Seizure: European Journal of Epilepsy 75 (2020) 145–152

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Seizure: European Journal of Epilepsy

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

Medical management of status epilepticus: Emergency room to intensive T

care unit
Ania A. Crawshawa, Hannah R. Cockb,*
a
Specialist Trainee Neurology, Atkinson Morley Regional Neuroscience Centre, St George’s University Hospitals NHS Foundation Trust, London, UK
b
Professor of Epilepsy & Medical Education, Consultant Neurologist. Atkinson Morley Regional Neuroscience Centre, St George’s University Hospitals NHS Foundation
Trust, and Institute of Medical & Biomedical Education, St George’s University of London, London, UK

ARTICLE INFO ABSTRACT

Keywords: In convulsive status epilepticus (SE), achieving seizure control within the first 1–2 hours after onset is a sig-
Status epilepticus nificant determinant of outcome. Treatment is also more likely to work and be cost effective the earlier it is
Treatment given. Initial first aid measures should be accompanied by establishing intravenous access if possible and ad-
Valproate ministering thiamine and glucose if required. Calling for help will support efficient management, and also the
Levetiracetam
potential for video-recording the events. This can be done as a best interests investigation to inform later
Benzodiazepines
Phenytoin
management, provided adequate steps to protect data are taken. There is high quality evidence supporting the
use of benzodiazepines for initial treatment. Midazolam (buccal, intranasal or intramuscular) has the most
evidence where there is no intravenous access, with the practical advantages of administration outweighing the
slightly slower onset of action. Either lorazepam or diazepam are suitable IV agents. Speed of administration and
adequate initial dosing are probably more important than choice of drug. Although only phenytoin (and its
prodrug fosphenytoin) and phenobarbitone are licensed for established SE, a now considerable body of evidence
and international consensus supports the utility of both levetiracetam and valproate as options in established
status. Both also have the advantage of being well tolerated as maintenance treatment, and possibly a lower risk
of serious adverse events. Two adequately powered randomized open studies in children have recently reported,
supporting the use of levetiracetam as an alterantive to phenytoin. The results of a large double blind study also
including valproate are also imminent, and together likely to change practice in benzodiazepine-resistant SE.

1. Introduction 2. Does speed really matter?

That status epilepticus (SE) requires emergency treatment has been It is widely acknowledged that age and etiology are the biggest
embedded in practice for decades, and the 2015 ILAE definition [1] determinants of outcome in SE. However, historical uncertainty about
emphasises both the need for rapid initiation of treatment and the risk the influence of duration as an independent predictor has now been
of permanent damage if seizures are not promptly controlled. There are addressed by several large case series. It is clear that achieving seizure
however many types of SE, and it is recognized that outcome is also control within the first 1–2 hours of onset is a significant determinant of
significantly influenced by seizure type and etiology, as well as the outcome [2] as summarized in Table 1. Systemic compromise [3], and
patient’s age and comorbidities. In this review we will focus on the brain damage, thought to be caused by a combination of direct damage
management of early and established convulsive SE for which there is from seizure-related activity and the secondary effects of the associated
most evidence to guide practice, though management of other types of metabolic cascade, both contribute to morbidity and mortality. Fur-
SE will also be briefly discussed. The management of refractory SE, thermore, the earlier treatment of SE is instituted, the more likely it is
where seizures have not been controlled by first or second line treat- to be successful. In one recent prospective study in children with re-
ment, is covered in a subsequent article in this supplement. fractory convulsive SE, benzodiazepine administration beyond the first
10 minutes was independently associated with a higher frequency of
death, use of continuous infusions, longer convulsion duration, and
hypotension [4]. Unsurprisingly prompt intervention, including pre-

⁎
Corresponding author.
E-mail address: [email protected] (H.R. Cock).

https://doi.org/10.1016/j.seizure.2019.10.006
Received 30 March 2019; Received in revised form 7 October 2019; Accepted 8 October 2019
1059-1311/ © 2019 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.
A.A. Crawshaw and H.R. Cock Seizure: European Journal of Epilepsy 75 (2020) 145–152

Table 1
Retrospective case series examining the influence of duration on outcome from convulsive status epilepticus.
Location year [ref] Number of cases, age Duration % Poor outcome*

USA 1994 [6] n = 253, >16y < > 1 hour 2.7 vs 32.0, OR 17.9
Finland 1997 [7] n = 65, <18y < > 2 hours 32.7 vs 68.8, p < 0.025
Turkey 1998 [8] n = 66, 6-77y < > 1 hour 3.0 vs 29.4, OR 2.41
India 2005 [9] n = 30, <18y < > 45 mins 9.5 vs 100.0, p < 0.001
USA 2009 [10] n = 119, 24-96y < > 10 hours 31.0 vs 69.0, p < 0.05
Norway 2016** [11] n = 56, 20-86y < > 2 hours 16.7 vs 52.3, OR 6.12

Bold = multivariate analysis. OR = odds ratio; *death or significant disability; ** Refractory cases only, including 38 non-convulsive status epilepticus [2].

Fig. 1. Flow diagram for general and pharmacological management of convulsive status epilepticus.
FBC – full blood count; U&E – urea and electrolytes; LFT – liver function tests; CRP – C-reactive protein; Mg – magnesium; TFT – thyroid function tests. PMH – past
medical history; AED – anti-epileptic drug; PNES – psychogenic non-epileptic seizure

hospital, is also likely to reduce healthcare costs [5]. Although no in- Vital signs should be monitored and cardiac monitoring instituted.
dividual study can definitively prove cause and effect, a clear message Cardiac complications are not infrequent [3], and some of the drugs
is coming through. used, particularly phenytoin can also have cardiac side effects. In-
travenous access should be established early, alongside checking blood
glucose, with further blood samples sent (see Fig. 1) to investigate the
3. General management and diagnostic issues
potential cause and consequences of SE. Investigations are also covered
in the preceding article in this supplement. If there are concerns re-
3.1. First aid and general medical considerations
garding alcohol excess or poor nutrition, 250 mg IV thiamine should be
given followed by 50 mL of 50% glucose IV if the patient is hypogly-
Key management considerations are summarized in Fig. 1. Given
caemic.
the importance of speed it is important to check the time at seizure
The above management should all be instituted as rapidly as pos-
onset and estimate duration if receiving handover from bystanders or
sible, ideally within the first few minutes of arrival at hospital or pre-
emergency medical services. Guidelines then advocate an ‘ABC’ ap-
hospital where possible. For this reason, amongst others, it is also im-
proach, necessitating that the airway be secured in the first instance.
portant to seek help early so that these steps can be carried out in
During convulsions, it is muscle (including laryngeal) spasm that re-
parallel by different members of the multi-disciplinary team.
stricts air entry, so this is best achieved by stopping the seizures. Any
attempt to insert an oral airway may cause injury in an actively seizing
patient. Airway manoeuvres such as head tilt and jaw thrust can be 3.2. Are you sure it’s epileptic status epilepticus?
helpful post-ictally, though many patients will require a nasophar-
yngeal airway with oxygen therapy to maintain adequate saturations. Whilst not the topic of this article, the importance of considering the

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Table 2 specifically lorazepam, diazepam, midazolam and clonazepam. The

Clinical Features helpful in distinguishing epileptic from dissociative seizures main questions addressed relate to which particular benzodiazepine is
[14,15]. preferable in terms of speed of onset and duration of action, safety, and
Favour Dissociative Seizures Not useful discriminators impact of route of administration.

Long (> 5 minutes) duration of individual Tongue biting (except possibly 4.1. Intravenous benzodiazepines
events lateral)
Fluctuating course (waxing and waning) Incontinence
Asynchronous rhythmic movementsa Gradual onset For all agents, there is consensus that if intravenous (IV) access is
Pelvic thrustinga Non-stereotyped already in place, IV administration of benzodiazepines leads to shorter
Side to side head/body movements during a Flailing/thrashing movements time to seizure termination [17]. IV lorazepam has been found to be at
convulsion
least as effective as IV diazepam in all meta-analyses performed
Closed eyes Opisthotonus
Ictal Crying Associated Injuries21
[18–20] whether in adult or paediatric populations. A potential ad-
Recall of items during eventb vantage of lorazepam is its longer duration of action compared with
diazepam. Some earlier studies report fewer patients needing repeat
a
Can be seen in frontal lobe focal seizures. bPatients often report being able doses or additional AEDs to terminate SE, but there is not strong evi-
to hear what is going on around them but not being able to respond. Features dence to support superiority of lorazepam. IV midazolam has also been
favouring epileptic seizures include prolonged post-event confusion and ster- shown to be as effective as both IV lorazepam and IV diazepam, al-
torous breathing. Table reproduced with permission from [16].
though in practice this has rarely been used as initial treatment [18]. IV
clonazepam, which has a long half-life and rapid onset of action, is also
possibility that persistent or recurrent convulsions might be dissociative
widely used across parts of Europe, although the evidence was until
(psychogenic non-epileptic seizures) rather than epileptic status epi-
recently based only on uncontrolled case series [21]. A randomized
lepticus must not be overlooked. Frequent admissions should be con-
prehospital trial in in 2016 [22] evaluated the use of IV clonazepam
sidered a red flag, and a reported diagnosis of epilepsy is not un-
plus either levetiracetam or placebo for the initial treatment of SE.
common – either due to prior misdiagnosis, or a dual diagnosis. There is
Seizures were stopped within 15 minutes of Clonazepam plus placebo in
no fool-proof clinical marker, but key features which can help distin-
84% of patients, so it is clearly effective but has not been compared
guish dissociative from epileptic seizures are summarized in Table 2.
with other IV benzodiazepines in a clinical trial setting.
Emergency physicians may be insufficiently experienced to confidently
distinguish the two. Perhaps inevitably, the team may initially manage
4.2. Non-intravenous benzodiazepines
as for epileptic status epilepticus. However, if there is any diagnostic
doubt at all, early video recording of the events in parallel with treat-
In or out of hospital, unless IV access is already in situ, non-IV routes
ment can be extremely helpful to the specialist later called in to advise
may be preferable as faster administration can offset the slightly slower
on longer term management. As with any form of imaging, whilst there
onset of action, meaning shorter time to seizure cessation overall. This
is often concern about the sensitive nature of a video, and inability to
was demonstrated most clearly in the RAMPART trial, which though set
take consent in this context, video should be considered a critical di-
up as a non-inferiority (10% difference) study demonstrated that in-
agnostic test, and is justifiable as a best interests intervention to inform
tramuscular (IM) midazolam is superior to IV lorazepam in the pre-
management [59]. EEG is rarely available in the emergency setting, but
hospital setting [23]. 893 adults were randomized to either drug. 73%
expert review of “home” video has been shown to be over 95% sensitive
of those receiving IM midazolam (10 mg in adults, 5 mg in children)
and specific [12] for the diagnosis of dissociative seizures. The use of
were seizure-free when arriving in the emergency department vs 63%
personal devices for recording is also not precluded, providing appro-
receiving IV lorazepam (4 mg in adults, 2 mg in children), with the
priate steps to protect the data are applied. These include using a
main advantage being shorter time to treatment initiation. Intranasal
password protected device, disabled cloud syncing, and transferring the
midazolam and buccal midazolam are also effective non-intravenous
files to the hospital records system as soon as possible using encrypted
options for initial management of SE [24], however the existing com-
systems. Patient consent can be sought on recovery, and the data de-
parative evidence for these is less strong than for IM midazolam [18].
leted if not given, with full documentation of decision making and ac-
Arya et al evaluated the efficacy of various non-venous medications for
tions throughout this process. Especially considering the risks of in-
acute convulsive seizures, incorporating data from 16 trials [25]. They
appropriate sedation and intensive care admission in this population,
concluded that IM and intranasal midazolam exhibit the best efficacy
including iatrogenic death [13] and the impact of the correct diagnosis
data for treatment of SE in the absence of IV access. Rectal diazepam is
on management, this is surely reasonable.
also well-established and relatively cheap, effective option. However,
non-IV forms of midazolam are not only associated with shorter time to
4. Initial pharmacological treatment of convulsive status seizure termination but are also more practical and often more socially
epilepticus acceptable to patients and care-givers than rectal medications [24,26].
There are a number of studies looking at non-IV lorazepam, in-
First line medical treatments for status epilepticus may be instituted cluding intranasal, sublingual or rectal administration [25]. Some stu-
in the community, by emergency medical services or in the hospital. dies suggest similar efficacy, but with less consistent data and smaller
Whilst the focus of this review is on hospital treatment, much of the numbers thus far, such that none are yet recommended as first line
evidence around initial treatment of convulsive SE comes from pre- options [17].
hospital studies. The most appropriate drug route will vary depending Overall, the evidence supports use of a non-IV benzodiazepine,
on the setting and consequent practicalities and safety considerations. preferably Midazolam where IV access is not already present, with
There have been dozens of adult and paediatric studies published on the choice of agent overall being less important than speed of administra-
efficacy and safety of benzodiazepines via various routes and several tion, particularly once IV access is established.
recent systematic reviews/meta-analyses. Methodological hetero-
geneity, including in study populations, trial design, primary outcome 4.3. Non-benzodiazepines as initial therapy for SE
definitions and approaches to analysis contribute to some differences in
conclusions between individual studies. Nevertheless, there is broad A few studies have looked at alternatives to benzodiazepines as
consensus to guide first line treatment, as summarized in Fig. 2. The initial treatment in SE. Drugs evaluated include phenobarbital, leve-
majority of trials have focused on the use of benzodiazepines, tiracetam, sodium valproate and phenytoin. One of the earliest, large

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Fig. 2. Benzodiazepines for initial treatment of status epilepticus.

All benzodiazepines can cause respiratory depression, sedation and hypotension at higher doses and in susceptible patients. + relative benefits and – disadvantages

randomized control trials in SE [27] demonstrated that IV lorazepam demonstrated which is not yet the case. That both require IV access is
0.1 mg/kg has similar efficacy to both IV phenobarbital 18 mg/kg and also a significant disadvantage as first line treatment.
to combined IV diazepam 0.15 mg/kg with phenytoin 18 mg/kg. IV
lorazepam was significantly more effective than phenytoin alone.
Phenobarbital may therefore be an effective option for initial treatment, 5. Second line antiepileptics for established SE
however in practice this is rarely used due to concerns about long term
side effects and potential respiratory depression. Evidence from this Although there is consensus and good evidence to support benzo-
trial suggests that phenytoin alone should not be recommended as a diazepines as the drug of choice for initial treatment of SE, until re-
first line treatment. cently there was much less evidence to help choose which AED should
There are no trials comparing sodium valproate alone with a ben- be used in established SE, when benzodiazepines have failed.
zodiazepine for initial treatment of SE. Three trials have been under- Choice of AED has been largely dictated by availability of IV for-
taken comparing sodium valproate with phenytoin, either alone mulations given the clinical context. Historically only phenytoin or
[28,29], or in combination with diazepam [30] as first line treatment. phenobarbitone were used and remain (including fosphenytoin) the
All are small and underpowered. One [27] suggested valproate was only currently licensed medications in established SE. Phenytoin in
more efficacious than phenytoin, and one suggested phenytoin had combination with a benzodiazepine, and phenobarbitone are both ef-
more adverse events [29]. Levetiracetam has also been evaluated as an fective as evidenced by the Trieman study cited in 4.3 [27]. However,
initial treatment of SE. In an open pilot study IV lorazepam (0.1 mg/kg) there is accumulating data suggesting clinical equipoise between phe-
controlled seizures in 75.6% of patients, compared to 76.3% given IV nytoin and newer AEDs such as sodium valproate or levetiracetam.
levetiracetam 20 mg/kg as initial treatment of convulsive status [31]. Each has specific potential advantages and disadvantages depending on
Seizure freedom at 24 hours was also comparable between the two the clinical context as summarized in Fig. 3, with a considerable body
groups. Lorazepam was associated with significantly higher need for supporting utility in practice. However, prior to 2019 much of the
intubation and ventilation. Rates of hypotension were also higher with published data was retrospective, and any clinical trials in established
lorazepam administration, though not significantly so. A more recent SE had substantial methodological limitations, making it difficult to
double-blinded randomized trial analyzed efficacy of levetiracetam draw firm conclusions. The best comparative data was from meta-
with clonazepam vs clonazepam with placebo [22]. In the modified analysis [32]. This estimated the efficacy of levetiracetam to be 68.5%
intention to treat analysis, seizures were terminated by 15 minutes in (95% CI: 56.2%–78.7%), phenobarbital 73.6% (95% CI: 58.3%–84.8%),
87% of 68 patients treated with clonazepam and placebo compared phenytoin 50.2% (95% CI: 34.2%–66.1%) and valproate 75.7% (95%
with 74% of the 68 pre-hospital patients receiving levetiracetam and CI: 63.7%–84.8%). However, the quality of evidence is such that this
clonazepam. There was no significant difference between the two can’t be considered definitive. Most studies had been underpowered;
groups. inclusion criteria were variable (many including a mix of convulsive,
Thus, as we will go onto discuss, although sodium valproate and non-convulsive and focal SE); definitions of treatment efficacy also
levetiracetam may be safe and effective, there is not enough evidence to varied; some included a high proportion with acute symptomatic epi-
recommend them as first line treatments of SE, unless and until such lepsy and consequent better outcomes; and most of the existing trials
time as any clear advantages compared to benzodiazepines are had been open label.

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Fig. 3. Effective treatment options for established status epilepticus.

(fos)Phenytoin doses shown are for phenytoin, or phenytoin equivalents for fosphenytoin. 1Relative contraindication. Status epilepticus also poses a risk to the
woman, and her unborn child. In an emergency situation, especially in a generalized epilepsy or where Levetiracetam is contraindicated, seizure control should take
priority. 2 Relative contraindication. This patient group anyway at high risk of fatigue and mood disorders, so may be more vulnerable to these adverse effects on
levetiracetam.

5.1. Phenytoin and fosphenytoin 1993. Doses ranging between 25–40 mg/kg have been shown to be both
safe and effective in SE [38]. Overall valproate is well tolerated with a
Phenytoin is one of the oldest drugs used in established SE. As low frequency of adverse events (<10%). In some patients it can cause
summarized in section 6, current efficacy data suggest a potentially dizziness, mild hypotension and mild thrombocytopenia. In light of the
lower efficacy than alternatives. Non-linear kinetics can result in sub- latter, it may be best avoided in acute stroke. It should also be avoided
therapeutic drug levels, despite recommended dosing at 18-20 mg/kg. in patients with known liver disease and/or metabolic encephalopathy.
To what extent this might impact on reported efficacy is uncertain, with Sodium valproate can be hepatotoxic with the potential to cause an
levels often not evaluated in trials, but in practice this is still a relevant encephalopathy, either with or without raised ammonia. It is also best
consideration. Commonly occurring side effects include thrombophle- avoided in patients aged less than 2 years old, particularly if as part of
bitis, cardiac arrhythmias (occassionally fatal) and hypotension, parti- polytherapy, due to increased potential hepatic dysfunction and as yet
cularly in more elderly patients [34]. Of particular note, from reports to undiagnosed metabolic problems [39].
the UK National Patient Safety Agency over 5 years [60], phenytion was Several open label trials have been published comparing sodium
the only drug in which loading dose errors were associated with valproate with phenytoin for treatment of benzodiazepine-resistant SE
fatalities. It also has the disadvantage of exacerbating seizures in some [28,29,40]. Although meta-analysis demonstrated only a non-sig-
patients with idiopathic generalised epilepsies such as juvenile myo- nificant trend towards valproate being more efficacious [32], but with
clonic epilepsy. fewer adverse events, especially less hypotension, compared to phe-
Its prodrug fosphenytoin has a number of comparative advantages nytoin. For patients who are already taking oral sodium valproate for
[35], including fewer infusion site reactions, and availability of an in- epilepsy, given that poor adherence is a common provoker of SE, it
tramuscular formulation allowing for potentially quicker and easier could be considered the drug of choice. Similarly, it may be preferable
administration. It is considerably more expensive than phenytoin in patients with contraindications to phenytoin such as brady-ar-
however, and cost-efficacy analyses have yielded contradictory re- rhythmias or in those with genetic/idiopathic generalised epilepsy
commendations regarding its use [36,37]. Furthermore, in contrast to where sodium channel blockers can be aggravating. As such, it is al-
valproate and levetiracetam, phenytoin is not currently recommended ready incorporated in some International SE guidelines [17] as an ef-
as an early maintenance treatment option for epilepsy so loading with fective alternative to phenytoin.
another agent may be preferable when continuation treatment is con-
sidered. Thus whilst phenytoin has traditionally been the drug of choice
5.3. Levetiracetam
in SE and undoubtedly can be effective, there is a growing body of
evidence to suggest that other antiepileptics may be preferable on ef-
Levetiracetam is a 2nd generation well-tolerated anti-epileptic drug
ficacy, safety and practical grounds.
which has been available as an IV preparation since 2006. Again, meta-
analysis [32] suggests at least similar efficacy to valproate and phe-
5.2. Sodium valproate nytoin, typically with reported loading doses of at least 20–30 mg/kg,
totalling between 1–3 g. A subsequent small open label study adds to
Sodium valproate is also a well-established first generation anti- this evidence, with seizure cessation achieved in 78.6% of 30 patients
epileptic drug, though it was not available as an IV formulation until [41]. Adverse events occur in <10%. They tend to be mild and

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transient, but can include drowsiness, thrombocytopenia, agitation and raising the possibility of ethnic influences on response, though metho-
post-ictal psychosis [42]. Levetiracetam is possibly thus best avoided in dological and study population differences may also account for this
patients with known brain injury or mood disorders as it may exacer- [46]. The main influence limiting utility of phenobarbitone where al-
bate behavioural disturbance. The drug is renally excreted, and so dose ternatives are available however is the higher frequency of adverse
adjustments are also recommended in renally impaired patients. Leve- events [47] including sedation, hypotension and respiratory depression.
tiracetam has been shown to be safe when given at much higher doses
(40–60 mg/kg), with the potential to be more effective than existing 5.6. Lacosamide and other new AEDs
studies have demonstrated. Based on current evidence, international
guidelines recommend levetiracetam as an option in established SE, Lacosamide has been available as an IV preparation since 2008. It is
with doses of 60 mg/kg up to a ceiling of 4500 mg [17], despite that, as licensed as an adjunctive treatment in patients with focal seizures with
with valproate, it is not yet licensed for this indication [43,44,61]. or without secondary generalisation, and increasingly used in SE,
summarized in a recent systematic review [48]. The most common
5.4. Recent randomised controlled trials doses used in SE include a loading dose of 400 mg with a subsequent
maintenance dose of 400 mg per day. The most appropriate dose in mg/
Two phase IV, well powered open randomized controlled trials re- kg, as would be the more usual approach in SE, has yet to be agreed.
ported during 2019 [44,45], with results from the pivotal USA double Some have suggested 6 mg/kg with a ceiling of 600 mg, though outside
blinded ESETT in adults and children [46,47] expected imminently. All of SE, doses up to 9 mg/kg are typically required to achieve therapeutic
enrolled individuals with ongoing convulsive SE despite minimum levels [49]. Side effects include dizziness and rash. Bradycardia and
adequate benzodiazepines, and relied on a clinical decision that con- hypotension have also rarely been reported, but overall it is a well-
vulsive SE had ended without other anticonvulsant medication as the tolerated at these doses, with a low risk of drug interactions.
primary outcome. Other key methodological differences and the pri- The majority of studies evaluating lacosamide in SE have been
mary outcome results where available are summarised in Table 3. Thus retrospective, descriptive studies with considerable heterogeneity in
far no significant differences in efficacy have been found. The incidence type of SE (including focal and non-convulsive SE). There was also
of key safety endpoints such as life threatening hypotension or ar- much variation in the stage that lacosamide was added, even within
rhythmia was very low, with expected rates of endotracheal intubation, individual studies. Some were in established status, but most were in
again with no significant differences between the agents. There are either refractory or super-refractory SE. A meta-analysis of these het-
methodological pros and cons with each of the studies, too numerous to erogenous studies found lacosamide to be 57% effective overall, and in
detail here. However, taking into account the broader safety profiles of a post hoc subgroup analysis, it was found to be 92% effective in focal
each of the agents given in the acute situation together with the prac- motor SE. Meta-analysis of studies in established convulsive SE [32]
ticalities of administration suggests levetiracetam at least may be pre- found from 13 papers evaluating lacosamide, only 4 patients who were
ferable to phenytoin in most cases, pending the release from ESETT. treated with lacosamide second line after benzodiazepine failure, lim-
Both levetiracetam and valproate can for example be given in less than iting conclusions.
5–10 minutes even in a large adult, have fewer drug interactions in a There is clearly considerable interest however, with two more re-
patient group who often have comorbidities or complications needing cently published studies: In an open trial from India [50] 66 patients
other treatments, and are commonly used maintenance treatments were randomised to valproate or lacosamide after initial benzodiaze-
thereafter. pine treatment had failed, with no significant differences in efficacy
though as with all the studies from this group thus far it was under-
5.5. Phenobarbitone powered, and had a high proportion of acute symptomatic seizures. A
more recent randomised non-inferiority prospective study in 2018
Phenobarbitone is also an effective and established drug for treat- compared lacosamide with fosphenytoin in 74 patients with non-con-
ment of both initial and established SE, with efficacy and safety de- vulsive status [51] and similarly found no significant differences in
monstrated in older [27] and more recent studies, [44]. It was first used efficacy or safety, though there was significant heterogeneity in the
as an AED in 1912, and has subsequently been developed in formula- number and choice of other AEDs which had already been employed.
tions for rectal, IV and subcutaneous administration. It is cheap with Overall there is not currently enough evidence to recommend use of
good global availability, though has fallen out of fashion in developed lacosamide in established SE, though arguably also not enough to dis-
countries where newer agents are more widely available. Meta-analysis count it as an option other than perhaps in idiopathic generalized
supports comparative efficacy with levetiracetam [32] and sodium epilepsies, where like phenytoin is may be less effective or even ag-
valproate [32,45]. A more recently published non-blinded Chinese RCT gravate seizures [52]. A number of case reports and case series have
randomised 73 patients to receive either 30 mg/kg sodium valproate or been published on other new AEDs in SE, including perampanel [53],
20 mg/kg phenobarbital. Valproate had an unusually low efficacy brivaracetam [54] and rufinamide [55]. However, unsurprisingly these
(44.4%), significantly lower than phenobarbital (81.1%) in this study, are typically used in cases of refractory and super-refractory SE, and it

Table 3
Phase IV Randomized trials of newer agents compared to Phenytoin reporting in 2019.
Trial [ref] Treatment arms (dose mg/kg, Age (n) Primary outcome
infusion minutes)

Definition Results*
PHT, LEV, VPA
EcLiPSE [44] PHT (20,20) 6 months < 18 years Time from randomisation to clinical cessation of convulsive 35 minutes, 45 minutes,
LEV (40,5) (286) status NA
ConSEPT [45] PHT (20,20) 3 months – 16 years Clinical cessation seizures 5 minutes after infusion completed 60%, 50%, NA
LEV (40,5) (233)
ESETT fosPHT (20,10) 1 – 94 years (400) Absence of clinically evident seizures and improving Imminent
LEV (60,10) consciousness 1 hour after infusion
VPA (40,10)

PHT = phenytoin; LEV = levetiracetam; VPA = valproate. N = total number recruits, equally randomised between treatment arms; *none significant.

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is likely to be many years if ever before there is sufficient evidence to and Stroke (NINDS).
consider them earlier in the treatment pathway.
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