50

Status epilepticus
Helen I Opdam

Status epilepticus (SE) is a medical emergency requiring prompt intervention to prevent the development of
irreversible brain damage.
DEFINITION AND CLASSIFICATION
The duration of seizure activity required to define SE
has not been universally agreed upon. Most authors
have defined SE as more than 30 minutes duration of
either a single seizure, or intermittent seizures with no
regaining of consciousness between seizures.14 This
definition is most useful for epidemiological research5
and is based on experimental studies that show irreversible neuronal damage occurs after 30 minutes of
seizure activity.6
There is general acceptance of an operational definition of SE as 5 minutes of continuous seizure activity,
or two or more discrete seizures with no intervening
recovery of consciousness. It has arisen from the need
to rapidly initiate treatment for SE and the observation
that seizures persisting beyond this duration are
unlikely to remit spontaneously.7 Promulgation of this
definition and resultant earlier treatment may be
responsible for a decline in the incidence of SE.5
Refractory SE is defined as failure of initial therapy,
such as benzodiazepines and phenytoin, usually necessitating treatment with agents that induce general
anaesthesia.810 Refractory SE develops in about one in
five patients presenting with an SE episode and is associated with a worse prognosis.9,11
Continuation or recurrence of SE beyond 24 hours
of anaesthetic therapy has been termed superrefractory SE.12
SE is commonly separated into two categories:
convulsive SE (GCSE): seizures are
Generalised
primary or secondarily generalised and the patient

has generalised tonic and/or clonic convulsive

movements with loss of consciousness.
Non-convulsive SE (NCSE): there is altered consciousness and electroencephalography (EEG) evidence
of seizures without convulsive movements. NCSE
is a heterogeneous disorder with multiple subtypes. NCSE may evolve from GCSE when electrical seizure activity continues with loss of motor
manifestations.

The incidence of SE is U-shaped, being greatest under

1 year and over 60 years of age.5
PATHOPHYSIOLOGY
Ongoing or recurrent seizures result from failure of
normal seizure terminating mechanisms and predominance of excitation causing seizure activity to
persist. The major inhibitory mechanism in the brain
is -aminobutyric acid A (GABAA) receptor-mediated
inhibition. With ongoing seizure activity GABAA receptors undergo cellular internalisation and subsequent
degradation, leading to loss of endogenous inhibition
and sustainability of seizures. This reduction in synaptic GABAA receptors explains the progressive phar
macoresistance to GABAergic anticonvulsants such as
benzodiazepines.13
Excitatory mechanisms are predominantly via
glutamine acting on N-methyl-D-aspartate (NMDA)
receptors. NMDA receptors increase on synapses
during ongoing epileptic activity, facilitating neuronal
excitability and persistence of seizures. This in contrast
explains the efficacy of NMDA antagonists, even late in
the course of SE.
The pathophysiological effects of seizures on the
brain are thought to result from both direct excitotoxic neuronal injury and secondary injury due to systemic complications such as hypotension, hypoxia and
hyperthermia. Ongoing excitation leads to neuronal
injury and death, predominantly through mitochondrial dysfunction. Experimental models and anecdotal
human evidence suggest also that SE is epileptogenic, although the mechanisms of this are not well
understood.13
AETIOLOGY
Status epilepticus may occur de novo (approximately
60% of presentations) or less commonly in a previously
diagnosed epileptic.5 In the situation where refractory
SE does not have a clear cause, more unusual conditions should be considered as their diagnosis may lead
to a specific therapy. These include autoimmune conditions, mitochondrial diseases and unusual infections.14
The aetiologies of SE are given in Box 50.1.2,5,14,15

Generalised convulsive status epilepticus (GCSE)

Box 50.1 Causes of status epilepticus in adults2,4,14,15
Low antiepileptic drug levels poor compliance, recent dose
reduction or discontinuation (most common cause in
patients with epilepsy)
Stroke vascular occlusion or haemorrhage
Metabolic disturbances electrolyte abnormalities (hyponatraemia, hypocalcaemia, hypomagnesaemia, hypophosphataemia), hyperglycaemia, hypoglycaemia
Organ failure uraemia, hepatic encephalopathy
CNS infection bacterial meningitis, viral encephalitis, cerebral toxoplasmosis, tuberculosis, other
Cerebral hypoxia/anoxia
Alcohol withdrawal or intoxication
Head trauma
Drug toxicity cephalosporins, isoniazid, tranexamic acid,
tacrolimus, cyclosporine, tricyclic antidepressants, olanzapine, phenothiazines, theophylline, cocaine, amphetamine, antiepileptic drugs, other
CNS tumours primary or secondary
Temporally remote causes (previous CNS injury) stroke,
trauma, tumour, meningitis
Hypertensive encephalopathy, eclampsia
Immunological disorders paraneoplastic syndromes, Hashimotos encephalopathy, anti-NMDA receptor encephalitis
(may have associated ovarian tumour), cerebral lupus,
thrombotic thrombocytopenic purpura, other
Mitochondrial diseases

GENERALISED CONVULSIVE STATUS

EPILEPTICUS (GCSE)
GCSE is the most common and most dangerous type of
SE and accounts for approximately 75%.2 It encompasses a broad spectrum of clinical presentations, from
overt generalised tonicclonic seizures to subtle convulsive movements in a profoundly comatose patient.16
CLINICAL
Typically, early in the evolution of seizures, patients are
unresponsive with obvious tonic (sustained contractions) and/or clonic (rhythmic jerking) movements
(overt GCSE). Motor manifestations may be symmetrical or asymmetrical.
With time, the clinical manifestations may become
subtle, and patients have only small-amplitude twitching movements of the face, hands, or feet, or nystagmoid jerking of the eyes (late or subtle GCSE).16
Later still some patients will have no observable
repetitive motor activity and the detection of ongoing
seizures requires EEG (electrical GCSE). Most authors
classify this as a form of NCSE.7,17 Such patients are still
at risk of CNS injury and require prompt treatment.
EEG CHANGES
Just as there is a progression from overt to increasingly
subtle motor manifestations, there is also a predictable

561

Box 50.2 Physiological changes in generalised

convulsive status epilepticus18
Hypoxia
Respiratory acidosis
Lactic acidosis
Hyperpyrexia
Hypertension (early)/hypotension (late)
Hyperglycaemia (early)/hypoglycaemia (late)
Tachycardia
Cardiac arrhythmias
Blood leucocytosis
CSF pleocytosis, increased CSF protein
Intracranial hypertension
Neurogenic pulmonary oedema
Aspiration pneumonitis
Rhabdomyolysis

sequence of EEG changes during untreated GCSE. Initially, discrete electrographic seizures merge to a
waxing and waning pattern of seizure activity, followed by continuous monomorphic discharges, which
become interspersed with increasing periods of electrographic silence and, eventually, periodic epileptiform
discharges on a relatively flat background.16 The presence of any of these EEG patterns should suggest the
diagnosis of GCSE.
ENDOCRINE AND METABOLIC EFFECTS
Early in GCSE there is a marked increase in plasma
catecholamines, producing systemic physiological
changes that resolve if SE is stopped early (Box 50.2).
However, if seizures continue, many of these early
physiological changes reverse and the resultant hypotension and hypoglycaemia may exacerbate neurological injury.18
Hyperthermia is due to both muscle activity and
central sympathetic drive, and thus may still occur
when paralysing agents prevent motor activity. In early
SE, both cerebral metabolic activity and cerebral blood
flow (CBF) are increased. In late SE, although cerebral
metabolic activity remains high, CBF may fall owing to
hypotension and loss of cerebral autoregulation leading
to cerebral ischaemia.
PSEUDOSEIZURES
An important differential diagnosis of generalised convulsive epilepsy is pseudoseizures.19 These can occur in
patients with or without a history of epilepsy. Clinical
features suggestive of pseudoseizures are listed in Box
50.3. Distinction between the two may be extremely
difficult, and can be made with complete certainty only
using EEG monitoring. Pseudostatus, misdiagnosed
as true SE, is often refractory to initial therapy and can
lead to patients receiving general anaesthesia and
mechanical ventilation.

562

Status epilepticus

Box 50.3 Features suggestive of pseudoseizures

Box 50.4 Investigations in status epilepticus

Lack of stereotyped seizures, with behavioural manifestations

varying from event to event
Lack of sustained convulsive activity onoff appearance
Increase in movement if restraint is applied
Abolition of motor movements with reassurance or
suggestion
Resistance to eye opening and gaze aversion
Poor response to treatment, refractory status epilepticus
Absence of pupillary dilatation
Normal tendon reflexes and plantar responses immediately
after convulsion
Lack of metabolic consequences despite some hours of
apparent fitting

Initial studies

NON-CONVULSIVE STATUS
EPILEPTICUS (NCSE)
This accounts for approximately 25% of SE, though its
incidence is probably underestimated because of failure
to recognise and diagnose the condition.
The diagnosis of NCSE generally requires a change
in behaviour and/or responsiveness from baseline for
at least 30 minutes, no overt seizure activity and an EEG
with epileptiform discharges.20 A response to intravenous antiepileptic drugs (e.g. benzodiazepines), with
clinical improvement and resolution or improvement in
EEG epileptic activity, is helpful in confirming the
diagnosis.21
The diagnosis of NCSE should be considered in any
patient with an unexplained altered conscious state,
particularly those with CNS injury, metabolic disturbance, hepatic encephalopathy or sepsis. Series where
EEG has been performed in critically ill patients with
an unexplained depressed conscious state have found
a high incidence of NCSE (818%).2224 EEG monitoring
is required in patients with GCSE who do not recover
consciousness after resolution of overt convulsive activity; in one study more than 14% of such patients had
NCSE.17
NCSE is a heterogeneous disorder with multiple
subtypes and published reports often describe diverse
cohorts of patients. Although attempts have been made
to define and classify this disorder, there is yet no universally accepted definition or classification.20,25
Traditionally NCSE is divided into absence status
epilepticus (ASE) and complex partial status epilepticus
(CPSE).21 ASE is associated with bilateral diffuse synchronous seizures and may be typical as characterised
by generalised 3Hz spike-wave EEG activity during
periods of altered behaviour, or responsiveness that
occurs in children with idiopathic generalised epilepsy
who are otherwise normal.21 Atypical ASE is a heterogeneous syndrome occurring in patients with mental
retardation and epilepsy with multiple seizure types.
CPSE may present with a wide variety of clinical
features and a variable degree of impairment of

Blood glucose, electrolytes (sodium, potassium, calcium,

magnesium), urea
Arterial blood gases
Anticonvulsant drug levels
Full blood count
Urinalysis

Further investigations after stabilisation

Liver function tests, lactate, creatine kinase

Toxicology screen
Lumbar puncture
Electroencephalogram
Brain imaging with computed tomography or magnetic resonance imaging

consciousness, which includes confusion, agitation,

bizarre or aggressive behaviour and coma.20 More
recently other possible classification systems have been
proposed.20,2527
The most important factor in determining outcome
in NCSE is the underlying cause.4,20,21
NCSE is often mistaken for other conditions, resulting in a delay in diagnosis and treatment. A high index
of suspicion must therefore be present to trigger investigation with an EEG.
The differential diagnosis of NCSE includes:

encephalopathy
metabolic
intoxication
drug
disease
cerebrovascular
psychiatric syndromes (dissociative reactions, acute
psychosis)
post-ictal confusion.
EPILEPTIFORM ENCEPHALOPATHIES

In many advanced coma stages, the EEG exhibits continuous or periodic EEG abnormalities, but in such situations it is unclear whether the abnormal discharges are
responsible for, or contribute to, the altered consciousness or are merely a reflection of a severe cerebral
insult.27
Some consider myoclonic SE that follows an anoxic
insult as part of this category, rather than as a form of
NCSE.27
INVESTIGATIONS
Not all of the investigations listed in Box 50.4 need
to be performed in every patient. The selection of
tests depends on both the patients history and the
presentation.
NEUROIMAGING
Most patients with SE should have a computed tomography (CT) scan of the brain performed, although this

Drugs for status epilepticus

563

may not always be necessary if another episode of SE

occurs in a patient with established epilepsy who has
previously been thoroughly evaluated. Magnetic
resonance imaging (MRI) may occasionally reveal
abnormalities not visualised on CT scans and should
be considered for non-emergency imaging. Imaging
should be performed only after control of SE and
patient stabilisation.28

barbiturates was terminated after 3 years with only 24

of the required 150 patients recruited.33
The EEG goal of treatment for refractory SE remains
controversial, with some advocating EEG background
suppression (isoelectric) and others suppression of seizures regardless of the EEG background activity.7,9,10,34
Various protocols for SE management have been
suggested.1,7,9,34 One approach is outlined in Box 50.5.

LUMBAR PUNCTURE

NON-CONVULSIVE STATUS EPILEPTICUS (NCSE)

In any patient, especially in young children with fever

and SE, CNS infection and lumbar puncture along
with blood cultures should be considered.29 Meningitis
is an uncommon cause of SE in adults and, unless the
suspicion of CNS infection is high, brain imaging
should be performed before a lumbar puncture. Contraindications to lumbar puncture include intracranial
hypertension, mass lesion and hydrocephalus. If meningitis is suspected and a lumbar puncture cannot be
performed expediently, antibiotics should be administered immediately rather than delayed. Approximately
20% of patients have a modest CSF white cell count
pleocytosis after SE and such patients should be
treated for suspected meningitis until the diagnosis
is excluded.1

Patients with NCSE are a heterogeneous group and

as such there is a variable response to treatment.25
Prognosis is most closely related to the underlying
aetiology.20,21
Clinical response to intravenous benzodiazepine is
predictive of a good outcome.35
There is considerable debate as to whether NCSE
presents the same degree of risk of neurological injury
as GCSE.36 Prompt treatment is generally recommended
and the use of additional non-anaesthetising anticonvulsants, such as levetiracetam, phenobarbital and valproate, has been suggested prior to embarking upon
general anaesthesia.7,21,37
The potential side-effects of aggressive treatment
(hypotension, immunosuppression) need to be balanced against the potential neurological morbidity of
NCSE.38 Particularly in elderly patients, aggressive
treatment and anaesthesia may be associated with more
risk than benefit and result in a worse outcome.20,38,39

MANAGEMENT
GENERALISED CONVULSIVE STATUS
EPILEPTICUS (GCSE)
An accurate history should be obtained, with particular emphasis on eye-witness accounts of the onset
and nature of the seizures, and a full physical examination performed. However, neither should delay
initial emergency management. Rapid control of seizures is crucial to prevent brain injury and the development of refractory SE. There is evidence that the
longer SE goes untreated the harder it is to control
with drugs.8,9,30,31
Management of SE involves termination of seizures,
treating precipitating causes and underlying conditions, and prevention of complications and recurrence
of seizures.
Few controlled data are available to support the use
of any particular agents. One of the few randomised,
double-blind clinical trials for treatment of GCSE found
that lorazepam, phenobarbital or diazepam followed
by phenytoin are all acceptable as initial treatment, but
that phenytoin alone was not as effective as lorazepam.31
Another randomised controlled trial in the pre-hospital
setting found intravenous lorazepam and diazepam to
be equally effective and superior to placebo in terminating GCSE.32
There are few data to guide the treatment of refractory SE, for which anaesthetising agents such as thiopental, propofol or midazolam infusions are commonly
used. A randomised controlled trial of propofol versus

DRUGS FOR STATUS EPILEPTICUS

BENZODIAZEPINES
Benzodiazepines are fast-acting antiseizure drugs and
are therefore preferred as initial therapy. They act
mainly by enhancing the neuroinhibitory effects of
-aminobutyric acidA (GABAA). The efficacy of benzodiazepines diminishes with duration of SE as a result
of a reduction in synaptic GABAA receptors with prolonged seizures.13
Diazepam is a highly lipid-soluble drug with rapid
CNS penetration, but then redistribution resulting in a
short duration of action. It can be administered either
intravenously or by the rectal route. Rectal administration can be achieved using a specially formulated rectal
gel, or the intravenous preparation can be diluted with
an equal amount of saline and flushed into the rectum.
Rectal administration should be considered when vascular access is delayed and may be particularly useful
in the pre-hospital setting.
Lorazepam has a longer duration of action and has
a lower incidence of seizure recurrence when used as a
single agent.31 A double-blind, randomised comparison
of intravenous diazepam, lorazepam and placebo in SE
in the pre-hospital setting found both benzodiazepines
to be associated with greater cessation of seizures and
lower requirement for intubation than placebo. There

564

Status epilepticus

Box 50.5 Protocol for management of SE

1. Assess A, B, C, GCS
2. Give O2 and consider need for intubation/ventilation
3. Monitor blood pressure, ECG, pulse oximetry
4. Obtain i.v. access and draw blood for investigations
5. If patient is hypoglycaemic, or if blood glucose estimation
is not available, give glucose:
adults: give thiamine 100mg i.v. and 50mL of 50%
glucose i.v.
children: give 2mL/kg of 25% glucose i.v.
6. Seizure control:
A. Give benzodiazepine,* for example:
diazepam: 0.2mg/kg i.v. at 5mg/min up to total
dose of 20mg;
lorazepam: 0.1mg/kg i.v. at 2mg/min up to total
dose of 10mg;
clonazepam: 0.010.02mg/kg i.v. at 0.5mg/min
up to total dose of 4mg.
If diazepam stops the seizures, phenytoin should be
given next to prevent recurrence.
Repeat dose every 25min if required. Note: risk of
respiratory depression with cumulative doses.
B. If seizures persist, give phenytoin:
phenytoin: 1520mg/kg (adults 50mg/min; children 1mg/kg/min) or fosphenytoin 1520 phenytoin equivalents (PE) mg/kg i.v. (adults 150mg/
min; children 3mg/kg per min).
Additional doses of 5mg/kg i.v., to a maximum dose
of 30mg/kg can be given for persistent seizures.
Monitor blood pressure and the ECG during infusion.
If hypotension or arrhythmias develop, stop or slow
the rate of the infusion.
C. If seizures persist (refractory SE), intubate and ventilate
patient. Give either:
thiopental: slow bolus 35mg/kg i.v., followed by
infusion 15mg/kg per h, or
propofol: slow bolus 12mg/kg i.v., followed by infusion 25mg/kg per h, or

was a trend toward lorazepam being more efficacious

than diazepam.32
Midazolam has a short duration of action and,
unlike other benzodiazepines, can be administered
via intramuscular, buccal and intranasal routes. These
alternative routes of administration may be more
convenient, acceptable and efficacious than diazepam
administered by the rectal route.40,41 A recent study
found that intramuscular midazolam was as safe and
efficacious as intravenous lorazepam and resulted in
faster and more reliable administration in the prehospital setting.42
Midazolam administered by intravenous bolus and
infusion may terminate seizures when other agents
have failed. It may also have fewer side effects than
alternative agents available for the treatment of refractory SE.43 A limiting factor in its use is tachyphylaxis,
which may necessitate a several-fold increase in the

midazolam: slow bolus 0.10.2mg/kg, followed by

infusion 0.11.0mg/kg per h.
Titrate doses based on clinical and electrographic evidence of seizures, targeting electrographic suppression of seizures or EEG background suppression
(isoelectric).
Monitor BP and maintain normotension by reducing
infusion rate and/or giving fluids/pressor agents.
D. Insert nasogastric tube and administer usual anticonvulsant medications if patient is receiving treatment for
pre-existing epilepsy.
E. Beware of ongoing unrecognised seizures.
Use EEG monitoring until seizures are controlled and
then for 12 hours after seizures stop. Continue to
monitor the EEG continuously, or for periods of more
than 30 minutes every 2 hours, during the maintenance phase.
Avoid muscle relaxants (use continuous EEG if giving
repeated doses of muscle relaxants).
F. Discontinue midazolam or thiopental, or start reducing
propofol, approximately 12 hours after resolution of
seizures. Use continuous EEG monitoring and observe
for further clinical and/or electrographic seizure activity. If seizures recur, reinstate the infusion and repeat
this step at 1224-hour intervals or longer if the
patients seizures remain refractory.
In addition:
Look for and treat cause and precipitant.
Look for and treat complications: hypotension, hyperthermia,
and rhabdomyolysis.

*If i.v. access is not obtainable, consider rectal diazepam, buccal/

sublingual or intranasal or i.m. midazolam, i.m. fosphenytoin.

High infusion rates for prolonged periods require caution.

In refractory SE, consider giving pyridoxine for children <18 months or

if isoniazid toxicity is suspected in adults.

dose to maintain seizure control.34 There is a wide

variation in recommended infusion rates, from 0.05
0.4mg/kg per hour7 to 0.22.9mg/kg per hour.10
Clonazepam has a longer duration of action than
diazepam and is given by intravenous bolus. Early
reports suggested that it has better efficacy and fewer
side-effects than diazepam, though there are no published comparisons.
PHENYTOIN
Phenytoin is useful for maintaining a prolonged antiseizure effect after rapid termination of seizures with a
benzodiazepine, or when benzodiazepines fail. When
used alone as initial therapy phenytoin is not as efficacious as benzodiazepines for terminating seizures.31
The recommended intravenous loading dose is
20mg/kg. The common practice of giving a standard

Drugs for status epilepticus

loading dose of 1000mg of phenytoin may provide
inadequate therapy for some adults.
When phenytoin is infused at the maximal adult recommended rate of 50mg/min, hypotension occurs in
up to 50% of patients and cardiac rhythm disturbance
occurs in 2%. These adverse effects are more common
in older patients and those with cardiac disease and are
due to the phenytoin itself as well as the propylene
glycol diluent. Blood pressure and the ECG should be
monitored during infusion of phenytoin and the infusion slowed or stopped if cardiovascular complications
occur.
Intramuscular administration of phenytoin is not
recommended as absorption is erratic and it can cause
local tissue reactions.
Fosphenytoin, a new water-soluble prodrug of
phenytoin, is converted to phenytoin by endogenous
phosphatases.44 Doses of fosphenytoin are expressed
as phenytoin equivalents (PE). Fosphenytoin can be
administered at rates of up to 150 PE mg/min, since it
is not formulated with propylene glycol, allowing therapeutic serum concentrations of fosphenytoin to be
attained within 10 minutes. However, this may not necessarily result in more rapid CNS penetration and onset
of action.45
Systemic side-effects are similar for phenytoin and
fosphenytoin, although reactions at the infusion site are
less common with fosphenytoin.44
Fosphenytoin can also be administered intramuscularly, although absorption is slower than with intravenous administration, and this route should be used only
when intravenous access is not possible.
SODIUM VALPROATE
There are reports of intravenous valproate being
used to treat both GCSE and NCSE in adults and children. It is non-sedating and it appears to be well tolerated with few reports of hypotension or respiratory
depression.46
It may be particularly useful as a second- or third-line
drug in situations where it is not possible, or it is pre
ferable to avoid the use of sedating anaesthetic agents
and the associated requirement for intubation.47
An initial dose of 10mg/kg followed by continuous
infusion or divided doses up to 20-40mg/kg daily is
recommended.7,48
LEVETIRACETAM
Although the data are mostly uncontrolled and retrospective, there is some evidence for the use of levetiracetam as second- or third-line therapy and in situations
where it is desirable to avoid intubation, such as in
NCSE and treatment of the elderly.8,37,47,49 Levetiracetam
may have particular utility in controlling seizures after
hypoxic brain injury.8
Levetiracetam may be given intravenously in bolus
doses of between 1000 and 3000mg.

565

BARBITURATES
Phenobarbital is a potent anticonvulsant with a long
duration of action. The usual dose is 1520mg/kg
intravenously. It has equal efficacy to benzodiazepines
and phenytoin when used first-line, but may cause
greater depression of respiration, blood pressure and
consciousness and therefore is often used only if these
agents fail. However, many would advocate alternative
and more aggressive measures for treatment of refractory SE at this point as the likelihood of phenobarbital
controlling seizures when these other agents have
failed is small.10
Thiopental is an intravenous anaesthetic agent used
for refractory SE. A dose of 35mg/kg is usually given
for intubation, followed by repeated doses of 0.51mg/
kg until seizures are controlled. Following bolus intravenous administration, the drug is rapidly redistributed into peripheral fat stores and an infusion of
15mg/kg per hour is required for ongoing suppression of seizures. Once lipid stores are saturated the
duration of action is prolonged and recovery may take
hours to days. Prolonged therapy requires the use of
EEG monitoring to ensure that the seizures remain suppressed and to allow titration to the lowest dose that
achieves the EEG target of seizure and/or EEG background suppression. Side-effects include hypotension,
myocardial depression and immunosuppression with
increased risk of infection.
Pentobarbital (the first metabolite of thiopental) is
available in the USA as the alternative to thiopental.
Compared with other agents used in refractory SE
(midazolam and propofol), barbiturates may result in a
lower frequency of short-term treatment failure and
breakthrough seizures, but result in more hypotension
and slower recovery from anaesthesia.50
PROPOFOL
Propofol (2,6-diisopropylphenol) is an anaesthetic
agent that has become increasingly popular for the
treatment of refractory SE. It is administered as an
intravenous bolus followed by infusion and intubation
and ventilation are required.
Compared with high-dose barbiturates (pentobarbital) in adult patients with refractory SE, propofol has
been found to control seizures more quickly and,
because of its shorter duration of action, allows earlier
re-emergence from anaesthesia.51 However, seizures
tend to recur with sudden discontinuation of propofol,
necessitating recommencement of the infusion and a
more gradual tapering of the dose, such that both drugs
ultimately may result in a similar duration of ventilation and ICU stay.51
There is concern that prolonged high-dose propofol
use (e.g. >5mg/kg per hour) may result in myocardial
failure, hypoxia, metabolic acidosis, lipaemia, rhabdomyolysis and death (propofol infusion syndrome).52
Early reports were in children and later adults and its

566

Status epilepticus

use requires caution. There are series, however, of prolonged high-dose propofol use in adults with SE
without major adverse effects.53
NEUROMUSCULAR-BLOCKING AGENTS
Paralysis is indicated if uncontrolled fitting causes difficulty with providing adequate ventilation or severe
lactic acidosis. Neuromuscular blockade should be
used only if continuous EEG monitoring is available, as
the clinical expression of seizure activity is abolished.

Box 50.6 Indications for EEG monitoring17

Refractory SE, to aid the titration of anticonvulsant anaesthetic drugs (minimizing dose and toxicity) and ensure
suppression of seizure activity*
Patients receiving neuromuscular blockade*
Patients who continue to have a poor conscious state after
apparent cessation of seizures
Suspected non-convulsive status epilepticus in a patient with
an altered conscious state
Suspected pseudoseizures
*Continuous or regular intermittent EEG monitoring recommended.

OTHER AGENTS OF POTENTIAL USE IN

REFRACTORY SE
Ketamine acts as an antagonist at the NMDA receptor
and may have a role in the treatment of prolonged
refractory SE.12
Intravenous lacosamide is a new anticonvulsant
drug available in intravenous and oral formulations
that may be an option for treatment of established SE
after failure of standard therapy, or when standard
agents are considered unsuitable. Evidence exists
mainly in the form of limited case series.54
Pregabalin appears to be an interesting option as
add-on treatment in refractory NCSE and may lessen
the requirement for ICU treatment.55
Magnesium is the drug of choice in eclamptic seizures and also is effective in seizures due to hypomagnesaemia, but there is little evidence to support its use
in other forms of SE.12
SURGERY
Surgery has occasionally been used in refractory SE
with procedures based on standard epilepsy surgery
techniques. Some success has been reported with focal
resections, subpial transection, corpus callosotomy,
hemispherectomy and vagus nerve stimulation.12,56
INTENSIVE CARE MONITORING
Monitoring using ECG, intra-arterial and central venous
catheters, capnography and pulse oximetry should be
considered in patients with, or at risk of, cardiorespiratory compromise. Indications for EEG monitoring are
listed in Box 50.6.17 Cerebral function monitors are
useful in titrating doses of anaesthetic agents to EEG
background suppression, but may not have sufficient
sensitivity to detect seizure activity. Intracranial pressure monitoring should be considered if elevated
intracranial pressure is present owing to the underlying
brain pathology.
OUTCOME
The prognosis of patients with SE is related to age,
aetiology, degree of impairment of consciousness at

presentation, and duration of SE.15,57 Refractory SE

is associated with a worse prognosis and very prolonged super-refractory SE an even higher mortality.
However, where no underlying irreversible brain
damage is present, good recovery is possible even after
weeks of SE.9,12
Children have a much lower mortality of 3%58
whereas those aged over 65 years have a mortality rate
of 30%.3,4
SE that is precipitated by low antiepileptic drug
levels, alcohol abuse or systemic infection has a very
low mortality, whereas SE secondary to an acute CNS
insult such as stroke or infection has a higher mortality.3,5 SE associated with hypoxic brain injury is most
often fatal.59 NCSE detected in comatose critically ill
patients, despite recognition and treatment, has a poor
outcome.24,39
Consequences of SE include brain damage resulting in permanent neurological deficits and also the
development of focal epilepsy (epileptogenesis). Multiorgan failure and death can result from uncontrolled
seizures, the underlying illness or complications of
treatment.
STATUS EPILEPTICUS IN CHILDREN 5861
Most paediatric cases of SE occur in young children,
with 80% occurring in those below 4 years of age.58 The
vast majority of cases are convulsive and generalised.28
The distribution of causes is highly age-dependent,
with febrile SE and that due to acute neurological
disease (e.g. CNS infection) being more common in children under 4 years. Remote symptomatic causes and SE
in a child with previously diagnosed epilepsy are more
common in older children.58 The most frequent aetiologies of SE in children are listed in Box 50.7.28,29,58
The likelihood of bacterial meningitis is much higher
in febrile children presenting with a first-ever episode
of SE (12%) as opposed to a brief seizure (1%) and a
high index of suspicion is required to investigate and
treat for meningitis.58
Treatment of SE in children is essentially the same
as in adults.60

Status epilepticus in children

Box 50.7 Causes of status epilepticus in
children28,29,58
Febrile previously neurologically normal, temp. >38C,
CNS infection excluded
Acute symptomatic meningitis, encephalitis, cerebrovascular disease, trauma, metabolic derangement, hypoxia,
sepsis, drug-related
Remote symptomatic causes previous traumatic brain injury
or insult, CNS malformation, cerebral palsy
Progressive neurological conditions tumours, degenerative,
autoimmune diseases
Cryptogenic

567

The underlying cause is the main determinant of

mortality, which is negligible for prolonged febrile
seizures and 1216% for acute symptomatic causes.61
Similarly, the risk of subsequent epilepsy is low in neurologically normal children but higher than 50% in
those with acute or remote symptomatic causes.61

Access the complete references list online at http://www.expertconsult.com

7. Meierkord H, Boon P, Engelsen B, et al. EFNS guideline on the management of status epilepticus in
adults. Eur J Neurol 2010;17(3):34855.
8. Holtkamp M. Treatment strategies for refractory
status epilepticus. Curr Opin Crit Care 2011;17(2):
94100.
9. Rossetti AO, Lowenstein DH. Management of refractory status epilepticus in adults: still more questions
than answers. Lancet Neurol 2011;10(10):92230.
12. Shorvon S, Ferlisi M. The treatment of superrefractory status epilepticus: a critical review of
available therapies and a clinical treatment protocol.
Brain 2011;134(Pt 10):280218.

13. Chen JW, Wasterlain CG. Status epilepticus: pathophysiology and management in adults. Lancet
Neurol 2006;5(3):24656.
14. Tan RY, Neligan A, Shorvon SD. The uncommon
causes of status epilepticus: a systematic review. Epilepsy Res 2010;91(2-3):11122.
20. Meierkord H, Holtkamp M. Non-convulsive status
epilepticus in adults: clinical forms and treatment.
Lancet Neurol 2007;6(4):32939.
60. Abend NS, Gutierrez-Colina AM, Dlugos DJ. Medical
treatment of pediatric status epilepticus. Semin
Pediatr Neurol 2010;17(3):16975.

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