BJA Education, 15 (3): 111–117 (2015)

doi: 10.1093/bjaceaccp/mku014
Advance Access Publication Date: 29 May 2014
Matrix reference 1A02,
2A03, 2A06, 3F00

Adult epilepsy and anaesthesia

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Eleanor L Carter FRCA1 and Ram M Adapa MD PhD FRCA2,*
1
Specialty Registrar in Anaesthesia, Norfolk and Norwich University Hospital, Colney Lane, Norwich NR4 7UY, UK,
and 2Consultant in Anaesthesia, Department of Anaesthesia, Addenbrooke’s Hospital, Hills Road, Cambridge CB2
0QQ, UK
*To whom correspondence should be addressed. Tel: +44 1223 217889; E-mail: [email protected]

Epileptic seizures and epilepsy

Key points
Diagnosis of epilepsy
• Epilepsy is a common neurological disorder affect-
ing 600 000 people in the UK. Epilepsy is conventionally diagnosed after two unprovoked sei-
zures occurring at least 24 h apart. This reflects the fact that
• The standard treatment for adults with epilepsy is after two non-febrile seizures, more than 70% of people will
antiepileptic drug (AED) therapy, but resective sur- have another seizure within 4 yr,4 whereas only 40–50% of people
gery may be considered in those patients in whom will go on to develop epilepsy after a single unprovoked seizure.5
seizure control is not achieved. The diagnosis of epilepsy depends on a convincing history, wit-
• AEDs have multiple drug interactions, which need nessed seizures, or both in combination with investigations in-
to be considered in the perioperative period. cluding EEG to detect abnormal neuronal discharges and
computed tomography (CT) or magnetic resonance imaging
• Perioperative care of patients with epilepsy should (MRI) to detect underlying structural brain abnormalities.6 More
focus on minimization of interference in normal than 60% of patients with epilepsy may have normal investiga-
AED regimes and avoiding physiological or pharma- tions (idiopathic epilepsy) and diagnosis is often difficult. As a re-
cological disturbances that may lower the seizure sult, it is believed that 5–30% of people diagnosed with epilepsy in
threshold. the UK may have an incorrect diagnosis.7
• Status epilepticus is a common medical emergency
with significant morbidity and mortality.
Classification of epilepsy
Epilepsy is not a single condition. There are more than 40 differ-
ent types of epilepsy consisting of at least 29 syndromes and a
Epilepsy is a disorder of the brain characterized by a predispos- further 12 or so clinically distinct groups defined by the specific
ition to generate abnormal synchronous neuronal activity. This cause.8 Classification systems typically focus on underlying aeti-
results in recurrent and unpredictable interruptions of normal ology or descriptions of clinical features such as seizure type.8
brain function, observed clinically as epileptic seizures.1 Epilepsy Common causes of epilepsy include congenital neurological or
is common; 50 million people worldwide are affected and the es- metabolic conditions, traumatic brain injury, stroke, brain tu-
timated prevalence of active epilepsy [continuing seizures or the mours, and central nervous system (CNS) infections. Underlying
need for antiepileptic drug (AED) treatment] is 4–10 per 1000 peo- genetic susceptibility and environmental factors may also con-
ple.2 Within the UK, ∼600 000 people have a diagnosis of epilepsy tribute to this condition. The precise aetiology of epilepsy is
and take antiepileptic medication.3 All anaesthetists will regular- often not important in the perioperative environment, but anaes-
ly encounter patients with epilepsy in their practice and should thetists should note if epilepsy is part of a multisystem syndrome
be aware of the special considerations when managing patients or disease process.
with this disorder. Planned and thoughtful care of these patients Epileptic seizures are subdivided into focal and generalized
can minimize the risk of seizure occurrence in the perioperative types. Focal seizures originate within neuronal networks limited
period. to one hemisphere, whereas generalized seizures rapidly engage

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111
Adult epilepsy and anaesthesia

Table 1 Major seizure type and subtype classifications Prognosis for patients with epilepsy

Generalized seizures In those patients with a defined epilepsy aetiology, their progno-
Tonic–clonic sis will depend on the underlying cause. Patients with idiopathic
Absence epilepsy have a normal lifespan if their seizures are well con-
Myoclonic trolled, but this falls if seizure control is not achieved. This re-
Clonic flects the higher incidence of accidents and suicides in this
Tonic group and also the risk of sudden unexpected death in epilepsy
Atonic (SUDEP). SUDEP is the sudden death of a seemingly healthy indi-
Focal seizures vidual with epilepsy, usually occurring during, or immediately
Simple after, a tonic–clonic seizure. The mechanisms are incompletely
Complex understood, but seizure-related respiratory depression, cardiac
Evolving to generalized arrhythmias, cerebral depression, and autonomic dysfunction

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Mixed seizures (focal and generalized) are all implicated.13 Risk factors for SUDEP include male sex,
Unclassified
long duration of epilepsy, frequent occurrence of tonic–clonic sei-
zures, and AED polytherapy. Patients should be counselled and
given advice regarding treatment and lifestyle choices to avoid
bilaterally distributed neuronal networks. Focal and generalized poor seizure control and minimize the risk of SUDEP.
epileptic seizures present with variable signs and symptoms that
depend on the spatial origin and extent of abnormal synchron-
Management of patients with epilepsy for
ous activity (Table 1). Within the UK, 60% of patients with epi-
routine surgery
lepsy have tonic–clonic seizures, 20% have complex focal
seizures, 12% have a mixed picture of several seizure types, 3% Preoperative evaluation
have simple focal seizures, and <5% have other seizure types.3,8
In addition to the standard preoperative history and examin-
ation, specific considerations in patients with epilepsy are de-
scribed below.
Management of epilepsy
The standard management of adults with a confirmed diagnosis Associated comorbidities
of epilepsy is AED therapy. The mechanism of action of AEDs is For patients with epilepsy of defined aetiology, there may be im-
via either suppression of excitatory impulses or facilitation of in- portant effects on other organ systems. For example, congenital
hibitory impulses in the brain (Fig. 1).9 Therapy choices are based syndromes often have multisystem involvement, and epilepsy
on the seizure type and aetiology of epilepsy, with consideration secondary to stroke is associated with other significant cardio-
taken of the patient’s comorbidities and medications and the vascular disease.
AED side-effect profile. The National Institute for Clinical Excel-
lence (NICE) produced recommended treatment guidelines in Seizure type and frequency
2012 (Table 2).7 AED monotherapy is preferable, but if this fails, It is important to establish how well a patient’s epilepsy is con-
patients may be managed on more than one AED. The character- trolled to predict the risk of postoperative seizure occurrence.
istics of the major AEDs are shown in Table 3.10 Awareness of the patient’s normal seizure pattern helps to deter-
Patients with poor seizure control despite AED polytherapy mine if postoperative events are likely to be part of their under-
should be referred to a specialist multidisciplinary epilepsy clinic. lying disorder.
Epilepsy surgery is a treatment option in these cases and may be
curative or palliative. Surgical options include implantation of a Antiepileptic medication
vagal nerve stimulator to reduce seizure frequency, curative resec- Current drug therapy, dosage regimes, time of most recent dose,
tive surgery such as an anterior temporal lobectomy, or disconnec- and any recent changes in the medication regime should be es-
tive procedures that interrupt the propagation of seizures such as a tablished. Attempts should be made to minimize disruption to
corpus callosotomy or a multiple pial transection. treatment regimes and anaesthetists should ensure that a pa-
Women of childbearing age should be counselled regarding tient has taken their scheduled medication on the morning of
the risk of teratogenicity from AEDs and the potential interaction surgery.
between AEDs and oral contraceptive drugs. Although some
AEDs are linked to fetal malformations, data especially from Driving licence status
newer drugs are limited and there are definite risks to the fetus Patients with epilepsy will usually be allowed to hold a driving li-
and mother if a woman has a tonic–clonic seizure during preg- cence if they have been totally seizure-free, or have only had sei-
nancy. In the period 2006–8, the UK Confidential Enquiries into zures in their sleep, or only had simple focal seizures with no
Maternal Deaths recorded 14 deaths during pregnancy as a con- functional impairment over a 1 yr period (sometimes 6 months
sequence of epilepsy.11 Decisions regarding epilepsy treatment in the case of a first seizure). A perioperative seizure in patients
during pregnancy are therefore complex and should be made in who hold driving licences can therefore have significant implica-
consultation with a neurologist and obstetrician. tions. The Driving and Vehicle Licensing Agency (www.gov.uk/
Individuals are no longer considered to have epilepsy if they government/organisations/driver-and-vehicle-licensing-
have remained seizure-free for at least 10 yr off antiseizure medi- agency) has detailed advice.
cines and there are no known risk factors associated with a high
probability (≥75%) of future seizures or if they had an age-depend-
Preoperative tests
ent epilepsy syndrome but are now past the applicable age. This
reflects the finding that the risk of recurrent seizures is very low Patients should have preoperative tests in line with National In-
after 10 yr being seizure-free off antiepileptic medication.12 stitute of Clinical Excellence guidelines (NICE, www.nice.org.uk)

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Fig 1 Proposed mechanisms of action of currently available AEDs at () excitatory and () inhibitory synapses (reproduced with permission from Bialer and White).9 AMPA,
α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid; GABA, γ-amino-butyric acid; GABA-T, GABA transaminase; GAD, glutamic acid decarboxylase; GAT1, GABA
transporter 1; NMDA, N-methyl--aspartate; SV2A, synaptic vesicle glycoprotein 2A.

depending on age, surgical severity, and ASA status. Within these controlled epilepsy or a history of unstable AED levels and before
guidelines, there are no specific recommendations regarding pre- major gastrointestinal surgery to establish baseline levels. Con-
operative measurement of AED levels, and levels are not routine- sultation with the patient’s neurologist before surgery is probably
ly measured. Exceptions to this are in patients who have poorly appropriate in such circumstances.

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Adult epilepsy and anaesthesia

Table 2 NICE guidelines for AED treatment7 to this is alfentanil, a particularly potent enhancer of EEG activity,
which should be avoided or used with caution. Meperidine and
Seizure type First line Adjunctive tramadol should also be avoided as they increase the risk of sei-
zures. Meperidine’s metabolite normeperidine is a potent pro-
Generalized tonic–clonic Carbamazepine Clobazam
convulsant, and tramadol lowers the seizure threshold
Lamotrigine Lamotrigine
Oxcarbazepine Levetiracetam ( probably because of its inhibition of monamine reuptake).
Sodium valproate Sodium valproate
Topiramate Neuromuscular blockers
Tonic or atonic Sodium valproate Lamotrigine Although succinylcholine has been observed to produce in-
Absence Ethosuximide Ethosuximide creased EEG activation, this has not been associated with seizure
Lamotrigine Lamotrigine activity.14 It is therefore considered safe to use except after pro-
Sodium valproate Sodium valproate longed status epilepticus where it may cause dangerous eleva-

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Myoclonic Levetiracetam Levetiracetam tions in serum potassium. Non-depolarizing neuromuscular
Sodium valproate Sodium valproate blockers (NMBs) are safe, but the enzyme-inducing effects of
Topiramate Topiramate AEDs may cause resistance to the effects of aminosteroid NMBs
Focal Carbamazepine Carbamazepine such as rocuronium, pancuronium, and vecuronium. It is advis-
Lamotrigine Clobazam able to monitor the neuromuscular block with a nerve stimulator,
Oxcarbazepine Gabapentin
as the dose and frequency of these drugs may need to be ad-
Sodium valproate Lamotrigine
justed. Laudanosine, a metabolite of atracurium, has epilepto-
Levetiracetam
genic potential, but seizures have only been reported in animal
Oxcarbazepine
studies.
Sodium valproate

Antiemetics
Dopamine antagonists are particularly associated with extrapyr-
Conduct of anaesthesia amidal effects and acute dystonic reactions, which might be con-
The multiple interactions between AEDs and anaesthetic agents fused with seizure activity. It is therefore advisable to avoid
are complex and beyond the scope of this article. However, a phenothiazines (e.g. prochlorperazine), benzamindes (e.g. meto-
number of common and important interactions will be discussed clopramide), and butyrophenones (e.g. droperidol).
with practical tips for management.
Local anaesthetics
I.V. anaesthetics Regional techniques are safe in patients with epilepsy and may
The effects of i.v. anaesthetic agents on the EEG are complex, but help to minimize disruption of normal AED regimes. However,
they are generally proconvulsant at low levels and anticonvul- close attention should be paid to safe dosing as local anaesthetics
sant at doses used for general anaesthesia. Thiopental is safe to can readily cross the blood–brain barrier and result in seizures if
use and is an established treatment for refractory status epilep- plasma levels are too high.
ticus because of its powerful anticonvulsant properties at anaes-
thetic doses. Propofol was previously avoided in patients with Seizures under anaesthesia
epilepsy because of the high rate of excitatory movements on in-
Seizures under general anaesthesia are relatively rare, but may
duction and emergence. However, it is now widely used because
occur in patients with poorly controlled epilepsy or in the context
of the recognition of its anticonvulsant properties at anaesthetic
of high-risk surgery such as neurosurgery. They are difficult to
doses and because the abnormal movements are usually easy to
diagnose, especially if NMBs have been used, but suggestive
distinguish from epileptic seizures. Etomidate has been reported
signs include increasing end-tidal carbon dioxide, tachycardia,
to be more frequently associated with postoperative seizures and
hypertension, increased muscle tone, pupillary dilatation, and
prolongs seizures when used for electroconvulsive therapy, and
increased oxygen consumption. Immediate management in-
is therefore generally avoided. Ketamine is often avoided, par-
cludes deepening of anaesthesia, administration of 100% oxygen,
ticularly as a co-induction agent, because of its proconvulsant
correction of precipitating factors such as hypoglycaemia, hyp-
properties at low doses. However, it is anticonvulsant at anaes-
oxia, and hypercarbia, and also consideration of differential diag-
thetic doses. Benzodiazepines are all potent anticonvulsants
noses. If available, EEG may help with diagnosis.
and safe to use.

Inhalation anaesthetics Postoperative care

Nitrous oxide has been observed to provoke seizures in animal Of particular importance in the management of patients with
models, but this has not been replicated in humans and it is con- epilepsy is minimization of disruption of their normal AED re-
sidered safe to use. Most inhalation agents cause burst suppres- gime. I.V. forms of phenytoin, sodium valproate, and leviterace-
sion on the EEG and again are safe to use. The exception to this is tam exist and carbamazepine can be given rectally. Early input
enflurane, which can produce epileptiform discharges on the EEG from a neurologist should be sought if a patient is likely to
and postoperative seizures, so should be avoided. be unable to resume their normal regime of oral AEDs after
operation.
Opioids Postoperative prescriptions for patients with epilepsy should
Opioid analgesics all possess some degree of proconvulsant ac- take into account the extensive pharmacokinetic and pharmaco-
tivity and are used to enhance EEG activity during seizure focus dynamic interactions of AEDs. Enzyme-inducing AEDs can re-
localization in epilepsy surgery. However, most opioids have a duce the serum concentration of multiple drugs, including
long history of safe use in patients with epilepsy. An exception some antimicrobials, paracetamol, and fentanyl. Conversely,

114 BJA Education | Volume 15, Number 3, 2015

 Adult epilepsy and anaesthesia

Table 3 Characteristics of AEDs (adapted with permission from Kofke).10 CNS, central nervous system; CYP2B, cytochrome P450 2B; DIC,
disseminated intravascular coagulation; t½, elimination half-life; UGT, UDP-glucuronosyltransferase

Drug Protein Effects on enzymes t½ (h) Elimination Disadvantages and adverse effects
binding (%) involved in drug route (%)
metabolism
Renal Liver

Carbamazepine 75 Broad-spectrum inducer 9–15 1 99 Diplopia, nystagmus, blurred vision, ataxia, dizziness,
sedation, hyponatraemia, rash
Clonazepam 85 Induce CYP2B family 20–60 <5 >90 Sedation
Ethosuximide 0 None 30–60 <20 <80 Nausea, vomiting, gastrointestinal distress, drowsiness,
ataxia
Felbamate 25 Mixed inducer and 13–22 50 50 Risk of aplastic anaemia and liver toxicity, CNS and

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inhibitor gastrointestinal side-effects, drug interactions, dizziness,
blurred vision, ataxia, weight loss
Gabapentin 0 None 5–7 100 0 Efficacy limited to partial epilepsies, multiple daily dosing,
high cost, mild drowsiness, encephalopathy, weight gain,
peripheral oedema, weight change
Lamotrigine 55 Induces UGTs 12–62 10 90 Need for slow titration, hypersensitivity reactions, rash,
Stevens–Johnson syndrome, toxic epidermal necrolysis
(especially with concurrent valproate), hepatic and renal
failure, DIC, arthritis, fever, red cell aplasia, tics, insomnia
Levetiracetam <10 None 6–8 100 0 Irritability, behaviour change, somnolence
Oxcarbazepine 40 Mixed inducer and 9 1 99 Interaction with oral contraceptives, hyponatraemia, rash
inhibitor
Phenobarbitol 45 Broad-spectrum inducer 75–110 25 75 Drowsiness, slurred speech, nystagmus, confusion,
somnolence, ataxia, respiratory depression, coma,
hypotension, sedation, behaviour disorders
Phenytoin 90 Broad-spectrum inducer 9–36 5 95 Vertigo, ataxia, slurred speech, nystagmus, diplopia,
somnolence, stupor, coma, gingival hyperplasia, hirsutism.
Hypotension and arrythmias (i.v.)
Primadone 0 Broad-spectrum inducer 6–8 100 0 Sedation and dizziness acutely, then similar to phenobarbital
Tigabine 96 None 7–9 2 98 CNS side-effects, interactions with oral contraceptives,
nephrolithiasis, open-angle glaucoma, hypohidrosis,
metabolic acidosis, weight loss
Topiramate 15 Mixed inducer and 12–24 65 35 CNS side-effects, nephrolithiasis, open-angle glaucoma,
inhibitor hypohidrosis, metabolic acidosis, weight loss, language
dysfunction
Valproate 90 Broad-spectrum 6–18 2 98 Sedation, gastric disturbance, weight gain, diarrhoea, tremors,
inhibitor ataxia, somnolence, coma, thrombocytopenia, platelet
dysfunction, hepatic failure, hair loss, drowsiness
Vigabatrin 0 None 5–7 100 0 Visual field defects, weight gain
Zonisamide 40 None 63 35 65 CNS side-effects, allergic reactions, rash, nephrolithiasis,
hypohidrosis, irritability, photosensitivity, weight loss

drugs, including some antimicrobials, can increase the serum loading dose of phenytoin (18 mg kg−1) should be given and neur-
concentration of AEDs by inhibiting their metabolism, risking ology advice sought. Patients with known epilepsy should be in-
AED toxicity. In addition, highly protein-bound AEDs can com- formed of the event as it may affect their lifestyle, for example,
pete with other protein-bound drugs for binding sites, altering driving or working with heavy machinery. In patients without
free drug levels (Table 3). Proconvulsant drugs including trama- known epilepsy, precipitating factors such as metabolic distur-
dol, meperidine, and ketamine should be avoided, as should bances or drug effects should be corrected and they should be re-
dopamine antagonists including haloperidol and antiemetics be- ferred for an urgent neurology opinion. The diagnosis of a first
cause of the risk of extrapyramidal side-effects. In view of the seizure in the postoperative setting should be made cautiously
many and complex interactions, all postoperative medications in view of the multiple other pathologies that may mimic a
should be checked for safety before prescribing. seizure.

Postoperative seizures Anaesthesia for epilepsy surgery

Abnormal movements in the postoperative setting may be sei- Patients with epilepsy refractory to AEDs may be suitable for sur-
zures or a number of other diagnoses (Table 4). Management gery to remove the epileptogenic foci. These patients can present
should focus on an ABC approach, determination of the likely to the anaesthetist in two situations: for the implantation of
cause and termination of seizures with benzodiazepines. If seiz- intracranial electrodes and for the resection of the epileptic
ure resolution does not occur with benzodiazepine therapy, a focus. Electrode implantation surgery is commonly performed

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Adult epilepsy and anaesthesia

Table 4 Cause of postoperative seizure-type episodes Status epilepticus

Epileptic seizure Convulsive status epilepticus
Underlying epilepsy
Convulsive status epilepticus (CSE) is a common medical emer-
Post-neurosurgery
Eclampsia
gency and is conventionally defined as >30 min of continuous
Metabolic disturbance seizure activity or sequential seizures without full recovery of
Alcohol withdrawal consciousness between seizures. However, it is recognized that
Postoperative shivering after 5 min of continuous seizure activity, spontaneous reso-
Acute dystonic drug reaction lution is unlikely to occur, so treatment is advised to start at
Dopamine antagonists this time point. Emergency pharmacological management of
Psychogenic non-epileptic seizure CSE is summarized in Figure 2. Of note is the addition of ketamine
Syncopal episode to the management options for refractory CSE. Ketamine has re-

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cently been shown to be effective for refractory CSE in a case ser-
ies of patients where other i.v. anaesthetics had not terminated
CSE and should be considered as a second-line option.17
under general anaesthesia with propofol or low levels of inhaled The management of CSE should include resuscitative mea-
agent. It is generally recommended that benzodiazepines be sures such as airway management, supplemental oxygen, and
avoided to prevent abolition of interictal epileptiform activity. In- establishing large-bore i.v. access in addition to cardiorespiratory
traoperative pharmacoactivation (to encourage seizure activity assessment, arranging emergency investigations, identification
under anaesthesia with the aim of identifying the seizure of and treatment of underlying aetiology, and arranging inten-
focus) may occasionally precipitate generalized seizures, which sive care admission in established/refractory cases. Emergency
are effectively managed by the application of cold saline to the investigations include arterial blood gases and venous blood
exposed part of the brain, small doses of propofol (10–30 mg) or sampling for glucose, calcium, and magnesium levels; renal
anticonvulsant drugs, or both. The patients subsequently under- and liver functions; a full blood count, clotting screen, AED
go telemetry monitoring in the postoperative period in order to level assay, and toxicology screen. Other investigations including
localize the focus of epileptiform activity before a planned crani- microbiology, lumbar puncture, and brain imaging will depend
otomy and resection of the appropriate brain area. Patients pre- on the presentation and likely aetiology. The EEG is useful to
senting for the surgical resection of the foci often have had monitor seizure activity in the anaesthetized and paralysed pa-
accurate presurgical localization using a multitude of investiga- tient. A neurologist opinion should be sought if non-epileptic sei-
tions [including CT, MRI, single photon emission computed tom- zures are suspected.
ography (SPECT), positron emission tomography (PET), and Complications of refractory CSE include excitotoxic CNS in-
magnetoencephalography (MEG)] and may also have intracorti- jury, hyperthermia, pulmonary oedema, arrhythmias, cardiovas-
cal/subdural electrodes in situ. Surgery in such situations is facili- cular collapse, metabolic derangement, acute kidney and liver
tated by either general anaesthesia or local anaesthesia (‘awake injury, rhabdomyolysis, and fractures. Refractory CSE has a
craniotomy’) if indicated. The latter technique may be preferable high-mortality rate and less than one-third of patients will return
when the epileptogenic zone is anatomically close to eloquent to their premorbid level of functioning.14
areas of the brain, as it allows cognitive testing to identify critical
functional regions of the brain.
The detailed perioperative management for these procedures Non-convulsive status epilepticus
is beyond the scope of this article and the reader is referred to re- Non-convulsive status epilepticus (NCSE) refers to the finding of
cent comprehensive reviews on this topic.15,16 EEG evidence of uncontrolled seizures but without clinically

Fig 2 Pharmacological management of the stages of CSE. Administer phenytoin via a large-bore peripheral cannula or central line as the highly alkaline solution produces
tissue necrosis if extravasated.

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 Adult epilepsy and anaesthesia

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