Terapeutica de Convulsiones

1. Introduction

2. Time to treatment in SE

3. Treatment choices in SE

4. Conclusion

5. Expert opinion

Review

Therapeutic choices in convulsivestatus epilepticusIvan Sanchez Fernandez & Tobias Loddenkemper†

†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. Benzodiaze-

pines that do not require intravenous administration like intranasal midazo-

lam or intramuscular midazolam are becoming more popular because of

easier administration in the field. Other benzodiazepines may also be effec-

tive. 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 fos-

phenytoin and phenobarbital, have a faster infusion time and better pharma-

cokinetic 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 ben-

zodiazepine 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. Addi-

tionally, 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 convul-sive status epilepticus (SE) during their professional lives and will be expected toprovide at least initial management to these patients. Convulsive SE is associatedwith a high burden of morbidity and mortality and an appropriate early treatmentis the main factor which can improve outcome and minimize cognitive and medicalcomplications.

In this review we summarize the main treatment strategies for convulsive SE withan emphasis on first-line treatments. The importance of an early treatment and atimely switch between antiepileptic drugs (AEDs) with different mechanisms ofaction is underlined. This review will not discuss non-convulsive SE, and for thepurposes 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 chil-dren. Incidence of SE is ~ 3.5 -- 12.5/100,000 and follows a ‘U’ distribution inwhich the highest incidence occurs in children < 10 years (14.3/100,000) and inadults > 50 years (28.4/100,000) [1]. SE-associated mortality is ~ 7 -- 22% in the

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short term (in-hospital or within 30 days of SE) and as high as43% in the long-term (within 10 years following initial sur-vival 30 days after SE) [2]. Mortality is lowest in childrenwith a short-term mortality of 3 -- 9%, and a long-term mor-tality 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 inthe elderly probably includes a significant proportion ofdeaths unrelated to SE) [2]. More recent series report even alower short-term mortality rate of 0 -- 3% in children [3-9].Both children and adults who survive SE present a significantburden of subsequent epilepsy, cognitive and behavioralsequelae [7,10].

2. Time to treatment in SE

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

less likely to spontaneously stop [11,12] and meet the definitionof ‘impending’ SE. At present, both duration thresholds coex-ist in the literature. The 5-min threshold is useful from anoperational point of view as it marks the point where seizureswill probably not stop unless actively treated. It is currentlyunknown whether defining SE as seizures that last for 5 or30 min identifies different patient populations with differentelectroclinical characteristics. A large series compared 226patients (91 children and 135 adults) with seizure durationof ‡ 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 withouttreatment (7 vs 43%) and a higher mortality rate (19 vs2.6%) [13]. Other characteristics were similar in the twogroups [13]. A recent study compared 149 children with seiz-ures of ‡ 30 min with 296 children with seizures of5 -- 29 min duration [14]. The group of patients with seizuresof ‡ 30 min was younger at the time of seizure onset but therewere no differences in seizure frequency, seizure types,presence of developmental delay and electroencephalogramabnormalities at baseline [14]. Mortality in this cohort incre-ased with seizure duration [14]. In a larger series of 1062patients from the same cohort, risk factors for SE were similarwhen using a 5- or a 30-min threshold [15]. Together, theseresults suggest that both thresholds identify very similar pop-ulations, although mortality is higher in patients with moreprolonged seizures.

2.2 Rationale behind the need for a rapid treatmentThere are three major known factors that determine prognosisin SE: age, etiology and SE duration [6,7,16,17]. Age is a non-modifiable factor and etiology may or may be modifiable ortreatable. In contrast, SE duration can be potentially modifiedwith an appropriate treatment administered in a timely fashion.

Current guidelines and protocols for the treatment of SErecommend a rapid administration of AEDs. This recommen-dation is based on results from basic and clinical research.Animal models of SE have demonstrated that prolonged seiz-ures per se cause brain damage [18]. In addition, several clinicalstudies have shown that more prolonged seizures are associ-ated with a worse outcome. In a series of 45 episodes of gen-eralized SE in children, the duration of SE was shorter (32 vs60 min) and the risk of recurrent seizures was lower (58 vs85%) in the 19 episodes treated with pre-hospital diazepamthan in the 26 episodes without pre-hospital treatment [19].In a study of 182 children with convulsive SE, for each min-ute delay from seizure onset to arrival at the emergencydepartment there was a 5% cumulative increase in the riskof SE lasting > 60 min [20]. In a series of 157 children withSE, a delay of > 30 min in administering the first AED wasassociated with worse response to treatment (time from theinitiation of the treatment to the end of the clinical seizureactivity) [21]. Another study reported 27 children, and first-line (benzodiazepine) and second-line (phenytoin or pheno-barbital) medications were effective in terminating SE in

Article highlights.

. Convulsive status epilepticus (SE) is a life-threateningemergency which requires immediate treatment asappropriate and rapid treatment may improve theoutcome and reduce the cognitive andmedical sequelae.

. The currently established first-line treatment forconvulsive SE is intravenous lorazepam. Non-intravenousfirst-line choices such as rectal diazepam, nasalmidazolam or intramuscular midazolam havedemonstrated similar efficacy and safety and are easierto administer in the field.

. After failure of one or two doses of benzodiazepines, arapid therapeutic escalation to non-benzodiazepineantiepileptic drugs (AEDs) is recommended.

. The most commonly used non-benzodiazepine AEDs arephenytoin (or fosphenytoin) and phenobarbital. Theefficacy and safety of other non-benzodiazepine AEDssuch as valproate or levetiracetam may be noninferior tophenytoin/fosphenytoin and phenobarbital and thesedrugs have a faster infusion time and a betterpharmacokinetic profile.

. When SE is resistant to benzodiazepines and non-benzodiazepine AEDs, continuous infusions of AEDs oranesthetics are usually tried. Midazolam, propofol andpentobarbital are the most commonly usedinitial infusions.

. Other therapies like ketamine infusion, immunotherapy,ketogenic diet, epilepsy surgery or hypothermia may beconsidered in cases of super-refractory SE after failure ofpreviously outlined therapies.

This box summarizes key points contained in the article.

I. Sanchez Fernandez & T. Loddenkemper

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

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86% when seizure duration was < 20 min at presentation andonly in 15% when seizure duration exceeded 30 min [22]. Asin children, in adults, a correlation between longer durationand worse prognosis has also been found in several studies.In a series of 66 adults with generalized tonic-clonic SE, majordeterminants of death were age, longer duration of SE beforeinitiation of treatment and CNS etiology [23]. Among 253adults with SE, those with SE duration < 1 h had a lower mor-tality than patients with SE duration ‡ 1 h (2.7 vs 32% after1 month of follow up) [24]. Furthermore, a series of 118 epi-sodes of generalized convulsive SE in 111 adults showedthat patients who received out-of-hospital treatment hadshorter SE duration [25]. Together, these results suggest thatan early and appropriate treatment may markedly reduce theduration of SE and likely improve the outcome.

2.3 Changes of neurotransmitter receptors in the

seizing brainChanges in neurotransmitter receptors explain the tendencyof seizures to become self-sustained and progressively moretreatment-resistant with increasing seizure duration.

Changes in the subunit composition of AMPA, NMDA andGABA receptors in the seizing brain promote self-sustainingseizures (Table 1) [26].

In addition, when the brain is exposed to prolonged seiz-ures, there is a rapid decrease in the number of functionalpostsynaptic GABAA receptors [27,28] and an increase in thenumber of functional postsynaptic NMDA receptors [29].This loss of inhibition and increase in excitation in the brainsynapses promote self-sustaining prolonged seizures (Figure 1).Furthermore, it may explain the loss of efficacy of benzodiaze-pines over time in animal models of SE [30] and the progres-sive pharmacoresistance to benzodiazepines with prolongedSE [21,22].

2.4 Delays in treatment administrationCompared with the vast number of series on efficacy of differ-ent AEDs, the topic of delays in AED administration in SEhas been studied less frequently. There are only a few studieson the topic of time from seizure onset to treatment adminis-tration. In a retrospective multicenter study of 542 episodes ofconvulsive seizure of ‡ 10-min duration in children, themedian (p25 -- p75) time from hospital arrival until adminis-tration of a non-benzodiazepine AED was 24 (15 -- 36)min [31]. In a retrospective study of 889 patients (625 adultsand 264 children) with SE, ~ 60% of patients received theirfirst AED after 30 min and ~ 25% after 60 min [32]. In a seriesof 199 children with febrile SE, the median time from seizureonset to administration of the first AED was 30 min [33].Among 82 adults with SE, the time elapsed since seizure onsetto administration of the first medication was 35 min, and themedian time from seizure onset to administration of non-benzodiazepine AED was 180 min [34]. A recent series of81 children with refractory convulsive SE specifically studied

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

3. Treatment choices in SE

3.1 Overview of treatment protocolsMost current SE protocols recommend a stepwise approach.The first step in the treatment of SE, as an emergency situa-tion, is to secure the airway, ensure adequate breathing andcirculation. Most seizures resolve spontaneously in < 5 min.However, when seizures last ‡ 5 min, they should be consid-ered as impending SE and treatment should be initiatedimmediately [36-38]. Benzodiazepines are the first-line treat-ment and intravenous lorazepam is frequently the preferredoption. When an intravenous line is not available, intramus-cular, rectal, intranasal or buccal medication applications arepotential alternatives. The first dose of benzodiazepines canbe repeated if seizures have lasted for < 10 min. However, asdiscussed above, seizures progressively become more refrac-tory to treatment. After 10 min of seizures it is recommendedto switch to non-benzodiazepine AEDs. Among those, themost commonly used is intravenous fosphenytoin (or phenyt-oin). If seizures do not stop, another non-benzodiazepineAED is recommended, with phenobarbital as the preferredoption. Other popular non-benzodiazepine AEDs are medica-tions that can also be applied intravenously, such as valproateand levetiracetam. However, once these two appropriate dosesof non-benzodiazepine AEDs have been administered and/orseizure duration is longer than 30 -- 60 min, then initiationof continuous infusions/anesthetic therapy is recommended(Figure 2).

3.2 Evidence supporting benzodiazepines as a

first-line treatmentIn a double-blind trial, 205 adults with out-of-hospital seiz-ures of at least 5 min duration were randomized to receiveeither intravenous lorazepam, intravenous diazepam or pla-cebo [39]. SE had been terminated on arrival at the emergencydepartment in more patients treated with lorazepam (59%) ordiazepam (43%) (not statistically significant differences intheir efficacy) than in patients treated with placebo(21%) [39]. The rates of respiratory or circulatory complica-tions 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 benzo-diazepines was more effective and even safer than not treating

Therapeutic choices in convulsive status epilepticus

Expert Opin. Pharmacother. (2014) 16(4) 3

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Table

1.Subunit

compositionofglutamate

andGABA

receptors

intheseizingbrain.

Authorandyear

Studydesign

Substudyfeatures

(ifapplicable)

AMPA

NMDA

GABA

Anim

almodelsofseizuresandSE

Brooks-Kayaletal.

(1998)[78]

Rats

withpilocarpine-inducedSEandsubsequent

developmentofspontaneoustemporallobe

seizures(comparedto

controlrats)

Hippocampus

24hafterSE

a1#*

a3"*

a4"*

a1/nona1

#*b1

#*b3

"*d"

*""*

1--4monthsafterSEandwith

spontaneoustemporallobe

seizures

a1#*

a4"*

a1/nona1

#*d"

*""*

b1#*

b3"*

Swannetal.(2007)[79]

Rats

withtetanustoxin-orflurothyl-induced

seizures(comparedto

controlrats)

Tetanustoxin-inducedseizures

atp10in

hippocampus

GluN1#

GluN2A

#GluN2B#

Flurothyl-inducedseizuresin

hippocampus

GluN2A

#

Flurothyl-inducedseizuresin

neocortex

GluN2A

#

Rajasekaranetal.

(2012)[80]

Rats

withpilocarpine-inducedSE(comparedto

controlrats)

GluA2surface

expression#

Data

from

epilepsy

surgery

perform

edforrefractory

epilepsy

Crinoetal.(2001)[81]

Individualneuronsfrom

dysplastic

tissuefrom

epilepsy

surgery

(comparedto

non-dysplastic

tissuefrom

epilepticpatients

andto

autopsy

specimensfrom

patients

whodiedfrom

non-

neurologicalcauses).Temporalneocortexand

dorsolateralfrontalneocortex

Dysplastic

neurons

GluA1#*

GluA4"*

GluN2A

#*GluN2B"*

GluN2C

"*

a1#*

a2#*

b1#*

b2#*

Heterotopic

neurons

GluA1#*

a1#*

a2#*

b2#*

Talosetal.(2008)[82]

Patients

withtuberoussclerosiscomplexand

epilepsy

whounderw

entepilepsy

surgery

(comparedto

patients

withepilepsy

without

Tissuefrom

tubers

GluA1"

GluA4"

GluA2#

GluA3#

GluN2B"

GluN3A

"

"Increased.

#Decreased.

Reproducedwithperm

ission

[26].

*RNA

studies.

EPI:Refractory

epilepsy;ESES:Electricalstatusepilepticusin

sleep;SE:Statusepilepticus.



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Table

1.Subunit

compositionofglutamate

andGABA

receptors

intheseizingbrain

(continued).

Authorandyear

Studydesign

Substudyfeatures

(ifapplicable)

AMPA

NMDA

GABA

tuberoussclerosisandto

autopsy

caseswithout

neurologicaldiseases)

Cortexfrom

epilepticpatients

withouttuberoussclerosis

GluA1"

GluA2#

GluN2B"

GluN3A

"Talosetal.(2012)[83]

Patients

withtuberoussclerosiscomplexand

epilepsy

whounderw

entepilepsy

surgery

or

whose

tissueswere

collectedatautopsy

and

patients

withfocalcorticaldysplasiaandepilepsy

whounderw

entepilepsy

surgery

toresect

the

epileptogenic

tissue(comparedto

autopsy

cases

withoutneurologicaldiseases)

Tubers

a1#

a4/a1"

FocalcorticaldysplasiaIIa

a4#

a4/a1#

FocalcorticaldysplasiaIIb

a1#

a4/a1"

Finardietal.(2006)[84]

Patients

withmalform

ationsofcortical

developmentundergoingepilepsy

surgery

because

ofrefractory

epilepsy

(comparedto

patients

withfocalepilepsy

withoutunderlying

malform

ationandto

non-epilepticpatients’

brain

tissueresectednext

toatumor)

Focalcorticaldysplasia

GluN2B"

Periventricularnodular

heterotopia

GluN1#

GluN2A

#GluN2B#

Data

from

epilepsy

surgery

perform

edforrefractory

SE

Loddenkemperetal.

(2014)[85]

Patients

withSEandESES(comparedto

epilepsy

surgery

patients

withoutSEEPIandto

autopsy

cases)

SE

GluN2B"

GluN2B/GluN2A

"

a2/a1"

a2"*

ESES

GluA1"

GluA1/GluA2"

GluN2B/GluNA

"EPI

GluA1/Glu2"

a2/a1"

a2"*

a2/a1"*

"Increased.

#Decreased.

Reproducedwithperm

ission

[26].

*RNA

studies.

EPI:Refractory

epilepsy;ESES:Electricalstatusepilepticusin

sleep;SE:Statusepilepticus.



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

order to determine optimal first-line treatment [40]. In thisstudy lorazepam was superior to phenytoin, but in an inten-tion-to-treat analysis there were no differences among thefour treatment groups [40].

Intracellularvacuole

A. B. Intracellularvacuole

Postsynaptic neuron Postsynaptic neuron

Presynapticneuron

PresynapticneuronGABA reception

NMDA reception

GABA reception

NMDA reception

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) neuro-

transmission. 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 minFirst 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

Second AED: Fosphenytoin 20 mg PE/Kg iv

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

Continuous infusions/anesthetics:Midazolam

pentobarbitalOther options: Ketamine, isoflurane, propofol

Impending SE

10 – 15 min

15 – 30 min

Established SE

30 – 60 min

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.



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3.3 Lorazepam as the preferred first-line drug for SEBased on the results of these studies, intravenous lorazepambecame widely regarded as the optimal first-line choice forSE. The results of the Veterans Affair study are frequentlyextrapolated to children even though there were no childrenin that study. In pediatrics, the preference of lorazepam asfirst-line therapy is essentially based on the large North Lon-don series of 182 children with SE, in which treatment withintravenous lorazepam was associated with a 3.7 (95% CI:1.7 -- 7.9) times greater likelihood of seizure cessation thantreatment with rectal diazepam [20].

Several studies also show efficacy of benzodiazepines asfirst-line treatment of SE but the superiority of one benzodi-azepine over the others is less clear [41]. In a recent double-blind study, 273 children with SE were randomized to receiveintravenous diazepam (n = 140) or intravenous lorazepam(n = 133) [42]. The primary efficacy outcome was cessationof SE by 10 min without recurrence within 30 min and theprimary safety outcome was the need for assisted ventila-tion [42]. The rate of SE cessation (72% on diazepam and73% on lorazepam) and the rate of requiring assisted ventila-tion (16% on diazepam, 18% on lorazepam) were similar [42].In a series of 48 children with prolonged seizures treated inthe emergency department, there were no differences in therate of seizure control between patients treated with intrave-nous diazepam (65%) and in patients treated with intrave-nous lorazepam (65%) [43]. In a series of 76 episodes ofpediatric seizures of at least 5 min duration treated with intra-venous midazolam bolus doses of 0.1 -- 0.2 mg/kg, seizurecontrol was achieved with the first bolus in 40/76 (53%)patients, with a second bolus in 20/36 (55%) and with a thirdbolus in 8/16 (50%) [44]. A recent series randomized893 patients (both children and adults) to receive intramuscu-lar midazolam or intravenous lorazepam as a first-line, out-of-hospital treatment [45]. Seizure resolution at the time of arrivalin the emergency department was 73% in the intramuscularmidazolam group and was 63% in the intravenous lorazepamgroup [45]. In a Cochrane review of three studies whichincluded 264 patients, intravenous lorazepam was slightlysuperior to intravenous diazepam on cessation of seizuresand was not different on requirement of ventilatory supportor other adverse effects [46,47]. Intravenous clonazepam hasbeen 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, intramuscu-lar midazolam and intravenous diazepam have demonstratedsimilar efficacy, with lorazepam being slightly superior insome studies and with intramuscular midazolam being nonin-ferior to intravenous lorazepam [45].

3.4 Need for other routes of administrationIntravenous lorazepam is associated with a major disadvan-tage: the need to obtain an intravenous line and the lack ofeasily accessible alternative route. Most episodes of SE start

out of the hospital and obtaining an intravenous line in anactively convulsing patient can be particularly challenging.Therefore, other non-intravenous first-line treatments arebeing increasingly considered. A meta-analysis concludedthat non-intravenous midazolam was at least as safe and effec-tive as intravenous or non-intravenous diazepam in childrenand young adults [50]. A series of 28 children with severe epi-lepsy at a residential school who presented with seizures of atleast 5 min duration were randomized to receive buccal mid-azolam or rectal diazepam [51]. In this series, buccal midazo-lam was shown to be at least as effective (75% seizurecontrol) as rectal diazepam (59%) with no clinically impor-tant adverse events in any of the groups [51]. A prospective ran-domized 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 treat-ment of acute seizures [52]. The median time from medicationadministration to seizure cessation was 3 min in the intranasalmidazolam group and 4.3 min in the rectal diazepamgroup [52]. There were no marked differences in the rate ofcomplications between the two groups [52]. In a prospectivestudy, 24 children with motor seizures of at least 10 min dura-tion were randomized to receive intramuscular midazolam orintravenous diazepam [53]. Patients in the midazolam groupreceived medication sooner (mean: 3.3 vs 7.8 min) and hadmore 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 midazolamor intravenous lorazepam as a first-line, out-of-hospital treat-ment [45]. The primary outcome was absence of seizures atthe time of arrival in the emergency department without theneed for rescue therapy [45]. As discussed above, seizure resolu-tion at the time of arrival in the emergency department wassimilar in the intramuscular midazolam group and in the intra-venous lorazepam group [45]. There were no significant differ-ences in the need for endotracheal intubation (14% in bothgroups) or the proportion of seizure recurrence (11% in bothgroups) [45]. In this study, the time saved using the intramuscu-lar route (1.2 min in the intramuscular midazolam group and4.8 min in the intravenous lorazepam group) appears to at leastoffset the delay in the drug onset of action (3.3 min inthe intramuscular midazolam group and 1.6 min in theintravenous lorazepam group) [45]. In summary, there arenon-intravenous alternatives to lorazepam which have similarefficacy and are easier and faster to administer.

3.5 Non-benzodiazepine AEDsAfter benzodiazepines have failed to control SE and/or SE haslasted for 10 min, a switch to non-benzodiazepine AED is rec-ommended. Although there are several options available, evi-dence supporting one AED versus the others is weak. Thereare few studies which have specifically addressed the efficacyof second-line AEDs in SE and their methodology and end



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points vary widely. Most of the evidence comes from observa-tional and retrospective studies.Currently, phenytoin (or fosphenytoin) is the recom-

mended first option as non-benzodiazepine AED and pheno-barbital is the most commonly used second option whenphenytoin (or fosphenytoin) fails to control SE [36-38]. Thesechoices are essentially based on the fact that these drugs havebeen available for much longer than any new AED [36-38].Therefore, they are time-tested and there is abundant litera-ture on their efficacy. In the North London series of 182 pedi-atric patients with convulsive SE, treatment with intravenousphenytoin as a second-line therapy was associated with anine times greater likelihood of seizure cessation as comparedto treatment with rectal paraldehyde [20]. However, when phe-nytoin is compared to newer drugs, there is no clear advantageof phenytoin. A retrospective series of 167 adults with SEcompared phenytoin, valproate and levetiracetam as second-line drugs (after failure of benzodiazepines as first-linedrugs) [54]. Valproate failed to control SE in 25% of patientsin whom it was prescribed, phenytoin in 41% and levetirace-tam in 48% [54]. After adjustment for SE severity, this studyshowed that valproate was more effective than levetiracetam(odds ratio comparing levetiracetam failure with valproatefailure: 2.69, 95% CI: 1.19 -- 6.08), whereas there was no dif-ference in the efficacy of phenytoin compared to valproate orphenytoin compared to levetiracetam [54]. A series of general-ized convulsive seizures that lasted > 5 min, which did notrespond to a bolus of intravenous diazepam, were randomlyassigned to either phenobarbital or valproate [55]. Althoughdifferences were not statistically significant, there was a ten-dency toward a higher rate of seizure cessation with valproatethan with phenobarbital (90 vs 77%) with fewer associatedclinically significant adverse events (24 vs 74%) [55]. A studyof 68 patients (children and adults) with SE randomlyassigned valproate or phenytoin as initial therapy [56]. Seizureswere aborted in 66% in the valproate group and in 42% in thephenytoin group [56]. As a second choice in refractory patients,valproate was effective in 79% and phenytoin was effective in25% [56]. There were no marked differences in side effectsbetween the two groups [56].A recent meta-analysis evaluated the efficacy of phenytoin,

phenobarbital, valproate, levetiracetam and lacosamide tostop SE after benzodiazepine failure [57]. For phenytoin, eightstudies reporting 294 SE episodes were analyzed with a meanefficacy of 50% (95% CI: 43 -- 66%) [57]. For phenobarbital,two studies reporting 42 SE episodes were analyzed with amean efficacy of 74% (95% CI: 58 -- 85%) [57]. For valproate,eight studies reporting 250 SE episodes were analyzed with amean efficacy of 76% (95% CI: 64 -- 85%) [57]. For levetira-cetam, eight studies reporting 204 SE episodes were analyzedwith a mean efficacy of 69% (95% CI: 56 -- 79%) [57]. Therewas insufficient detail in patients treated with lacosamide toperform a meta-analysis [57], although this drug shows somepromising results [58,59]. In summary, observational studiesshow that new drugs like valproate or levetiracetam have a

similar, if not superior, efficacy than phenytoin (fospheny-toin) and phenobarbital. Apart from efficacy, relatively newdrugs such as valproate and levetiracetam have potential prac-tical advantages: in general, they can be administered fasterthan phenytoin (or fosphenytoin), have a better pharmacoki-netic profile and have a lower risk of hypotension and respira-tory depression [60]. It should be emphasized that althoughvalproate is a generally safe drug in adults and children, it dis-rupts organic acid metabolism and can lead to serious toxicityin children with underlying metabolic disorders (often undi-agnosed 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 arandomized controlled trial to definitively establish whethervalproate and/or levetiracetam are superior to phenytoin assecond-line treatment for SE [60].

3.6 Refractory SEWhen SE persists despite the administration of appropriatedoses of benzodiazepines, and one or two doses of non-benzodiazepine AEDs, continuous infusions of AEDs or anes-thetic therapies are recommended [36]. If the patient is notalready on mechanical ventilation, this should be institutedbefore initiating treatment with continuous infusions. Inaddition, vasopressor agents may be required because of hypo-tension and cardiopulmonary depression. The most com-monly used continuous infusions are midazolam, propofol(with the caveat of worsening underlying metabolic condi-tions) and pentobarbital with insufficient evidence to recom-mend any one in particular over the others [62-64]. Otheroptions may also include ketamine or inhalation anesthetics,among others.

Midazolam infusion (0.2 mg/kg loading dose followed by0.2 -- 0.6 mg/kg/h) is relatively safe, causes less hypotensionthan pentobarbital infusion and is frequently used as theinitial continuous drip [65]. Tachyphylaxis often developswithin 24 -- 48 h, so the perfusion dose should be increasedto maintain a constant pharmacological action [65]. In a seriesof patients with refractory SE, continuous infusion of midazo-lam (mean infusion rate: 2 µg/kg/min) controlled seizures in19 of 20 (95%) children after a mean interval of 0.9 h afterthe initiation of the infusion [66]. In another series of childrenwith refractory SE, a continuous infusion of midazolam(mean infusion rate: 3.1 µg/kg/min) controlled seizures in26 of 27 (96%) cases within 65 min of the initiation of themidazolam infusion.

Pentobarbital infusion (5 mg/kg loading dose followed by1 -- 5 mg/kg/h) has a long half-life making both uptitrationand weaning challenging. In a retrospective series of childrenwith refractory SE treated with pentobarbital infusion (meanloading dose of 5.4 mg/kg followed by an initial infusion of1.1 mg/kg/h and maximum infusion of 4.8 mg/kg/h), 10 of30 (33%) achieved sustained burst suppression withoutrelapse during therapy [67]. Of the patients who experiencedseizure relapse, 12 of 20 (60%) eventually re-achieved burst



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suppression [67]. The rate of adverse effects in this series wasparticularly high with hypotension requiring inotropes in93% of patients, infection in 66%, metabolic acidosis in10% and pancreatitis in 10% [67].

Propofol infusion (2 mg/kg loading dose followed by2 -- 5 mg/kg/h) has a short half-life. Its main disadvantage isits potential to cause propofol infusion syndrome, a poten-tially fatal complication most often seen in critically ill chil-dren undergoing long-term propofol infusion at high doses.Propofol infusion syndrome mechanism is based on thepropofol-mediated impairment of free fatty acid utilizationand mitochondrial activity [68]. An imbalance between energydemand and utilization is a key pathogenetic mechanismwhich may lead to cardiac and peripheral muscle necrosis [68].The main clinical features of propofol infusion syndrome arecardiocirculatory collapse with lactic acidosis, hypertriglyceri-demia and rhabdomyolysis [68]. As this syndrome is frequentlylethal, propofol infusions with doses of at least 5 mg/kg/h arenot recommended for > 48 h, especially in children [68]. In aseries of children with refractory SE, propofol infusion con-trolled 14 of 22 (64%) episodes [69]. Propofol infusion hadto be stopped on four occasions: one patient had rhabdomyol-ysis and three patients developed hypertriglyceridemia whichnormalized after stopping propofol [69].

3.7 Super-refractory SEWhen SE does not respond to the abovementioned medica-tions, it is considered super-refractory. A more precise defini-tion is ‘status epilepticus that continues for 24 hours or moreafter the onset of anesthesia, including those cases in whichthe status epilepticus recurs on the reduction or withdrawalof anesthesia’ [70]. When patients have super-refractory SE,

several therapeutic approaches should be tried sequentiallyalthough evidence on their efficacy is generally limited tocase reports or small case series (Table 2) [70].

3.8 Autoimmune SE and immune therapiesThe possibility of autoimmune encephalitis should be consid-ered, especially when SE is refractory or super refractory. Auto-immune encephalitis is a rare etiology of SE, but it is potentiallytreatable and requires specific therapies. Patients of any age whodevelop rapidly progressing symptoms including a combina-tion of seizures or SE, behavioral changes and encephalopathywith no other explanation for them should be evaluated inserum and cerebrospinal fluid for autoantibodies [71,72]. Thesuspicion or confirmation of autoimmune encephalitis shouldraise the possibility of treatment with immunotherapy such assteroids, intravenous immunoglobulins or plasma exchange,although the response is variable [73,74] and not all cases ofinflammatory SE may be amenable to immunotherapy [75].

4. Conclusion

Current SE treatment protocols emphasize the need for atimely administration of AEDs in a stepwise approach [36-38].There is reasonably good evidence supporting the efficacy ofbenzodiazepines as initial SE treatment. Although intravenouslorazepam is widely regarded as the best initial treatment,other benzodiazepines with non-intravenous route of admin-istration have demonstrated similar efficacy and advantageson the route of administration [45,51,52]. Once SE has notresponded to benzodiazepines, there is a wide variety ofnon-benzodiazepine AED alternatives. Although phenytoin(fosphenytoin) and phenobarbital are time-tested alternatives,

Table 2. Treatment alternatives for refractory and super-refractory SE.

Comments Adverse events

Thiopental [69,86] Metabolized to pentobarbital Hypotension,respiratory depression,cardiac depression

Ketamine [87,88] Mechanism of action particularly well suited to treatrefractory and super-refractory SE (NMDA receptorantagonist)

High intracranial pressure,hypotension,hallucinations

Inhaled anesthetics [89] High complication rate;needs closed system (gas recovery)

Hypotension,infection,paralytic ileus

Ketogenic diet [90-92] Relatively safe (no respiratory and cardiocirculatory instability);slow onset of action;requires skilled dietician

Gastroesophageal reflux,constipation,acidosis,hypertriglyceridemia

Lidocaine [93,94] Minor respiratory depression compared with other drugs Cardiocirculatory instability,possible induction of seizures

Hypothermia [95] Only transitory control (cannot be a prolonged therapy) Hypotension,cardiovascular instability,impaired coagulation (bleeding risks)

Resective surgery [96-99] Long-term treatment of seizures;not all patients are eligible

Surgical risks

SE: Status epilepticus.



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newer AEDs such as valproate or levetiracetam are beingincreasingly considered as they may be at least noninferior [57].Treatment for refractory SE is based on continuous infusionsof midazolam, propofol and/or pentobarbital. Once SEbecomes super refractory, different therapeutic options withlimited supporting evidence may be tried sequentially [70].There are delays in AED administration in the treatmentof SE [34,35].

5. Expert opinion

The field of SE treatment is experiencing significant and excit-ing developments in the past few years. The establishedsequence of treatment with intravenous lorazepam, intrave-nous phenytoin (fosphenytoin) and intravenous phenobarbi-tal 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 SEand fast and easy to administer. Rectal diazepam is a time-tested drug widely used to stop SE in young children. How-ever, its absorption through the rectal mucosa is unpredictable,and administration in older patients may be perceived as stig-matizing and socially embarrassing. More straightforwardroutes of delivery are being tested. Intramuscular midazolamhas demonstrated noninferiority compared to intravenous lor-azepam and is being widely used by different emergency med-ical services. Intranasal and buccal midazolam are gainingpopularity and small series have demonstrated that their effi-cacy and safety is comparable to other benzodiazepines [76].Limitations of intranasal and buccal midazolam include unpre-dictable absorption through the buccal and nasal mucosa andnot being approved and commercially available in manycountries. In the near future, it is likely that intramuscular mid-azolam auto-injectors and intranasal and buccal midazolamwill 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 willevaluate whether valproate and levetiracetam are better thanintravenous phenytoin (fosphenytoin) for treatment ofbenzodiazepine-resistant SE [60]. This international collabora-tion is developing a blinded comparative randomized clinicaltrial with a goal of 1500 patients from at least 50 centers [60].It is likely that in the near future valproate and levetiracetamwill become initial options after benzodiazepine failure.The Pediatric SE Research Group (pSERG) is a multicen-

ter network within the US that tries to develop an evidence-based approach for the management of pediatric SE [77].

The data obtained from this prospective collection of currentclinical practice can inform future decisions about care andtreatment trials both in the out-of-hospital setting, emergencydepartment and intensive care unit [77]. In an initial phase,this consortium is analyzing data on treatment choices andhealthcare delivery for SE in large reference pediatric hospi-tals [77]. During a later phase, this consortium will performrandomized clinical trials to evaluate the best therapeuticoptions in pediatric SE. Results from this consortium includethe description of significant delays in AED administration inpediatric SE [35]. In the future, pSERG will further researchon causes of treatment delay and will develop recommenda-tions for policy changes that optimize the timing of AEDadministration based on comparative effectiveness data. Inorder to optimize timing of AED administration, it can beuseful in considering shifting from the classic stepwiseapproach to a treatment protocol in which several drugs areadministered simultaneously.

Further research is needed on the best treatment options forrefractory and super-refractory SE. Because of the rarity ofthese conditions, this research may only advance in large mul-ticenter consortia. The ultimate goal of research in this field isto stop SE as soon as possible so that complications andsequelae are minimal and outcome is optimized.

Declaration of interest

I Sanchez Fernandez is funded by a grant for the study of IvanSanchez Fernandez is funded by a grant for the study of Epi-leptic Encephalopathies from “Fundacion Alfonso MartınEscudero” and the HHV6 Foundation. Tobias Loddenkemperserves on the Laboratory Accreditation Board for Long Term(Epilepsy and Intensive Care Unit) Monitoring, on the Coun-cil of the American Clinical Neurophysiology Society, on theAmerican Board of Clinical Neurophysiology, as an AssociateEditor for Seizure, as Contributing Editor for Epilepsy Cur-rents, and as an Associate Editor for Wyllie’s Treatment ofEpilepsy 6th edition. He is part of pending patent applicationsto detect seizures and to diagnose epilepsy. He receivesresearch support from the American Epilepsy Society, the Epi-lepsy 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 relevantaffiliations or financial involvement with any organization orentity with a financial interest in or financial conflict withthe subject matter or materials discussed in the manuscriptapart from those disclosed.



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AffiliationIvan Sanchez Fernandez1,2 MD &

Tobias Loddenkemper†3 MD†Author for correspondence1Epilepsy 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, USA2Universidad de Barcelona, Hospital Sant Joan de

D�eu, Department of Child Neurology, Barcelona,

Spain3Associate 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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mailto:[email protected]

mailto:[email protected]


Terapeutica de Convulsiones

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