Seizure 47 (2017) 17–24

Contents lists available at ScienceDirect

Seizure
journal homepage: www.elsevier.com/locate/yseiz

Review

Challenges in the treatment of convulsive status epilepticus

Gaetano Zaccaraa,* , Gianfranco Giannasib , Roberto Oggionic , Eleonora Rosatid ,
Luciana Tramacerea , Pasquale Palumbod , on behalf of the convulsive status epilepticus
study group of the uslcentro Toscana, Italy1
a
Unit of Neurology, Department of Medicine, Uslcentro Toscana Health Authority, Firenze, Italy
b
Emergency Department, Uslcentro Toscana Health Authority, Firenze, Italy
c
Intensive Unit, Uslcentro Toscana Health Authority, Firenze, Italy
d
Unit of Neurology, Uslcentro Toscana Health Authority, Prato, Italy

A R T I C L E I N F O A B S T R A C T

Article history:
Received 28 October 2016 Convulsive status epilepticus (CSE) is a medical emergency associated with high mortality and morbidity.
Received in revised form 23 February 2017 The most recent definition of CSE is a convulsive seizure lasting more than 5 min or consecutive seizures
Accepted 24 February 2017 without recovery of consciousness. In adults, for the treatment of the early stages of CSE, diazepam,
lorazepam or midazolam are the most common treatments, although the choice of agent seems less
Keywords: important than rapid treatment. Midazolam, when administered intramuscularly (best evidence),
Status epilepticus buccally, or nasally, is effective and safe in the pre-hospital setting.
Convulsive status epilepticus The antiepileptic drugs, phenytoin, valproate, levetiracetam and, more recently lacosamide, are used in
Refractory status epilepticus
CSE that persists after first-line treatments (established CSE). Phenytoin is more difficult to administer
Anaesthetics
and is less well tolerated. Evidence of the efficacy of lacosamide is scarce.
Anti-epileptic drugs
New onset-refractory status epilepticus Anaesthetics are the drugs of choice for the treatment of refractory CSE (not responding to second-line
drugs). Midazolam seems to be the best tolerated and is the most often used drug, followed by propofol
and thiopental (pentobarbital in the USA). A few studies indicate that ketamine is effective with the
possible advantage that it can be co-administered with other anaesthetics, such as midazolam or
propofol.
CSE becomes super-refractory after more than 24 h of appropriate treatments and may last weeks.
Several anaesthetics have been proposed but evidence is scarce. Autoimmune refractory CSE has been
recently identified, and early treatment with immuno-modulatory agents (corticosteroids and IV
immunoglobulins and also second-line agents such as cyclophosphamide and rituximab followed by
chronic immunosuppressive treatment) is now recommended by many experts.
© 2017 Published by Elsevier Ltd on behalf of British Epilepsy Association.

1. Introduction motor symptoms (episodes of excessive abnormal muscle con-

Status epilepticus (SE) is the second-most common neurologic
emergency with an annual incidence of 10–41 cases per 100,000
population [1–3].
Convulsive subtype, which is the most severe, accounts for
45%–74% of all cases of SE [4], is associated with a mortality ranging
from 7.2% to nearly 20% [3,5,6]. Its clinical presentation is
characterized by impairment of consciousness and prominent
* Corresponding author at: Unit of Neurology, San Giovanni di Dio Hospital, Via Di
Torregalli n 3, 50143, Firenze, Italy.
E-mail addresses: gaetano.zaccara@asf.toscana.it, gaetanozaccara@yahoo.it
(G. Zaccara).
1
Members of the convulsive status epilepticus study group of the uslcentro
Toscana, Italy can be found in Appendix A.
tractions, usually bilateral, which may be interrupted or sustained)
[7]. There is evidence that a long duration of convulsive SE (CSE) is
associated with a worst prognosis, also because it becomes less
responsive to treatment. It has been demonstrated that ongoing
seizure activity makes GABAergic drugs less effective because of
the internalization of GABA receptors [8]. Other factors including
the upregulation of drug-efflux transporters such as P-glycoprotein
or an increased secretion of pro-inflammatory agents [9] might
also determine a reduced drug response in SE.
The International League Against Epilepsy (ILAE) recently
defined SE as follows: a condition resulting either from the failure
of the mechanisms responsible for seizure termination or from the
initiation of mechanisms, which lead to abnormally, prolonged
seizures (after time point t 1). It is a condition that can have long-
term consequences (after time point t 2), including neuronal death,

http://dx.doi.org/10.1016/j.seizure.2017.02.015
1059-1311/© 2017 Published by Elsevier Ltd on behalf of British Epilepsy Association.
18 G. Zaccara et al. / Seizure 47 (2017) 17–24

neuronal injury, and alteration of neuronal networks, depending
on the type and duration of seizures [7]. For CSE, time point T1 has
been set at 5 min, since after this time, it is likely that a seizure will
continue if not treated. T2 is 30 min, which is the time after which
there is a risk of long-term consequences [9,10].
According to the duration and drug response, CSE may be
divided into different stages which differ in terms of the sensitivity
to the drugs used, the need for different treatments and also the
different morbidity and mortality. This review provides an
overview of the treatment of all different stages of CSE in adults
using currently available clinical data. A PubMed literature search
was performed for relevant articles describing human subjects and
published in the English language up to October 2016, using the
following terms: status epilepticus, refractory seizures, and
individual anti-seizure treatments.
Table 1 presents a treatment algorithm with details on drug
doses used in the various stages Table 2 presents the most
important pharmacological characteristics of the drugs used in this
condition.
2. Treatment phases of convulsive status epilepticus
✔
2.1. Pre-hospital management
2.1.1. Stage 1 (early or impending CSE)
This is a condition in which only a few minutes have elapsed
from the beginning of convulsions. Benzodiazepines, which
enhance the neurotransmission of GABA at the GABAA receptor,
are the drugs of choice [4]. Intravenous (IV) lorazepam is most
commonly used, although, more recently, midazolam for intra-
muscular (IM), nasal or buccal injection was found to have a similar
efficacy and is easier to administer [11]. Unfortunately, in several
countries this drug has still not been authorized for use in this
condition in adults [12]. Diazepam for rectal and, possibly, nasal
administration has also been used [13]. Sedation and respiratory
depression are the most common adverse effects of benzodiaze-
pines [14].
In a recent double-blind study carried out in the pre-hospital
setting called RAMPART (Rapid Anticonvulsant Medication Prior to

Table 1
Proposed algorithm of treatment of convulsive status epilepticus.

Stage 1 – Pre-hospital management

Time: Still seizing after 5 min.
Impending (or early) status epilepticus
Lorazepam 2 mg IV over 2 min up to 0.1 or 1.5 mg/kg
If no IV access
Midazolam 10 mg IM/intranasal/buccal (using IV solution)
Diazepam 20 mg per rectum (using IV solution)
ABC (airway, breathing, circulation)
Obtain IV access
Check finger stick glucose
Glucose 33%
Monitoring: O2, HR, BP, EKG
Give thiamine 100 mg IV prior to dextrose
Stage 2 – Hospital management in the emergency unit
Time: Still seizing 30 min after the admission and after benzodiazepine administration
Established status epilepticus
All drugs are given IV
Valproate: 20–40 mg/kg (over 10 min). Additional dose 20 mg/kg over 5 mins,
OR
Levetiracetam: 1000–4000 mg over 5–15 min Additional dose 1500–3000 mg
OR
Phenytoin: 15–20 mg/kg (50 mg/min). Additional dose 5–10 mg/kg
OR
Lacosamide: 400 mg IV(over a few mins). Additional dose 200 mg over 10 min
Additional boluses may be given if patient is still seizing. For breaktrough seizures repeat bolus.
Antiepileptic drugs can be combined
AND
Midazolam: loading dose: 0.2 mg/kg at 2 mg/min with repeated boluses of 0.2–0.4 mg/kg until seizures have stopped (max 2 mg/kg)
Infusion: initial 0.1 mg/kg/h and titrated up to 2 mg/kg/h as required; rates as high as 2.9 mg/kg/h have been described
OR
Propofol: Loading dose 1–2 mg/kg, repeat every 3–5 min (max 10 mg/kg)
Infusion: starting at a rate of 20 mcg/kg/min up to as high as 200 mcg/kg/min [48]
Midazolam or propofol cannot be given in patients not intubated
Stage 3 – Hospital management in the intensive care unit
Time: still seizing or seizures recurring 60 min after second line drug administration
Refractory status epilepticus
Treatment with anaesthetics for 24–48 h.
Continue midazolam or propofol infusion
OR
Thiopental: loading dose of 2–7 mg/kg (infused at a rate <50 mg/min), with additional doses of 1–2 mg/kg as needed, followed by a continuous infusion at a rate of 0.5–
5 mg/kg/h.
OR
Ketamine: loading doses 1–2 mg/kg, every 3–5 min until seizure stop (max 4.5 mg/kg) followed by continuous infusion ranging from 1 to 10 mg/kg/h.
AND
Continue all anti-epileptic drugs already started. Use IV formulations, if available.
Patients should be intubated, mechanically ventilated, and on complete hemodynamic support. Electroencephalographic monitoring
Monitor and treat aggressively hypotension, sepsis, atelectasis, or pneumonia and deep venous thrombosis.
Total parenteral nutrition is needed.
Stage 4 – Hospital management in the intensive care unit
Time: still seizing or seizures recurring after 24–48 h when tapering the doses of anaesthetics
Super-refractory status epilepticus
 G. Zaccara et al. / Seizure 47 (2017) 17–24 19

Table 1 (Continued)
Repeat anaesthetic infusion at higher doses for a longer period (5 days?) OR
Use alternative therapies (in the following order):
Ketamine coadministered with midazolam [38,55]
OR
Isoflurane or desiflurane
AND
Add other antiepileptic drugs through orogastric tube (if no increased stomach residuals): gabapentin or levetiracetam (in acute intermittent porphyria) [56,57] or
topiramate or oxcarbazepine or zonisamide at high therapeutic doses
AND
Pyridoxine 100–600 mg/day IV
CONSIDER
Magnesium 4 g bolus IV and 2–6 g/h infusion (keep serum levels <6 mEq/L)
CONSIDER
Methylprednisolone 1 g/day IV for 5 days, followed by prednisone
1 mg kg 1 day 1 for 1 week
AND
IVIG 0.4 g kg 1 day 1 IV for 5 days or Plasmapheresis for 5 sessions
CONSIDER
Hypothermia 33–35  C for 24–48 h and rewarming by 0.1–0.2  C/h
CONSIDER
Ketogenic diet
CONSIDER
Neurosurgical resection of epileptogenic focus if any,
CONSIDER
Vagal nerve stimulation or deep brain stimulation or transcranial magnetic stimulation or electroconvulsive therapy
After several weeks
In those patients in whom several attempts to wean anaesthetic drugs have failed over a period of weeks, consider withdrawal of life support after discussion with family
or surrogate decision maker

Data are from Brophy et al. [25]; Shorvon and Ferlisi [53]; Lo Pinto et al. [71]; Falco-Walter and Bleck [10]; Cuero and Varelas [65]; Reznik et al. [39], Grover et al. [38] if no
otherwise specified. Disclaimer: This clinical algorithm is not intended to establish a community standard of care, and may not be valid for all patients.

Arrival Trial), patients with CSE randomized to 10 mg of IM
midazolam had a better outcome than those randomized to 4 mg of
IV lorazepam in spite of the longer time required for therapeutic
serum concentrations and the therapeutic effect for IM midazolam
[15]. This difference was interpreted as being due to the time
required to obtain IV access. In a secondary analysis limited to
paediatric patients, both treatments were equally effective [11].
A network meta-analysis comparing 16 randomised clinical
trials of non-venous drug treatments for acute convulsive seizures
and convulsive status epilepticus, showed that IM midazolam is
superior to other nonvenous medications [16]. This analysis also
demonstrated that intranasal midazolam was effective for seizure
cessation within 10 min of administration [15]. Further indirect
comparison meta-analyses have shown that intranasal and buccal
midazolam share a similar efficacy in the treatment of early SE in
children [17]. In addition these meta-analyses showed that non-IV
midazolam is as effective and safe as intravenous or rectal
diazepam in terminating early SE in children [18] although there is
no evidence of the superiority of IV lorazepam over IV diazepam
[19]. A practical consideration favouring the use of midazolam is
that lorazepam but not midazolam, has a poor stability in
unrefrigerated conditions [20]. Recent guidelines state that IM
midazolam has a superior effectiveness compared to intravenous
lorazepam in adults with CSE without established intravenous
access (Level A) [21]. Finally, a prospective observational study
comparing the efficacy of clonazepam, lorazepam or midazolam as
a first-line CSE treatment, found that clonazepam was associated
with a similar efficacy to lorazepam [22].
2.2. Hospital management in the emergency unit
2.2.1. Stage 2 (Established SE): CSE persisting after first-line
treatments
At this stage, although treatment with benzodiazepines is
sometimes continued as an infusion, the vast majority of authors
recommend starting IV infusion of an antiepileptic drug (AED). In a
prospective randomized controlled trial, the relative efficacy and
safety of IV valproate or continuous diazepam infusion as second-
line anticonvulsants were evaluated. Although both medications
were found to be equally effective, tolerability (hypotension,
respiratory depression and need for vasopressor support) was
worse with diazepam [23]. In terms of their tolerability profile,
benzodiazepines are usually not considered as second-line drugs
for the treatment of CSE.
Phenytoin (fosphenytoin in the USA) is still most commonly
used, mainly because of the familiarity with its use as well as its
long half-life. Today, at least four other drugs should be considered
as second-line agents following benzodiazepine: valproic acid,
levetiracetam, phenobarbital and, more recently, lacosamide [10].
In clinical practice guidelines from the European Federation of
Neurological Sciences (EFNS) released in 2010, phenytoin was still
recommended as the standard first-line agent for the management
of CSE in this stage [24]. However, in more recent clinical practice
guidelines from the Neurocritical Care Society and the American
Epilepsy Society [25], published in 2012, this was questioned. In
these latter guidelines, evidence of efficacy included: valproate,
class IIa, evidence level A, phenytoin, class IIa, level B, and
levetiracetam class IIb, level C [25]. Interestingly, a survey of
experts [26] showed that the selection of the agent for the second-
line treatment of CSE, is driven by the individual patient’s
characteristics and includes three drugs: phenytoin/fosphenytoin,
valproate sodium, and levetiracetam.
In 2013, a descriptive meta-analysis of drugs used as the
second-line treatment of CSE was published [27]. Twenty-two,
mostly non randomized studies, were identified, which assessed
five drugs: phenobarbital, phenytoin, levetiracetam, lacosamide
and valproate in patients who had a CSE (almost all cases) that had
failed to respond to a benzodiazepine. Although heterogeneity and
possible sources of bias due to the different characteristics of the
patients and methods of assessment weaken the results of the
meta-analysis, and the efficacy of these drugs was not significantly
different, it is worth mentioning that valproate was effective
20 G. Zaccara et al. / Seizure 47 (2017) 17–24

Table 2
Mechanism of action, safety and drug interactions of the agents most often intravenously used in different stages of convulsive status epilepticus.

Stage Benzodiazepines enhance neurotransmission of GABA at the GABAA receptor, increasing the frequency of chloride ion channel opening in response to GABA.
1 Diazepam rapidly penetrate the blood-brain barrier, resulting in a rapid onset of action. However, as a result of its lipophilic nature, it also rapidly redistributes
from the brain to other lipophilic tissues in the body, which determine the relatively short duration of the antiseizure effect after IV administration [73].
Lorazepam has a slower onset of action due to a lower entry of this agent into the brain but has a longer anticonvulsant action than diazepam [74].
Midazolam has a relatively short half-life after a single dose. A significantly increased half-life may be observed after prolonged infusion [75]. Drug metabolism
includes hydroxylation from CYP 3A4 and 3A5 [76]. Levels of midazolam are affected by enzyme inducing AEDs and by other medications that are inducers or
inhibitors, particularly during continuous infusion [77].
Adverse effects are similar for all benzodiazepines and include sedation, dizziness, weakness, unsteadiness, respiratory depression, and hypotension. There are
additive effects when several benzodiazepines are co-administered.
Stage Valproate prolongs sodium channel inactivation, attenuates calcium mediated transient currents and augments GABA.
2 Target levels: 75–100 mg/L.
It is a cytochrome P450 inhibitor, thus interacting with many medications [78].
Main adverse effects: hepatotoxicity, thrombocyte dysfunction, hyperammonemia, and acute hemorrhagic pancreatitis [79].
Valproate may be dangerous in patients with mitochondriopathy [80].
Levetiracetam modulate synaptic neurotransmitter release through binding to the synaptic vesicle protein SV2A in the brain.
It does not affect the cytochrome P450 enzymes [80].
It has a good tolerability profile.
Phenytoin blocks voltage gated sodium channels.
It has a worse than valproate and levetiracetam side-effect profile and several drug-drug interactions (cytochrome P450 inducer).
Two hours after the loading dose, phenytoin drug levels should be checked [10].
Target level: 15–20 mg/L.
Blood pressure and electrocardiographic monitoring is needed.
Caution in patients with AV block, atrial fibrillation and atrial flutter. PR interval should be <200 ms. [10].
Adverse effects: Hypotension, bradycardia, sino-atrial block, second- and third-degree atrio-ventricular block, severe tissue necrosis after paravenous infusion
[10]. A black box warning exists for cardiovascular risk with rapid infusions.
Lacosamide is a functionalized amino acid that enhances slow inactivation of voltage-gated sodium channels.
Caution in patients with AV block, atrial fibrillation and atrial flutter.
It has a relatively good tolerability profile.
Phenobarbital has been used in the past as a second or even a first line agent. It may cause respiratory depression and is a strong enzyme inducer which increases
the rate of metabolism of several drugs. Its efficacy has been demonstrated [81].
Stage Midazolam, for the mechanism of action and kinetic see above.
3 During continuous infusion, tachyphylaxis, may necessitate progressively higher doses.
At doses used in stage 2–3 it causes respiratory depression, requiring intubation for the duration of therapy.
Propofol has ultra-fast onset and rapid clearance even after extended infusion [82].
It is metabolized primarily through hepatic glucuronidation with subsequent renal excretion, though a significant portion is also metabolized by cytochrome
P450 isozymes [54].
Propofol is not indicated in young children [39].
Monitor lactate, creatine kinase, triglycerides, and potassium in prolonged use.
Adverse effects: hypotension (may require vasopressors), respiratory depression, and bradycardia. Hypertriglyceridemia is common (its formulation is a lipid
emulsion). Propofol-related infusion syndrome (PRIS: severe metabolic acidosis, rhabdomyolysis, renal failure, and circulatory collapse), is most often observed
in children, but has also been associated with prolonged infusions in refractory CSE in adults [83].
Thiopental has a nonlinear metabolism and a long half-life (ranging from 11 to 36 h) [84,85].
Autoinduction of its metabolism, which typically takes days to occur, is observed as well as several drug interactions.
Hepatically metabolized and highly protein-bound in plasma [86].
Therapeutic monitoring of pentobarbital levels should not be used to guide therapy for refractory CSE [39].
Adverse effects: hypotension, cardio-respiratory depression; and pancreatic and hepatic toxicity.
Ketamine may be used in conjunction with another anaesthetic, preferably one with GABAergic action. It has high lipid solubility leading to a fast onset and
extensive distribution, with an elimination half-life of around 2–3 h.
Metabolised by the cytochrome P450 system (especially CYP3A4) into the active metabolite norketamine [87].
Not associated with cardiac depression and hypotension or respiratory depression.
Induces a positive sympathetic response, sometimes leading to drug-induced hypertension. Dangerous in patients with coronary disease or cardiomyopathy.
Adverse effects: possible increase in intracranial pressure [39,51]. Hypersalivation may be relevant.
Agitation, confusion, and psychosis may be observed after ketamine is stopped.

When no otherwise specified, data are from Meldrum [88]; Falco Wolter and Bleck [10]; Reznik et al. [39]; Brophy et al. [25].

(cessation of seizure activity) in 75.7% of cases, phenobarbital in
73.6% and levetiracetam in 68.5%, while phenytoin showed the
lowest mean efficacy of 50.2%. There were insufficient data for the
efficacy assessment of lacosamide.
Recently, in a randomized study performed in India, 150 adult
subjects with established CSE (CSE not controlled by lorazepam),
were randomized to phenytoin, valproate and levetiracetam, and
no significant differences were observed between these drugs,
with success rates of 68%, 68% and 78%, respectively [28]. For a
comparison between levetiracetam, valproic acid and phenytoin,
one retrospective study showed that levetiracetam was signifi-
cantly less effective than valproate and phenytoin [29].
In recent years, several case reports [30] and small retrospective
studies with heterogeneous case series [31–33] have highlighted
the efficacy of lacosamide in this stage, however no precise
information can be drawn because this agent had been adminis-
tered at least in some patients, after a second line AED [31].
In conclusion, we should acknowledge that several methodo-
logical problems hamper an assessment of the comparative
efficacy of drugs used for the treatment of established CSE, much
more than the comparison of first-line treatments. In established
CSE, case series are more heterogeneous, and also the assessment
of results seems to be more influenced by the different outcome
measures adopted in the various studies [34]. In future studies,
efficacy criteria for the analysis of AEDs in the treatment of
established CSE should be standardized and a sufficient number of
patients should be recruited [35]. In the meantime, safety,
tolerability and ease of use of each individual drug should be
considered first in the selection of the most appropriate AED in this
stage of CSE.
 G. Zaccara et al. / Seizure 47 (2017) 17–24
2.3. Hospital management in the intensive care unit
2.3.1. Stage 3 (refractory CSE): CSE persisting after second-line
treatments
Between 23–44% of patients with CSE still have seizures after
second -line treatments and therefore, 60 min after the adminis-
tration of these agents, should be considered as affected by
refractory CSE [36–39]. Electroencephalography (EEG) with clinical
examination may be necessary to determine the persistence of CSE
at this stage. Neurocritical Care Society and American Epilepsy
Society guidelines recommend immediately starting anaesthetic
agents in combination with critical care treatments [25]. In the
meantime repeating additional doses of previously administered
second-line AEDs may be considered (see Table 1). At this stage,
CSE mortality has been calculated to vary between 16% and 39%
[40].
The most commonly used agents are midazolam, propofol, and
thiopental (pentobarbital in USA), which are given as bolus and/or
continuous infusions. Bolus doses can be added for breakthrough
seizures [38]. A fourth anaesthetic, ketamine, has also been
increasingly described for the treatment of this condition [37,38].
At this stage, the goal of total seizure suppression cannot be
achieved without inducing a therapeutic coma, and the intensity of
treatment is usually dictated by the cessation of electrographic
seizures or by a burst suppression pattern on the electroencepha-
logram (EEG) [25]. However, there is no clear finding that
therapeutic coma reduces mortality [41]. In addition, there is
evidence that patients with SE who receive anaesthetics have a
higher proportion of infection and an increased risk of death
compared to patients not receiving this treatment [42].
In a narrative meta-analysis of 28 open studies, it emerged that
titration of the anaesthetic agent to EEG background suppression
was associated with a significantly lower frequency of break-
through seizures than titration to seizure suppression, however
this was also associated with a significantly higher frequency of
complications (mainly hypotension). The choice of anaesthetic on
the other hand, did not seem to influence immediate treatment
failure and mortality [43].
Only one comparative, single blind, randomized, multi-center
trial compared two anaesthetic agents (propofol and barbiturates)
in the treatment of refractory CSE in adults [44]. Although 150
patients would have been randomized, this trial was terminated
after 3 years, with only 24 patients recruited, which demonstrates
the difficulty in conducting randomized trials in this condition. No
difference was observed between the two drugs, although
barbiturate were associated with a significantly longer mechanical
ventilation.
In a retrospective case series of 49 consecutive episodes of
refractory CSE which were treated with barbiturates, propofol or
midazolam, it was concluded that the outcome was independent of
the specific coma-inducing agent used and the extent of EEG burst
suppression [45].
There have been no prospective comparative trials for mid-
azolam, however a study was performed in which high and low
doses of this drug were compared [46]. Patients treated with high
doses (2.9 mg/kg/h) had fewer withdrawal seizures after weaning
midazolam infusion and a significantly lower mortality. Since in
refractory CSE, due to the internalization of GABA receptors,
benzodiazepines are ineffective or have a low efficacy, there is no
clear explanation for the effect of midazolam in this stage and it
may be due to a still unknown mechanism of action.
Several case series of patients treated with propofol have been
described, with generally favourable findings [47–50].
Ketamine is the fourth and least used anaesthetic agent for the
treatment of refractory CSE. A retrospective review of medical
records of 60 episodes of refractory CSE treated with this drug,
21
revealed that ketamine was believed to have contributed to the
permanent control of CSE in 32% of cases, although this drug had
often been added after other unsuccessful anaesthetic agents [51].
It has been suggested that the efficacy of this drug may be higher if
introduced earlier [34].
Due to the lack of sufficiently powered randomized studies, a
registry was developed in which patients who required general
anaesthesia for the control of SE could be prospectively included
[52]. Of the 488 cases registered, the most widely used anaesthetic
of first choice was found to be midazolam (59%), followed by
propofol and barbiturates. The anaesthetic agents most often used
after failure of a first anaesthetic agent were barbiturates followed
by midazolam. Ketamine was used in most severe cases, always as
a second, third, or fourth choice.
At this stage, guidelines traditionally recommend continuing
anaesthetic infusion for 24–48 h, followed by a gradual weaning off
the infusion [25,38]. Should seizures recur, an anaesthetic agent
infusion is resumed often at a higher dose [25].
In these patients, AEDs administered intravenously, through a
nasogastric tube or percutaneous endoscopic gastrostomy, should
be given in all cases, so that when the anaesthetic agent is
withdrawn, there is adequate antiepileptic cover [53]. There are no
data suggesting that any specific AED may be more indicated than
another. In a review of the literature, the AEDs most often used in
these circumstances were in the following order: topiramate,
levetiracetam, lacosamide and pregabalin [53]. It has been claimed
that weaning off thiopental (or pentobarbital) is associated with a
lower incidence of recurrence when phenobarbital is added before
weaning [38]. In the absence of any literature evidence, experts
suggest avoiding more than 2 drugs, to avoid frequent switches, as
rapid withdrawal can facilitate rebound seizures. On the other
hand, a rapid titration may facilitate allergic reactions. In order to
avoid drugs with a primarily GABAergic mechanism, drugs with
multiple mechanisms of action are recommended, with low
interaction potential and predictable kinetics [53].
2.4. Hospital management in the intensive care unit
2.4.1. Stage 4 (super-refractory CSE): CSE persisting for more than
24 hours after administration of third-line treatments
Recently, a new CSE stage was proposed for patients who are
not controlled by third-line anaesthetic compounds. Super-
refractory CSE has been defined as CSE that persists or recurs
for 24 h or more following a first course of anaesthetics for
therapeutic coma induction, and includes those cases in which CSE
recurs on the reduction or withdrawal of anaesthesia [58,59].
Approximately 10-15 10–15% of all patients presenting to
hospital with CSE develop super refractory CSE [53], although in a
recent retrospective study, a lower proportion of 4% was reported
[60]. In a retrospective analysis of a cohort of patients with CSE
admitted to a neurointensive care unit, super refractory CSE was
most often associated with encephalitis [61].
Short-term mortality is higher in super-refractory CSE than that
observed in refractory CSE [62].
This condition has been mainly described in two clinical
scenarios: 1) after a severe brain injury, 2) without any apparent
cause in patients with no history of epilepsy (new-onset refractory
status epilepticus-NORSE) [63–65]. Patients with NORSE, are
frequently young [66].
With the use of EEG, in these patients anaesthetic treatment
should be titrated to burst suppression, targeting an interburst
interval of about 10 s for 24 h [22]. However more recently the
amount of epileptiform activity in bursts was found to correlate
with success or failure to be weaned off anaesthetic treatment [67].
Anaesthesia can be reversed every 24–48 h and be re-established if
seizures reoccur. In patients who are in a coma state, seizures are
22 G. Zaccara et al. / Seizure 47 (2017) 17–24

Table 3
Drugs used in autoimmune status epilepticus.

Immunomodulatory agents
Newly onset refractory status epilepticus (NORSE) is a condition which may be caused by autoimmune mechanisms.
In the case status epilepticus is refractory to anticonvulsants and there is no other known cause, the inflammatory nature of CSE should be explored trough
neuroradiological examinations (cerebral MRI), and the search for inflammatory markers in the cerebrospinal fluid. Furthermore, the search for autoantibody in liquor
and blood should be undertaken [92]. Diagnosis of autoimmune SE is now feasible with antibody tests although in several cases, these tests are not readily available and,
in the case of negative findings of such tests, this diagnosis is not excluded. In those cases where this suspect is clinically justified, empiric immunomodulatory therapy
may be recommended [71,92–95].
Corticosteroids
IV methylprednisolone: 1 g daily for 5 days then weekly for 4–6 weeks
AND/OR
IV immunoglobulins: 0.4 g/kg daily for 3–5 days, then weekly for 4–6 weeks
OR
Plasmapheresis
In the case of positive response consider chronic immunosuppression (mycophnolate mofetil or azathioprine)
Second line immunosoppressive agents
Antibody antagonists are increasingly used, often in association with other immunosuppressant agents.
Rituximab (375 mg/m2 every week for 4 weeks) is the most used. Natalizumab and tocilizumab have also been used.
Immunosuppressants: cyclophophamide (750 mg/m2), given with the first dose of rituximab, followed by monthly cycles. Tacrolimus or cyclosporine A are also used
[93,94].

usually non convulsive, and the only way to assess seizure
recurrence is with an EEG [25]. Cycles of anaesthesia should be
repeated and, if CSE continues to recur, often in the form of “subtle”
SE, the duration of individual cycles should be increased and
anaesthesia continued for up to 5 days at a time [38]. The risk of
complications of these procedures should be weighed in the
individual patient.
In patients who do not respond to continuous infusion of a first
anaesthetic, the dose should be increased or another agent should
be started [38].
Ketamine is a second-line anaesthetic agent which increases
blood pressure, and thus may counteract the hemodynamic side
effects of other anaesthetic infusions. Very recently, a retrospective
analysis was published of 67 patients with super-refractory CSE
who received both propofol and ketamine with good results [68].
Recently, NORSE, which accounts for approximately 40% of
refractory CSE cases, was shown to be autoimmune or paraneo-
plastic in nature in several cases [69,70]. Early immuno-
modulatory treatments are thus increasingly becoming the
mainstay of treatment, in addition to traditional anti-epileptic
agents [65,71]. Therapy with high-dose steroids and a course of
intravenous immunoglobulin or plasma exchange is usually
started (see Table 3).
Hypothermia has been used in a few cases, although there is a
very low evidence of efficacy in this condition [72]. Deep levels
may be unsafe [25,42]. Finally, there is also low efficacy evidence
for other treatments such as a ketogenic diet, or magnesium or
pyridoxine infusions [53]. In rare cases, good long-term effects
have been reported with neurosurgery, including focal resection,
multiple subpial transection, corpus callosectomy or hemispher-
ectomy [53].
3. Conclusions
not seem more effective, and perhaps is less effective than
valproate, it is certainly associated with several risks and is not
easy to administer [26,27]. It requires a loading dose and a slow
infusion rate with a consequent delay in the onset of action. A
further disadvantage which needs emphasizing, is that this drug
is an enzymatic inducer which may have serious consequences
particularly in patients who need other drugs whose metabo-
lism may be induced, such as midazolam, corticosteroids and
other immunosuppressive agents [89]. The Established Status
Epilepticus Treatment Trial (ESETT), which is currently enrolling
patients, is in the process of comparing the three most
commonly used agents (valproate, phenytoin, and levetirace-
tam) and will hopefully provide important information on this
point [90,91].
3) In stages 3 (refractory CSE), and 4 (super-refractory CSE),
thiopental or pentobarbital (in the USA) are strong inducers
which may affect several treatments [39]. They also have a
long half-life, a lot of adverse effects [39,41] and, where
possible, should be avoided. From a theoretical point of view, a
combination of ketamine with midazolam or propofol [39],
might also be interesting to assess in randomized studies.
4) Finally, in refractory CSE and super-refractory CSE, particularly
when these serious conditions appear in non epileptic subjects
(NORSE) with no apparent cause for this condition, an
autoimmune CSE should be suspected [59,65]. In these cases,
even without finding positive antibodies, it might be appropri-
ate to start immunosuppressive treatments (corticosteroids and
IV immunoglobulins). However it should be also taken into
account that these conditions may not be responsive to first-
line drugs and that in some cases, also second-line immuno-
suppressive agents might be required such as cyclophospha-
mide, rituximab [92,93] or even cyclosporine A, tacrolimus and
other immunosuppressants [94,95].

The treatment of CSE is still challenging. Almost all evidence of

efficacy regards the early stages of this serious and life-threatening
Funding
condition. In the most severe forms, all treatment decisions are
only based on case series and expert opinions.
The authors received no funding for this study.
Here we summarise the most important findings in the field:

1) In the early stages, the most important issue is time. In the Disclosure
prehospital setting, IM midazolam may be preferable due to the
rapidity of administration which offsets the faster effect of IV GZ has received speaker’s or consultancy fees from EISAI,
formulations [15]. Jansen-Cilag, and UCB Pharma. GG, RO, LT, and ER report no
2) In stage 2, established status epilepticus, phenytoin can no disclosures.
longer be considered as the first choice. While phenytoin does
 G. Zaccara et al. / Seizure 47 (2017) 17–24 23

Appendix A. guidelines for the evaluation and management of status epilepticus. Neurocrit
Care 2012;17:3–23.
[26] Riviello Jr. JJ, Claassen J, LaRoche SM, Sperling MR, Alldredge B, Bleck TP, et al.
Members of the convulsive status epilepticus study group of the Neurocritical care society status epilepticus guideline writing committee.
uslcentro Toscana, Italy. Treatment of status epilepticus: an international survey of experts. Neurocrit
Paola Bartalucci, Alessandra Borgheresi, Roberto Campostrini, Care 2013;18:193–200.
[27] Yasiry Z, Shorvon S. The relative effectiveness of five antiepileptic drugs in
Barbara Chiocchetti, Massimo Cincotta, Fabio Daviddi, Giovanni treatment of benzodiazepine-resistant convulsive status epilepticus: a meta-
Del Sorbo, Lucia Devito, Camilla Ferrari, Maria Lombardi, Marco analysis of published studies. Seizure 2014;23:167–74.
Monfardini, Mario Rugna, Emma Sirabella, Milena Taglioli, Laura [28] Mundlamuri RC, Sinha S, Subbakrishna DK, Prathyusha PV, Nagappa M, Bindu
PS, et al. Management of generalised convulsive status epilepticus (SE): a
Tirelli, Gino Volpi. prospective randomised controlled study of combined treatment with
intravenous lorazepam with either phenytoin, sodium valproate or levetir-
References acetam – Pilot study. Epilepsy Res 2015;114:52–8.
[29] Alvarez V, Januel J, Burnand B, Rossetti AO. Second-line status epilepticus
treatment: comparison of phenytoin, valproate and levetiracetam. Epilepsia
[1] DeLorenzo RJ, Hauser WA, Towne AR, Boggs JG, Pellock JM, Penberthy L, et al. A
2011;52:1292–6.
prospective, population-based epidemiologic study of status epilepticus in
[30] Grosso S, Zamponi N, Bartocci A, Cesaroni E, Cappanera S, Di Bartolo R, et al.
Richmond, Virginia. Neurology 1996;46:1029–35.
Lacosamide in children with refractory status epilepticus: a multicenter Italian
[2] Hesdorffer DC, Logroscino G, Cascino G, Annegers JF, Hauser WA. Incidence of
experience. Eur J Paediatr Neurol 2014;18:604–8.
status epilepticus in Rochester, Minnesota, 1965–1984. Neurology
[31] Moreno Morales EY, Fernandez Peleteiro M, Bondy Peña EC, Domínguez
1998;50:735–41.
Lorenzo JM, Pardellas Santiago E, Fernández A. Observational study of
[3] Sánchez S, Rincon F. Status epilepticus: epidemiology and public health needs.
intravenous lacosamide in patients with convulsive versus non-convulsive
J Clin Med 20165(8).
status epilepticus. Clin Drug Investig 2015;35:463–9.
[4] Betjemann JP, Lowenstein DH. Status epilepticus in adults. Lancet Neurol
[32] Arkilo D, Gustafson M, Ritter FJ. Clinical experience of intravenous lacosamide
2015;14:615–24.
in infants and young children. Eur J Paediatr Neurol 2016;20:212–7.
[5] Logroscino G, Hesdorffer DC, Cascino G, Annegers JF, Hauser WA. Short-term
[33] Poddar K, Sharma R, Ng YT. Intravenous lacosamide in pediatric status
mortality after a first episode of status epilepticus. Epilepsia 1997;38:1344–9.
epilepticus: an open-label efficacy and safety study. Pediatr Neurol
[6] Logroscino G, Hesdorffer DC, Cascino G, Annegers JF, Hauser WA. Time trends
2016;61:83–6.
in incidence, mortality, and case-fatality after first episode of status
[34] Redecker J, Wittstock M, Benecke R, Rösche J. Comparison of the effectiveness
epilepticus. Epilepsia 2001;42:1031–5.
of four antiepileptic drugs in the treatment of status epilepticus according to
[7] Trinka E, Cock H, Hesdorffer D, Rossetti AO, Scheffer IE, Shinnar S, et al. A
four different efficacy criteria. Epilepsy Behav 2015;49:351–3.
definition and classification of status epilepticus—report of the ILAE Task Force
[35] Brigo F, Bragazzi N, Nardone R, Trinka E. Direct and indirect comparison meta-
on Classification of Status Epilepticus. Epilepsia 2015;56:1515–23.
analysis of levetiracetam versus phenytoin or valproate for convulsive status
[8] Niquet J, Baldwin R, Suchomelova L, Lumley L, Naylor D, Eavey R, et al.
epilepticus. Epilepsy Behav 2016;64:110–5.
Benzodiazepine-refractory status epilepticus: pathophysiology and principles
[36] Novy J, Logroscino G, Rossetti AO. Refractory status epilepticus: a prospective
of treatment. Ann N Y Acad Sci 2016;1378:166–73.
observational study. Epilepsia 2010;51:251–6.
[9] Löscher W. Molecular mechanisms of drug resistance in status epilepticus.
[37] Rossetti A, Lowenstein DH. Management of refractory status epilepticus in
Epilepsia 2009;50(Suppl. 8):19–21.
adults: still more questions than answers. Lancet Neurol 2011;10:922–30.
[10] Falco-Walter JJ, Bleck T. Treatment of established status epilepticus. J Clin Med
[38] Grover EH, Nazzal Y, Hirsch LJ. Treatment of convulsive status epilepticus. Curr
20165(5).
Treat Options Neurol 2016;18:11.
[11] Welch RD, Nicholas K, Durkalski-Mauldin VL, Lowenstein DH, Conwit R,
[39] Reznik ME, Berger K, Claassen J. Comparison of intravenous anesthetic agents
Mahajan PV, et al. Intramuscular midazolam versus intravenous lorazepam for
for the treatment of refractory status epilepticus. J Clin Med 20165(5).
the prehospital treatment of status epilepticus in the pediatric population.
[40] Holtkamp M, Othman J, Buchheim K, Meierkord H. Predictors and prognosis of
Epilepsia 2015;56:254–62.
refractory status epilepticus treated in a neurological intensive care unit. J
[12] https://www.medicines.org.uk/emc/medicine/23636.
Neurol Neurosurg Psychiatry 2005;76:534–9.
[13] Alldredge BK, Gelb AM, Isaacs SM, Corry MD, Allen F, Ulrich S, et al. A
[41] Alvarez V, Lee JW, Westover MB, Drislane FW, Novy J, Faouzi M, et al.
comparison of lorazepam, diazepam, and placebo for the treatment of out-of-
Therapeutic coma for status epilepticus: differing practices in a prospective
hospital status epilepticus. N Engl J Med 2001;345:631–7.
multicenter study. Neurology 2016(September) pii: 10.1212/
[14] Ochoa JG, Kilgo WA. The role of benzodiazepines in the treatment of epilepsy.
WNL.0000000000003224.
Curr Treat Options Neurol 2016;18(4):18.
[42] Sutter R, Marsch S, Fuhr P, Kaplan PW, Rüegg S. Anesthetic drugs in status
[15] Silbergleit R, Durkalski V, Lowenstein D, Conwit R, Pancioli A, Palesch Y, et al.
epilepticus: risk or rescue? A 6-year cohort study. Neurology 2014;82:656–64.
Intramuscular versus intravenous therapy for prehospital status epilepticus. N
[43] Claassen J, Hirsch LJ, Emerson RG, Mayer SA. Treatment of refractory status
Engl J Med 2012;366:591–600.
epilepticus with pentobarbital, propofol, or midazolam: a systematic review.
[16] Arya R, Kothari H, Zhang Z, Han B, Horn PS, Glauser TA. Efficacy of nonvenous
Epilepsia 2002;43:146–53.
medications for acute convulsive seizures: a network meta-analysis.
[44] Rossetti AO, Milligan TA, Vulliémoz S, Michaelides C, Bertschi M, Lee JW. A
Neurology 2015;85:1859–68.
randomized trial for the treatment of refractory status epilepticus. Neurocrit
[17] Brigo F, Nardone R, Tezzon F, Trinka E. A common reference-based indirect
Care 2011;14:4–10.
comparison meta-analysis of buccal versus intranasal midazolam for early
[45] Rossetti AO, Logroscino G, Bromfield EB. Refractory status epilepticus: effect of
status epilepticus. CNS Drugs 2015;29:741–57.
treatment aggressiveness on prognosis. Arch Neurol 2005;62:1698–702.
[18] Brigo F, Nardone R, Tezzon F, Trinka E. Nonintravenous midazolam versus
[46] Fernandez A, Lantigua H, Lesch C, Shao B, Foreman B, Schmidt JM, et al. High-
intravenous or rectal diazepam for the treatment of early status epilepticus: a
dose midazolam infusion for refractory status epilepticus. Neurology
systematic review with meta-analysis. Epilepsy Behav 2015;49:325–36.
2014;82:359–65.
[19] Brigo F, Bragazzi NL, Bacigaluppi S, Nardone R, Trinka E. Is intravenous
[47] Prasad A, Worrall BB, Bertram EH, Bleck TP. Propofol and midazolam in the
lorazepam really more effective and safe than intravenous diazepam as first-
treatment of refractory status epilepticus. Epilepsia 2001;42:380–6.
line treatment for convulsive status epilepticus? A systematic review with
[48] Stecker MM, Kramer TH, Raps EC, O’Meeghan R, Dulaney E, Skaar DJ. Treatment
meta-analysis of randomized controlled trials. Epilepsy Behav 2016;64:29–36.
of refractory status epilepticus with propofol: clinical and pharmacokinetic
[20] De Winter S, Vanbrabant P, Spriet I, Desruelles D, Indevuyst C, Knockaert D,
findings. Epilepsia 1998;39:18–26.
et al. A simple tool to improve medication reconciliation at the emergency
[49] Parviainen I, Uusaro A, Kalviainen R, Mervaala E, Ruokonen E. Propofol in the
department. Eur J Intern Med 2011;22:382–5.
treatment of refractory status epilepticus. Intensive Care Med 2006;32:1075–
[21] Glauser T, Shinnar S, Gloss D, Alldredge B, Arya R, Bainbridge J, et al. Evidence-
9.
based guideline: treatment of convulsive status epilepticus in children and
[50] Power KN, Flaatten H, Gilhus NE, Engelsen BA. Propofol treatment in adult
adults: report of the guideline committee of the american epilepsy society.
refractory status epilepticus: mortality risk and outcome. Epilepsy Res
Epilepsy Curr 2016;16:48–61.
2011;94:53–60.
[22] Alvarez V, Lee JW, Drislane FW, Westover MB, Novy J, Dworetzky BA, et al.
[51] Gaspard N, Foreman B, Judd LM, Brenton JN, Nathan BR, McCoy BM, et al.
Practice variability and efficacy of clonazepam, lorazepam, and midazolam in
Intravenous ketamine for the treatment of refractory status epilepticus: a
status epilepticus: a multicenter comparison. Epilepsia 2015;56:1275–85.
retrospective multicenter study. Epilepsia 2013;54:1498–503.
[23] Chen WB, Gao R, Su YY, Zhao JW, Zhang YZ, Wang L, et al. Valproate versus
[52] Ferlisi M, Hocker S, Grade M, Trinka E, Shorvon S. International Steering
diazepam for generalized convulsive status epilepticus: a pilot study. Eur J
Committee of the StEp Audit: preliminary results of the global audit of
Neurol 2011;18:1391–6.
treatment of refractory status epilepticus. Epilepsy Behav 2015;49:318–24.
[24] Meierkord H, Boon P, Engelsen B, Göcke K, Tinuper P, Holtkamp M. EFNS
[53] Ferlisi M, Shorvon S. The outcome of therapies in refractory and super-
guideline on the management of status epilepticus in adults. Eur J Neurol
refractory convulsive status epilepticus and recommendations for therapy.
2010;17:348–55.
Brain 2012;135:2314–28.
[25] Brophy GM, Bell R, Claassen J, Alldredge B, Bleck TP, Glauser T, et al.
[54] Kanto J, Gepts E. Pharmacokinetic implications for the clinical use of propofol.
Neurocritical care society status epilepticus guideline writing committee:
Clin Pharmacokinet 1989;17:308–26.
24 G. Zaccara et al. / Seizure 47 (2017) 17–24
[55] Sabharwal V, Ramsay E, Martinez R, Shumate R, Khan F, Dave H, et al. Propofol-
ketamine combination therapy for effective control of super-refractory status
epilepticus. Epilepsy Behav 2015;52:264–6.
[56] Pandey CK, Singh N, Bose N, Sahay S. Gabapentin and propofol for treatment of
status epilepticus in acute intermittent porphyria. J Postgrad Med
2003;49:285.
[57] Bhatia R, Vibha D, Srivastava MV, Prasad K, Tripathi M, Bhushan Singh M. Use of
propofol anesthesia and adjunctive treatment with levetiracetam and
gabapentin in managing status epilepticus in a patient of acute intermittent
porphyria. Epilepsia 2008;49:934–6.
[58] Shorvon S, Trinka E. Status epilepticus – making progress. Epilepsia 2011;52
(Suppl. 8):1–2.
[59] Shorvon S, Ferlisi M. The treatment of super-refractory status epilepticus: a
critical review of available therapies and a clinical treatment protocol. Brain
2011;134:2802–18.
[60] Delaj L, Novy J, Ryvlin P, Marchi NA, Rossetti AO. Refractory and super-
refractory status epilepticus in adults: a 9-year cohort study. Acta Neurol
Scand 2017;135:92–9.
[61] Jayalakshmi S, Ruikar D, Vooturi S, Alladi S, Sahu S, Kaul S, et al. Determinants
and predictors of outcome in super refractory status epilepticus – a developing
country perspective. Epilepsy Res 2014;108:1609–17.
[62] Giovannini G, Monti G, Polisi MM, Mirandola L, Marudi A, Pinelli G, et al. A one-
year prospective study of refractory status epilepticus in Modena, Italy.
Epilepsy Behav 2015;49:141–5.
[63] Rathakrishnan R, Wilder-Smith EP. New onset refractory status epilepticus
(NORSE). J Neurol Sci 2009;284:220.
[64] Khawaja AM, De Wolfe JL, Miller DW, Szaflarski JP. New-onset refractory status
epilepticus (NORSE)—the potential role for immunotherapy. Epilepsy Behav
2015;47:17–23.
[65] Cuero MR, Varelas PN. Super-refractory status epilepticus. Curr Neurol
Neurosci Rep 2015;15:74.
[66] Holtkamp M, Othman J, Buchheim K, Meierkord H. Predictors and prognosis of
refractory status epilepticus treated in a neurological intensive care unit. J
Neurol Neurosurg Psychiatry 2005;76:534–9.
[67] Johnson EL, Martinez NC, Ritzl EK. EEG characteristics of successful burst
suppression for refractory status epilepticus. Neurocrit Care 2016(July).
[68] Sabharwal V, Ramsay E, Martinez R, Shumate R, Khan F, Dave H, et al. Propofol-
ketamine combination therapy for effective control of super-refractory status
epilepticus. Epilepsy Behav 2015;52:264–6.
[69] Gaspard N, Foreman BP, Alvarez V, Cabrera Kang C, Probasco JC, Jongeling AC,
et al. New-onset refractory status epilepticus: etiology, clinical features, and
outcome. Neurology 2015;85:1604–13.
[70] Spatola M, Novy J, Du Pasquier R, Dalmau J, Rossetti AO. Status epilepticus of
inflammatory etiology. Neurology 2015;85:464–70.
[71] Lopinto-Khoury C, Sperling MR. Autoimmune status epilepticus. Curr Treat
Options Neurol 2013;15:545–56.
[72] Zeiler FA, Zeiler KJ, Teitelbaum J, Gillman LM, West M. Therapeutic
hypothermia for refractory status epilepticus. Can J Neurol Sci
2015;42:221–9.
[73] Ramsay RE, Hammond EJ, Perchalski RJ, Wilder BJ. Brain uptake of phenytoin,
phenobarbital, and diazepam. Arch Neurol 1979;36:535–9.
[74] Greenblatt DJ, Ehrenberg BL, Gunderman J, Scavone JM, Tai NT, Harmatz JS,
et al. Kinetic and dynamic study of intravenous lorazepam: comparison with
intravenous diazepam. J Pharmacol Exp Ther 1989;250:134–40.
[75] Bodmer M, Link B, Grignaschi N, Kummer O, Ruegg S, Haschke M, et al.
Pharmacokinetics of midazolam and metabolites in a patient with refractory
status epilepticus treated with extraordinary doses of midazolam. Ther Drug
Monit 2008;30:120–4.
[76] Bebin M, Bleck TP. New anticonvulsant drugs focus on flunarizine,
fosphenytoin, midazolam and stiripentol. Drugs 1994;48:153–71.
[77] Bolon M, Boulieu R, Flamens C, Paulus S, Bastien O. Sedation induced by
midazolam in intensive care: pharmacologic and pharmacokinetic aspects.
Ann Fr Anesth Reanim 2002;21:478–92.
[78] Zaccara G, Messori A, Moroni F. Clinical pharmacokinetics of valproic acid–
1988. Clin Pharmacokinet 1988;15:367–89.
[79] Zaccara G, Franciotta D, Perucca E. Idiosyncratic adverse reactions to
antiepileptic drugs. Epilepsia 2007;48:1223–44.
[80] Radtke RA. Pharmacokinetics of levetiracetam. Epilepsia 2001;42(Suppl.
4):24–7.
[81] Treiman DM, Meyers PD, Walton NY, Collins JF, Colling C, Rowan AJ, et al. A
comparison of four treatments for generalized convulsive status epilepticus:
Veterans Affairs Status Epilepticus Cooperative Study Group. N Engl J Med
1998;339(September (12)):792–8.
[82] Bailie GR, Cockshott ID, Douglas EJ, Bowles BJM. Pharmacokinetics of propofol
during and after long term continuous infusion for maintenance of sedation in
icu patients. Br J Anaesth 1992;68:486–91.
[83] Vasile B, Rasulo F, Candiani A, Latronico N. The pathophysiology of propofol
infusion syndrome: a simple name for a complex syndrome. Intensive Care
Med 2003;29:1417–25.
[84] Steudel H, Steudel A, von Unruh GE. Assay for cyclo-, seco- and pentobarbital
by multiple ion detection: kinetics after a single dose. J Clin Chem Clin
Biochem 1982;20:267–9.
[85] Russo H, Bressolle F, Brès J, Duboin MP. Nonlinear pharmacokinetics of high-
dose thiopental following long term treatment. Clin. Drug Investig
2012;11:32–42.
[86] Morgan DJ, Blackman JL, Paull JD, Wolf LJ. Pharmacokinetics and plasma
binding of thiopental. I: studies in surgical patients. Anesthesiology
1981;54:468–73.
[87] Mion G, Villevieille T. Ketamine pharmacology: an update (pharmacodynam-
ics and molecular aspects, recent findings). CNS Neurosci Ther 2013;19:370–
80.
[88] Meldrum BS. Update on the mechanism of action of antiepileptic drugs.
Epilepsia 1996;37(Suppl. 6):S4–11.
[89] Zaccara G, Perucca E. Interactions between antiepileptic drugs, and between
antiepileptic drugs and other drugs. Epileptic Disord 2014;16:409–31.
[90] Cock HR, ESETT Group. Established status epilepticus treatment trial (ESETT).
Epilepsia 2011;52(Suppl. 8):50–2.
[91] Bleck T, Cock H, Chamberlain J, Cloyd J, Connor J, Elm J, et al. The established
status epilepticus trial 2013. Epilepsia 2013;54:89–92.
[92] Kadoya M, Onoue H, Kadoya A, Ikewaki K, Kaida K. Refractory status epilepticus
caused by anti-NMDA receptor encephalitis that markedly improved following
combination therapy with rituximab and cyclophosphamide. Intern Med
2015;54:209–13.
[93] Melvin JJ, Huntley Hardison H. Immunomodulatory treatments in epilepsy.
Semin Pediatr Neurol 2014;21:232–7.
[94] Toledano M, Britton JW, McKeon A, Shin C, Lennon VA, Quek AM, et al. Utility of
an immunotherapy trial in evaluating patients with presumed autoimmune
epilepsy. Neurology 2014;82:1578–86.
[95] Bakpa OD, Reuber M, Irani SR. Antibody-associated epilepsies: clinical
features, evidence for immunotherapies and future research questions.
Seizure 2016;41:26–41.