Status Epilepticus: Current Understanding

VIDYABRATA GHOSH, *NEETU AGARWAL AND DEVENDRA MISHRA

DEPARTMENTS OF PEDIATRICS, MAULANA AZAD MEDICAL COLLEGE, DELHI AND
* GR MEDICAL COLLEGE, GWALIOR, MADHYA PRADESH
Correspondence: drdmishra@gmail.com

Status epilepticus is the most common neurological emergency in childhood and is

life-threatening with risk of neurological sequelae.

Status epilepticus (SE) is

associated with a high mortality rate that is largely contingent on the duration of
the condition before initial treatment, the etiology of the condition, and the age of
the patient.
WHAT IS STATUS EPILEPTICUS?
In 1993, the American Epilepsy Society Working Group on Status Epilepticus had put
forward an operational definition of SE as 'seizure lasting more than 30 min or
occurrence of two or more seizures without recovery of consciousness in between.'
In the past 10 years, there has been considerable rethinking about duration to be
designated as SE. The duration of what is accepted as SE has been shrinking
progressively. From 30 min specified in the guidelines of the Epilepsy Foundation of
America's Working Group on Status Epilepticus it was reduced to 20 min; the
Veterans Affairs Status Epilepticus Cooperation Study stipulated 10 min and, most
recently, a length of 5 min has been proposed. Lowenstein et al. have proposed that
SE be defined as a continuous, generalized, convulsive seizure lasting >5 min, or
two or more seizures during which the patient does not return to baseline
consciousness. More practically, any patient presenting seizuring to a healthcare
facility should be considered to have a SE.
Despite the paucity of clinical trials comparing medication regimens for acute
seizures, there is broad consensus that immediate diagnosis and treatment are
necessary to reduce the morbidity and mortality of this condition. Moreover,
investigators have reported that status epilepticus often is not considered in
1

patients with altered consciousness in the intensive care setting. In patients with
persistent alteration of consciousness for which there is no clear etiology,
physicians should be more quickly prepared to obtain electroencephalography to
identify status epilepticus. Physicians should rely on a standardized protocol for
management of status epilepticus to improve care for this neurologic emergency.
CLASSIFICATION
Various approaches to classifying status epilepticus have been suggested. One
version classified status epilepticus into generalized (tonic-clonic, myoclonic,
absence, atonic, akinetic) and partial (simple or complex) status epilepticus.
Another version divides the condition into generalized status epilepticus (overt or
subtle) and nonconvulsive status epilepticus (simple partial, complex partial,
absence). Another version takes a different approach, classifying status epilepticus
by life stage (confined to the neonatal period, infancy and childhood, childhood and
adulthood, adulthood only).
STAGES OF SE
SE may be broadly divided into two stages. The first stage is characterized by
generalized convulsive tonic-clonic seizures that are associated with an increase in
autonomic activity, resulting in hypertension, hyperglycemia, sweating, salivation,
and hyperpyrexia. During this phase, cerebral blood flow is increased due to
increased cerebral metabolic demands. After approximately 30 min of seizure
activity, patients enter the second phase, which is characterized by the failure of
cerebral autoregulation, decrease in cerebral blood flow, increase in intracranial
pressure,

and

systemic

hypotension.

During

this phase,

electromechanical

dissociation may occur in which, although electrical cerebral seizure activity

continues, the clinical manifestations may be restricted to minor twitching.
SE may pass through five distinct electrographic stages: (a) discrete
electrographic seizures, (b) merging of electrographic seizures - waxing and waning
of ictal discharges, (c) continuous ictal discharges, (d) continuous ictal discharges
punctuated by flat periods, and (e) periodic epileptiform discharges against a
relatively flat background.
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Refractory Status Epilepticus

About 9-31% of patients with SE may fail to respond to standard treatment. RSE is
defined as continuous or repetitive seizures lasting longer than 60 min despite
treatment with a benzodiazepine (lorazepam) and another standard anticonvulsant
(usually phenytoin/fosphenytoin) in adequate loading dose. Malignant SE is a severe
variant of RSE, in which the seizure fails to respond to aggressive treatment with
even anesthetic agents. Central nervous system (CNS) infections may predominate
in children to cause RSE and cerebral malaria can be a common cause in malaria
endemic area. In patients with SE and CNS infection, 24.3% had a refractory status
that was associated with a high mortality.
EPIDEMIOLOGY
The incidence of status epilepticus was bimodally distributed, occurring most
frequently during the first year of life and after the age of 60 years. Geography, sex,
age, and race influence the epidemiology of SE. An incidence of 6.2-18.3 per
100,000 population has been reported in the US. A variety of etiologies accounted
for the condition. It has been estimated that up to 150,000 cases of SE occur
annually in the US, with 55,000 associated deaths. Status epilepticus of partial onset
is the commonest type. One epidemiologic study1 on status epilepticus found that
64 % of episodes in children were partial onset, followed by secondarily generalized
status epilepticus.
PATHOPHYSIOLOGY
Status epilepticus is associated with serious systemic physiologic changes resulting
from the metabolic demands of repetitive seizures. Many of these systemic changes
result from the profound autonomic changes that occur during status epilepticus,
including

tachycardia,

arrhythmias,

hypertension,

pupillary

dilation,

and

hyperthermia because of the massive cat-echolamine discharge associated with

continuous generalized seizures. Systemic changes requiring medical intervention
include

hypoxia,

hypercapnia,

hypoglycemia,

electrolyte disturbances.
3

metabolic

acidosis,

and

other

DIAGNOSIS
Fulminant tonic-clonic movements with frothing, and dysautonomic features with
loss of consciousness are important pointers to the diagnosis of SE.
Diagnosis of NCSE can be challenging. It may not be considered in patients
who present in altered sensorium or coma following a convulsion. All comatose
patients should therefore be carefully examined for evidence of minor twitching,
which may involve the face, hands, or feet or may present as nystagmoid jerking of
the eyes. Continuous EEG monitoring can be helpful in such instances. Towne and
colleagues evaluated 236 patients with coma and no overt seizure activity and found
that 8% of the patients had NCSE, as determined by EEG monitoring. Therefore, it is
essential that an urgent EEG be performed in patients with unexplained coma.

ROLE OF ELECTROENCEPHALOGRAPHY
Electroencephalography (EEG) is extremely useful, but underutilized in the
diagnosis and management of status epilepticus. EEG can establish the diagnosis in
less obvious circumstances. EEG also can help to confirm that an episode of status
epilepticus has ended, particularly when questions arise about the possibility of
recurrent episodes of more subtle seizures. In a study, investigators monitored
patients for at least 24 hours after clinical signs of status epilepticus had ended.
They found that nearly one half of their patients continued to demonstrate electrographic seizures that often had no clinical correlation. The investigators concluded
that EEG monitoring after presumed control of status epilepticus is essential for
optimal management.
Patients with status epilepticus who fail to recover rapidly and completely
should be monitored with EEG for at least 24 hours after an episode to ensure that
recurrent seizures are not missed. Monitoring also is advised if periodic discharges
appear in the EEG of a patient with altered consciousness who has not had obvious
seizures. Periodic discharges in these patients suggest the possibility of preceding
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status epilepticus, and careful monitoring may clarify the etiology of the discharges
and allow the detection of recurrent status epilepticus.
MANAGEMENT
General Measures
The treatment includes the basics of pediatric resuscitation (airway, breathing, and
circulation), and administration of appropriate anticonvulsant medication to
terminate ongoing seizure activity.
The first step would be to ensure an adequate airway and to provide
respiratory support. The patient should be positioned such that self-injury is
prevented during seizure activity. Earlier teaching was to make the patients rolled
onto their side during a seizure. Now it has been demonstrated that this may cause
more harm than good. They are at greater risk for self-injury, such as a dislocated
shoulder. As patients are not breathing during a generalized tonic-clinic seizure,
they are not at high risk for aspiration until the event ends. Immediately following
the seizure, patients usually take a deep breath. Therefore, the patient should be
rolled over onto his or her side immediately after the motor activity ceases.
Likewise, to prevent injury to the patient, suction of the oropharynx can wait until
the end of the seizure.
To avoid injuries to oral structures, do not forcibly introduce a tongue
depressor or other hard objects between locked teeth. Gentle suction can be applied
to remove saliva and blood. Two large-gauge intravenous (IV) catheters should be
inserted to facilitate fluid resuscitation and pharmacotherapy. The maintenance of
adequate hydration is necessary to prevent myoglobin-induced renal failure. Should
peripheral venous access be difficult, the placement of a central venous catheter is
recommended. Despite the periods of apnea and cyanosis that occur during the
tonic or clonic phases of the seizure, most patients in SE breathe sufficiently well as
long as the airway remains clear. However, in this situation precautions should be
taken to avoid aspiration, and a nasogastric tube should be placed to ensure that
the stomach is empty. Endotracheal intubation will be required in patients who
continue to experience seizures despite receiving first-line therapy. Most of the
patients who require endotracheal intubation will be comatose or would have
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received lorazepam or some other benzodiazepine. Hence a hypnotic agent may not
be required for intubation. In some situations, an anesthetic induction dose of
propofol or midazolam may terminate the seizure activity and facilitate intubation.
Neuromuscular blockade will be required to facilitate intubation if the patient
continues to have tonic-clonic seizure activity despite these pharmacologic
interventions. Rocuronium (1 mg/kg), a short-acting, nondepolarizing muscle
relaxant that has little effect on blood pressure and intracranial pressure is the
preferred agent.
Although relatively uncommon, metabolic causes for status epilepticus must
be investigated, as treatment of SE with anticonvulsant medications may be
ineffective without correction of the metabolic abnormality. In addition, the
identification of hypoglycemia is of paramount importance not only to identify the
etiology of the SE, but also because of the potential adverse effects on central
nervous system function. If prompt measurement of blood glucose level is not
possible, the patient should receive bolus of

dextrose (ref for older children). A

review of class III studies of children presenting with SE demonstrated that 3.8% of
cases were associated with either electrolyte disturbances or hypoglycemia. Further
evaluation of these data revealed that hyponatremia was present in 1.5%,
hypocalcemia in 0.5%, and hypoglycemia in 0.5% of patients. It is important to
obtain a chemistry profile (electrolytes and glucose) in all patients with SE.
The American Academy of Neurology and the Practice Committee of the Child
Neurology Society has provided some guidelines for the assessment of a child with
SE. There recommendations are: Although common clinical practice is that blood
cultures and lumbar puncture are obtained if there is a clinical suspicion of a
systemic or CNS infection, there are insufficient data to support or refute
recommendations as to whether blood cultures or lumbar puncture should be done
on a routine basis in children in whom there is no clinical suspicion of a systemic or
CNS infection (Level U). AED levels should be considered when a child with treated
epilepsy develops SE (Level B). Toxicology studies and metabolic studies for inborn
errors of metabolism may be considered in children with SE when there are clinical
indicators for concern or when the initial evaluation reveals no etiology (Level C). An
EEG may be considered in a child with SE as it may be helpful in determining
6

whether there are focal or generalized epileptiform abnormalities that may guide
further testing for the etiology of SE, when there is a suspicion of pseudostatus
epilepticus (nonepileptic SE), or nonconvulsive SE, and may guide treatment (Level
C). Neuroimaging may be considered after the child with SE has been stabilized if
there are clinical indications or if the etiology is unknown (Level C). There is
insufficient evidence to support or refute routine neuroimaging in a child presenting
with SE (Level U).
Management of the Seizures
In the management of SE, the response to treatment depends on the duration of the
status before

anti-epileptic medications are administered. This was amply

demonstrated in the study in San Francisco in the 1980s, where the authors found
that if the AED was administered within 30 minutes of the onset of SE, the response
rate was as high as 80%, whereas in those treated after the 30 minute period, the
response

rate

fell

to

40%.

The ideal drug to control status should be easy to administer, should produce the
effect immediately, have long-lasting effect, and should not depress cardiorespiratory function or the consciousness. Benzodiazepines like diazepam and
barbiturates carry the risk of respiratory depression and also depress consciousness
in a dose-dependant manner. Phenytoin and fosphenytoin can cause hypotension
and cardiac arrhythmias if administered too fast; Phenytoin has the advantages of
the availability of an injectable preparation, and till recently was the only other antiepileptic drug whose plasma levels could be rapidly brought to the therapeutic
range. In addition it has a long duration of action. In a five-year randomized, doubleblind trial comparing the efficacy of lorazepam alone, phenytoin alone, diazepam
with phenytoin, and phenobarbital alone for the treatment of generalized SE, the
treatments were equally effective, except that lorazepam alone was more effective
than phenytoin alone, when seizures were assessed 20 minutes after the
administration began. When the cause of the SE is a reversible one, such as subtherapeutic drug concentration or an acute metabolic process, then lorazepam
alone may be sufficient and obviate the need for Phenytoin or Fosphenytoin. .

In

accordance with published trials and guidelines, neurologists most often use
lorazepam followed by phenytoin or fosphenytoin as first-line and second-line
7

therapies for SE. There is no consensus for third-line or fourth-line treatment for
RSE. The treatment of RSE needs to be studied in a large, prospective, randomized,
multicenter trial.
Benzodiazepines
The benzodiazepines including diazepam, lorazepam, and midazolam are the
preferred initial choice for therapy. Benzodiazepine-receptor-mediated enhancement
of GABAergic transmission is their primary mode of action. In addition, they also
block sustained repetitive neuronal firing in a manner similar to carbamazepine and
phenytoin. All benzodiazepines rapidly enter CSF, with peak concentrations usually
attained within 15 min of dosage.
The pharmacokinetic properties of lorazepam favor its use over that of
diazepam. Lorazepam has an extremely rapid onset of action. The anticonvulsant
effect of a single dose of diazepam is very brief (20 min), whereas that of lorazepam
is much longer (> 6 h); also, the risk of respiratory depression may be greater with
diazepam. Although diazepam has a much longer elimination half-life, it is rapidly
redistributed from the brain to the peripheral fat stores due to its high lipid
solubility, which accounts for its shorter anticonvulsant activity. Lorazepam should
be stored in light-proof containers and should be restocked every 4-6 months. In a
retrospective analysis comparing the treatment of SE with diazepam and
lorazepam, both were found to be equally effective, but there were fewer
recurrences with lorazepam, and fewer repeat doses were required. Though
lorazepam is less lipid-soluble, and therefore its serum and CSF levels rise much
more slowly than that of diazepam, it remains longer in brain than in the serum,
leading to increasing brain: serum ratios over time. In a randomized, double-blind
trial comparing standard doses of diazepam and lorazepam, both were found to be
equally effective, the median time to termination of seizure also being similar (two
minutes for diazepam, three for lorazepam). Despite these similarities, the
important difference between diazepam and lorazepam is their duration of actions
(12 to 24 hours for lorazepam versus 15 to 20 minutes for diazepam), and it is this
property which makes lorazepam superior in the acute treatment of SE. Adverse
effects occur in 13% of the lorazepam-treated patients and in 12% of the diazepamtreated patients. One problem with continued use of benzodiazepine in SE is that
8

prolonged seizures of SE rapidly alter the functional properties of hippocampal

dentate granule cell GABA(A) receptors leading to loss of sensitivity of the animals
to diazepam during SE. Since this is not seen with barbiturates, they are preferred
for refractory SE
Phenytoin and Fosphenytoin
Phenytoin still has many advantages not offered by the other medications. Its use in
the acute setting is most useful in three situations: (1) after rapid control of seizure
with benzodiazepines, for prolonged effect; (2) as initial therapy for SE, and (3)
when benzodiazepines fail to control seizures. The most common problem with its
use is hypotension in 28-30% of patients, and cardiac arrhythmias (bradycardia or
ectopic beats) in 2%, especially in those above 50 years age and those with preexisting cardiac disease. These cardiovascular side-effects are attributed to
phenytoin itself and its propylene glycol diluent, and can be mitigated by slowing
the rate of administration. In a known epileptic who is already on phenytoin,
presenting with SE, the serum phenytoin level is likely to be sub-therapeutic but not
zero, and that is why it is common practice to administer a half-loading dose of
phenytoin. Physician should not hesitate to administer additional phenytoin if the
seizures remain uncontrolled. When a typical loading dose is given t, it takes about
20-25 minutes for maximal effect.
Fosphenytoin is the disodium phosphate ester pro-drug of phenytoin for parenteral
use. It has little intrinsic pharmacologic activity. After parenteral administration, it is
rapidly and completely converted by serum and tissue alkaline phosphatases to free
phenytoin. The conversion half-life is approximately 8 to 15 minutes. Fosphenytoin
has been recommended over conventional phenytoin for SE mainly for three
reasons; (1) It has a pH of 8.5 as against 12 for phenytoin, (2) The vehicle does not
contain

propylene

glycol

or

ethanol,

thereby

reducing

the

potential

for

cardiovascular or cutaneous side-effects, and (3) It can be administered much faster

than phenytoin; Intravenous fosphenytoin is tolerated at infusion rates up to three
times faster than those for phenytoin, and therapeutic concentrations are
established within 10 minutes. No clinically significant hypotension or cardiovascular side-effects have been reported with fosphenytoin, and injection-siterelated problems like phlebitis and soft-tissue damage are less common with
9

fosphenytoin.

Another

potential

advantage

of

substituting

fosphenytoin

for

phenytoin is the prevention of the "purple glove syndrome", which is reported in 6%

of patients receiving intravenous phenytoin administration, characterized by
progressive distal limb edema, discoloration, and pain.
Veterans Affairs Cooperative Study. The Study Group compared response rates for
four different treatments in 384 patients with overt (presumably early) status
epilepticus and 134 patients with subtle (presumably late) status epilepticus. The
four regimens consisted of 0.15 mg per kg of diazepam followed by phenytoin (18
mg per kg), lorazepam (0.1 mg per kg), phenobarbital (15 mg per kg), or phenytoin
alone (18 mg per kg). For overt status epilepticus, the highest response occurred in
patients who received lorazepam (64.9 %), followed by those who received
phenobarbital

(58.2%),

diazepam

with

phenytoin

(55.8 %),

and

phenytoin

monotherapy (43.6%).
Patients with subtle status epilepticus, which is often a late manifestation of
status epilepticus, had significantly lower response rates to all treatments.
Phenobarbital-treated patients had the highest response rate at 24.2%, followed by
those receiving lorazepam (17.9%), diazepam plus phenytoin (8.3%), and phenytoin
monotherapy (7.7%). However, the authors noted no statistically significant
differences between treatments for overt and subtle status epilepticus. There also
were no differences between the treatments with respect to recurrence during the
12-hour study period, the incidence of adverse reactions, or the outcome at 30
days.
These data help to underscore the difference in response between early and
late status epilepticus and the differing efficacies of medications, depending on the
duration of the condition. Furthermore, the dramatic drop in response rate between
early and late status epilepticus emphasizes the importance of early treatment. The
authors conclude that lorazepam is the easiest medication to use among first-line
agents in patients with status epilepticus.
In the VA study, the aggregate response rate to a second drug from the firstline agents was 7% and to a third drug it was only a meager 2.3%. If seizures
continue after administration of lorazepam and fosphenytoin in appropriate
10

dosages, a provisional diagnosis of RSE needs to be made. Such patients would

require aggressive treatment under assisted ventilation.
Facilities for endotracheal intubation and ventilation may not be available in
most of the peripheral hospitals in India and other developing countries. Recently,
new regimens that avoid assisted ventilation have been tried in the management of
SE. Their mechanisms of action are different from that of benzodiazepines and
phenytoin, which depend upon GABAergic inhibition and sodium channel blocking,
respectively.
Intravenous valproate
Sodium valproate is recently been evaluated as an intravenous preparation for the
treatment of SE. Intravenous valproate (IV VPA) is a therapeutic option for those
patients with cardiorespiratory impairment, 'do not ventilate' status, and myoclonic
SE. It is a nonsedating drug with a good safety profile and is easy to use.

In a

recent trial, 68 patients with CSE were randomized to receive either IV VPA (30
mg/kg) or phenytoin (18 mg/kg); Those who received IV VPA had significantly higher
rate of cessation of seizures (66%) when compared to the IV phenytoin group (42%).
Tolerability did not differ between the two groups. There was no hemodynamic
instability. IV VPA had an overall efficacy of 63.3% and rapid administration was well
tolerated. It was efficacious even when used as the second, third, or fourth drug.
Intravenously administered valproate is found to be effective in partial onset,
nonconvulsive, absence, and myoclonic SE. The standard loading dose for IV is 25
mg/kg; a higher doses of 30-60 mg/kg can be used. It is well tolerated at relatively
fast infusion rates of 5-6 mg/kg/min. Experience with IV VPA in the treatment of SE
is too limited to allow recommendation of its use as a first-line agent.
Contraindications for its use are severe liver dysfunction, thrombocytopenia, and
active bleeding. Its main advantages are the lack of sedation and the fact that
intubation for assisted ventilation can be avoided.
Intravenous Levetiracetam and oral Topiramate
Newer drugs such as levetiracetam and topiramate have a potentially important
place in the management of SE. Their mechanism of action is independent of GABA11

mediated inhibition, which tends to become ineffective beyond the first few minutes
of SE. These AEDs are well tolerated even at rapid infusion rates and may not
aggravate multiple organ dysfunction. They can be administered without ventilator
assistance as they cause little sedation. Nevertheless, their safety and efficacy in
controlling SE need to be confirmed through well-designed controlled trials. Recently
Levetiracetam is

approved for intravenous use in

patients who are on

levetiracetam and had developed SE. Higher doses of 2500 mg given in 5 min and
4000 mg over 15 min have been found to be well tolerated and safe in healthy
volunteers. Topiramate when administered by nasogastric tube, it was effective in
aborting RSE. In a small study conducted in children with RSE, seizures were
terminated with topiramate given in a loading dose of 10 mg/kg/day followed by a
maintenance dose of 5 mg/kg/day.
Management with Ventilator Assistance
Patients with RSE who have not responded to the first-line treatment will require
admission to the intensive care unit for more aggressive management under
assisted ventilation. Continuous EEG monitoring is helpful at this stage. Arterial
access is necessary. Continuous infusion of phenobarbital, midazolam, propofol, or
pentobarbital, preferably under continuous EEG monitoring, can be tried. The
electroencephalographic objective is the burst-suppression pattern, which needs to
be continued for 12 h after the last seizure. Infusion of the anesthetic agent can be
reduced every 3 h with EEG monitoring and if there are no clinical or EEG seizures,
the patient can be weaned off the ventilator. If seizure recurs, the same agent to
which it had responded earlier must be restarted, with weaning attempted after 12
h. No difference in mortality was found between the groups treated with different
regimens. Mortality was related to the patient's age and duration of SE rather than
the choice of AED. This recommendation is just based on 100 cases treated with
these agents having been reported.
Phenobarbital
Phenobarbitone is a long-acting barbiturate that acts by potentiation of GABA and
by interfering with sodium and potassium transport across the cell membrane.
Phenobarbital typically is used after a benzodiazepine or phenytoin has failed to
control status epilepticus. The loading dose is 20 mg/kg IV, with a maximum
12

infusion rate of 50-100 mg/min. The elimination half-life is 72 h. Contraindications

include severe liver dysfunction. Because high-dose phenobarbital is sedating,
airway protection is an important consideration, and aspiration is a major concern.
The main side effects are respiratory depression (patients will often require
intubation and ventilation), allergy (including Stevens-Johnson syndrome), and
blood dyscrasias. It is diluted in 60 to 80% propylene glycol, which is associated
with a number of complications, including renal failure, myocardial depression, and
seizures. These limitations relegate phenobarbital to use in patients who have not
responded to other agents.
Propofol
Propofol is a global CNS depressant. It directly activates the GABA receptor. In
addition,

inhibits the NMDA receptor, modulates calcium influx through slow

calcium ion channels, and has antioxidant activity. The two main advantages of
propofol are a rapid onset and short duration of action. Propofol is a highly lipophilic
agent with a large volume of distribution. This property results in its rapid uptake
and elimination from the CNS, thereby giving it rapid onset of action and allowing
rapid recovery upon discontinuation. Recovery is rapid even after prolonged use. No
dose reduction is required in patients with hepatic or renal disease. Concomitant IV
benzodiazepine allows use of a lower and safer dose of propofol, i.e., the
benzodiazepine infusion is used as a propofol 'dose-sparing' technique.
The usual loading dose ranges from 3-5 mg/kg but loading doses as high as
10 mg/kg have been safely used. This should be followed by a maintenance infusion
at the rate of 30-100 g/kg/min, which should be titrated to burst-suppression
pattern. SE stops within 10 min in most situations. After 12 h of seizure suppression,
the dose can be gradually reduced by 50% over the next 12 h and if there is no
relapse it can be withdrawn slowly over the subsequent 12 h. If seizures relapse
during the weaning period, a further loading dose of 1-3 mg/kg can be administered
and the maintenance infusion can be continued until a 12-h seizure-free period
occurs.
The most severe complication associated with propofol is the 'propofol
infusion syndrome.' It is a rare fatal complication that occurs when the dosage
exceeds 5 mg/kg/h for more than 48 h. This condition characterized by severe
13

metabolic acidosis, hyperlipidemia, rhabdomyolysis, and cardiovascular collapse.

The syndrome tends to occur only in those individuals with a genetic susceptibility.
However, the risk appears to be higher in children. Other contraindications include
allergy to soybean oil, egg lecithin, or glycerol. It should be used with caution in
combination with carbonic anhydrase inhibitors such as zonisamide and topiramate
due to the risk of refractory acidosis. Hyperlipidemia and creatine kinase levels can
be useful early markers of this syndrome. More recently a meta-analysis of 22
studies with original data on the use of propofol in SE, has raised serious doubts
about the safety of propofol in refractory SE, because two non-randomized studies
and several case reports show an increased risk of mortality. The authors of this
meta-analysis advise that guidelines should not recommend the use of propofol as a
routine treatment in refractory SE before a proper randomized trial has been
performed.
Midazolam
Midazolam is a fast-acting, water-soluble benzodiazepine with a half-life of 4-6 h. It
acts by binding to GABA-A receptors. Midazolam is typically started after securing
endotracheal intubation and ventilator assistance. Midazolam is given in a bolus
dose of 0.2 mg/kg slow intravenous push, followed by 0.75 to 10 g/kg per minute.
In a recent report of the treatment of 27 pediatric patients with refractory
generalized convulsive SE, midazolam infusion at a rate of 3.1 g/kg/min was found
to be effective and safe in 26, without adverse effects such as hypotension,
bradycardia or respiratory depression. In a randomized open-label study in children
at the PGIMER, Chandigarh, comparing the efficacy of midazolam and diazepam in
refractory SE, both were found to be equally effective, with median time to seizure
control of 16 minutes; however in the midazolam group, seizures recurred in more
children (57% versus 16% in diazepam group; P <0.05) and the mortality was
higher in the midazolam group (38%) as compared to the diazepam group (10.5%, P
<0.1>0.05). The maximum dose (mean SD) of midazolam and diazepam required
was 5.3 2.6 g/kg/min and 0.04 0.02 mg/kg/min, respectively. Thus the
experience with midazolam also is varied and mixed, though overall it appears to be
equally effective and marginally safer. One of the major disadvantages of
midazolam is tachyphylaxis, because of which the dose often has to be increased
several fold to maintain seizure control. Furthermore, with prolonged infusion,
14

midazolam accumulates in the body, which may result in a prolonged time to

awakening.
High-dose barbiturate therapy is a treatment option in RSE. This regimen is
often associated with hemodynamic instability and immune paresis. Due to these
side effects, high-dose barbiturate therapy is reserved for those patients who do not
respond to midazolam or propofol infusion. Intravenous pentobarbitone and
thiopentone are two regimens that are often tried. Most institutions prefer
pentobarbitone for induction and maintenance of drug-induced coma in patients
who have failed propofol/midazolam. The loading dose is 5 mg/kg; boluses of 5
mg/kg can be repeated until seizures stop. The maximum bolus rate is 25-50
mg/min (depending on the blood pressure). The usual maintenance dose is 0.5-10
mg/kg/h, traditionally titrated to suppression-burst on EEG.
Role of Inhalational Anesthetics
Inhalational anesthetics offer an alternative approach to the treatment of RSE.
Isoflurane and desflurane are the two agents that have been tried in the treatment
of RSE because of the safety associated with their long-term administration.
Regardless of seizure type, isoflurane and desflurane have consistently stopped
epileptic discharges with adequate, sustained electrographic burst suppression
within minutes of initiation of therapy. Prolonged use of inhalational anesthetics is
well tolerated.
Neurosurgical Treatment of Refractory Status Epilepticus
In selected cases of RSE that have failed to respond to medical management,
surgical intervention can be considered as a last resort. This is particularly
applicable to cases with an underlying surgically remediable lesion.
Patients with RSE of focal origin may be potentially amenable to resective
surgery. The literature is limited to isolated case reports or small case series
involving multiple subpial transections, cortical resection, corpus callosotomy, or
implantation of a vagus nerve stimulator. At the Jefferson Comprehensive Epilepsy
Center, patients with medically intractable SE who fail to respond to three courses
of cerebral suppressant therapy for approximately 2 weeks are considered for
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surgical treatment in the absence of any known remitting etiology. When structural
or functional neuroimaging shows a focal lesion, or the EEG displays focal changes,
they prefer focal resection and/or subpial transection. Corpus callosotomy is used
for patients with generalized or non-localizable intractable SE. Bingaman and
colleagues at the Cleveland Clinic performed resective surgery in the acute setting
for refractory SE in 10 patients with focal epileptogenesis when High Dose
Suppressive Therapy (HDST) failed; 7 (10%) became seizure-free, and 3 (30%) had
significant improvement in epilepsy.
A Protocol for
Management of Status Epilepticus in Children
will be discussed during the presentation

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FURTHER READING
1. Appleton R, Macleod S, Martland T. Drug management for acute tonic-clonic
convulsions including convulsive status epilepticus in children (Review). The
Cochrane Library 2010, Issue 10.
2. ER Freilich, T Zelleke, WD Gaillard. Identification and Evaluation of the Child in
Status Epilepticus. Semin Pediatr Neurol. 2010; 17:144-149.
3. JJ Riviello, Jr, S Ashwal, D Hirtz, et al. Medical Treatment of Pediatric Status
Epilepticus epilepticus (an evidence-based review): Report of the Quality
Standards Subcommittee of the American Academy of Neurology and the
Practice Committee of the Child Neurology Society. Neurology. 2006;67;15421550.
4. NS Abend, AM Gutierrez-Colina, DJ Dlugos. Medical Treatment of Pediatric
Status Epilepticus. Semin Pediatr Neurol. 2010; 17:169-175.
5. S Sinha, P Satishchandra, A Mahadevan, BC Bhimani, JME Kovur, SK Shankar.
Fatal status epilepticus: A clinico-pathological analysis among 100 patients:
From a developing country perspective. Epilep Res. 2010; 91, 193204.
6. R Helbok, J Claassen. Multimodal invasive monitoring in status epilepticus:
What is the evidence it has a place? Epilepsia. 2013; 54(Suppl. 6):5760.

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