British Journal of Anaesthesia 108 (4): 56271 (2012)

Advance Access publication 8 March 2012 . doi:10.1093/bja/aes027

REVIEW ARTICLES

Anaesthesia and epilepsy

A. Perks 1*, S. Cheema 3 and R. Mohanraj2
1
3

Department of Anaesthesia and 2 Department of Neurology, Salford Royal Hospital, Stott Lane, Salford M6 8HD, UK
Bradford Royal Infirmary, Duckworth Lane, Bradford BD9 6RJ, UK

* Corresponding author. E-mail: anna.perks@srft.nhs.uk

Editors key points

The authors have reviewed the mechanism
of action of old and new antiepileptic drugs.

Status epilepticus, refractory to two

antiepileptic drugs carries a high morbidity
and requires general anaesthesia.
For uncontrolled seizures, treatment with
midazolam, thiopental, or propofol is
acceptable; opioids should be avoided.

Keywords: anaesthesia; anticonvulsants; epilepsy; status epilepticus

Epilepsy is a tendency to have recurrent unprovoked seizures.

It is the most common serious neurological disorder with a
prevalence of 0.51% of the population. The highest incidence
is at the extremes of age and in those with structural or developmental brain abnormalities. The International League
against Epilepsy (ILAE) has classified seizures into focal (or
partial) seizures which arise from one hemisphere and generalized seizures which show electrographic seizure onset over
both hemispheres.1 2 Lamotrigine and carbamazepine are
considered drugs of choice in focal epilepsies, while valproate
is probably the most effective drug for primary generalized seizures.3 4 If the initial antiepileptic drug (AED) results in adverse
effects, an alternative AED is tried as monotherapy. If, on the
other hand, seizures continue in spite of adequate doses,
combination therapy is often necessary.
In the last 20 yr, there has been an influx of a new generation of AEDs.5 Many of these are the products of rational
drug development programmes, while others are modifications of previously existing molecules that result in
improved pharmacokinetic properties. The newer AEDs are
generally associated with fewer adverse effects and drug
interactions. Many anaesthetic agents affect the propensity
to seizures, both in patients with epilepsy and in those with
no prior history of seizures. In patients taking AEDs, drug
interactions and maintenance dosing of AEDs during
periods of starvation are important considerations in the
perioperative period.
Patients with epilepsy often require anaesthesia for
elective and emergency surgery. Appropriate perioperative

management of AED therapy is vital in maintaining seizure

control in these patients. Anaesthetists need to be aware of
the pharmacological properties of commonly used AEDs.
Patients with epilepsy may also require anaesthetic care
during treatment of status epilepticus, either for airway management or induction of general anaesthesia for refractory
status epilepticus. This article aims to examine the current
treatment of epilepsy, the mode of action of antiepileptics,
the effect of AEDs on anaesthesia, and the effect of anaesthesia on epilepsy in adults. The use of anaesthetic agents in the
management of refractory status epilepticus is also discussed.

Mechanisms of action of AEDs

In simple terms, a seizure can be seen as the result of imbalance between excitatory and inhibitory neuronal activity.
This leads to the generation of hyper-synchronous firing of
a large number of cortical neurones. Traditional AEDs exert
antiseizure activity by the following mechanisms:
reduce the inward voltage-gated positive currents
(Na+, Ca2+),
increase inhibitory neurotransmitter activity (GABA),
decrease excitatory neurotransmitter activity (glutamate, aspartate).
The effects are summarized in Table 1. In addition, many
new AEDs possess novel mechanisms of action. Novel sites
of drug binding include synaptic vesicle (SV2) protein (levetiracetam), steroid binding sites on GABAA receptors (ganaxolone), and voltage-gated potassium channel (retigabine).6 7

& The Author [2012]. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved.
For Permissions, please email: journals.permissions@oup.com

Downloaded from http://bja.oxfordjournals.org/ by guest on February 21, 2015

Awareness is required regarding

seizure-provoking properties of certain
anaesthetic drugs.

Summary. Epilepsy is the most common serious neurological disorder, with a

prevalence of 0.51% of the population. While the traditional antiepileptic
drugs (AEDs) still play a significant role in treatment of seizures, there has been
an influx of newer agents over the last 20 yr, which are now in common usage.
Anaesthetists are frequently faced with patients with epilepsy undergoing
emergency or elective surgery and patients suffering seizures and status
epilepticus in the intensive care unit (ICU). This review examines perioperative
epilepsy management, the mode of action of AEDs and their interaction with
anaesthetic agents, potential adverse effects of anaesthetic agents, and the
acute management of seizures and refractory status epilepticus on the ICU.
Relevant literature was identified by a Pubmed search of epilepsy and status
epilepticus in conjunction with individual anaesthetic agents.

BJA

Anaesthesia and epilepsy

Effect of antiepileptics on anaesthesia

Effect of anaesthetic agents on epilepsy

Many of the agents used possess both pro-convulsant and
anticonvulsant properties, which could impact on the
choice of anaesthetic.14

Inhalational anaesthetics
Nitrous oxide (N2O) provokes seizures in animal models
(cats), but this has not been replicated in humans. In mice,

Opioids
Meperidine is the opioid with the strongest association with
myoclonus and tonic-clonic seizure activity.24 However, fentanyl, alfentanil, sufentanil, and morphine have been
reported to cause generalized seizure patients after
low-to-moderate dose,25 26 particularly after intrathecal
use.27 29 Fentanyl and its analogues have not been shown
to possess any anticonvulsant properties.
Opioid anaesthetic agents are used to enhance EEG activity in patients with focal epilepsy. Both remifentanil and
alfentanil have been used to induce spike activity in localizing epileptogenic zones intraoperatively during epilepsy
surgery,30 although alfentanil appears to be the more
potent activator.31 The addition of alfentanil to propofol anaesthesia for electroconvulsive therapy (ECT) also increases
seizure duration.32

I.V. anaesthetic agents

The barbiturates (thiopental, methohexital, and pentobarbital) and propofol are well established as agents for the
treatment of refractory status epilepticus.33 35 All agents
have been reported to produce excitatory activity, such as

Table 1 Main modes of action of commonly used AEDs.6 7 *From the evidence, it is not clear which of the actions of valproate is responsible for
its actions. Lamotrigine is primarily a sodium channel blocker with some effects on T-type calcium channels
Mode of action

Antiepileptic drug

Increase GABA activity

Increased frequency of Cl channel opening

Benzodiazepines (binds to BZ2 receptors); tiagabine (prevents reuptake);

gabapentin (prevents reuptake)

Increased mean Cl channel opening duration

Barbiturates

Blocks GABA transaminase (blocking GABA catabolism

within the neurone)

Vigabatrin

Glutamate antagonist

Topiramate (at AMPA receptor)

Reduction of inward voltage-gated positive currents

Phenytoin (Na+ channel); carbamazepine (Na+ channel); ethosuximide (Ca2+ channel)

Increased outward voltage-gated positive currents

Sodium valproate (K+ channel)

Pleotropic sites of action

Sodium valproate (1, 2, 3 and 4)*; lamotrigine (2 and 3)*; topiramate (1, 2, and 3)

563

Downloaded from http://bja.oxfordjournals.org/ by guest on February 21, 2015

There are important pharmacokinetic and pharmacodynamic

interactions between AEDs and drugs commonly used in anaesthesia. These affect both drug efficacy and the risk of
seizure activity intraoperatively.8
Induction and inhibition of the cytochrome P450 isoenzymes in hepatic metabolism constitutes the most significant
mechanism of drug interactions involving AEDs. Many of the
older-generation AEDs, such as carbamazepine, phenytoin,
phenobarbital, and primidone, have potent enzyme-inducing
properties. This leads to a decreased plasma concentration of
many medications including immunosuppressants, antibacterials, and cardiovascular drugs, particularly amiodarone,
b-blockers (propranolol, metoprolol), and calcium channel
antagonists (nifedipine, felodipine, nimodipine, and verapamil).9 In patients taking warfarin, introduction or withdrawal
of enzyme-inducing AEDs requires close monitoring of the
international normalized ratio. Oxcarbazepine and eslicarbazepine are weaker inducers of hepatic microsomal enzymes compared with carbamazepine, but the effects may be clinically
significant.10 Topiramate also induces hepatic microsomal
enzymes in a dose-dependent manner. Valproate is an inhibitor
of hepatic microsomal enzyme systems and may reduce the
clearance of many concurrently administered medications, including other AEDs. Gabapentin, lamotrigine, levetiracetam,
tiagabine, and vigabatrin do not induce hepatic enzymes.11
Macrolide antibiotics, particularly erythromycin, are potent
inhibitors of CYP3A4, which is involved in carbamazepine metabolism and can lead to carbamazepine toxicity. Concomitant use of carbapenem antibiotics can lead to a
significant decrease in serum valproate concentrations.12 13

withdrawal seizures have been seen after short exposures

to N2O.15 During a case of electrocorticographic monitoring
for epilepsy surgery, N2O visibly suppressed epileptiform activity, which manifested again on N2O withdrawal.16 Myoclonus has been observed in volunteers exposed to hyperbaric
(1.5 atm) N2O17 and when used in combination with isoflurane or halothane.18
There are multiple case reports of sevoflurane-provoking
seizure-like activity, particularly in children19 and where
high concentrations are used in conjunction with hypocapnea.20 In high concentration, enflurane exhibits periods of
suppression with paroxysmal epileptiform discharges in
cats and rats.21 There have been multiple reports of seizure
activity in humans after enflurane anaesthesia.18 22 Isoflurane has well-characterized anticonvulsant properties. Both
isoflurane and desflurane can be used in refractory status
epilepticus, described in a later section.23

BJA
myoclonus, opisthotonus, and rarely generalized seizures on
induction of anaesthesia. The highest incidence appears to
be with etomidate,36 followed by thiopental, methohexital,
and propofol. Etomidate has been shown to increase
seizure duration in ECT when compared with thiopental.37
At higher doses, all agents act as anticonvulsants.38 39
Ketamine is a non-competitive glutamate antagonist
acting at N-methyl-D-aspartate receptors, a property which
could be beneficial in management of status epilepticus refractory to other agents (see below). As with the other i.v.
agents, low doses may facilitate seizures, but at doses that
produce sedative or anaesthetic effects, ketamine shows
anticonvulsant properties.40

Benzodiazepines

Local anaesthetics
Local anaesthetic agents readily cross the blood brain
barrier, causing sedation and analgesia followed by generalized convulsions at higher doses.42 43 High blood levels result
from an accidental i.v. administration or rapid systemic absorption from a highly vascular area.44
I.V. lidocaine has been used to treat status epilepticus in
several small series, mainly in children.45 47 It was not associated with any major adverse events in these reports, but its
efficacy and role in management of status epilepticus in
adults remain to be proven.

Neuromuscular blocking agents

None of the neuromuscular blocking agents appear to have
any pro-convulsant or anticonvulsant effects. Laudanosine,
the primary metabolite of atracurium, has been known to
cause EEG and clinical evidence of seizures in animals.48
This has not been replicated in humans, but the possibility
should be considered in patients with hepatic failure in
whom the half-life of laudanosine is significantly prolonged.
Succinylcholine produces EEG activation related to an increase in cerebral blood flow afferent muscle spindle activity;
an effect blunted by prior administration of non-depolarizing
neuromuscular blocking agents. It has not been associated
with seizure activity.49

Anticholinergics and anticholinesterases

The increase in acetylcholine via administration of atropine
or scopolamine can produce central cholinergic blockade
(or central anticholinergic syndrome). This manifests as
agitation with seizures, hallucinations, and restlessness
or stupor, coma, and apnoea. The most effective treatment for this is physostigmine.50 Glycopyrrolate does not
cross the blood brain barrier, so does not produce these
effects.

564

Perioperative management of AEDs

In patients with a history of well-controlled epilepsy, it is vital
that efforts are made to avoid disruption of antiepileptic
medication perioperatively. Patients should be advised to
take their regular medications on the morning of surgery
and regular dosing should be re-established as early as practicable after surgery. If a single dose is missed (such as that
might occur with day-case surgery), it should be taken as
soon as possible after surgery. Where multiple doses are
likely to be missed, AEDs should be administered parenterally
where possible. I.V. forms of phenytoin, sodium valproate,
and levetiracetam are available (where i.v. doses are equivalent to oral doses) and carbamazepine is available as a suppository. If the patients regular AED is not available in
parenteral formulation, advice should be sought from a neurologist regarding alternatives that may be used to cover the
perioperative period.
In general, routine drug level monitoring is not required
perioperatively as anaesthetic agents do not significantly
alter the pharmacokinetics of AEDs. However, prolonged intensive care unit (ICU) stay, with attendant changes in
serum pH and albumin levels and also the use of drugs
that interact with AEDs, can affect their serum concentrations. Of the commonly used AEDs, phenytoin presents the
greatest challenge because of its unique pharmacokinetic
properties. In patients admitted to ICU, it is necessary to
check serum concentrations of phenytoin daily to guide
dosing.

Status epilepticus
Status epilepticus is a common medical emergency. The
traditional definition of status epilepticus as a seizure
lasting or recurring without regaining of consciousness over
a 30 min period is primarily useful for epidemiological purposes. In clinical practice, most convulsive seizures abate
within 2 3 min and a seizure that continues for more than
5 min has a low chance of terminating spontaneously, so
should be treated with emergency antiepileptic
medications.51

Physiological changes seen in status epilepticus

During the first stage of convulsive status epilepticus (CSE),
there is an increase in cerebral metabolism, increased
blood flow, and increased glucose and lactate concentration.
This is associated with massive catecholamine release, raised
cardiac output, hypertension, tachycardia, and increased
central venous pressure. These compensatory mechanisms
prevent cerebral damage in the first 3060 min.52
Beyond this time, if seizures are not controlled, the compensatory mechanisms start to fail and cerebral damage may
occur. Cerebral auto-regulation fails, leading to hypoxia, hypoglycaemia, an increase in intracranial pressure, and cerebral
oedema. The net result is of hyponatraemia, potassium imbalance, and an evolving metabolic acidosis, which will lead to a
consumptive coagulopathy, rhabdomyolysis, and multi-organ
failure. These changes are represented in Figure 1. It should be

Downloaded from http://bja.oxfordjournals.org/ by guest on February 21, 2015

All benzodiazepines in clinical practice possess potent anticonvulsant properties.41 Diazepam, midazolam, and lorazepam are widely used to terminate episodes of status
epilepticus (see below).

Perks et al.

BJA

Anaesthesia and epilepsy

Generalized
convulsions

Motor

Myo

Isolated

PEDS

Lengthen
Phase II
AP normal
Glucose
pH Lactate

Phase I
AP
Lactate Glucose

Systemic

Electromechanical
dissolution

us

Seizures

Recurrent seizures

EEG

clon

Respiratory compromise
Hypothermia

Transition

Con

Brain
damage

Brain
utilization

nvu

lsive

1
CBF

Oxygen
utilization

2
3

Brain glucose
4

Brain energy state

Brain lactate
0

30
Minute

60
Time

Hour

Fig 1 Physiological changes occurring during prolonged status epilepticus. Adapted from Shorvon.106 PED, periodic epileptic discharge; CBF,
cerebral blood flow. 1, Loss of reactivity of brain oxygen tension; 2, mismatch between the sustained increase in oxygen and glucose utilization
and a decrease in cerebral blood flow; 3, a depletion of cerebral glucose and glycogen concentrations; 4, a decline in cerebral energy state.

noted that these changes occur more rapidly in CSE, but can
also occur in non-CSE (NCSE).52

Stages of GCSE and drug treatment

Intervention is required for all convulsive seizures that have
continued beyond 2 min longer than the patients habitual
seizures. In most cases, this means that treatment should
be administered if the seizure is continuing at 5 min. Benzodiazepines are the first-line agents. There is evidence that
the longer seizures continue, the less efficacious treatment
becomes.53 This is related to altered localization of GABA
receptors on neuronal membrane induced by seizures.54
Treatment with benzodiazepines should therefore be administered as soon as it is apparent that the seizure is not selfterminating. Patients who have suffered one episode of CSE,
especially those with structural brain abnormalities and
learning disability should be prescribed benzodiazepines to
be used in the community to prevent the development of

refractory CSE. Rectal diazepam has traditionally been used

for this purpose, but buccal or nasal midazolam appears
equally effective and is more acceptable to adult and paediatric patients (Table 2).55 56
Emergency investigations should include arterial blood
gas measurement, glucose, renal and liver function,
calcium and magnesium, full blood count (including platelets), coagulation, and AED levels. Consider saving blood
and urine samples for future analysis, including toxicology
if cause is unclear. Chest radiograph can be used to
exclude aspiration pneumonia. Other investigations will be
directed at potential aetiology, such as brain imaging or
lumbar puncture.52 During the management of CSE, due to
the sedative nature of the drug treatments used, respiratory
depression requiring intubation is not uncommon.
The underlying cause of CSE should be identified and
treated wherever possible. Alcohol withdrawal and metabolic
disturbances including hypoglycaemia and hyponatraemia

565

Downloaded from http://bja.oxfordjournals.org/ by guest on February 21, 2015

Brain
metabolism

ive

-co
Non

Brain parenchyma
oxygenation
Glucose utilization

vuls

BJA

Perks et al.

Table 2 Drug administration details for CSE.102 Doses are i.v. unless stated otherwise
Drug

Dose

Other information

Premonitory stage of status

Midazolam

10 mg nasal or buccal

Diazepam

10 20 mg p.r. or 0.2 0.3 mg kg21

Dose can be repeated if necessary

Early status epilepticus

Lorazepam

0.1 mg kg21; or 4 8 mg i.v. bolus

Diazepam

I.V.same dose as above

Dose can be repeated if necessary

Established CSE
Phenytoin

15 18 mg kg21 loading dose given at 50 mg min21

Administer slowly through a large-bore cannula via

a 0.2 mm filter, immediately after reconstitution

Phenobarbital

10 15 mg kg21 given at 100 mg min21

Risk of respiratory depression

Sodium
valproate107

25 mg kg21 over 30 min then 100 mg h21 for 24 h

Levetiracetam

2000 3000 mg day21

Refractory CSE
100 250 mg i.v. bolus (then 50 mg increments until seizures
controlled) then 3 5 mg kg21 h21

Adjust dose to maintain burst suppression. All will require

intensive care and ventilatory support
Titrate infusion doses to EEG burst suppression
Corticosteroid replacement required if etomidate
infusion is used

Midazolam

0.1 0.3 mg kg21 bolus then 0.05 0.4 mg kg21 h21 infusion

Consider as an alternative to barbiturates

Propofol

2 mg kg21 i.v. bolus, then 5 10 mg kg21 h21

Ketamine

0.4 mg kg21 h21 then titrate up to response

Dose from case reports108 up to 7.5 mg kg21 h21 109

can present with seizures. In patients with epilepsy, failure to

adhere to prescribed medications and the resultant rapid decrease in serum levels can precipitate SE. Infective and inflammatory conditions of the brain can present with CSE,
which can negatively affect the prognosis of these conditions. Failure to treat the underlying cause of CSE is a
common cause of seizures remaining refractory to antiepileptic medication.

used, but the risk of seizure relapse is higher owing to its

rapid redistribution.61 Where i.v. access is delayed, further
doses of rectal diazepam or buccal or nasal midazolam
may be tried. I.M. midazolam may be an alternative, and a
randomized controlled trial is currently underway comparing
it with i.v. lorazepam, the current gold standard in the treatment of early CSE.62

Pre-monitory stage (out of hospital or first 5 min)

Established CSE (5 30 min)

Buccal midazolam or rectal diazepam can be administered

by the patients carers or emergency medical personnel.

At present, four agents can be considered as options in the

treatment of established CSEphenytoin (or its prodrug,
fosphenytoin), valproate, phenobarbital, and levetiracetam.63
There is little evidence regarding the relative efficacy of these
agents and adequate trials are urgently needed.
Phenytoin is probably the most widely used drug in the UK
for management of SE that continues after benzodiazepine
administration. It is water insoluble and the vehicle for i.v.
administration has a highly alkaline pH.64 Phenytoin should
therefore only be administered via a large-bore i.v. cannula
or a central line as extravasation can result in extensive
tissue necrosis. Cardiac rhythm and arterial pressure should
also be monitored as hypotension and bradycardia can
occur, especially in the elderly. Fosphenytoin, a prodrug of
phenytoin, is rapidly converted to phenytoin after i.v. administration.64 It can be administered more rapidly i.v. or as an
i.m. injection and is generally associated with fewer injection
site complications. It is, however, significantly more expensive than phenytoin and not widely available in UK hospitals.

Early stage (first 5 10 min)

Initial management of seizures is supportive with airway protection, supplemental oxygen, and assessment of cardiorespiratory function with establishment of i.v. access. If
hypoglycaemic seizures are suspected, glucose (50 ml of
50% dextrose) should be administered immediately. In
patients suspected of impaired nutrition or alcohol abuse,
high-dose thiamine (250 mg), should be administered with
glucose.57
Benzodiazepines are used as first line in early GCSE.58
While all benzodiazepines share the same receptor site on
the GABA receptor a subunit, their pharmacokinetic properties vary.59 Lorazepam has been shown to result in higher
rates of seizure control compared with phenytoin, phenobarbital, and phenytoin with diazepam, and is the agent of
choice.60 If lorazepam is unavailable, diazepam may be

566

Downloaded from http://bja.oxfordjournals.org/ by guest on February 21, 2015

Thiopental

BJA

Anaesthesia and epilepsy

Refractory status (30 60 min)

Refractory CSE (RSE), where SE continues in spite of administration of two AEDs (e.g. benzodiazepines and phenytoin), is
associated with a high risk of complications. These include
tachyarrhythmias, pulmonary oedema, hyperthermia,
rhabdomyolysis, and aspiration pneumonia. RSE has a high
mortality rate and less than one-third of patients recover
to their pre-morbid level of functioning.84 85
In patients not responding to other measures, general anaesthesia should be induced and maintained with midazolam,
propofol, or barbiturates (thiopental or pentobarbital).52 Highdose propofol infusion should be considered with caution due
to the risk of propofol infusion syndrome, and for this reason is

not recommended in children.86 EEG is needed to titrate doses

and to ensure that electrographic seizures have been abolished. Maximal therapy should be maintained until 12 24 h
after the last clinical or electrographic seizure, after which
the dose should be tapered. If seizures recur, therapy can be
re-instituted or altered.87
Both propofol and thiopental are effective treatments for
RSE. Where one treatment has failed, another may be successful.88 89 Thiopental has a lower rate of treatment
failure and breakthrough seizures, but a prolonged recovery,
duration of ventilation, and hospital stay.90 91 There has been
increasing concern relating to the prolonged use of highdose propofol, due to the risk of propofol infusion syndrome.
Cardiovascular collapse and mortality has been reported in
patients with no prior history of cardiac disease.92 93
Ketamine can be effective in cases of status epilepticus refractory to other agents.94 There is also experimental evidence that neuronal loss induced by status epilepticus may
be reduced by treatment with ketamine.95 However, these
potential benefits have to be balanced against the risk of
ketamine-related neurotoxicity which has been observed in
some cases.96 In patients who do not respond to i.v. anaesthetics, inhalation anaesthetics, such as isoflurane and desflurane, have been shown to cause effective EEG burst
suppression. In a case series of seven patients, concentrations of 1.2 5% isoflurane were used over a mean of 19
days, with some recurrence after cessation of treatment.
The authors see this as a tool to control seizures while
regular treatment is instituted.23 However, there are clearly
technical difficulties with administration of volatile agents.

Non-convulsive status epilepticus

NCSE is the term applied to the finding of electrographic
seizure patterns on EEG without clinically detectable
seizure phenomena. In the intensive care setting, such
patients are usually unconscious.97 Such cases may represent advanced CSE, where the motor activity has become
attenuated over time. This is a grave situation with almost
uniformly poor outcome. A variety of acute neurological
insults (encephalitis, stroke, trauma, and post-cardiac
arrest) may also present with coma and electrographic seizures on EEG.98 100 The finding of NCSE usually indicates a
poorer prognosis for the underlying neurological condition.
However, a proportion of these patients show improvement
in consciousness level after treatment with AEDs. Therefore,
treatment with i.v. AEDs should be mandatory in all patients
in whom EEG diagnosis of status epilepticus is made. The EEG
diagnosis of NCSE, however, is not straightforward and EEG
patterns that require treatment can be difficult to
determine.101
In the literature, the term NCSE is also used to describe
absence or complex partial status epilepticus.102 Absence
status occurs in a variety of idiopathic and symptomatic
generalized epilepsies. Complex partial seizures are
probably under recognized and may be more common in
the elderly.103 The typical manifestations of impaired

567

Downloaded from http://bja.oxfordjournals.org/ by guest on February 21, 2015

Phenobarbital has been in use as an AED for nearly a

century and remains the most commonly used AED worldwide. I.V. phenobarbital is an alternative to phenytoin as a
second-line agent for management of status epilepticus.
High doses are often required, with the attendant risk of sedation.65 66 It is not commonly used, for fear of provoking respiratory depression when administered to patients who
have already received benzodiazepines.
Sodium valproate has been available as i.v. preparation
since the late 1990s and is being used increasingly in the
treatment of established CSE. In a randomized comparison
of i.v. valproate and phenytoin as the first-line treatment
for CSE in 68 patients, valproate had a better seizure cessation rate as the first-line treatment (66% vs 42%, P,0.05)
and when crossed over as the second-line treatment (79%
vs 25%, P,0.005), where the other drug had failed.67 Participants in this study did not receive benzodiazepines as the
first-line therapy, which would be the accepted standard of
care. The data regarding the relative efficacy of the study
drugs should therefore be treated with caution. Moreover,
another study comparing the two agents used as initial
treatment for SE and acute repetitive seizures failed to find
significant differences in efficacy, but valproate appeared to
be better tolerated.68 Acute encephalopathy and hyperammonaemia remain potentially serious but fortunately rare
complications of valproate therapy.69
The newer AED levetiracetam has been reported to be effective in several small case series of CSE.70 74 It has very favourable
pharmacokinetic characteristics, with no clinically significant
interactions or sedative properties.75 Its efficacy as a secondline agent for the treatment of CSE remains to be established.
Prospective studies are lacking, but a retrospective analysis of
187 cases of CSE treated with levetiracetam, phenytoin, or valproate as second-line agents has been published recently. The
authors reported that levetiracetam was more likely to fail
(48.3%) than valproate (25.4%) (odds ratio 2.69, 95% confidence interval: 1.196.08). Phenytoin was not statistically different from the other two agents (41.4%).76
Of other AEDs, topiramate77 79 and lacosamide80 83 have
been reported to be effective in controlling CSE in small retrospective case series. Their role in the management of status
epilepticus remains uncertain.

BJA
consciousness with automatisms may not always be present.
This should be considered in the differential diagnosis of all
confusional states, especially if there is a previous history
of epilepsy or a structural brain abnormality. Absence and
complex partial status are not associated with the same
extent of cerebral damage as generalized tonic-clonic seizures. The risk-associated aggressive treatment with i.v.
drugs is therefore thought not to be justifiable. Optimizing
existing AED therapy and use of oral benzodiazepines is
often sufficient to improve consciousness level. The EEG diagnosis may require administration of rapidly acting i.v. AEDs
such as diazepam during EEG recording to observe clinical
and EEG response.101

Perks et al.

lacosamide) and Eisai (manufacturers of zonisamide, rufinamide, and eslicarbazepine).

Funding
None.

References
1

Non-epileptic attack disorder (psychogenic

non-epileptic seizure)
3

Conclusions

Anaesthetists encounter epilepsy commonly in the perioperative setting. They may also be involved in airway management and administration of general anaesthesia for
treatment of status epilepticus. Awareness of pharmacological properties of AEDs and potential interactions with
drugs used in anaesthesia is essential for adequate management of patients with epilepsy. While certain anaesthetic
agents can provoke seizures, recovery from anaesthesia can
be associated with shivering and myoclonus, which does
not indicate epilepsy. Patients with epilepsy may experience
breakthrough seizures in the perioperative period, but psychogenic non-epileptic attacks can also occur in this setting.
Status epilepticus is a common neurological emergency
and requires urgent management. Loss of benzodiazepine
responsiveness is a prominent feature in established CSE
and prompt treatment is important for seizure termination,
in addition to appropriate resuscitation. Second-line agents
include phenytoin or fosphenytoin and valproate, with
newer agents such as levetiracetam and lacosamide yet to
demonstrate clear evidence of efficacy. For refractory status
epilepticus, general anaesthesia with midazolam, propofol,
or thiopental is the currently accepted treatment. Opioids
should be avoided. Clinical seizures can become less prominent over time and electrographic monitoring is mandatory to
ensure that seizure control is achieved. NCSE should be considered in the unconscious patient where the cause is
unclear.

Declaration of interest
Speaker fee and conference hospitality given to R.M. from
both UCB pharma (manufacturers of levetiracetam and

568

7
8
9

10

11

12

13

14
15
16

17

Downloaded from http://bja.oxfordjournals.org/ by guest on February 21, 2015

It must be noted that in specialist centres, the number of

psychogenic pseudo-status outnumber the number of
status epilepticus episodes.104 Psychogenic non-epileptic
attacks may also be particularly likely to occur in the perioperative period.105 There are a number of clinical features
that can help distinguish this condition from epileptic seizurescareful clinical observation is key.

Commission on Classification and Terminology of the International League against Epilepsy. Proposal for revised classification of epilepsies and epileptic syndromes. Epilepsia 1989; 30:
38999
Berg AT, Berkovic SF, Brodie MJ, et al. Revised terminology and
concepts for organization of seizures and epilepsies: report of
the ILAE Commission on Classification and Terminology,
20052009. Epilepsia 2010; 51: 676 85
Marson AG, Al-Kharusi AM, Alwaidh M, et al. The SANAD study of
effectiveness of carbamazepine, gabapentin, lamotrigine, oxcarbazepine, or topiramate for treatment of partial epilepsy: an
unblinded randomised controlled trial. Lancet 2007; 369:
100015
Marson AG, Al-Kharusi AM, Alwaidh M, et al. The SANAD study of
effectiveness of valproate, lamotrigine, or topiramate for generalised and unclassifiable epilepsy: an unblinded randomised
controlled trial. Lancet 2007; 369: 101626
Brodie MJ. Antiepileptic drug therapy the story so far. Seizure
2010; 19: 6505
Rogawski MA, Bazil CW. New molecular targets for antiepileptic
drugs: alpha(2)delta, SV2A, and K(v)7/KCNQ/M potassium channels. Curr Neurol Neurosci Rep 2008; 8: 345 52
Meldrum BS, Rogawski MA. Molecular targets for antiepileptic
drug development. Neurotherapeutics 2007; 4: 18 61
Anderson J, Moor CC. Antiepileptic drugs: a guide for the nonneurologist. Clin Med 2010; 10: 54 8
Patsalos PN, Perucca E. Clinically important drug interactions in
epilepsy: interactions between antiepileptic drugs and other
drugs. Lancet Neurol 2003; 2: 47381
Johannessen Landmark C, Patsalos PN. Drug interactions involving the new second- and third-generation antiepileptic drugs.
Expert Rev Neurother 2010; 10: 11940
Patsalos PN, Perucca E. Clinically important drug interactions in
epilepsy: general features and interaction between antiepileptic
drugs. Lancet Neurol 2003; 2: 347 56
Haroutiunian S, Ratz Y, Rabinovich B, Adam M, Hoffman A.
Valproic acid plasma concentration decreases in a
dose-independent manner following administration of meropenem: a retrospective study. J Clin Pharmacol 2009; 49: 1363 9
Mancl EE, Gidal BE. The effect of carbapenem antibiotics on
plasma concentrations of valproic acid. Ann Pharmacother
2009; 43: 20827
Kofke WA. Anesthetic management of the patient with epilepsy
or prior seizures. Curr Opin Anesthesiol 2010; 23: 3919
Vaughn LK, Pruhs RJ. Strain-dependent variability in nitrous
oxide withdrawal seizure frequency. Life Sci 1995; 57: 112530
Artru AA, Lettich E, Colley PS, Ojemann GA. Nitrous oxide: suppression of focal epileptiform activity during inhalation, and
spreading of seizure activity following withdrawal. J Neurosurg
Anesthesiol 1990; 2: 18993
Hornbein TF, Eger EI II, Winter PM, Smith G, Weststone D,
Smith KH. The minimum alveolar concentration of nitrous
oxide in man. Anesth Analg 1982; 61: 553 6

Anaesthesia and epilepsy

39 Smith M, Smith SJ, Scott CA, Harkness WF. Activation of the electrocorticogram by propofol during surgery for epilepsy. Br J
Anaesth 1996; 76: 499502
40 Myslobodsky MS, Golovchinsky V, Mintz M. Ketamine: convulsant
or anti-convulsant? Pharmacol Biochem Behav 1981; 14: 27 33
41 Modica PA, Tempelhoff R, White PF. Pro- and anticonvulsant
effects of anesthetics (Part II). Anesth Analg 1990; 70: 43344
42 Usubiaga JE, Moya F, Wikinski JA, Wikinski R, Usubiaga LE. Relationship between the passage of local anaesthetics across the
bloodbrain barrier and their effects on the central nervous
system. Br J Anaesth 1967; 39: 9437
43 Steen PA, Michenfelder JD. Neurotoxicity of anesthetics.
Anesthesiology 1979; 50: 437 53
44 Veering BT. Complications and local anaesthetic toxicity in regional anaesthesia. Curr Opin Anaesthesiol 2003; 16: 4559
45 Pascual J, Ciudad J, Berciano J. Role of lidocaine (lignocaine) in
managing status epilepticus. J Neurol Neurosurg Psychiatry
1992; 55: 49 51
46 Hamano S, Sugiyama N, Yamashita S, et al. Intravenous lidocaine for status epilepticus during childhood. Dev Med Child
Neurol 2006; 48: 220 2
47 Yildiz B, Citak A, Ucsel R, Karabocuoglu M, Aydinli N, Uzel N. Lidocaine treatment in pediatric convulsive status epilepticus.
Pediatr Int 2008; 50: 359
48 Katz Y, Weizman A, Pick CG, et al. Interactions between laudanosine, GABA, and opioid subtype receptors: implication for laudanosine seizure activity. Brain Res 1994; 646: 23541
49 Lanier WL, Milde JH, Michenfelder JD. Cerebral stimulation following succinylcholine in dogs. Anesthesiology 1986; 64: 551 9
50 Schneck HJ, Rupreht J. Central anticholinergic syndrome (CAS) in
anesthesia and intensive care. Acta Anaesthesiol Belg 1989; 40:
219 28
51 Lowenstein DH, Bleck T, Macdonald RL. Its time to revise the
definition of status epilepticus. Epilepsia 1999; 40: 1202
52 Kelso ARC, Cock HR. Status epilepticus. Practical Neurol 2005; 5:
322 33
53 Kapur J, Macdonald RL. Rapid seizure-induced reduction of
benzodiazepine and Zn2+ sensitivity of hippocampal dentate
granule cell GABAA receptors. J Neurosci 1997; 17: 753240
54 Naylor DE, Liu H, Wasterlain CG. Trafficking of GABA(A) receptors,
loss of inhibition, and a mechanism for pharmacoresistance in
status epilepticus. J Neurosci 2005; 25: 7724 33
55 Ashrafi MR, Khosroshahi N, Karimi P, et al. Efficacy and usability
of buccal midazolam in controlling acute prolonged convulsive
seizures in children. Eur J Paediatr Neurol 2010; 14: 4348
56 Nakken KO, Lossius MI. Buccal midazolam or rectal diazepam for
treatment of residential adult patients with serial seizures
or status epilepticus. Acta Neurol Scand 2011; 124:
99 103
57 Aylward RL. Epilepsy: a review of reports, guidelines, recommendations and models for the provision of care for patients with
epilepsy. Clin Med 2008; 8: 4338
58 Meierkord H, Poon B, Engelsen B, et al. EFNS guideline on the
management of status epilepticus in adults. Eur J Neurol 2010;
17: 348 55
59 Schmidt D, Wilensky A. Benzodiazepines. In: Engel J, Pedly T,
eds. Epilepsy: A Comprehensive Textbook, 2nd Edn. Philadelphia,
PA: Lippincott Williams & Wilkins, 2008; 153141
60 Treiman DM, Meyers PD, Walton NY, et al. A comparison of four
treatments for generalized convulsive status epilepticus. Veterans Affairs Status Cooperative Study Group. N Engl J Med
1998; 339: 7928

569

Downloaded from http://bja.oxfordjournals.org/ by guest on February 21, 2015

18 Modica PA, Tempelhoff R, White PF. Pro- and anticonvulsant

effects of anesthetics (Part I). Anesth Analg 1990; 70: 30315
19 Constant I, Seeman R, Murat I. Sevoflurane and epileptiform EEG
changes. Paediatr Anaesth 2005; 15: 26674
20 Mohanram A, Kumar V, Iqbal Z, Markan S, Pagel PS. Repetitive
generalized seizure activity during emergence from sevoflurane
anesthesia. Can J Anaesth 2007; 54: 65761
21 Sleigh JW, Vizuete JA, Voss L, et al. The electrocortical effects of
enflurane: experiment and theory. Anesth Analg 2009; 109:
125362
22 Kruczek M, Albin MS, Wolf S, Bertoni JM. Postoperative seizure
activity following enflurane anesthesia. Anesthesiology 1980;
53: 175 6
23 Mirsattari SM, Sharpe MD, Young R. Treatment of refractory
status epilepticus with inhalational anesthetic agents isoflurane
and desflurane. Arch Neurol 2004; 61: 12549
24 Yillar DO, Akkan AG, Akcasu A, Ozuner Z, Eskazan E,
Kucukhuseyin C. The effect of oral and subcutaneous meperidine on the maximal electroshock seizure (MES) in mice.
J Basic Clin Physiol Pharmacol 2009; 20: 15968
25 Tortella F. Endogenous opioid peptides and epilepsy: quieting
the seizing brain? Trends Pharmacol Sci 1988; 9: 36672
26 Saboory E, Derchansky M, Ismaili M, et al. Mechanisms of morphine enhancement of spontaneous seizure activity. Anesth
Analg 2007; 105: 172935
27 Parkinson SK, Bailey SL, Little WL, Mueller JB. Myoclonic seizure
activity in chronic high-dose spinal opioid administration.
Anesthesiology 1990; 72: 743 5
28 Shih CJ, Doufas AG, Chang HC, Lin CM. Recurrent seizure activity
after epidural morphine in a post-partum woman. Can J Anaesth
2005; 52: 727 9
29 Borgeat A, Biollaz J, Depierraz B, Neff R. Grand mal seizure
after extradural morphine analgesia. Br J Anaesth 1988; 60:
733 5
30 Grnlykke L, Knudsen ML, Hgenhaven H, Moltke FB, Madsen FF,
Kjaer TW. Remifentanil-induced spike activity as a diagnostic
tool in epilepsy surgery. Acta Neurol Scand 2008; 117: 90 3
31 McGuire G, El-Beheiry H, Manninen P, Lozano A, Wennberg R. Activation of electrocorticographic activity with remifentanil and
alfentanil during neurosurgical excision of epileptogenic focus.
Br J Anaesth 2003; 91: 6515
32 Akcaboy ZN, Akcaboy EY, Yigitbasl B, et al. Effects of remifentanil
and alfentanil on seizure duration, stimulus amplitudes and recovery parameters during ECT. Acta Anaesthesiol Scand 2005;
49: 1068 71
33 Lowenstein D, Aminoff M, Simon R. Barbiturate anesthesia in the
treatment of status epilepticus: clinical experience with 14
patients. Neurology 1988; 38: 395400
34 Brown A, Horton J. Status epilepticus treated by intravenous infusion of thiopentone sodium. Br Med J 1967; 1: 27 8
35 Power KN, Flaatten H, Gilhus NE, Engelsen BA. Propofol treatment in adult refractory status epilepticus. Mortality risk and
outcome. Epilepsy Res 2011; 94: 5360
36 Hymes JA. Seizure activity during isoflurane anesthesia. Anesth
Analg 1985; 64: 367 8
37 Trzepacz PT, Weniger FC, Greenhouse J. Etomidate anesthesia
increases seizure duration during ECT. A retrospective study.
Gen Hosp Psychiatry 1993; 15: 115 20
38 Reddy R, Moorthy S, Dierdorf S, Deitch R, Link L. Excitatory effects
and electroencephalographic correlation of etomidate, thiopental, methohexital, and propofol. Anesth Analg 1993; 77:
100811

BJA

BJA

570

82 Koubeissi MZ, Mayor CL, Estephan B, Rashid S, Azar NJ. Efficacy

and safety of intravenous lacosamide in refractory nonconvulsive status epilepticus. Acta Neurol Scand 2011; 123: 142 6
83 Kellinghaus C, Berning S, Immisch I, et al. Intravenous lacosamide for treatment of status epilepticus. Acta Neurol Scand
2011; 123: 13741
84 Helmstaedter C. Cognitive outcome of status epilepticus in
adults. Epilepsia 2007; 48(Suppl. 8): 85 90
85 Cooper AD, Britton JW, Rabinstein AA. Functional and cognitive
outcome in prolonged refractory status epilepticus. Arch
Neurol 2009; 66: 15059
86 Vasile B, Rasulo F, Candiani A, Latronico N. Propofol infusion syndrome. Intensive Care Med 2003; 29: 141725
87 Holtkamp M. The anaesthetic and intensive care of status epilepticus. Curr Opin Neurol 2007; 20: 188 93
88 MacKenzie S, Kapadia F, Grant I. Propofol infusion for control of
status epilepticus. Anaesthesia 1990; 45: 1043 5
89 Pitt-Miller P, Elcock B, Maharaj M. The management of status
epilepticus with a continuous propofol infusion. Anesth Analg
1994; 78: 11934
90 Parviainen I, Kalviainen R, Ruokonen E. Propofol and barbiturates for the anesthesia of refractory convulsive status epilepticus: pros and cons. Neurol Res 2007; 29: 667 71
91 Rossetti AO, Logroscino G, Liaudet L, et al. Status epilepticus: an
independent outcome predictor after cerebral anoxia. Neurology
2007; 69: 255 60
92 Zarovnaya EL, Jobst BC, Harris BT. Propofol-associated fatal myocardial failure and rhabdomyolysis in an adult with status epilepticus. Epilepsia 2007; 48: 10026
93 Iyer V, Hoel R, Rabinstein AA. Propofol infusion syndrome in
patients with refractory status epilepticus: an 11-year clinical
experience. Crit Care Med 2009; 37: 3024 30
94 Hsieh CY, Sung PS, Tsai JJ, Huang CW. Terminating prolonged refractory status epilepticus using ketamine. Clin Neuropharmacol
2010; 33: 165 7
95 Fujikawa DG. Neuroprotective effect of ketamine administered
after status epilepticus onset. Epilepsia 1995; 36: 186 95
96 Ubogu EE, Sagar SM, Lerner AJ, Maddux BN, Suarez JI, Werz MA.
Ketamine for refractory status epilepticus: a case of possible
ketamine-induced neurotoxicity. Epilepsy Behav 2003; 4: 70 5
97 Towne AR, Waterhouse EJ, Boggs JG, et al. Prevalence of nonconvulsive status epilepticus in comatose patients. Neurology
2000; 54: 340 5
98 Waterhouse EJ, Vaughan JK, Barnes TY, et al. Synergistic effect
of status epilepticus and ischemic brain injury on mortality.
Epilepsy Res 1998; 29: 175 83
99 Vespa PM, Nuwer MR, Nenov V, et al. Increased incidence and
impact of nonconvulsive and convulsive seizures after traumatic
brain injury as detected by continuous electroencephalographic
monitoring. J Neurosurg 1999; 91: 75060
100 Rossetti AO, Milligan TA, Vulliemoz S, Michaelides C, Bertschi M,
Lee JW. A randomized trial for the treatment of refractory status
epilepticus. Neurocrit Care 2011; 14: 410
101 Jirsch J, Hirsch LJ. Nonconvulsive seizures: developing a rational
approach to the diagnosis and management in the critically ill
population. Clin Neurophysiol 2007; 118: 166070
102 Shorvon S. What is nonconvulsive status epilepticus, and what
are its subtypes? Epilepsia 2007; 48(Suppl. 8): 35 8
103 Beyenburg S, Elger CE, Reuber M. Acute confusion or altered
mental state: consider nonconvulsive status epilepticus.
Gerontology 2007; 53: 388 96

Downloaded from http://bja.oxfordjournals.org/ by guest on February 21, 2015

61 Cock HR, Schapira AH. A comparison of lorazepam and diazepam as initial therapy in convulsive status epilepticus. QJM
2002; 95: 225 31
62 Towne AR, DeLorenzo RJ. Use of intramuscular midazolam for
status epilepticus. J Emerg Med 1999; 17: 323 8
63 Trinka E. What is the relative value of the standard anticonvulsants: phenytoin and fosphenytoin, phenobarbital, valproate,
and levetiracetam? Epilepsia 2009; 50(Suppl. 12): 40 3
64 Stern J, Perrucca E, Browne T. Phenytoin, fosphenytoin and other
hydantoins. In: Engel J, Pedly T, eds. Epilepsy: A Comprehensive
Textbook, 2nd Edn. Philadelphia, PA: Lippincott Williams &
Wilkins, 2008; 16202
65 Crawford TO, Mitchell WG, Fishman LS, Snodgrass SR.
Very-high-dose phenobarbital for refractory status epilepticus
in children. Neurology 1988; 38: 1035 40
66 Lee WK, Liu KT, Young BW. Very-high-dose phenobarbital for
childhood refractory status epilepticus. Pediatr Neurol 2006;
34: 63 5
67 Misra UK, Kalita J, Patel R. Sodium valproate vs phenytoin
in status epilepticus: a pilot study. Neurology 2006; 67:
340 2
68 Gilad R, Izkovitz N, Dabby R, et al. Treatment of status epilepticus
and acute repetitive seizures with i.v. valproic acid vs phenytoin.
Acta Neurol Scand 2008; 118: 296300
69 Segura-Bruna N, Rodriguez-Campello A, Puente V, Roquer J.
Valproate-induced hyperammonemic encephalopathy. Acta
Neurol Scand 2006; 114: 17
70 Moddel G, Bunten S, Dobis C, et al. Intravenous levetiracetam: a
new treatment alternative for refractory status epilepticus.
J Neurol Neurosurg Psychiatry 2009; 80: 68992
71 Berning S, Boesebeck F, van Baalen A, Kellinghaus C. Intravenous levetiracetam as treatment for status epilepticus. J Neurol
2009; 256: 163442
72 Gamez-Leyva G, Aristn JL, Fernandez E, Pascual J. Experience
with intravenous levetiracetam in status epilepticus: a retrospective case series. CNS Drugs 2009; 23: 983 7
73 Beyenburg S, Reuber M, Maraite N. Intravenous levetiracetam for
epileptic seizure emergencies in older people. Gerontology 2009;
55: 27 31
74 Eue S, Grumbt M, Muller M, Schulze A. Two years of experience in
the treatment of status epilepticus with intravenous levetiracetam. Epilepsy Behav 2009; 15: 4679
75 Uges JW, van Huizen MD, Engelsman J, et al. Safety and
pharmacokinetics of intravenous levetiracetam infusion as
add-on in status epilepticus. Epilepsia 2009; 50: 415 21
76 Alvarez V, Januel JM, Burnand B, Rossetti AO. Second-line status
epilepticus treatment: comparison of phenytoin, valproate, and
levetiracetam. Epilepsia 2011; 52: 12926
77 Towne AR, Garnett LK, Waterhouse EJ, Morton LD, DeLorenzo RJ.
The use of topiramate in refractory status epilepticus. Neurology
2003; 60: 332 4
78 Bensalem MK, Fakhoury TA. Topiramate and status epilepticus:
report of three cases. Epilepsy Behav 2003; 4: 757 60
79 Perry MS, Holt PJ, Sladky JT. Topiramate loading for refractory
status epilepticus in children. Epilepsia 2006; 47: 1070 1
80 Albers JM, Moddel G, Dittrich R, et al. Intravenous lacosamide
an effective add-on treatment of refractory status epilepticus.
Seizure 2011; 20: 428 30
81 Goodwin H, Hinson HE, Shermock KM, Karanjia N, Lewin JJ III.
The use of lacosamide in refractory status epilepticus. Neurocrit
Care 2011; 14: 34853

Perks et al.

Anaesthesia and epilepsy

104 Howell SJ, Owen L, Chadwick DW. Pseudostatus epilepticus. QJM

1989; 71: 507 19
105 Reuber M, Enright SM, Goulding PJ. Postoperative pseudostatus: not
everything that shakes is epilepsy. Anaesthesia 2000; 55: 748
106 Shorvon SD. Emergency treatment of acute seizures, serial seizures, seizure cluster and status epilepticus. In: Shorvon SD,
ed. Handbook of Epilepsy Treatment. Oxford: Blackwell
Science, 2000

BJA
107 Olsen KB, Tauboll E, Gjerstad L. Valproate is an effective, welltolerated drug for treatment of status epilepticus/serial
attacks in adults. Acta Neurol Scand Suppl 2007; 187:
51 4
108 Pruss H, Holtkamp M. Ketamine successfully terminates malignant status epilepticus. Epilepsy Res 2008; 82: 219 22
109 Sheth RD, Gidal BE. Refractory status epilepticus: response to
ketamine. Neurology 1998; 51: 1765 66

Downloaded from http://bja.oxfordjournals.org/ by guest on February 21, 2015

571