You are on page 1of 10

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

Downloaded from http://bja.oxfordjournals.org/ at New York University on August 6, 2015


† Awareness is required regarding
seizure-provoking properties of certain emergency or elective surgery and patients suffering seizures and status
anaesthetic drugs. epilepticus in the intensive care unit (ICU). This review examines perioperative
† Status epilepticus, refractory to two epilepsy management, the mode of action of AEDs and their interaction with
antiepileptic drugs carries a high morbidity anaesthetic agents, potential adverse effects of anaesthetic agents, and the
and requires general anaesthesia. acute management of seizures and refractory status epilepticus on the ICU.
† For uncontrolled seizures, treatment with Relevant literature was identified by a Pubmed search of epilepsy and status
midazolam, thiopental, or propofol is epilepticus in conjunction with individual anaesthetic agents.
acceptable; opioids should be avoided.
Keywords: anaesthesia; anticonvulsants; epilepsy; status epilepticus

Epilepsy is a tendency to have recurrent unprovoked seizures. management of AED therapy is vital in maintaining seizure
It is the most common serious neurological disorder with a control in these patients. Anaesthetists need to be aware of
prevalence of 0.5–1% of the population. The highest incidence the pharmacological properties of commonly used AEDs.
is at the extremes of age and in those with structural or devel- Patients with epilepsy may also require anaesthetic care
opmental brain abnormalities. The International League during treatment of status epilepticus, either for airway man-
against Epilepsy (ILAE) has classified seizures into focal (or agement or induction of general anaesthesia for refractory
partial) seizures which arise from one hemisphere and gener- status epilepticus. This article aims to examine the current
alized seizures which show electrographic seizure onset over treatment of epilepsy, the mode of action of antiepileptics,
both hemispheres.1 2 Lamotrigine and carbamazepine are the effect of AEDs on anaesthesia, and the effect of anaesthe-
considered drugs of choice in focal epilepsies, while valproate sia on epilepsy in adults. The use of anaesthetic agents in the
is probably the most effective drug for primary generalized sei- management of refractory status epilepticus is also discussed.
zures.3 4 If the initial antiepileptic drug (AED) results in adverse
effects, an alternative AED is tried as monotherapy. If, on the Mechanisms of action of AEDs
other hand, seizures continue in spite of adequate doses, In simple terms, a seizure can be seen as the result of imbal-
combination therapy is often necessary. ance between excitatory and inhibitory neuronal activity.
In the last 20 yr, there has been an influx of a new gen- This leads to the generation of hyper-synchronous firing of
eration of AEDs.5 Many of these are the products of rational a large number of cortical neurones. Traditional AEDs exert
drug development programmes, while others are modifica- antiseizure activity by the following mechanisms:
tions of previously existing molecules that result in
† reduce the inward voltage-gated positive currents
improved pharmacokinetic properties. The newer AEDs are
(Na+, Ca2+),
generally associated with fewer adverse effects and drug
† increase inhibitory neurotransmitter activity (GABA),
interactions. Many anaesthetic agents affect the propensity
† decrease excitatory neurotransmitter activity (glutam-
to seizures, both in patients with epilepsy and in those with
ate, aspartate).
no prior history of seizures. In patients taking AEDs, drug
interactions and maintenance dosing of AEDs during The effects are summarized in Table 1. In addition, many
periods of starvation are important considerations in the new AEDs possess novel mechanisms of action. Novel sites
perioperative period. of drug binding include synaptic vesicle (SV2) protein (levetir-
Patients with epilepsy often require anaesthesia for acetam), steroid binding sites on GABAA receptors (ganaxo-
elective and emergency surgery. Appropriate perioperative lone), 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
Anaesthesia and epilepsy BJA
Effect of antiepileptics on anaesthesia withdrawal seizures have been seen after short exposures
to N2O.15 During a case of electrocorticographic monitoring
There are important pharmacokinetic and pharmacodynamic
for epilepsy surgery, N2O visibly suppressed epileptiform ac-
interactions between AEDs and drugs commonly used in an-
tivity, which manifested again on N2O withdrawal.16 Myoclo-
aesthesia. These affect both drug efficacy and the risk of
nus has been observed in volunteers exposed to hyperbaric
seizure activity intraoperatively.8
(1.5 atm) N2O17 and when used in combination with isoflur-
Induction and inhibition of the cytochrome P450 isoen-
ane or halothane.18
zymes in hepatic metabolism constitutes the most significant
There are multiple case reports of sevoflurane-provoking
mechanism of drug interactions involving AEDs. Many of the
seizure-like activity, particularly in children19 and where
older-generation AEDs, such as carbamazepine, phenytoin,
high concentrations are used in conjunction with hypocap-
phenobarbital, and primidone, have potent enzyme-inducing
nea.20 In high concentration, enflurane exhibits periods of
properties. This leads to a decreased plasma concentration of
suppression with paroxysmal epileptiform discharges in
many medications including immunosuppressants, antibacter-
cats and rats.21 There have been multiple reports of seizure
ials, and cardiovascular drugs, particularly amiodarone,
activity in humans after enflurane anaesthesia.18 22 Isoflur-
b-blockers (propranolol, metoprolol), and calcium channel
ane has well-characterized anticonvulsant properties. Both
antagonists (nifedipine, felodipine, nimodipine, and verap-
isoflurane and desflurane can be used in refractory status
amil).9 In patients taking warfarin, introduction or withdrawal
epilepticus, described in a later section.23

Downloaded from http://bja.oxfordjournals.org/ at New York University on August 6, 2015


of enzyme-inducing AEDs requires close monitoring of the
international normalized ratio. Oxcarbazepine and eslicarbaze-
Opioids
pine are weaker inducers of hepatic microsomal enzymes com-
pared with carbamazepine, but the effects may be clinically Meperidine is the opioid with the strongest association with
significant.10 Topiramate also induces hepatic microsomal myoclonus and tonic-clonic seizure activity.24 However, fen-
enzymes in a dose-dependent manner. Valproate is an inhibitor tanyl, alfentanil, sufentanil, and morphine have been
of hepatic microsomal enzyme systems and may reduce the reported to cause generalized seizure patients after
clearance of many concurrently administered medications, in- low-to-moderate dose,25 26 particularly after intrathecal
cluding other AEDs. Gabapentin, lamotrigine, levetiracetam, use.27 – 29 Fentanyl and its analogues have not been shown
tiagabine, and vigabatrin do not induce hepatic enzymes.11 to possess any anticonvulsant properties.
Macrolide antibiotics, particularly erythromycin, are potent Opioid anaesthetic agents are used to enhance EEG activ-
inhibitors of CYP3A4, which is involved in carbamazepine me- ity in patients with focal epilepsy. Both remifentanil and
tabolism and can lead to carbamazepine toxicity. Concomi- alfentanil have been used to induce spike activity in localiz-
tant use of carbapenem antibiotics can lead to a ing epileptogenic zones intraoperatively during epilepsy
significant decrease in serum valproate concentrations.12 13 surgery,30 although alfentanil appears to be the more
potent activator.31 The addition of alfentanil to propofol an-
Effect of anaesthetic agents on epilepsy aesthesia for electroconvulsive therapy (ECT) also increases
Many of the agents used possess both pro-convulsant and seizure duration.32
anticonvulsant properties, which could impact on the
choice of anaesthetic.14 I.V. anaesthetic agents
The barbiturates (thiopental, methohexital, and pentobar-
Inhalational anaesthetics bital) and propofol are well established as agents for the
Nitrous oxide (N2O) provokes seizures in animal models treatment of refractory status epilepticus.33 – 35 All agents
(cats), but this has not been replicated in humans. In mice, 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 Vigabatrin
within the neurone)
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
BJA Perks et al.

myoclonus, opisthotonus, and rarely generalized seizures on Perioperative management of AEDs


induction of anaesthesia. The highest incidence appears to
In patients with a history of well-controlled epilepsy, it is vital
be with etomidate,36 followed by thiopental, methohexital,
that efforts are made to avoid disruption of antiepileptic
and propofol. Etomidate has been shown to increase
medication perioperatively. Patients should be advised to
seizure duration in ECT when compared with thiopental.37
take their regular medications on the morning of surgery
At higher doses, all agents act as anticonvulsants.38 39
and regular dosing should be re-established as early as prac-
Ketamine is a non-competitive glutamate antagonist
ticable after surgery. If a single dose is missed (such as that
acting at N-methyl-D-aspartate receptors, a property which
might occur with day-case surgery), it should be taken as
could be beneficial in management of status epilepticus re-
soon as possible after surgery. Where multiple doses are
fractory to other agents (see below). As with the other i.v.
likely to be missed, AEDs should be administered parenterally
agents, low doses may facilitate seizures, but at doses that
where possible. I.V. forms of phenytoin, sodium valproate,
produce sedative or anaesthetic effects, ketamine shows
and levetiracetam are available (where i.v. doses are equiva-
anticonvulsant properties.40
lent to oral doses) and carbamazepine is available as a sup-
pository. If the patient’s regular AED is not available in
Benzodiazepines parenteral formulation, advice should be sought from a neur-
All benzodiazepines in clinical practice possess potent anti- ologist regarding alternatives that may be used to cover the

Downloaded from http://bja.oxfordjournals.org/ at New York University on August 6, 2015


convulsant properties.41 Diazepam, midazolam, and loraze- perioperative period.
pam are widely used to terminate episodes of status In general, routine drug level monitoring is not required
epilepticus (see below). perioperatively as anaesthetic agents do not significantly
alter the pharmacokinetics of AEDs. However, prolonged in-
Local anaesthetics tensive care unit (ICU) stay, with attendant changes in
serum pH and albumin levels and also the use of drugs
Local anaesthetic agents readily cross the blood –brain
that interact with AEDs, can affect their serum concentra-
barrier, causing sedation and analgesia followed by general-
tions. Of the commonly used AEDs, phenytoin presents the
ized convulsions at higher doses.42 43 High blood levels result
greatest challenge because of its unique pharmacokinetic
from an accidental i.v. administration or rapid systemic ab-
properties. In patients admitted to ICU, it is necessary to
sorption from a highly vascular area.44
check serum concentrations of phenytoin daily to guide
I.V. lidocaine has been used to treat status epilepticus in
dosing.
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
Status epilepticus
adults remain to be proven. Status epilepticus is a common medical emergency. The
traditional definition of status epilepticus as a seizure
Neuromuscular blocking agents lasting or recurring without regaining of consciousness over
a 30 min period is primarily useful for epidemiological pur-
None of the neuromuscular blocking agents appear to have poses. In clinical practice, most convulsive seizures abate
any pro-convulsant or anticonvulsant effects. Laudanosine, within 2– 3 min and a seizure that continues for more than
the primary metabolite of atracurium, has been known to 5 min has a low chance of terminating spontaneously, so
cause EEG and clinical evidence of seizures in animals.48 should be treated with emergency antiepileptic
This has not been replicated in humans, but the possibility medications.51
should be considered in patients with hepatic failure in
whom the half-life of laudanosine is significantly prolonged. Physiological changes seen in status epilepticus
Succinylcholine produces EEG activation related to an in-
During the first stage of convulsive status epilepticus (CSE),
crease in cerebral blood flow afferent muscle spindle activity;
there is an increase in cerebral metabolism, increased
an effect blunted by prior administration of non-depolarizing
blood flow, and increased glucose and lactate concentration.
neuromuscular blocking agents. It has not been associated
This is associated with massive catecholamine release, raised
with seizure activity.49
cardiac output, hypertension, tachycardia, and increased
central venous pressure. These compensatory mechanisms
Anticholinergics and anticholinesterases prevent cerebral damage in the first 30–60 min.52
The increase in acetylcholine via administration of atropine Beyond this time, if seizures are not controlled, the compen-
or scopolamine can produce central cholinergic blockade satory mechanisms start to fail and cerebral damage may
(or central anticholinergic syndrome). This manifests as occur. Cerebral auto-regulation fails, leading to hypoxia, hypo-
agitation with seizures, hallucinations, and restlessness glycaemia, an increase in intracranial pressure, and cerebral
or stupor, coma, and apnoea. The most effective treat- oedema. The net result is of hyponatraemia, potassium imbal-
ment for this is physostigmine.50 Glycopyrrolate does not ance, and an evolving metabolic acidosis, which will lead to a
cross the blood – brain barrier, so does not produce these consumptive coagulopathy, rhabdomyolysis, and multi-organ
effects. failure. These changes are represented in Figure 1. It should be

564
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

Downloaded from http://bja.oxfordjournals.org/ at New York University on August 6, 2015


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 refractory CSE. Rectal diazepam has traditionally been used
also occur in non-CSE (NCSE).52 for this purpose, but buccal or nasal midazolam appears
equally effective and is more acceptable to adult and paedi-
Stages of GCSE and drug treatment atric patients (Table 2).55 56
Intervention is required for all convulsive seizures that have Emergency investigations should include arterial blood
continued beyond 2 min longer than the patient’s habitual gas measurement, glucose, renal and liver function,
seizures. In most cases, this means that treatment should calcium and magnesium, full blood count (including plate-
be administered if the seizure is continuing at 5 min. Benzo- lets), coagulation, and AED levels. Consider saving blood
diazepines are the first-line agents. There is evidence that and urine samples for future analysis, including toxicology
the longer seizures continue, the less efficacious treatment if cause is unclear. Chest radiograph can be used to
becomes.53 This is related to altered localization of GABA exclude aspiration pneumonia. Other investigations will be
receptors on neuronal membrane induced by seizures.54 directed at potential aetiology, such as brain imaging or
Treatment with benzodiazepines should therefore be admi- lumbar puncture.52 During the management of CSE, due to
nistered as soon as it is apparent that the seizure is not self- the sedative nature of the drug treatments used, respiratory
terminating. Patients who have suffered one episode of CSE, depression requiring intubation is not uncommon.
especially those with structural brain abnormalities and The underlying cause of CSE should be identified and
learning disability should be prescribed benzodiazepines to treated wherever possible. Alcohol withdrawal and metabolic
be used in the community to prevent the development of 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

Downloaded from http://bja.oxfordjournals.org/ at New York University on August 6, 2015


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 used, but the risk of seizure relapse is higher owing to its
adhere to prescribed medications and the resultant rapid de- rapid redistribution.61 Where i.v. access is delayed, further
crease in serum levels can precipitate SE. Infective and in- doses of rectal diazepam or buccal or nasal midazolam
flammatory conditions of the brain can present with CSE, may be tried. I.M. midazolam may be an alternative, and a
which can negatively affect the prognosis of these condi- randomized controlled trial is currently underway comparing
tions. Failure to treat the underlying cause of CSE is a it with i.v. lorazepam, the current gold standard in the treat-
common cause of seizures remaining refractory to antiepi- ment of early CSE.62
leptic medication.

Pre-monitory stage (out of hospital or first 5 min) Established CSE (5 – 30 min)


Buccal midazolam or rectal diazepam can be administered At present, four agents can be considered as options in the
by the patient’s carers or emergency medical personnel. treatment of established CSE—phenytoin (or its prodrug,
fosphenytoin), valproate, phenobarbital, and levetiracetam.63
Early stage (first 5 – 10 min) There is little evidence regarding the relative efficacy of these
Initial management of seizures is supportive with airway pro- agents and adequate trials are urgently needed.
tection, supplemental oxygen, and assessment of cardio- Phenytoin is probably the most widely used drug in the UK
respiratory function with establishment of i.v. access. If for management of SE that continues after benzodiazepine
hypoglycaemic seizures are suspected, glucose (50 ml of administration. It is water insoluble and the vehicle for i.v.
50% dextrose) should be administered immediately. In administration has a highly alkaline pH.64 Phenytoin should
patients suspected of impaired nutrition or alcohol abuse, therefore only be administered via a large-bore i.v. cannula
high-dose thiamine (250 mg), should be administered with or a central line as extravasation can result in extensive
glucose.57 tissue necrosis. Cardiac rhythm and arterial pressure should
Benzodiazepines are used as first line in early GCSE.58 also be monitored as hypotension and bradycardia can
While all benzodiazepines share the same receptor site on occur, especially in the elderly. Fosphenytoin, a prodrug of
the GABA receptor a subunit, their pharmacokinetic proper- phenytoin, is rapidly converted to phenytoin after i.v. admin-
ties vary.59 Lorazepam has been shown to result in higher istration.64 It can be administered more rapidly i.v. or as an
rates of seizure control compared with phenytoin, phenobar- i.m. injection and is generally associated with fewer injection
bital, and phenytoin with diazepam, and is the agent of site complications. It is, however, significantly more expen-
choice.60 If lorazepam is unavailable, diazepam may be sive than phenytoin and not widely available in UK hospitals.

566
Anaesthesia and epilepsy BJA
Phenobarbital has been in use as an AED for nearly a not recommended in children.86 EEG is needed to titrate doses
century and remains the most commonly used AED world- and to ensure that electrographic seizures have been abol-
wide. I.V. phenobarbital is an alternative to phenytoin as a ished. Maximal therapy should be maintained until 12 –24 h
second-line agent for management of status epilepticus. after the last clinical or electrographic seizure, after which
High doses are often required, with the attendant risk of sed- the dose should be tapered. If seizures recur, therapy can be
ation.65 66 It is not commonly used, for fear of provoking re- re-instituted or altered.87
spiratory depression when administered to patients who Both propofol and thiopental are effective treatments for
have already received benzodiazepines. RSE. Where one treatment has failed, another may be suc-
Sodium valproate has been available as i.v. preparation cessful.88 89 Thiopental has a lower rate of treatment
since the late 1990s and is being used increasingly in the failure and breakthrough seizures, but a prolonged recovery,
treatment of established CSE. In a randomized comparison duration of ventilation, and hospital stay.90 91 There has been
of i.v. valproate and phenytoin as the first-line treatment increasing concern relating to the prolonged use of high-
for CSE in 68 patients, valproate had a better seizure cessa- dose propofol, due to the risk of propofol infusion syndrome.
tion rate as the first-line treatment (66% vs 42%, P,0.05) Cardiovascular collapse and mortality has been reported in
and when crossed over as the second-line treatment (79% patients with no prior history of cardiac disease.92 93
vs 25%, P,0.005), where the other drug had failed.67 Partici- Ketamine can be effective in cases of status epilepticus re-
pants in this study did not receive benzodiazepines as the fractory to other agents.94 There is also experimental evi-

Downloaded from http://bja.oxfordjournals.org/ at New York University on August 6, 2015


first-line therapy, which would be the accepted standard of dence that neuronal loss induced by status epilepticus may
care. The data regarding the relative efficacy of the study be reduced by treatment with ketamine.95 However, these
drugs should therefore be treated with caution. Moreover, potential benefits have to be balanced against the risk of
another study comparing the two agents used as initial ketamine-related neurotoxicity which has been observed in
treatment for SE and acute repetitive seizures failed to find some cases.96 In patients who do not respond to i.v. anaes-
significant differences in efficacy, but valproate appeared to thetics, inhalation anaesthetics, such as isoflurane and des-
be better tolerated.68 Acute encephalopathy and hyperam- flurane, have been shown to cause effective EEG burst
monaemia remain potentially serious but fortunately rare suppression. In a case series of seven patients, concentra-
complications of valproate therapy.69 tions of 1.2– 5% isoflurane were used over a mean of 19
The newer AED levetiracetam has been reported to be effect- days, with some recurrence after cessation of treatment.
ive in several small case series of CSE.70 – 74 It has very favourable The authors see this as a tool to control seizures while
pharmacokinetic characteristics, with no clinically significant regular treatment is instituted.23 However, there are clearly
interactions or sedative properties.75 Its efficacy as a second- technical difficulties with administration of volatile agents.
line agent for the treatment of CSE remains to be established.
Prospective studies are lacking, but a retrospective analysis of Non-convulsive status epilepticus
187 cases of CSE treated with levetiracetam, phenytoin, or val- NCSE is the term applied to the finding of electrographic
proate as second-line agents has been published recently. The seizure patterns on EEG without clinically detectable
authors reported that levetiracetam was more likely to fail seizure phenomena. In the intensive care setting, such
(48.3%) than valproate (25.4%) (odds ratio 2.69, 95% confi- patients are usually unconscious.97 Such cases may repre-
dence interval: 1.19–6.08). Phenytoin was not statistically dif- sent advanced CSE, where the motor activity has become
ferent from the other two agents (41.4%).76 attenuated over time. This is a grave situation with almost
Of other AEDs, topiramate77 – 79 and lacosamide80 – 83 have uniformly poor outcome. A variety of acute neurological
been reported to be effective in controlling CSE in small retro- insults (encephalitis, stroke, trauma, and post-cardiac
spective case series. Their role in the management of status arrest) may also present with coma and electrographic sei-
epilepticus remains uncertain. zures on EEG.98 – 100 The finding of NCSE usually indicates a
poorer prognosis for the underlying neurological condition.
Refractory status (30 – 60 min) However, a proportion of these patients show improvement
Refractory CSE (RSE), where SE continues in spite of adminis- in consciousness level after treatment with AEDs. Therefore,
tration of two AEDs (e.g. benzodiazepines and phenytoin), is treatment with i.v. AEDs should be mandatory in all patients
associated with a high risk of complications. These include in whom EEG diagnosis of status epilepticus is made. The EEG
tachyarrhythmias, pulmonary oedema, hyperthermia, diagnosis of NCSE, however, is not straightforward and EEG
rhabdomyolysis, and aspiration pneumonia. RSE has a high patterns that require treatment can be difficult to
mortality rate and less than one-third of patients recover determine.101
to their pre-morbid level of functioning.84 85 In the literature, the term NCSE is also used to describe
In patients not responding to other measures, general an- absence or complex partial status epilepticus.102 Absence
aesthesia should be induced and maintained with midazolam, status occurs in a variety of idiopathic and symptomatic
propofol, or barbiturates (thiopental or pentobarbital).52 High- generalized epilepsies. Complex partial seizures are
dose propofol infusion should be considered with caution due probably under recognized and may be more common in
to the risk of propofol infusion syndrome, and for this reason is the elderly.103 The typical manifestations of impaired

567
BJA Perks et al.

consciousness with automatisms may not always be present. lacosamide) and Eisai (manufacturers of zonisamide, rufina-
This should be considered in the differential diagnosis of all mide, and eslicarbazepine).
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
Funding
extent of cerebral damage as generalized tonic-clonic sei- None.
zures. The risk-associated aggressive treatment with i.v.
drugs is therefore thought not to be justifiable. Optimizing
References
existing AED therapy and use of oral benzodiazepines is
1 Commission on Classification and Terminology of the Inter-
often sufficient to improve consciousness level. The EEG diag-
national League against Epilepsy. Proposal for revised classifica-
nosis may require administration of rapidly acting i.v. AEDs tion of epilepsies and epileptic syndromes. Epilepsia 1989; 30:
such as diazepam during EEG recording to observe clinical 389–99
and EEG response.101 2 Berg AT, Berkovic SF, Brodie MJ, et al. Revised terminology and
concepts for organization of seizures and epilepsies: report of
Non-epileptic attack disorder (psychogenic the ILAE Commission on Classification and Terminology,
non-epileptic seizure) 2005–2009. Epilepsia 2010; 51: 676– 85
3 Marson AG, Al-Kharusi AM, Alwaidh M, et al. The SANAD study of

Downloaded from http://bja.oxfordjournals.org/ at New York University on August 6, 2015


It must be noted that in specialist centres, the number of
effectiveness of carbamazepine, gabapentin, lamotrigine, oxcar-
psychogenic pseudo-status outnumber the number of
bazepine, or topiramate for treatment of partial epilepsy: an
status epilepticus episodes.104 Psychogenic non-epileptic unblinded randomised controlled trial. Lancet 2007; 369:
attacks may also be particularly likely to occur in the peri- 1000–15
operative period.105 There are a number of clinical features 4 Marson AG, Al-Kharusi AM, Alwaidh M, et al. The SANAD study of
that can help distinguish this condition from epileptic sei- effectiveness of valproate, lamotrigine, or topiramate for gener-
zures—careful clinical observation is key. alised and unclassifiable epilepsy: an unblinded randomised
controlled trial. Lancet 2007; 369: 1016–26
Conclusions 5 Brodie MJ. Antiepileptic drug therapy the story so far. Seizure
2010; 19: 650–5
Anaesthetists encounter epilepsy commonly in the peri- 6 Rogawski MA, Bazil CW. New molecular targets for antiepileptic
operative setting. They may also be involved in airway man- drugs: alpha(2)delta, SV2A, and K(v)7/KCNQ/M potassium chan-
agement and administration of general anaesthesia for nels. Curr Neurol Neurosci Rep 2008; 8: 345– 52
treatment of status epilepticus. Awareness of pharmaco- 7 Meldrum BS, Rogawski MA. Molecular targets for antiepileptic
logical properties of AEDs and potential interactions with drug development. Neurotherapeutics 2007; 4: 18 –61
drugs used in anaesthesia is essential for adequate manage- 8 Anderson J, Moor CC. Antiepileptic drugs: a guide for the non-
ment of patients with epilepsy. While certain anaesthetic neurologist. Clin Med 2010; 10: 54 –8
agents can provoke seizures, recovery from anaesthesia can 9 Patsalos PN, Perucca E. Clinically important drug interactions in
epilepsy: interactions between antiepileptic drugs and other
be associated with shivering and myoclonus, which does
drugs. Lancet Neurol 2003; 2: 473–81
not indicate epilepsy. Patients with epilepsy may experience
10 Johannessen Landmark C, Patsalos PN. Drug interactions involv-
breakthrough seizures in the perioperative period, but psy- ing the new second- and third-generation antiepileptic drugs.
chogenic non-epileptic attacks can also occur in this setting. Expert Rev Neurother 2010; 10: 119–40
Status epilepticus is a common neurological emergency 11 Patsalos PN, Perucca E. Clinically important drug interactions in
and requires urgent management. Loss of benzodiazepine epilepsy: general features and interaction between antiepileptic
responsiveness is a prominent feature in established CSE drugs. Lancet Neurol 2003; 2: 347– 56
and prompt treatment is important for seizure termination, 12 Haroutiunian S, Ratz Y, Rabinovich B, Adam M, Hoffman A.
in addition to appropriate resuscitation. Second-line agents Valproic acid plasma concentration decreases in a
include phenytoin or fosphenytoin and valproate, with dose-independent manner following administration of merope-
nem: a retrospective study. J Clin Pharmacol 2009; 49: 1363– 9
newer agents such as levetiracetam and lacosamide yet to
13 Mancl EE, Gidal BE. The effect of carbapenem antibiotics on
demonstrate clear evidence of efficacy. For refractory status
plasma concentrations of valproic acid. Ann Pharmacother
epilepticus, general anaesthesia with midazolam, propofol, 2009; 43: 2082–7
or thiopental is the currently accepted treatment. Opioids 14 Kofke WA. Anesthetic management of the patient with epilepsy
should be avoided. Clinical seizures can become less promin- or prior seizures. Curr Opin Anesthesiol 2010; 23: 391–9
ent over time and electrographic monitoring is mandatory to 15 Vaughn LK, Pruhs RJ. Strain-dependent variability in nitrous
ensure that seizure control is achieved. NCSE should be con- oxide withdrawal seizure frequency. Life Sci 1995; 57: 1125–30
sidered in the unconscious patient where the cause is 16 Artru AA, Lettich E, Colley PS, Ojemann GA. Nitrous oxide: sup-
unclear. pression of focal epileptiform activity during inhalation, and
spreading of seizure activity following withdrawal. J Neurosurg
Anesthesiol 1990; 2: 189–93
Declaration of interest
17 Hornbein TF, Eger EI II, Winter PM, Smith G, Weststone D,
Speaker fee and conference hospitality given to R.M. from Smith KH. The minimum alveolar concentration of nitrous
both UCB pharma (manufacturers of levetiracetam and oxide in man. Anesth Analg 1982; 61: 553– 6

568
Anaesthesia and epilepsy BJA
18 Modica PA, Tempelhoff R, White PF. Pro- and anticonvulsant 39 Smith M, Smith SJ, Scott CA, Harkness WF. Activation of the elec-
effects of anesthetics (Part I). Anesth Analg 1990; 70: 303–15 trocorticogram by propofol during surgery for epilepsy. Br J
19 Constant I, Seeman R, Murat I. Sevoflurane and epileptiform EEG Anaesth 1996; 76: 499–502
changes. Paediatr Anaesth 2005; 15: 266–74 40 Myslobodsky MS, Golovchinsky V, Mintz M. Ketamine: convulsant
20 Mohanram A, Kumar V, Iqbal Z, Markan S, Pagel PS. Repetitive or anti-convulsant? Pharmacol Biochem Behav 1981; 14: 27– 33
generalized seizure activity during emergence from sevoflurane 41 Modica PA, Tempelhoff R, White PF. Pro- and anticonvulsant
anesthesia. Can J Anaesth 2007; 54: 657–61 effects of anesthetics (Part II). Anesth Analg 1990; 70: 433–44
21 Sleigh JW, Vizuete JA, Voss L, et al. The electrocortical effects of 42 Usubiaga JE, Moya F, Wikinski JA, Wikinski R, Usubiaga LE. Rela-
enflurane: experiment and theory. Anesth Analg 2009; 109: tionship between the passage of local anaesthetics across the
1253–62 blood–brain barrier and their effects on the central nervous
22 Kruczek M, Albin MS, Wolf S, Bertoni JM. Postoperative seizure system. Br J Anaesth 1967; 39: 943–7
activity following enflurane anesthesia. Anesthesiology 1980; 43 Steen PA, Michenfelder JD. Neurotoxicity of anesthetics.
53: 175– 6 Anesthesiology 1979; 50: 437– 53
23 Mirsattari SM, Sharpe MD, Young R. Treatment of refractory 44 Veering BT. Complications and local anaesthetic toxicity in re-
status epilepticus with inhalational anesthetic agents isoflurane gional anaesthesia. Curr Opin Anaesthesiol 2003; 16: 455–9
and desflurane. Arch Neurol 2004; 61: 1254–9 45 Pascual J, Ciudad J, Berciano J. Role of lidocaine (lignocaine) in
24 Yillar DO, Akkan AG, Akcasu A, Ozuner Z, Eskazan E, managing status epilepticus. J Neurol Neurosurg Psychiatry
Kucukhuseyin C. The effect of oral and subcutaneous meperi- 1992; 55: 49– 51

Downloaded from http://bja.oxfordjournals.org/ at New York University on August 6, 2015


dine on the maximal electroshock seizure (MES) in mice. 46 Hamano S, Sugiyama N, Yamashita S, et al. Intravenous lido-
J Basic Clin Physiol Pharmacol 2009; 20: 159–68 caine for status epilepticus during childhood. Dev Med Child
25 Tortella F. Endogenous opioid peptides and epilepsy: quieting Neurol 2006; 48: 220– 2
the seizing brain? Trends Pharmacol Sci 1988; 9: 366–72 47 Yildiz B, Citak A, Uçsel R, Karaböcüoğlu M, Aydinli N, Uzel N. Lido-
26 Saboory E, Derchansky M, Ismaili M, et al. Mechanisms of mor- caine treatment in pediatric convulsive status epilepticus.
phine enhancement of spontaneous seizure activity. Anesth Pediatr Int 2008; 50: 35–9
Analg 2007; 105: 1729–35 48 Katz Y, Weizman A, Pick CG, et al. Interactions between laudano-
27 Parkinson SK, Bailey SL, Little WL, Mueller JB. Myoclonic seizure sine, GABA, and opioid subtype receptors: implication for lauda-
activity in chronic high-dose spinal opioid administration. nosine seizure activity. Brain Res 1994; 646: 235–41
Anesthesiology 1990; 72: 743– 5 49 Lanier WL, Milde JH, Michenfelder JD. Cerebral stimulation fol-
28 Shih CJ, Doufas AG, Chang HC, Lin CM. Recurrent seizure activity lowing succinylcholine in dogs. Anesthesiology 1986; 64: 551– 9
after epidural morphine in a post-partum woman. Can J Anaesth 50 Schneck HJ, Rupreht J. Central anticholinergic syndrome (CAS) in
2005; 52: 727– 9 anesthesia and intensive care. Acta Anaesthesiol Belg 1989; 40:
29 Borgeat A, Biollaz J, Depierraz B, Neff R. Grand mal seizure 219– 28
after extradural morphine analgesia. Br J Anaesth 1988; 60: 51 Lowenstein DH, Bleck T, Macdonald RL. It’s time to revise the
733– 5 definition of status epilepticus. Epilepsia 1999; 40: 120–2
30 Grønlykke L, Knudsen ML, Høgenhaven H, Moltke FB, Madsen FF, 52 Kelso ARC, Cock HR. Status epilepticus. Practical Neurol 2005; 5:
Kjaer TW. Remifentanil-induced spike activity as a diagnostic 322– 33
tool in epilepsy surgery. Acta Neurol Scand 2008; 117: 90 –3 53 Kapur J, Macdonald RL. Rapid seizure-induced reduction of
31 McGuire G, El-Beheiry H, Manninen P, Lozano A, Wennberg R. Ac- benzodiazepine and Zn2+ sensitivity of hippocampal dentate
tivation of electrocorticographic activity with remifentanil and granule cell GABAA receptors. J Neurosci 1997; 17: 7532–40
alfentanil during neurosurgical excision of epileptogenic focus. 54 Naylor DE, Liu H, Wasterlain CG. Trafficking of GABA(A) receptors,
Br J Anaesth 2003; 91: 651–5 loss of inhibition, and a mechanism for pharmacoresistance in
32 Akcaboy ZN, Akcaboy EY, Yigitbasl B, et al. Effects of remifentanil status epilepticus. J Neurosci 2005; 25: 7724– 33
and alfentanil on seizure duration, stimulus amplitudes and re- 55 Ashrafi MR, Khosroshahi N, Karimi P, et al. Efficacy and usability
covery parameters during ECT. Acta Anaesthesiol Scand 2005; of buccal midazolam in controlling acute prolonged convulsive
49: 1068– 71 seizures in children. Eur J Paediatr Neurol 2010; 14: 434–8
33 Lowenstein D, Aminoff M, Simon R. Barbiturate anesthesia in the 56 Nakken KO, Lossius MI. Buccal midazolam or rectal diazepam for
treatment of status epilepticus: clinical experience with 14 treatment of residential adult patients with serial seizures
patients. Neurology 1988; 38: 395–400 or status epilepticus. Acta Neurol Scand 2011; 124:
34 Brown A, Horton J. Status epilepticus treated by intravenous in- 99– 103
fusion of thiopentone sodium. Br Med J 1967; 1: 27 –8 57 Aylward RL. Epilepsy: a review of reports, guidelines, recommen-
35 Power KN, Flaatten H, Gilhus NE, Engelsen BA. Propofol treat- dations and models for the provision of care for patients with
ment in adult refractory status epilepticus. Mortality risk and epilepsy. Clin Med 2008; 8: 433–8
outcome. Epilepsy Res 2011; 94: 53–60 58 Meierkord H, Poon B, Engelsen B, et al. EFNS guideline on the
36 Hymes JA. Seizure activity during isoflurane anesthesia. Anesth management of status epilepticus in adults. Eur J Neurol 2010;
Analg 1985; 64: 367– 8 17: 348– 55
37 Trzepacz PT, Weniger FC, Greenhouse J. Etomidate anesthesia 59 Schmidt D, Wilensky A. Benzodiazepines. In: Engel J, Pedly T,
increases seizure duration during ECT. A retrospective study. eds. Epilepsy: A Comprehensive Textbook, 2nd Edn. Philadelphia,
Gen Hosp Psychiatry 1993; 15: 115– 20 PA: Lippincott Williams & Wilkins, 2008; 1531–41
38 Reddy R, Moorthy S, Dierdorf S, Deitch R, Link L. Excitatory effects 60 Treiman DM, Meyers PD, Walton NY, et al. A comparison of four
and electroencephalographic correlation of etomidate, thiopen- treatments for generalized convulsive status epilepticus. Veter-
tal, methohexital, and propofol. Anesth Analg 1993; 77: ans Affairs Status Cooperative Study Group. N Engl J Med
1008–11 1998; 339: 792–8

569
BJA Perks et al.

61 Cock HR, Schapira AH. A comparison of lorazepam and diaze- 82 Koubeissi MZ, Mayor CL, Estephan B, Rashid S, Azar NJ. Efficacy
pam as initial therapy in convulsive status epilepticus. QJM and safety of intravenous lacosamide in refractory nonconvul-
2002; 95: 225– 31 sive status epilepticus. Acta Neurol Scand 2011; 123: 142– 6
62 Towne AR, DeLorenzo RJ. Use of intramuscular midazolam for 83 Kellinghaus C, Berning S, Immisch I, et al. Intravenous lacosa-
status epilepticus. J Emerg Med 1999; 17: 323– 8 mide for treatment of status epilepticus. Acta Neurol Scand
63 Trinka E. What is the relative value of the standard anticonvul- 2011; 123: 137–41
sants: phenytoin and fosphenytoin, phenobarbital, valproate, 84 Helmstaedter C. Cognitive outcome of status epilepticus in
and levetiracetam? Epilepsia 2009; 50(Suppl. 12): 40 –3 adults. Epilepsia 2007; 48(Suppl. 8): 85 –90
64 Stern J, Perrucca E, Browne T. Phenytoin, fosphenytoin and other 85 Cooper AD, Britton JW, Rabinstein AA. Functional and cognitive
hydantoins. In: Engel J, Pedly T, eds. Epilepsy: A Comprehensive outcome in prolonged refractory status epilepticus. Arch
Textbook, 2nd Edn. Philadelphia, PA: Lippincott Williams & Neurol 2009; 66: 1505–9
Wilkins, 2008; 1620–2 86 Vasile B, Rasulo F, Candiani A, Latronico N. Propofol infusion syn-
65 Crawford TO, Mitchell WG, Fishman LS, Snodgrass SR. drome. Intensive Care Med 2003; 29: 1417–25
Very-high-dose phenobarbital for refractory status epilepticus 87 Holtkamp M. The anaesthetic and intensive care of status epi-
in children. Neurology 1988; 38: 1035– 40 lepticus. Curr Opin Neurol 2007; 20: 188– 93
66 Lee WK, Liu KT, Young BW. Very-high-dose phenobarbital for 88 MacKenzie S, Kapadia F, Grant I. Propofol infusion for control of
childhood refractory status epilepticus. Pediatr Neurol 2006; status epilepticus. Anaesthesia 1990; 45: 1043– 5
34: 63– 5 89 Pitt-Miller P, Elcock B, Maharaj M. The management of status

Downloaded from http://bja.oxfordjournals.org/ at New York University on August 6, 2015


67 Misra UK, Kalita J, Patel R. Sodium valproate vs phenytoin epilepticus with a continuous propofol infusion. Anesth Analg
in status epilepticus: a pilot study. Neurology 2006; 67: 1994; 78: 1193–4
340– 2 90 Parviainen I, Kalviainen R, Ruokonen E. Propofol and barbitu-
68 Gilad R, Izkovitz N, Dabby R, et al. Treatment of status epilepticus rates for the anesthesia of refractory convulsive status epilep-
and acute repetitive seizures with i.v. valproic acid vs phenytoin. ticus: pros and cons. Neurol Res 2007; 29: 667– 71
Acta Neurol Scand 2008; 118: 296–300 91 Rossetti AO, Logroscino G, Liaudet L, et al. Status epilepticus: an
69 Segura-Bruna N, Rodriguez-Campello A, Puente V, Roquer J. independent outcome predictor after cerebral anoxia. Neurology
Valproate-induced hyperammonemic encephalopathy. Acta 2007; 69: 255– 60
Neurol Scand 2006; 114: 1–7 92 Zarovnaya EL, Jobst BC, Harris BT. Propofol-associated fatal myo-
70 Möddel G, Bunten S, Dobis C, et al. Intravenous levetiracetam: a cardial failure and rhabdomyolysis in an adult with status epi-
new treatment alternative for refractory status epilepticus. lepticus. Epilepsia 2007; 48: 1002–6
J Neurol Neurosurg Psychiatry 2009; 80: 689–92 93 Iyer V, Hoel R, Rabinstein AA. Propofol infusion syndrome in
71 Berning S, Boesebeck F, van Baalen A, Kellinghaus C. Intraven- patients with refractory status epilepticus: an 11-year clinical
ous levetiracetam as treatment for status epilepticus. J Neurol experience. Crit Care Med 2009; 37: 3024– 30
2009; 256: 1634–42 94 Hsieh CY, Sung PS, Tsai JJ, Huang CW. Terminating prolonged re-
72 Gámez-Leyva G, Aristı́n JL, Fernández E, Pascual J. Experience fractory status epilepticus using ketamine. Clin Neuropharmacol
with intravenous levetiracetam in status epilepticus: a retro- 2010; 33: 165– 7
spective case series. CNS Drugs 2009; 23: 983– 7 95 Fujikawa DG. Neuroprotective effect of ketamine administered
73 Beyenburg S, Reuber M, Maraite N. Intravenous levetiracetam for after status epilepticus onset. Epilepsia 1995; 36: 186– 95
epileptic seizure emergencies in older people. Gerontology 2009; 96 Ubogu EE, Sagar SM, Lerner AJ, Maddux BN, Suarez JI, Werz MA.
55: 27– 31 Ketamine for refractory status epilepticus: a case of possible
74 Eue S, Grumbt M, Müller M, Schulze A. Two years of experience in ketamine-induced neurotoxicity. Epilepsy Behav 2003; 4: 70– 5
the treatment of status epilepticus with intravenous levetirace- 97 Towne AR, Waterhouse EJ, Boggs JG, et al. Prevalence of non-
tam. Epilepsy Behav 2009; 15: 467–9 convulsive status epilepticus in comatose patients. Neurology
75 Uges JW, van Huizen MD, Engelsman J, et al. Safety and 2000; 54: 340– 5
pharmacokinetics of intravenous levetiracetam infusion as 98 Waterhouse EJ, Vaughan JK, Barnes TY, et al. Synergistic effect
add-on in status epilepticus. Epilepsia 2009; 50: 415– 21 of status epilepticus and ischemic brain injury on mortality.
76 Alvarez V, Januel JM, Burnand B, Rossetti AO. Second-line status Epilepsy Res 1998; 29: 175– 83
epilepticus treatment: comparison of phenytoin, valproate, and 99 Vespa PM, Nuwer MR, Nenov V, et al. Increased incidence and
levetiracetam. Epilepsia 2011; 52: 1292–6 impact of nonconvulsive and convulsive seizures after traumatic
77 Towne AR, Garnett LK, Waterhouse EJ, Morton LD, DeLorenzo RJ. brain injury as detected by continuous electroencephalographic
The use of topiramate in refractory status epilepticus. Neurology monitoring. J Neurosurg 1999; 91: 750–60
2003; 60: 332– 4 100 Rossetti AO, Milligan TA, Vulliemoz S, Michaelides C, Bertschi M,
78 Bensalem MK, Fakhoury TA. Topiramate and status epilepticus: Lee JW. A randomized trial for the treatment of refractory status
report of three cases. Epilepsy Behav 2003; 4: 757– 60 epilepticus. Neurocrit Care 2011; 14: 4–10
79 Perry MS, Holt PJ, Sladky JT. Topiramate loading for refractory 101 Jirsch J, Hirsch LJ. Nonconvulsive seizures: developing a rational
status epilepticus in children. Epilepsia 2006; 47: 1070– 1 approach to the diagnosis and management in the critically ill
80 Albers JM, Möddel G, Dittrich R, et al. Intravenous lacosamide— population. Clin Neurophysiol 2007; 118: 1660–70
an effective add-on treatment of refractory status epilepticus. 102 Shorvon S. What is nonconvulsive status epilepticus, and what
Seizure 2011; 20: 428– 30 are its subtypes? Epilepsia 2007; 48(Suppl. 8): 35– 8
81 Goodwin H, Hinson HE, Shermock KM, Karanjia N, Lewin JJ III. 103 Beyenburg S, Elger CE, Reuber M. Acute confusion or altered
The use of lacosamide in refractory status epilepticus. Neurocrit mental state: consider nonconvulsive status epilepticus.
Care 2011; 14: 348–53 Gerontology 2007; 53: 388– 96

570
Anaesthesia and epilepsy BJA
104 Howell SJ, Owen L, Chadwick DW. Pseudostatus epilepticus. QJM 107 Olsen KB, Tauboll E, Gjerstad L. Valproate is an effective, well-
1989; 71: 507– 19 tolerated drug for treatment of status epilepticus/serial
105 Reuber M, Enright SM, Goulding PJ. Postoperative pseudostatus: not attacks in adults. Acta Neurol Scand Suppl 2007; 187:
everything that shakes is epilepsy. Anaesthesia 2000; 55: 74–8 51– 4
106 Shorvon SD. Emergency treatment of acute seizures, serial sei- 108 Prüss H, Holtkamp M. Ketamine successfully terminates malig-
zures, seizure cluster and status epilepticus. In: Shorvon SD, nant status epilepticus. Epilepsy Res 2008; 82: 219– 22
ed. Handbook of Epilepsy Treatment. Oxford: Blackwell 109 Sheth RD, Gidal BE. Refractory status epilepticus: response to
Science, 2000 ketamine. Neurology 1998; 51: 1765– 66

Downloaded from http://bja.oxfordjournals.org/ at New York University on August 6, 2015

571