The definition of SE has varied over time. In 1981 the International League Against Epilepsy (ILAE) described SE as a “seizure that persists for a sufficient length of time or is repeated frequently enough that recovery between attacks does not occur” [
Proposal for revised clinical and electroencephalographic classification of epileptic seizures. From the Commission on Classification and Terminology of the International League Against Epilepsy.
]. Subsequent definitions included a time threshold of 60 min, but in 1993 the American Epilepsy Society defined a time threshold of 30 min that since then became widely used [
]. This classical SE definition with a 30 min’ cut-off reflects the loss of auto-regulatory mechanisms, metabolic decompensation, and often irreversible neuronal damage that occurs with prolonged convulsive seizures, as demonstrated in previously healthy primate models [
]. Therefore, in 2015, the ILAE updated the definition of SE to reflect these concepts with an operational definition of an initial time point (t1) when a seizure is less likely to stop spontaneously, leading to protracted seizures which may have long-term consequences after a second-time point (t2) [
]. Although BZD are effective during the early course of SE, their efficacy decreases the longer seizures persists, at least in part potentially due to diminished GABAA-mediated inhibition [
]. Two studies using in-vitro models of status epilepticus demonstrated prolonged epileptiform bursting and reduced GABAA-mediated synaptic inhibition due to GABAAR internalization after one hour [
]. Changes in neurotransmitter receptor (NTR) localization may be etiologically dependent. A recent study comparing status epilepticus in rats due to either kainic acid (KA-SE) or lithium-pilocarpine (LiPilo-SE)_demonstrated increased GABAAR internalization in the LiPilo-SE model compared to the KA-SE animals, in addition to differential surface expression of Kv4.2 potassium channels [
Fig. 1Changes in neurotransmitter receptor concentrations at baseline and during prolonged seizures. A. At baseline, GABA (inhibitory) neurotransmission predominates over NMDA (excitatory) neurotransmission. B. During seizures, GABA receptors are internalized and NMDA receptors accumulate in the postsynaptic membrane. These changes favor self-sustaining seizures and resistance to antiepileptic drugs with a GABAergic mechanism, like benzodiazepines.
]. N-Methyl-d-aspartic acid receptors (NMDAR) facilitate neuronal depolarization in the presence of glutamate through a cellular influx of cations. Prolonged seizures induce NMDAR to move from the cell interior to the synaptic and extra-synaptic cell wall sites, increasing neuronal excitability [
] (Fig. 1). Furthermore, NMDAR activation may indirectly lead to GABA resistance through an increase in intracellular Ca2, which activates the phosphatase calcineurin, leading to a decrease in the number of GABAARs in the soma [
]. This mechanism was reinforced by another study where pretreatment with phosphatase inhibitors maintained the expression of the GABAAR γ2 subunit in SE slices similar to controls due to an increase in receptor stability [
]. Calcineurin and other phosphatases may therefore act as mediators of BZD resistance in prolonged seizures, and could be a potential target for treatment in SE [
While GABAA and NMDA NTR relocate during SE, the subunit composition of several NTR may also change during prolonged seizures. Sustained or repeated epileptiform activity modifies the subunit composition of GABAA and glutamate receptors, mimicking subunit compositions of the immature brain [
]. In the rapidly developing brain of newborns, infants, and small children, neuronal excitation predominates over inhibition and facilitates learning [
]. However, an imbalance towards hyperexcitability also makes the immature brain more susceptible to seizures and epileptogenesis, similar to later stages of SE in older children and adults [
Studies on changes in human NTR subunit composition have been possible through the use of samples collected during epilepsy surgery or autopsy. They have revealed GABA and glutamate receptor subunit composition similar to immature brains and animal models of SE: increased alpha2/alpha1 ratio in GABAR, increased NMDAR GluN2B/GluN2A ratio, and increased alpha-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid receptor (AMPAR) GluA1/GluA2 ratio [
]. These findings suggest a common pathway of response to chronic epileptiform activity, although it is currently unknown whether these changes in subunit composition occur in acute SE.
Molecular mechanisms may in part explain why synaptic GABAergic agonist ASM lose efficacy early during SE [
]. In the future, a better understanding of the molecular changes during prolonged seizures may allow targeting specific molecules during SE treatment [
]. During the early seizure presentation, a crucial time window for optimal BZD effects exists. After seizures become more refractory to BZDs, a rapid switch to other second and third line treatments is necessary [
]. In a rat model of SE, all animals responded to diazepam administered within 5 min from seizure onset and rarely when treatment was given after 15 min [
]. In contrast, a comparative study of KA-SE and LiPilo-SE in a rat model of SE demonstrated preserved efficacy of BZD after 3 h in the KA-SE model where GABAR surface expression was preserved compared to the LiPilo-SE animals, which developed BZD resistance associated with decreased surface expression of GABAR [
]. These animal models support the development of progressive pharmaco-resistance with longer seizures duration, which may be etiologically-dependent.
But what are the consequences of longer seizures? In 1973, a study on previously healthy monkeys observed physiological changes during SE and described loss of auto-regulatory mechanisms and metabolic decompensation in the later phases of SE [
]. Rats that underwent kainic acid-induced SE during early development demonstrated impairment in short- and long-term spatial learning at all ages and increased anxiety compared to controls [
]. In a kainate seizure model, older rats (postnatal day 45) suffered more extensive neuronal injury and demonstrated decreased spatial learning performance if they had a history of seizures induced as young pups (postnatal day 15) [
]. In a series of 182 children with SE, lack of prehospital treatment and more than two doses of BZD were associated with SE episodes lasting longer than 60 min [
]. For every minute of delay from CSE onset to the arrival at the emergency department, there was a 5% cumulative increase in risk of having a SE episode that lasted longer than one hour [
]. Intervention less than 30 min from seizure onset was associated with an 80% response to first-line medications. In comparison, less than 40% responded when treated after 2 h [
]. Jointly, these studies support the notion that prompt treatment may improve response.
If we treat patients more rapidly, SE episodes are shorter. But does earlier treatment improve SE outcomes? A recent multicenter study of 218 patients with refractory SE demonstrated an independent association between an untimely first BZD (administered after 10 min) and in-hospital mortality after adjusting for confounders [
]. Untimely treatment was also associated with a greater need of continuous infusions, longer convulsive seizure duration and more frequent hypotension [
A different study also highlighted the significance of workflow delay. In this study of 70 adults, univariate analysis showed an association between delays in diagnosis, time to second-line medication, time to consciousness and long anesthetic treatments with negative cognitive outcomes (GOS score <3) [
]. Although multivariate analysis did not identify an independent predictor of outcome, the authors hypothesized the accumulation of different delays in this treatment chain may be influencing outcomes [
]. In a different study including 100 adults, a good recovery (defined as no significant disability in a modified Rankin Scale) occurred in 82% of patients treated within 1 h of seizure onset, and in 46% of patients treated after 1 h [
Prolonged SE is more common in the presence of treatment delays and increases morbidity and mortality. In a series of 228 adult and pediatric patients, patients with seizures lasting longer than 30 min had a mortality of 19%, compared with 3% mortality in patients with seizures lasting 10 to 29 min [
]. Another series of 184 adults and children demonstrated that patients with SE lasting longer than 24 h had increased mortality compared to patients with episodes of less than 2 h [
]. Further, biomarkers provide evidence of brain injury in prolonged seizures. Levels of serum neuron-specific enolase, a marker of acute brain injury and blood-brain barrier dysfunction [
]. Prehospital therapy significantly shortened duration of SE (32 min vs 60 min) and reduced the seizure recurrence rate (58% vs 85%) in children who received diazepam compared to children untreated in the prehospital setting [
]. Seven focused on children, seven on adults, and one on both. These studies reported a total of 2212 patients, with a mean age of 26 years, and 52.4% of males. Fifty-six percent of patients had refractory SE, 43.3% (802/1854) of patients had a prior epilepsy diagnosis and 22.2% (151/681) had prior SE episodes.
The mean of all reported SE durations was 862.9 min (when considering a total of 1871 reported patients) and 122.8 min, when considering 1340 patients with convulsive SE only. Although these studies encompassed different patient populations and designs, we summarized main results to provide an overview on the timing in SE treatment (Table 2). The median time to the first ASM reported by ten studies and 1134 patients was 42.4 min, and 40.2 min when considering 902 patients who only had CSE. The mean time from SE onset to EMS arrival was 22 min (427 patients); and the mean time from SE to hospital arrival was 56 min (1391 patients). Two studies also reported mean time from in-hospital SE onset to treatment, with overlapping populations, with a total of 8 min (IQR 4–24) [
]. In 86% (1182/1374) of cases, BZD was the first choice when treating SE (Table 3), and diazepam was the most commonly administered drug in the pre-hospital setting [57.6% (624/1083)], followed by lorazepam [34.4% (181/526)].
Table 2Time in the treatment of SE.
Author
Year
SE type
Time to first treatment
Prehospital time to first treatment
Epilepsy history
SE history
Time to EMS arrival
Time to hospital arrival
Median
Range
Median (range)
%
%
Mean
Range
Mean
Range
Gaínza-Lein, et al.
2018
CSE
17 (218 pts)
5–45b
25 (10–60)b (139 pts)
51.4% (112/218)
21.6% (47/218)
16 (63 pts)
10–25b
45a (106 pts)
30–80b
Kamppi et al.
2018
CSE
30 (67 pts)
0−485
–
65.7% (46/70)
–
–
–
145a (70 pts)
37–16660c
Cheng
2016
CSE (97 pts) NCSE (54 pts)
60 (151 pts)
0–10080
–
33% (49/149)
–
–
–
–
–
Sánchez Fernández et al.
2015
CSE
28 (81 pts)
6–67
30 (12–60)b (64 pts)
46.9% (38/81)
17.3% (14/81)
49.4 (26 pts)
2–875
81.8 (50 pts)
11–920
Alvarez et al.
2015
CSE (168) NCSE (9 pts)
45 (99 CSE pts)
5–2880 (99 CSE pts)
–
–
–
–
–
–
–
Seinfeld et al.
2014
Febrile SE
30 (161 pts)
1–175
22.3 (12.5 min + 9.8 min) (161 pts)
–
–
20 (161 pts)
0–95
38 (161 pts)
0–239
Kamppi et al.
2013
CSE (74 pts) NCSE (8 pts)
35 (81 pts)
0−4625
–
62.2% (51/82)
–
9 (68 pts)
0−45
69 (68 pts)
10–182
Hillman et al.
2013
CSE
70a (109 pts)
–
70a (109 pts)
43% (47/109)
32% (35/109)
30a (109 pts)
–
105a (109 pts)
–
Aranda et al.
2010
CSE (101) NCSE (17)
90 (101 CSE pts)
50–187
–
60% (61/101)
19% (19/101)
–
–
–
–
Lewena et al.
2009
CSE
–
–
–
35% (190/542)
–
–
–
45a (542 pts)
3–3960
Chin et al.
2008
CSE
–
–
–
24% (44/182)
–
–
–
39a (182 pts)
5–514
Lewena et al.
2006
CSE
–
–
–
65%d (24/37)
–
–
–
48 (37 pts)
–
Alldredge et al. (LZP)
2001
CSE
34 (mean) (66 pts)
17.8 (SD)
–
54.6%d (36/66)
–
–
–
50.2 (66 pts)
–
Coeytaux et al.
2000
CSE NCSE
–
–
–
42.4% (74/172)
20.9% (36/172)
–
–
–
–
Alldredge et al.
1995
CSE
–
–
–
66.7% (30/45)d
–
–
–
–
–
Total
–
–
42.4 (1134 all pts), 40.2 (902 CSE pts)
0-10080 (all pts), 0–485 (CSE pts)
35.1 (473 CSE pts)
43.3% (802/1854)
22.2% (151/681)
22.0 (427 pts)
0−875
56.0 (1391 pts)
0−16660
Legend: Time to treatment reported in different studies on SE. Total percentages or averages were weighted by the number of patients reported by each study. All timings are in minutes. aA median was reported instead of mean. bAn IQR was reported instead of a range. c time to tertiary hospital. d prior seizures.
SE: status epilepticus. SE: status epilepticus. LZP: lorazepam group. EMS: emergency medical services. Pts: patients. CSE: convulsive status epilepticus. NCSE: non-convulsive status epilepticus.
Table 3Drug administration in the pre-hospital setting.
Author
Year
Prehospital treatment
First line drug choices
Drug by EMS%
Drug by family%
Pts with prior SE treated by family%
Any BZD
DZP
LZP
MDZ
CLZ
Kamppi et al.
2018
87.1% (61/70)
–
–
98.6% (69/70)
80% (56/70)
18.6% (13/70)
0% (0/70)
0% (0/70)
Sánchez Fernández et al.
2015
35.9% (23/64)
9.4% (6/64)
33.3% (3/9)
96.3% (78/81)
–
–
–
–
Alvarez et al.
2015
–
–
–
74.5% (177/238)
–
46.3% (82/177)
13.0% (23/177)
40.6% (72/177)
Seinfeld et al.
2014
41% (73/179)
1% (2/179)
–
96.1% (172/179)
46.4% (83/179)
46.4% (83/179)
3.4% (6/179)
–
Kamppi et al.
2013
91.5% (75/82)
–
–
96.3% (78/82)
–
–
–
–
Aranda et al.
2010
71% (66/93)
–
–
60% (60/100)
26% (26/100)
3% (3/100)
0% (0/100)
31% (31/100)
Lewena et al.
2009
48% (260/542)
–
–
94% (510/542)
55% (299/542)
–
39% (211/542)
–
Chin et al.
2008
38.8% (93/240)
22.5% (54/240)
72.9% (35/48)
–
96% (141/147)
–
–
–
Lewena et al.
2006
51% (19/37)
–
–
51% (19/37)
–
–
–
–
Coeytaux et al.
2000
58.7% (101/172)
–
–
–
–
–
–
–
Alldredge et al.
1995
42.2% (19/45)
–
–
42.2% (19/45)
42.2% (19/45)
–
–
–
Total
–
51.8% (790/1524)
12.8% (62/483)
66.7% (38/57)
86.0% (1182/1374)
57.6% (624/1083)
34.4% (181/526)
22.5% (240/1068)
29.7% (103/347)
Legend: only studies with available information (complete or partial) on the pre-hospital drug administration in patients with SE were included in this table. Total percentages were weighted by the number of patients reported by each study.
SE: status epilepticus. EMS: emergency medical services. BZD: benzodiazepine drug. DZP: diazepam. LZP: lorazepam. MDZ: midazolam. CLZ: clonazepam.
These data reveal prehospital treatment occurred often later than commonly recommended, and delays were multifactorial. First, the time from SE onset to EMS arrival exceeds the time interval recommended for first line BZD administration (Table 2). Second, prehospital treatment was not ubiquitous, even when considering patients with a previous diagnosis of epilepsy or with prior SE episodes. Among patients treated in the prehospital setting, 12.8% (62/483) were treated by their families, and 51.8% (790/1524) were treated by EMS. Furthermore, 66.7% (38/57) of patients with prior SE episodes were treated by their families (Table 3).
6.2 Timing of prehospital status epilepticus treatment
Many patients did not receive any pre-hospital treatment, despite its association with improved outcomes. Prehospital treatment is associated with shorter SE duration [
]. Additionally, initial ASM administration was delayed compared to recommendations. Patients with a prior diagnosis of epilepsy received the first non-BZD ASM later than patients without prior diagnosis [
]. Also, patients with a prior history of SE received an earlier first BZD, and having an intermittent RSE was associated with delays in the second line treatment [
Although data support prehospital treatment, administration may be challenging. Family members or caregivers may not have had education on how to administer rescue medications or may not feel confident about application of medication. A survey of 100 families of patients with epilepsy revealed most of them (87%) had a rescue medication prescription but only 61% reported receiving training on how to use it [
]. Prehospital administration of BZD may also intermittently be overlooked during ASM escalation after hospital arrival, as patients repeateadly tend to receive BZDs at the hospital that had already failed [
], suggesting lack of hand offs or care coordination between the out-of-hospital and in-hospital treatment. The route of drug administration may also influence time to treatment. For example, the time to administration of intravenous BZD was longer than the time needed to administer rectal BZD [
]. In a randomized clinical trial, the median time to administer intramuscular midazolam was 1.2 min vs 4.8 min in the intravenous lorazepam group, and was similar in terms of safety and efficacy [
We highlight several areas of opporunity to improve SE time to treatment and outcomes.
7.1 ASM choices
Current SE treatment algorithms recommend a stepwise approach with BZD, a second-line IV antiseizure medication such as phenytoin, phenobarbital, levetiracetam or valproic acid, and eventually anesthetic therapies [
Evidence-based guideline: treatment of convulsive status epilepticus in children and adults: report of the guideline committee of the american epilepsy society.
Evidence-based guideline: treatment of convulsive status epilepticus in children and adults: report of the guideline committee of the american epilepsy society.
]. Only the first line treatment with BZD is supported by high-level evidence, with no strong evidence for second and third line treatment strategies [
Evidence-based guideline: treatment of convulsive status epilepticus in children and adults: report of the guideline committee of the american epilepsy society.
]. Phenytoin and phenobarbital have been available for much longer than any new ASM and therefore, have a larger body of literature on their efficacy. However, a meta-analysis that compared phenytoin, phenobarbital, valproate, and levetiracetam in SE treatment yielded the following efficacy rates: phenytoin 50% (95% CI: 43%-66%), phenobarbital 74% (95% CI: 58%-85%), valproate 76% (95% CI: 64%-85%), and levetiracetam 69% (95% CI: 56%-79%) [
The relative effectiveness of five antiepileptic drugs in treatment of benzodiazepine-resistant convulsive status epilepticus: a meta-analysis of published studies.
]. Therefore, large randomized trials comparing the efficacy of non-benzodiazepine ASM are urgently needed. Several multicenter studies are currently underway to examine second-line ASM. The Established Status Epilepticus Treatment Trial (ESETT) is in the process of comparing valproate, levetiracetam, and phenytoin (or fosphenytoin) for the treatment of SE refractory to BZD, although final data are not yet available [
The relative effectiveness of five antiepileptic drugs in treatment of benzodiazepine-resistant convulsive status epilepticus: a meta-analysis of published studies.
]. The TRENdS trial delivered preliminary demographic and enrollment data on the comparison between lacosamide and fosphenytoin, although efficacy data have not been reported [
Emergency treatment with levetiracetam or phenytoin in status epilepticus in children-the EcLiPSE study: study protocol for a randomised controlled trial.
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.
Gaps and opportunities in refractory status epilepticus research in children: a multi-center approach by the Pediatric Status Epilepticus Research Group (pSERG).
]. We anticipate these studies will soon provide higher level evidence for medical management steps of SE.
7.2 Early polytherapy
The recommended treatment of SE follows a stepwise approach: a new ASM is tried after the prior ASM has failed to stop seizures, partially to minimize adverse effects of ASM. However, morbidity and mortality in SE are high and the risks associated with ongoing SE may be greater than the risks associated with overtreatment [
]. Catch-up dosing or combined dosing of first and second line medications may be considered during delayed initial therapy due to the increased likelihood of treatment resistance.
7.3 Targeted therapies
ASM management for established SE may be guided by insight into the physiologic changes in NTR during prolonged seizures described earlier (Fig. 1). These mechanisms may partially explain why some animal models become more resistant to BZD, phenytoin, and phenobarbital [
Another potential target for SE treatment that works through both synaptic and extrasynaptic GABAA receptors is allopregnanolone, a neuroactive steroid derived from progesterone [
Other treatments are under investigation to treat SE, including flupirtine, a potassium channel modulator that facilitates GABAAR function. In one study, three rodent models of SE were used to evaluate flupirtine effectiveness: induced by administration of lithium and pilocarpine, by electrical stimulation of the hippocampus or by diisopropylfluorophosphate [
]. SE was controlled within 60 min by the combination flupirtine and diazepam in the 3 models, shortening the duration of the SE. This provides evidence that SE is terminated faster with a combination of synergistic drugs [
Neurosteroids and flupirtine represent ASM candidates under current study, among many others, and we anticipate more future candidates based on the increasing utilization of genetic anlysis. Seizures stop spontaneously in most patients, and may continue in few patients [
], suggesting that there may be a genetic predisposition to prolonged seizures. If the mechanism leading to seizure termination is elucidated, it is reasonable to speculate that treatments targeting this pathway may reduce seizure duration. This may prove a promising pathway to an era of personalized medicine for SE.
7.4 Quality improvement
While ASM choice may affect SE treatment efficacy, it is possible that changes in second-line treatment trials to date may have been confounded by time to treatment. Delays in ASM administration are frequent in published series [
]. A recent AAN quality measure has indentified third-line ASM administration within 60 min of in-hospital seizure or emergency department arrival as a method for improving care in SE [
]. These areas provide opportunities for improving outcomes in SE.
Seizure diagnosis and pre-hospital treatment are often delayed. Seizure detection devices may help identify seizures early and, in the future, may, to a certain extent, even operate as closed-loop treatment systems [
]. Furthremore, education of families and EMS on the importance of early treatment may help increase the proportion of patients who receive treatment in the prehospital setting [
]. A study on 100 families of patients with epilepsy showed that families who had a seizure action plan were more knowledgeable about the rescue medication indications, and the schools were also more involved [
]. The concept that convulsive SE is a life-threatening, time-sensitive emergency may require further education of patients, families, care providers and of additional stake holders, such as schools and EMS.
Additionally, further measures of care coordination and integration at crucial times of care hand off, such as between the in-patient and outpatient setting, and more rigorous implementation of current care knowledge through implementation research methodology may provide further improvements [
]. Epileptologists may learn from stroke specialists and related health care system improvements, that, in convulsive status epilepticus, ‘time is brain’, too.
Finally, quality improvement methodologies within the hospital setting could improve the adherence to guidelines and protocols [
]. Preliminary data from a study using quality improvement methodologies demonstrated a significant reduction in critical care utilization and hospital charges after improving the proportion of patients with SE who were treated with a BZD in less than 10 min [
]. The study focused on several areas of intervention, including more rapid initial assessment, utilizing non-IV BZD formulations and other process improvements [
SE is a life-threatening and time-sensitive emergency that requires immediate treatment. Multiple physiological changes make prolonged seizures more difficult to treat with increasing duration. While treatment guidelines have been established, the evidence on which they are founded remains lower quality, and several well-designed studies are underway to fill this particular knowledge gap. In the future, treatments targeting specific molecular changes during prolonged seizures may further improve efficacy.
While optimization of ASM choices is desirable, the most important gap in SE treatment is time to treatment administration. Literature review of 15 studies reporting 2212 patients with SE showed an average time to treatment of 42.4 min and time to hospital arrival of 56 min. Also, only 51.8% of patients received treatment by EMS and 12.8% by their families. Methods of improving these deficiencies include improved education, care coordination, implementation research, early seizure detection and rapid ASM delivery. Quality improvement methodologies may provide an avenue for addressing these areas and improving outcomes in SE.
Author contributions
Marina Gaínza-Lein participated in study design, performed the literature search, literature revision and interpretation, drafted the manuscript, reviewed, and edited for important intellectual content.
Iván Sánchez Fernández participated in study design, participated in the interpretation of data in the literature, reviewed, and edited the manuscript for important intellectual content.
Adriana Ulate-Campos participated in the interpretation of data in the literature, reviewed, and edited the manuscript for important intellectual content.
Tobias Loddenkemper participated in the interpretation of data in the literature, reviewed, and edited the manuscript for important intellectual content.
Adam P. Ostendorf participated in the interpretation of data in the literature, reviewed, and edited the manuscript for important intellectual content.
Acknowledgements
This study was funded by the Epilepsy Research Fund.
Marina Gaínza-Lein was funded by the Epilepsy Research Fund.
Iván Sánchez Fernández was funded by Fundación Alfonso Martín Escudero and the HHV6 Foundation and is funded by the Epilepsy Research Fund.
Tobias Loddenkemper reported serving on the Laboratory Accreditation Board for Long Term (Epilepsy and Intensive Care Unit) Monitoring, on the council of the American Clinical Neurophysiology Society (as treasurer), and on the American Board of Clinical Neurophysiology; being an associate editor for Seizure, a contributing editor for Epilepsy Currents, and an associate editor for Wyllie’s Treatment of Epilepsy, 6th edition; being part of pending patent applications to detect and predict seizures and to diagnose epilepsy; receiving research support from the Epilepsy Research Fund, the American Epilepsy Society, the Epilepsy Foundation of America, the Epilepsy Therapy Project, the Patient-Centered Outcomes Research Institute, the Pediatric Epilepsy Research Foundation, CURE, and the HHV-6 Foundation as well as research grants from Lundbeck, Eisai, Upsher-Smith, Acorda, and Pfizer; serving as a consultant for Zogenix, Upsher-Smith, and Lundbeck; and receiving speaker honorariums from national societies, including the American Academy of Neurology, American Epilepsy Society, and American Clinical Neurophysiology Society.
Adam P. Ostendorf receives research grants from GW Pharmaceuticals and the Pediatric Epilepsy Research Foundation.
Evidence-based guideline: treatment of convulsive status epilepticus in children and adults: report of the guideline committee of the american epilepsy society.
Proposal for revised clinical and electroencephalographic classification of epileptic seizures. From the Commission on Classification and Terminology of the International League Against Epilepsy.
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