Keywords
Status Epilepticus - Refractory - Super-Refractory - Antiseizure Medications
INTRODUCTION
Status epilepticus (SE) is considered the most extreme form of seizure and the most
severe presentation of epilepsy. It consists in abnormally-prolonged or recurrent
seizures without recovery of the baseline status between them. Previous classifications
of seizures defined SE as a seizure that “persists for a sufficient length of time
or is repeated frequently enough that recovery between attacks does not occur.”[1] More recently, SE has been defined considering two distinct time frames, which will
be discussed in the following sections.
Status epilepticus affects all age groups, though with different etiologies and outcomes.
It causes higher mortality and morbidity in elderly people, while it has better outcomes
in children and adolescents.
DEFINITION
Status epilepticus has long been defined as abnormally-prolonged or recurrent seizures.[2] In 2015, the International League Against Epilepsy (ILAE) Task Force on Classification
of Status Epilepticus published a definition and classification of SE.[3] According to the current ILAE proposal, SE is defined as “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 t1). It is a condition which can have long-term consequences (after time point
t2), including neuronal death, neuronal injury, and alteration of neuronal networks,
depending on the type and duration of seizures”. Therefore, two time points are defined
in the evolution of prolonged seizures. For the most severe type of SE – convulsive
SE –, these time points are best defined, and have clinical significance: time 1 (t1)
is 5 minutes, as after this time it is unlikely that the seizure will resolve spontaneously,
therefore requiring initiation of therapy; and time 2 (t2) is 30 minutes, as seizures
that last beyond this time are more likely to cause long-term consequences. From a
clinical point of view, one should start treatment at t1, aggressively enough so that
the seizure does not last until t2. For other types of seizures, evidence supporting
these time frames is less conclusive ([Table 1]).
Table 1
Time points t1 and t2 according to seizure type in status epilepticus (SE)
|
t1, when a seizure is likely to be prolonged
|
t2, when a seizure may cause long-term consequences
|
|
Convulsive SE
|
5 minutes
|
30 minutes
|
|
Focal SE
|
10 minutes
|
> 60 minutes
|
|
Absent SE
|
10–15 minutes
|
Unknown
|
Note: Adapted from Trinka et al.[3]
The report of the ILAE Task Force[3] also proposes 4 axes for classification of SE: semiology; etiology; electroencephalogram
(EEG) correlates; and age.
With respect to semiology, two criteria are used to define the type of SE: the presence
or absence of prominent motor symptoms and the degree of consciousness impairment.
In convulsive SE, there are prominent motor symptoms along with impairment of consciousness, whereas
in nonconvulsive SE consciousness impairment occurs without accompanying motor symptoms. Most of the
data on the treatment of SE is based on studies addressing convulsive SE; the evidence
for the treatment of nonconvulsive SE is much scarcer. The underlying cause of SE
is categorized into known etiologies, when SE is caused by a known disorder, or unknown,
or cryptogenic, if the etiology is not defined after the diagnostic investigation.
Etiologies known to cause SE include acute causes, such as stroke, encephalitis, intoxication,
and others; remote causes, including poststroke and posttraumatic; and progressive
diseases, such as brain tumors and neurodegenerative diseases. Status epilepticus
can also occur in the context of defined electroclinical syndromes, in which SE is
a severe presentation of seizures.
EPIDEMIOLOGY
The annual incidence of SE ranges from 14 to 35 per 100 thousand children[4]
[5] and from 5 to 36 per 100 thousand adults,[6] although different methodologies in various studies, as well as the introduction
of the new diagnostic criteria and classification,[7] limit the comparison of results among the epidemiological studies. Most epidemiological
studies refer to convulsive SE, so data reflects more likely this type of SE. The
incidence of SE, as that of epilepsy, presents a bimodal age distribution:[7]
[8] it is higher in children and in older adults, with different causes in the two groups;
in children, febrile illnesses constitute the most common cause of SE, while in adults,
stroke is the leading cause.[6]
[8]
[9]
TREATMENT
Status epilepticus is a common neurological emergency, with high morbidity and mortality,
especially in its convulsive form. Early recognition of this condition should lead
to prompt initiation of therapy, as early treatment is associated with improved outcomes.[10]
Most data on the treatment of SE pertains to convulsive SE, as evidence on the treatment
of nonconvulsive SE is much scarcer. In the following section, we will discuss the
approach to children and adults with convulsive SE. The recommendations for treatment
are largely based on previously published guidelines,[11]
[12] which have adapted to the current availability of antiseizure medications (ASMs)
in Brazil.
Initial approach
As with any medical emergency, the treatment of convulsive SE begins with an accurate
diagnosis, followed by clinical stabilization and the administration of ASMs. The
primary treatment objectives can be summarized in three steps, which should be performed
simultaneously:
-
Assessing if airway, breathing, and circulation are secure and adequate;
-
Using ASMs to stop the seizure; and
-
Identifying the etiology of seizures/SE and initiating specific treatment when possible.
Heart rate, blood pressure, breathing and pulse oximetry should be monitored in all
patients, particularly in those with ongoing convulsions. Transient apnea and hypoxemia
are common in patients with convulsive SE. In those with cyanosis and/or low oxygen
levels by pulse oximetry, 100% oxygen should be provided, either by nasal catheter
or bag-mask ventilation. If these measures fail to maintain adequate breathing and
oxygenation, endotracheal intubation and mechanical ventilation should be considered.
For intubation, an agent with antiseizure properties, such as propofol or midazolam,
may be used.
To obtain blood samples for laboratory tests and to facilitate the intravenous (IV)
administration of ASMs, peripheral IV access is required, preferably with at least
two catheters. A finger-stick glucose test should be performed immediately, and if
hypoglycemia is detected, it should be treated promptly with thiamine and a dextrose
solution. Initial blood and urine tests are shown in [Table 2].
Table 2
Initial blood and urine tests
|
Complete blood count;
Serum glucose;
Serum electrolytes;
Liver function tests;
Urine and blood toxicology;
Pregnancy test (blood or urine) in women of childbearing age; and
Serum levels of antiseizure medications (in patients taking them)
|
A 12-lead electrocardiogram (ECG) should be performed as soon as possible, and cardiac
troponin levels may be considered, as cardiac injury can complicate prolonged seizures
and SE.[13]
After clinical stabilization and seizure control with ASMs, a neuroimaging exam should
be performed. Magnetic resonance imaging (MRI) of the brain is preferred over a head
computed tomography (CT) to identify the cause of SE; however, CT is typically more
accessible in the emergency department. If a brain imaging study excludes a brain
lesion, a lumbar puncture for cerebrospinal fluid analysis may be performed if a central
nervous system (CNS) infection is clinically suspected. If prompt brain imaging is
not possible and there is a high suspicion of infection, empirical antibiotics should
be initiated.
Treatment with ASMs
Along with clinical stabilization of the patient, treatment of prolonged seizures
and SE should be started immediately. The primary goal of treatment is to stop the
seizure and prevent secondary neurological damage.
First-line treatment
It has long been established that the first phase of treatment of convulsive SE is
the rapid administration of benzodiazepines (BZDs). The seminal study by Treiman et
al.[14] laid the foundations for the use of BZDs. In this multicenter study, adult patients
with overt SE, defined as continuous generalized tonic-clonic (GTC) seizure lasting
10 minutes or longer, or 2 or more GTC seizures without full recovery of consciousness,
were randomly allocated to 1 of 4 arms of treatment, all with IV medications: lorazepam
(0.1 mg/kg); diazepam (0.15 mg/kg) followed by phenytoin (18 mg/kg); phenobarbital
(18 mg/kg); and phenytoin alone (18 mg/kg). Lorazepam was found to be superior to
phenytoin in stopping seizures within 20 minutes of IV infusion, with no recurrence
prior to 60 minutes (p = 0.001). Interestingly, lorazepam was no more efficacious than phenobarbital or
diazepam and phenytoin, but the authors[14] argued it was easier to use. Since then, lorazepam remains as the first line of
treatment in convulsive SE.
Which is the ideal BZD for the treatment of convulsive SE? The ideal agent should
be safe, easy to administer, have long-lasting antiseizure effect, and no relevant
side effects.[15] No single drug fulfills all of these requirements, and the choice of BZD must be
based on existing guidelines and availability.
Intravenous lorazepam has been compared with IV diazepam in a class-II study,[16] and there was no significant difference with respect to seizure control. The Paramedic
Treatment of Prolonged Seizures by Intramuscular Versus Intravenous Anticonvulsant
Medications (RAMPART) trial,[17] published in 2012, brought a highly-important contribution to the issue of BZD choice
in convulsive SE. In this study, intramuscular midazolam was compared with IV lorazepam
in adults and children with SE, defined as convulsive seizures lasting more than 5 minutes
and still occurring after paramedic arrival. Patients received either 10 mg (or 5 mg
in children weighing between 13 and 40 kg) of intramuscular (IM) midazolam or 4 mg
(or 2 mg in children weighing between 13 and 40 kg) of IV lorazepam. The aim of the
trial was to demonstrate the noninferiority of IM midazolam when compared with IV
lorazepam. Seizure cessation was achieved in 73% of subjects in the IM midazolam group,
compared with 63% in the IV lorazepam group.[17] This result met the prespecified noninferiority requirement; moreover, it also demonstrated
superiority of midazolam in patients without established IV access.
Intravenous lorazepam is not available in Brazil. Therefore, IV diazepam or IM midazolam
are recommended ([Figure 1]). For patients without established IV access, IM midazolam is preferred to avoid
delays in initiating the treatment. When IV access is not promptly available, midazolam
may also be administered by nasal spray, which is has been approved by the United
States Food and Drug Administration (FDA) for the acute treatment of seizure clusters
in patients aged ≥ 12 years, or by oromucosal solution, which has been approved in
Europe for prolonged seizures in children aged ≥ 3 months.[15] A recent systematic review[18] analyzed 12 studies with 929 patients who received intranasal midazolam for the
treatment of prolonged seizures or SE, in single doses varying from 2.5 to 20 mg.
Seizure termination was achieved in 72.7% of the patients, although seizures recurred
in 36.5%.[18] Diazepam nasal spray has also been approved by the FDA for the acute treatment of
seizure clusters in patients aged ≥ 6 years.[15] However, nasal midazolam and diazepam sprays, as well as midazolam oromucosal solutions,
are not commercially available in Brazil.
Figure 1 Treatment algorithm for convulsive status epilepticus.
As with stroke treatment, the aphorism “time is brain” should be kept in mind when
treating SE, as treatment delays are independently associated with prolonged time
until SE cessation.[10] Also, the dosing of the chosen BZD should be appropriate for each patient. In the
clinical practice, treatment guidelines are not followed in a substantial proportion
of patients. In a registry study of 1,049 patients,[10] the median latency between SE onset and the first treatment was of 30 minutes in
patients with convulsive SE, and, in 76% of these cases, the bolus doses in the initial
treatment step were lower than recommended. Treatment delays and underdosing were
associated with failure to achieve SE cessation.[10] The Established Status Epilepticus Treatment Trial (ESETT)[19] studied the patterns of BZD use as the first-line treatment of SE and the association
of BZD doses with response to second-line agents. In 460 patients who received 1,170
doses of BZDs (669 of lorazepam, 398 of midazolam, and 103 of diazepam), the first
dose of the first BZD was lower than that recommended in the guideline in 76% of midazolam
administrations and in 81% of lorazepam administrations. Among all administrations, > 85%
of those of midazolam and > 76% of those of lorazepam were lower than recommended,
and the authors[20] concluded that underdosing of BZD in SE treatment is both pervasive and difficult
to remediate.
Given the current recommendations for BZD use as the first-line treatment of SE, it
is worth emphasizing that appropriate timing and dosing are more important than the
choice of the BZD itself, as earlier and more effective treatment of SE will lead
to a better outcome.
Second-line treatment
The second stage of treatment of SE begins when seizures persist after one or two
doses of BZD. If the seizures respond to BZD, second-line medications should also
be administered to prevent seizure recurrence,[11] as treatment with BZD alone carries a high risk of recurrence,[14]
[17] maybe with the exception of patients in whom a rapidly-reversible cause of SE has
been identified and treated, such as severe hyponatremia of hypoglycemia;[11] with respect to hyponatremia, it is worth noting that the rapid treatment of this
disturbance carries risk of complications, mainly osmotic demyelination syndrome.
In this stage, the mainstay of treatment is the use of IV ASMs. Currently, five ASMs
can be loaded intravenously: phenytoin (or fosphenytoin), valproic acid, levetiracetam,
phenobarbital, and lacosamide.
Until recently, the choice among these ASMs was guided by low-quality evidence, consisting
in observational studies and small clinical trials, insufficient to recommend the
choice of one specific ASM over the others.[21]
[22] In 2019, the ESETT[19] provided high-quality evidence for the choice of second-line treatment of SE. In
this trial, 384 pediatric and adult patients with convulsive SE refractory to BZD
were enrolled and randomly allocated to receive either fosphenytoin (20 mg/kg, phenytoin
equivalents), valproate (40 mg/kg), or levetiracetam (60 mg/kg, all loaded intravenously).
There was capping of weight-based dosing at 75 kg; therefore, heavier patients received
a lower dose. The outcome of the study was cessation of SE and improvement in the
level of consciousness at 60 minutes, which was achieved in 47% of the levetiracetam
group, in 46% of the valproate group, and in 45% of the fosphenytoin group. In conclusion,
the three ASMs were equally effective and yielded similar rates of adverse effects.
In the same year, two studies compared the effectiveness of phenytoin and levetiracetam
in the treatment of convulsive SE refractory to BZD in children. The Levetiracetam
versus Phenytoin for Second-Line Treatment of Convulsive Status Epilepticus in Children
(ConSEPT) trial[23] was an open, multicenter, randomized trial conducted in centers in Australia and
New Zealand. The Levetiracetam versus Phenytoin for Second-Line Treatment of Paediatric
Convulsive Status Epilepticus (EcLiPsE) trial,[24] also an open, multicenter, randomized trial, was conducted in 30 centers in the
United Kingdom. In both trials, children aged between 3 months and 16 years (ConSEPT)
and between 6 months and 18 years (EcLiPsE) were randomly allocated to receive levetiracetam
(40 mg/kg) or phenytoin (20 mg/kg). In ConSEPT, the primary outcome was clinical cessation
of seizure activity 5 minutes after the completion of infusion in the study group,
which was achieved in 68 (60%) patients in the phenytoin group and in 60 (50%) patients
in the levetiracetam group (p = 0.16, not statistically significant). In EcLiPsE, the primary outcome was time
until cessation of convulsive SE. Convulsive SE was terminated in 106 (70%) children
in the levetiracetam group and in 86 (64%) in the phenytoin group. The median time
from randomization to cessation of convulsive SE was of 35 minutes in the levetiracetam
group and 45 minutes in the phenytoin group (p = 0.20, not statistically significant). In the two trials,[23]
[24] levetiracetam was equivalent to phenytoin with respect to seizure cessation and
occurrence of adverse events. Given its safety profile and comparative ease of administration,
levetiracetam could be an appropriate alternative to phenytoin as the first choice
of second-line ASM in the treatment of pediatric convulsive SE.
Intravenous valproate is not available in Brazil. Therefore, based on the best available
evidence, IV levetiracetam or IV phenytoin are recommended as second-line ASMs in
convulsive SE. [Figure 1] shows the suggested dosing for these medications.
Intravenous levetiracetam has recently become available for use in Brazil. This should
lead to revisions in the current guidelines for the treatment of SE in the country.
Levetiracetam is safe and easy to use. The loading dose may me infused in 5 to 15 minutes.[25]
[26] The rapid infusion (over 5 minutes) of doses up to 4,500 mg IV is safe and well
tolerated.[25]
[27] Due to its safety profile and pharmacological characteristics, levetiracetam may
be preferred in patients with liver failure, cardiac arrhythmias (which can be aggravated
by IV phenytoin) or hemodynamic instability, although there is insufficient high-quality
data to make these indications. The absence of significant drug interactions and a
favorable tolerability profile are additional advantages when transitioning to long-term
maintenance therapy. [Table 3] details the doses of IV levetiracetam in children and adult patients, based on the
aforementioned studies comparing levetiracetam to other ASMs.[19]
[23]
[24]
Table 3
Levetiracetam dosing in children and adults with convulsive status epilepticus
|
Trial
|
Loading dose
|
Maximum dose
|
Age
|
Route
|
Infusion rate
|
Efficacy and safety
|
|
ESETT[19]
|
60 mg/kg
|
4,500 mg
|
1–94 years
|
IV
|
10 minutes
|
Comparable to f-PHT and VPA
|
|
ConSEPT[23]
|
40 mg/kg
|
3,000 mg
|
3 months–16 years
|
IV or IO
|
5 minutes
|
Comparable to PHT
|
|
EcLiPsE[24]
|
40 mg/kg
|
3,000 mg
|
6 months–18 years
|
IV or IO
|
5 minutes
|
Comparable to PHT
|
Abbreviations: ConSEPT, Levetiracetam versus Phenytoin for Second-Line Treatment of Convulsive Status
Epilepticus in Children; EcLiPsE Levetiracetam versus Phenytoin for Second-Line Treatment
of Convulsive Status Epilepticus; ESETT Established Status Epilepticus Treatment Trial;
f-PHT, fosphenytoin; IO, intraosseous; IV, intravenous; PHT, phenytoin; VPA, valproic
acid.
There is less evidence regarding the use of phenobarbital and lacosamide as second-line
treatment in convulsive SE.[21]
[22] Phenobarbital is very effective in the treatment of prolonged seizures and SE, with
rates of seizure control of up to 60%.[21]
[22]
[28]
[29] However, phenobarbital causes prolonged sedation and carries a higher risk of hypotension
and hypoventilation; therefore, it is less frequently used in the second stage of
convulsive SE treatment. The initial dose is of 20 mg/kg, infused at a rate of 30
to 50 mg/minute. Ιntubation may be required to protect the airway, especially if phenobarbital
is used after BZD. Intravenous lacosamide (200–400 mg IV bolus) has been used as an
alternative for the second-line treatment of convulsive SE.[30]
[31]
[32] It is usually well tolerated, although atrioventricular block has rarely been reported;[30] ECG monitoring is recommended, especially when it is used along with other drugs
that may prolong the PR interval. A systematic review[33] has suggested that lacosamide has an overall efficacy rate of 57% in treating SE
and is more effective in focal motor SE. Lacosamide is comparable to fosphenytoin
for the treatment of refractory nonconvulsive ѕeizures,[34] but evidence supporting its use in convulsive SE is lacking.[21]
[29] As of 2024, lacosamide has not been approved for the treatment of SE in Brazil.
Refractory status epilepticus
Refractory status epilepticus
Refractory SE is defined as seizures persisting despite the administration of at least
two appropriately-selected and dosed parenteral medications, including a BZD.[11]
[35] No specific seizure duration is required. Refractory SE occurs in 1/5 to 1/4 cases
of SE, and it causes elevated morbidity and mortality.[36]
[37]
[38]
[39]
[40]
For most cases of refractory convulsive SE, continuous infusion of IV anesthetic drugs
(IVADs) should be initiated. The patient should be transferred to the intensive care
unit (ICU), as endotracheal intubation and mechanical ventilation are likely to be
needed. A neurological consultation should be requested, and, if possible, continuous
EEG monitoring should be initiated, particularly in patients sedated with continuous
IVADs.
The IVADs used for SE treatment are midazolam, propofol, and pentobarbital/thiopental.
In Brazil, thiopental is the barbiturate available for continuous infusion. In some
cases, ketamine may also be indicated. Although there is insufficient data to support
the choice of a specific IVAD, the usual consensus is to initiate therapy with midazolam
or propofol, because they have a shorter duration of sedation and fewer side effects
when compared with barbiturates. Individual patient characteristics, physician preference
and experience, as well as local institutional practice also guide the choice of IVAD.
A recent systematic review[41] compared outcome measures associated with the initial choice of continuous IVAD
in refractory SE. A total of 66 studies with 1,637 patients were included. Significant
differences among IVADs – midazolam, propofol, and barbiturates – were observed in
certain outcome measures. Short-term failure was more common with midazolam and propofol,
while hypotension and dose-limiting hypotension were more frequent with barbiturates.
Additionally, the need to switch IVAD was higher in patients initially treated with
midazolam. In line with a previously published systematic review,[42] IVAD choice was not a predictor of mortality.
Midazolam is often the first choice to initiate the treatment of refractory SE due
to its safety profile and widespread familiarity in most centers. However, a major
drawback of midazolam in SE treatment is tachyphylaxis – the reduction in antiseizure
effectiveness with prolonged use –, which can increase the likelihood of recurrent
seizures and the need to switch the IVAD.[41]
[42] Withdrawal seizures and recurrence of SE are also relatively common, although this
outcome may be improved with the use of higher doses. Fernandez et al.[43] compared two treatment protocols of refractory SE with continuous midazolam infusion:
low-dose (median dose of 0.2 mg/kg/h) and high-dose (median dose of 0.4 mg/kg/h),
both with similar duration of infusion. Withdrawal seizures (occurring within 48 hours
of discontinuation of midazolam) were less frequent in the high-dose group; failure
of midazolam treatment, requiring change to a different IVAD, as well as incidence
of hospital complications, were not different between the groups. More importantly,
patients treated with higher doses presented lower mortality.
Propofol is a gamma-aminobutyric acid (GABA) A receptor agonist with potent antiseizure
effect.[44] The main concern regarding this drug is the propofol infusion syndrome (PRIS), consisting
in rhabdomyolysis, severe metabolic acidosis, and cardiac and renal failures.[45] It is more common in children and in patients with acute neurological illnesses
– especially traumatic brain injury[46]–or acute inflammatory diseases, complicated by severe infections or sepsis. It is
associated with prolonged use (longer than 48 hours) and with infusion rates higher
than 5 mg/kg per hour.[45]
[47]
[48] Special attention should be paid to patients receiving drugs with carbonic anhydrase
inhibitor effect, such as acetazolamide and topiramate. Due to the risk of PRIS, the
use of continuous propofol in children with refractory SE is limited.[48]
Barbiturates are associated with a myriad of side effects, including hypotension,
cardiac depression, hepatotoxicity, respiratory infections, ileus, and immune dysfunction.[49] When compared with midazolam and propofol, barbiturates more often cause hypotension
leading to treatment discontinuation.[41]
[42] The half-lives of pentobarbital and thiopental may increase with prolonged use,
mainly due to accumulation in adipose tissue, leading to prolonged sedation after
weaning of the drug. In patients with recurrent seizures after the tapering of barbiturates,
phenobarbital is a good option for maintenance therapy.[49]
Data on the use of ketamine as the initial IVAD for refractory SE is scarcer.[41] Ketamine is an N-methyl-D-aspartate (NMDA) receptor antagonist, a mechanism of action
that may be especially valuable in the later stages of SE, when GABAergic drugs –
such as benzodiazepines, propofol, and barbiturates – have diminished effectiveness.[50]
[51]
[52]
[53] Recent data suggest that ketamine may be more effective than midazolam when administered
as the first-line anesthetic infusion in pediatric SE, but this has yet to be confirmed
by controlled studies.[54]
[55] Due to its mechanism of action and pharmacological characteristics, ketamine has
even been suggested as a second-line option for the treatment of SE, after BZD failure,
as an alternative to other ASMs.[56] Ketamine has a clinical advantage over the more commonly used IVADs: it rarely causes
hypotension; therefore, it is useful in treating patients with hemodynamical instability.
On the other hand, caution should be exercised when treating patients with hypertension.[50] Continuous IV infusion should be started with a loading dose of 2 mg/kg, followed
by an infusion rate of 1 to 10 mg/kg/hour.
The infusion of continuous IVAD aims to control clinical as well as electrographic
seizure. The appropriate titration of these drugs is only feasible with the aid of
continuous EEG monitoring; if continuous monitoring is not available, daily EEG control
is recommended. If EEG is not available at all, only recurrent clinical seizures will
be diagnosed. After control of motor seizures in convulsive SE, electrographic seizures
may occur in up to half of patients who do not recover normal consciousness.[57]
There is no clear evidence to suggest any level of sedation or duration of therapeutic
coma with continuous IVAD in refractory SE. Most guidelines suggest that coma should
be induced for 24 to 48 hours.[11]
[12]
[58] However, this is based mainly on retrospectively collected data. Prolonged sedation
increases the risk of complication and prolongs the length of stay in the ICU.[59] Also, coma induction with IVAD may be independently associated with prolonged hospitalizations,
infection risk, and poor functional outcomes.[60]
[61]
[62] The use of IVADs in SE has been associated with increased in-hospital mortality,
independently of confounding factors,[63] although this is still a matter of debate.[64] The EEG endpoint for continuous IVAD infusion is also not clearly defined. Many
experts suggest that aiming at burst-suppression pattern on EEG is superior to the
mere cessation of clinical and EEG seizures, but this strategy may carry a higher
risk of complications.[42]
[65] Based on current evidence, it is reasonable to aim for the control of clinical and
EEG seizures; if seizures recur after IVAD weaning, 24 to 48 hours of deeper sedation
may be tried, aiming at burst-suppression on EEG.
Along with continuous infusion of IVAD, treatment with long-acting ASMs should be
optimized. In addition to the ASM initially used, other ASMs may be added to achieve
and maintain seizure control and to facilitate weaning off the continuous IVAD. Parenteral
ASMs are preferred, as it is possible to achieve therapeutic serum levels more rapidly.
Therefore, phenytoin and levetiracetam (if not previously administered), as well as
valproate, lacosamide, and phenobarbital, can be loaded intravenously in this stage
of the treatment. If needed, other ASMs, such as topiramate, clobazam, perampanel,
and vigabatrin, can also be administered via a nasoenteric feeding tube.
The Treatments Committee of the American Epilepsy Society published a review[66] on the treatment of convulsive refractory SE, aiming to determine the strength of
evidence for parenteral ASMs and other therapies used in special circumstances related
to convulsive SE. The searches conducted by the committee identified no class-I, no
class-II, 9 class-III, and multiple class-IV studies on the use of 13 ASMs in the
treatment of convulsive refractory SE, highlighting the marked absence of high-quality
data on this issue. The review[66] concluded that there is not enough data to support the efficacy of levetiracetam,
valproate, lacosamide, brivaracetam, midazolam, propofol, pentobarbital, and ketamine
either as the last ASM in treating convulsive refractory SE or compared to others
of these drugs. Moreover, medications that have been used with variable efficacy in
special situations, such as adrenocorticotropic hormone, intravenous immunoglobulin,
corticosteroids, magnesium sulfate, and pyridoxine, have not been appropriately studied
for convulsive refractory SE.
Super-refractory status epilepticus
Super-refractory status epilepticus
Super-refractory SE is defined as seizures persisting at least 24 hours after onset
of anesthesia, either without interruption despite appropriate treatment with anesthesia,
recurring while on appropriate anesthetic treatment, or recurring after withdrawal
of anesthesia and requiring anesthetic reintroduction.[35]
[40] The IVADs used in the treatment of SE include midazolam, propofol, pentobarbital,
thiopental, ketamine, and others, as long as they are used at anesthetic doses. Approximately
15% of all the cases of SE admitted to the hospital will become super-refractory.[40] If anesthetics are needed for at least 7 days, the term prolonged super-refractory SE applies, while the term prolonged refractory SE is used for SE of the same duration, but without the persisting need for anesthetics.[67] Super-refractory SE is a very severe condition, with high morbidity and mortality.
The mortality rate increases the longer the episode of SE lasts, due to various complications
of both the SE and its treatment:[40]
[68] with prolonged SE and treatment, complications such as hypotension, cardiorespiratory
collapse and failure, hepatic failure, renal failure, disseminated intravascular coagulation
and disorders of bleeding, infection, rhabdomyolysis, and ileus and gastrointestinal
disturbances become progressively more incident.
When it comes to evidence-based medicine, the landscape for super-refractory SE is
even more uncertain compared with refractory SE. Several points compromise the assessment
of therapies which have been tried in super-refractory SE: first and foremost, the
lack of randomized or controlled studies; the small number of individuals treated
in the trials; co-medication and changing doses of co-medication; and publication
bias.[69] In addition, super-refractory SE is a heterogeneous condition, in which factors
such as age and etiology play a very important role, limiting the comparison of different
treatments.[68]
[70]
Ochoa et al.[71] reviewed studies on effectiveness of hypothermia, ketogenic diet (KD), vagus nerve
stimulation (VNS), brain surgery, inhalational anesthetics, and other ASMs such as
topiramate, pregabalin, lidocaine, and perampanel in the treatment of super-refractory
SE. No class-I, 1 class-II, and multiple class-IV studies were identified on the use
of therapeutic trials. After reviewing the available evidence, the authors[71] concluded that there is insufficient evidence that any of the ASMs reviewed, inhalational
anesthetics, KD, acute VNS, brain surgery, or therapeutic hypothermia are effective
treatments.
Therefore, when treating patients with super-refractory SE, one should bear in mind
that it is likely that the patient has already received several different therapies
and is already dealing with many clinical complications. At this point of treatment,
given the lack of evidence to recommend a specific treatment, the choice of treatment
should be individualized, and clinical judgement should be exercised in each case.
NORSE and FIRES
Refractory and super-refractory SE may occur in patients with neither previous history
of epilepsy nor clearly-defined etiology. New-onset refractory SE (NORSE) is a clinical
presentation, not a specific diagnosis, in a patient without active epilepsy or other
preexisting relevant neurological disorders, with new onset of refractory SE without
a clear acute or active structural, toxic, or metabolic cause.[35] More often, NORSE is super-refractory. Febrile infection-related epilepsy syndrome
(FIRES) is a subcategory of NORSE that requires a previous febrile infection, with
fever starting between 2 weeks and 24 hours prior to the onset of refractory SE, with
or without fever at the onset of the SE.[35] Both definitions apply to all age groups. If no explanation for the clinical presentation
of NORSE (or FIRES) is found after diagnostic workup, cryptogenic NORSE is defined.
Both NORSE and FIRES present a significant treatment challenge, particularly because,
in the absence of a known etiology, the options to target the underlying cause of
the seizures are limited. There are no randomized controlled trials or consensus guidelines
for the diagnostic evaluation and treatment of patients who present with NORSE/FIRES.
A group of international experts in this field proposed a series of recommendations[72] for the diagnostic evaluation and management of NORSE/FIRES. An extensive diagnostic
evaluation is recommended, aiming at defining the underlying cause of SE. In cases
of cryptogenic NORSE, if SE persists after 48 to 72 hours, immunotherapy with methylprednisolone
or intravenous immunoglobulin (IVIg) should be considered. In cases of incomplete
response, second-line immunotherapy and/or KD should be considered after 7 days. The
choice of the therapy depends on the clinical presentation.[72]
[73]
In conclusion, SE is a relatively common and severe condition associated with high
morbidity and mortality. Prompt recognition is essential to ensure the timely initiation
of the appropriate treatment. From the outset, patient stabilization and correct administration
of ASMs must be prioritized. Additionally, identifying the underlying cause is crucial,
and a thorough diagnostic workup should be conducted alongside treatment.
In treating patients with SE, the well-known aphorism from vascular neurology applies:
“time is brain.” Delays in recognizing and treating SE are associated with poorer
outcomes. During the initial stage of therapy, timely administration of BZDs at correct
doses is essential. Following BZD use, IV ASM should be administered. In Brazil, IV
levetiracetam is now available as an option, alongside phenytoin. If convulsive seizures
persist after BZDs and IV ASM, the next step is to induce therapeutic coma using IVADs.
Treating refractory and super-refractory SE is challenging, as evidence supporting
specific treatments remains limited. In the absence of randomized controlled trials,
treatment should rely on the physician's experience, clinical judgment, and previously
reported therapeutic options. Some patients may achieve good outcomes despite prolonged
SE; therefore, intensive treatment should be continued as long as a favorable outcome
remains possible.
Bibliographical Record
Luis Otavio Caboclo. Treatment of convulsive status epilepticus in Brazil: a review.
Arq Neuropsiquiatr 2025; 83: s00451801872.
DOI: 10.1055/s-0045-1801872
