British Journal of Anaesthesia 108 (4): 562–71 (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
Department of Anaesthesia and 2 Department of Neurology, Salford Royal Hospital, Stott Lane, Salford M6 8HD, UK
3
Bradford Royal Infirmary, Duckworth Lane, Bradford BD9 6RJ, UK
* Corresponding author. E-mail: anna.perks@srft.nhs.uk

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

Editor’s key points prevalence of 0.5–1% of the population. While the traditional antiepileptic
† The authors have reviewed the mechanism drugs (AEDs) still play a significant role in treatment of seizures, there has been
of action of old and new antiepileptic drugs. 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

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† Awareness is required regarding
seizure-provoking properties of certain
anaesthetic 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.
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.
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 0.5–1% of the population. The highest incidence
is at the extremes of age and in those with structural or devel-
opmental brain abnormalities. The International League
against Epilepsy (ILAE) has classified seizures into focal (or
partial) seizures which arise from one hemisphere and gener-
alized 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 sei-
zures.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 gen-
eration of AEDs.5 Many of these are the products of rational
drug development programmes, while others are modifica-
tions 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 man-
agement 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 anaesthe-
sia 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 imbal-
ance 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 (glutam-
ate, 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 (levetir-
acetam), steroid binding sites on GABAA receptors (ganaxo-
lone), and voltage-gated potassium channel (retigabine).6 7

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Anaesthesia and epilepsy
Effect of antiepileptics on anaesthesia
There are important pharmacokinetic and pharmacodynamic
interactions between AEDs and drugs commonly used in an-
aesthesia. These affect both drug efficacy and the risk of
seizure activity intraoperatively.8
Induction and inhibition of the cytochrome P450 isoen-
zymes 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, antibacter-
ials, and cardiovascular drugs, particularly amiodarone,
b-blockers (propranolol, metoprolol), and calcium channel
antagonists (nifedipine, felodipine, nimodipine, and verap-
amil).9 In patients taking warfarin, introduction or withdrawal
of enzyme-inducing AEDs requires close monitoring of the
international normalized ratio. Oxcarbazepine and eslicarbaze-
pine are weaker inducers of hepatic microsomal enzymes com-
pared 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, in-
cluding 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 me-
tabolism and can lead to carbamazepine toxicity. Concomi-
tant use of carbapenem antibiotics can lead to a
significant decrease in serum valproate concentrations.12 13
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,
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
Increase GABA activity
Increased frequency of Cl channel opening
Increased mean Cl channel opening duration
Blocks GABA transaminase (blocking GABA catabolism
within the neurone)
Glutamate antagonist
Reduction of inward voltage-gated positive currents
Increased outward voltage-gated positive currents
Pleotropic sites of action
BJA
withdrawal seizures have been seen after short exposures
to N2O.15 During a case of electrocorticographic monitoring
for epilepsy surgery, N2O visibly suppressed epileptiform ac-
tivity, which manifested again on N2O withdrawal.16 Myoclo-
nus has been observed in volunteers exposed to hyperbaric
(1.5 atm) N2O17 and when used in combination with isoflur-
ane 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 hypocap-
nea.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 Isoflur-
ane has well-characterized anticonvulsant properties. Both
isoflurane and desflurane can be used in refractory status
epilepticus, described in a later section.23
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Opioids
Meperidine is the opioid with the strongest association with
myoclonus and tonic-clonic seizure activity.24 However, fen-
tanyl, 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 activ-
ity in patients with focal epilepsy. Both remifentanil and
alfentanil have been used to induce spike activity in localiz-
ing epileptogenic zones intraoperatively during epilepsy
surgery,30 although alfentanil appears to be the more
potent activator.31 The addition of alfentanil to propofol an-
aesthesia for electroconvulsive therapy (ECT) also increases
seizure duration.32
I.V. anaesthetic agents
The barbiturates (thiopental, methohexital, and pentobar-
bital) 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
Antiepileptic drug
Benzodiazepines (binds to BZ2 receptors); tiagabine (prevents reuptake);
gabapentin (prevents reuptake)
Barbiturates
Vigabatrin
Topiramate (at AMPA receptor)
Phenytoin (Na+ channel); carbamazepine (Na+ channel); ethosuximide (Ca2+ channel)
Sodium valproate (K+ channel)
Sodium valproate (1, 2, 3 and 4)*; lamotrigine (2 and 3)*; topiramate (1, 2, and 3)
563
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 re-
fractory 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
All benzodiazepines in clinical practice possess potent anti-
convulsant properties.41 Diazepam, midazolam, and loraze-
pam are widely used to terminate episodes of status
epilepticus (see below).
Local anaesthetics
Local anaesthetic agents readily cross the blood –brain
barrier, causing sedation and analgesia followed by general-
ized convulsions at higher doses.42 43 High blood levels result
from an accidental i.v. administration or rapid systemic ab-
sorption 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 asso-
ciated 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 in-
crease 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 treat-
ment for this is physostigmine.50 Glycopyrrolate does not
cross the blood – brain barrier, so does not produce these
effects.
564
Perks et al.
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 prac-
ticable 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 equiva-
lent to oral doses) and carbamazepine is available as a sup-
pository. If the patient’s regular AED is not available in
parenteral formulation, advice should be sought from a neur-
ologist regarding alternatives that may be used to cover the
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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 in-
tensive 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 concentra-
tions. 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 pur-
poses. 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 30–60 min.52
Beyond this time, if seizures are not controlled, the compen-
satory mechanisms start to fail and cerebral damage may
occur. Cerebral auto-regulation fails, leading to hypoxia, hypo-
glycaemia, an increase in intracranial pressure, and cerebral
oedema. The net result is of hyponatraemia, potassium imbal-
ance, 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
Anaesthesia and epilepsy BJA

Generalized
convulsions
Myo Electro-
clon
us mechanical
dissolution
Motor
Recurrent seizures Seizures
EEG
Isolated Lengthen PEDS

Phase II
Phase I AP normal Respiratory compromise
Systemic AP Glucose Hypothermia
Lactate Glucose pH Lactate
ive
vuls
Con
lsive

Transition
-co nvu
Brain Non

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damage

Brain parenchyma
1
oxygenation
Glucose utilization CBF

Brain Brain Oxygen

metabolism utilization utilization 2
3
Brain glucose
4
Brain energy state

Brain lactate

0 30 60
Minute 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 patient’s habitual
seizures. In most cases, this means that treatment should
be administered if the seizure is continuing at 5 min. Benzo-
diazepines 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 admi-
nistered as soon as it is apparent that the seizure is not self-
terminating. 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 paedi-
atric 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 plate-
lets), 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
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 Dose can be repeated if necessary
Diazepam 10 –20 mg p.r. or 0.2 – 0.3 mg kg21
Early status epilepticus
Lorazepam 0.1 mg kg21; or 4 – 8 mg i.v. bolus Dose can be repeated if necessary
Diazepam I.V.—same dose as above
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 25 mg kg21 over 30 min then 100 mg h21 for 24 h
valproate107
Levetiracetam 2000 –3000 mg day21

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Refractory CSE
Thiopental 100 –250 mg i.v. bolus (then 50 mg increments until seizures Adjust dose to maintain burst suppression. All will require
controlled) then 3 –5 mg kg21 h21 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 de-
crease in serum levels can precipitate SE. Infective and in-
flammatory conditions of the brain can present with CSE,
which can negatively affect the prognosis of these condi-
tions. Failure to treat the underlying cause of CSE is a
common cause of seizures remaining refractory to antiepi-
leptic 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 treat-
ment 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 patient’s carers or emergency medical personnel.
Early stage (first 5 – 10 min)
Initial management of seizures is supportive with airway pro-
tection, supplemental oxygen, and assessment of cardio-
respiratory 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 proper-
ties vary.59 Lorazepam has been shown to result in higher
rates of seizure control compared with phenytoin, phenobar-
bital, and phenytoin with diazepam, and is the agent of
choice.60 If lorazepam is unavailable, diazepam may be
At present, four agents can be considered as options in the
treatment of established CSE—phenytoin (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. admin-
istration.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 expen-
sive than phenytoin and not widely available in UK hospitals.

566
Anaesthesia and epilepsy
Phenobarbital has been in use as an AED for nearly a
century and remains the most commonly used AED world-
wide. 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 sed-
ation.65 66 It is not commonly used, for fear of provoking re-
spiratory 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 cessa-
tion 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 Partici-
pants 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 hyperam-
monaemia remain potentially serious but fortunately rare
complications of valproate therapy.69
The newer AED levetiracetam has been reported to be effect-
ive 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 second-
line 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 val-
proate 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% confi-
dence interval: 1.19–6.08). Phenytoin was not statistically dif-
ferent 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 retro-
spective case series. Their role in the management of status
epilepticus remains uncertain.
Refractory status (30 – 60 min)
Refractory CSE (RSE), where SE continues in spite of adminis-
tration 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 an-
aesthesia should be induced and maintained with midazolam,
propofol, or barbiturates (thiopental or pentobarbital).52 High-
dose propofol infusion should be considered with caution due
to the risk of propofol infusion syndrome, and for this reason is
BJA
not recommended in children.86 EEG is needed to titrate doses
and to ensure that electrographic seizures have been abol-
ished. 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 suc-
cessful.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 high-
dose 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 re-
fractory to other agents.94 There is also experimental evi-
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dence 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. anaes-
thetics, inhalation anaesthetics, such as isoflurane and des-
flurane, have been shown to cause effective EEG burst
suppression. In a case series of seven patients, concentra-
tions 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 repre-
sent 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 sei-
zures 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
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 sei-
zures. 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 diag-
nosis may require administration of rapidly acting i.v. AEDs
such as diazepam during EEG recording to observe clinical
and EEG response.101
Non-epileptic attack disorder (psychogenic
non-epileptic seizure)
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 peri-
operative period.105 There are a number of clinical features
that can help distinguish this condition from epileptic sei-
zures—careful clinical observation is key.
Conclusions
Anaesthetists encounter epilepsy commonly in the peri-
operative setting. They may also be involved in airway man-
agement and administration of general anaesthesia for
treatment of status epilepticus. Awareness of pharmaco-
logical properties of AEDs and potential interactions with
drugs used in anaesthesia is essential for adequate manage-
ment 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 psy-
chogenic 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 promin-
ent over time and electrographic monitoring is mandatory to
ensure that seizure control is achieved. NCSE should be con-
sidered 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
Perks et al.
lacosamide) and Eisai (manufacturers of zonisamide, rufina-
mide, and eslicarbazepine).
Funding
None.
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