Anaesthesia and Epilepsy

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REVIEW ARTICLES

Anaesthesia and epilepsy

A. Perks1*, S. Cheema3 and R. Mohanraj2

1

Department of Anaesthesia and

2

Department of Neurology, Salford Royal Hospital, Stott Lane, Salford M6 8HD, UK3 Bradford Royal Infirmary, Duckworth Lane, Bradford BD9 6RJ, UK

* Corresponding author. E-mail: [email protected]

Editors key points

The authors have reviewed the mechanism

of action of old and new antiepileptic drugs.

Awareness is required regarding

seizure-provoking properties of certain

anaesthetic drugs.

Status epilepticus, refractory to two

antiepileptic drugs carries a high morbidityand requires general anaesthesia.

For uncontrolled seizures, treatment with

midazolam, thiopental, or propofol is

acceptable; opioids should be avoided.

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

prevalence of 0.5 1% 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.

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

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

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

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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 theolder-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 microsomalenzymes in a dose-dependent manner. Valproateis 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,

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 wherehigh 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

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

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 BZ2receptors); 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 va lproate (1, 2, 3 and 4)*; lamo trigine (2 and 3)*; topiramate (1, 2, and 3)

Anaesthesia and epilepsy BJA

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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 agentsNone 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 bloodbrain barrier, so does not produce these

effects.

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 assoon 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 patients 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

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 inserum 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 overa 30 min period is primarily useful for epidemiological pur-

poses. In clinical practice, most convulsive seizures abate

within 23 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 increasedcentral venous pressure. These compensatory mechanisms

prevent cerebral damage in the first 3060 min.52

Beyond this time, if seizures are notcontrolled,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. Itshould be

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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. 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 (Table2).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 bloodand 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

Generalizedconvulsions

Recurrent seizures

Isolated Lengthen

Seizures

Convu

lsive

Non-co

nvulsiv

e

PEDS

Respiratory compromiseHypothermia

Electro-mechanicaldissolution

Phase IIAP normalGlucosepH Lactate

Motor

EEG

Braindamage

Brainmetabolism

Systemic

Brain parenchymaoxygenation

Glucose utilization

Phase IAPLactate Glucose

CBF

Brainutilization

Brain glucose

Brain energy state

Brain lactate

Oxygenutilization

1

2

3

0 30 60

TimeMinute Hour

Transition

4

Myoclonus

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.


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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.

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

Buccal midazolam or rectal diazepam can be administered

by the patients carers or emergency medical personnel.

Early stage (first 510 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. Inpatients 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

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

Established CSE (530 min)

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 shouldtherefore 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.

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 1020 mg p.r . or 0.20.3 mg kg21

Early status epilepticus

Lorazepam 0.1 mg kg21

; or 4 8 mg i.v. bolus Dose can be repeated if necessaryDiazepam 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 0.2mm filter, immediately after reconstitution

Phenobarbital 1015 mg kg21 given at 100 mg min21 Risk of respiratory depression

Sodium

valproate10725 mg kg21 over 30 min then 100 mg h21 for 24 h

Levetiracetam 20003000 mg day21

Refractory CSE

Thiopental 100250mg i.v.bolus(then50 mgincrements until seizures

controlled) then 35 mg kg21 h21Adjust 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 0.050.4 mg kg21 h21 infusion Consider as an alternative to barbiturates

Propofol 2 mg kg21 i.v. bolus, then 510 mg kg21 h21

Ketamine 0.4 mg kg21 h21 then titrate up to response Dose from case reports108 up to 7.5 mg kg21 h21109

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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. preparationsince 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%

vs25%,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

ThenewerAED levetiracetam hasbeen reported to be effect-

iveinseveralsmallcaseseriesofCSE. 70 74 It hasveryfavourable

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. Theauthors reported that levetiracetam was more likely to fail

(48.3%) than valproate (25.4%) (odds ratio 2.69, 95% confi-

dence interval: 1.196.08). 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 (3060 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 includetachyarrhythmias, 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 shouldbe induced and maintained with midazolam,

propofol, or barbiturates (thiopental or pentobarbital).52 High-

dose propofol infusion should be considered with caution due

to the riskof propofolinfusion syndrome, and forthisreason is

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 1224 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 treatmentfailure 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-

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 1.25% 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 detectableseizure 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 EEGdiagnosis 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


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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 isoften 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 (psychogenicnon-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 featuresthat can help distinguish this condition from epileptic sei-

zurescareful 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

lacosamide) and Eisai (manufacturers of zonisamide, rufina-

mide, and eslicarbazepine).

Funding

None.

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