Epilepsy & Behavior 17 (2010) 87–89

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Epilepsy & Behavior

journal homepage: www.elsevier.com/locate/yebeh

Effect of general anesthesia in patients with epilepsy: A population-based study

Sarah M. Benish a,b,1, Gregory D. Cascino a,b,*, Mary E. Warner c, Gregory A. Worrell a,b, C. Thomas Wass c
a
Division of Epilepsy, Mayo Clinic, Rochester, MN, USA
b
Department of Neurology, Mayo Clinic, Rochester, MN, USA
c
Department of Anesthesiology, Mayo Clinic, Rochester, MN, USA

a r t i c l e i n f o a b s t r a c t

Article history: General anesthesia may be required for particular diagnostic and therapeutic procedures in patients with
Received 3 September 2009 seizure disorders. There is concern regarding the safety of anesthetic drugs in these individuals because
Revised 12 October 2009 of the reported proconvulsant effect of selected medications. Potentially, general anesthesia may be asso-
Accepted 12 October 2009
ciated with perioperative seizures or increased adverse effects in people with epilepsy. The rationale for
Available online 11 November 2009
the present study was to evaluate the outcome of general anesthesia in a population-based cohort with
seizure disorders undergoing interventions that were unlikely to alter the seizure tendency, for example,
Keywords:
magnetic resonance imaging study. Seizures were observed in only 6 of 297 (2%) anesthetic procedures,
Epilepsy
General anesthesia
and intravenous therapy was required in only one patient. None of the patients had any reported adverse
Proconvulsant effect from general anesthesia. The current findings may be useful in counseling and guiding patients
Seizures with seizure disorders, their caregivers, and their guardians regarding the risk of general anesthesia.
Ó 2009 Published by Elsevier Inc.

1. Introduction related adverse effects in patients with epilepsy undergoing general

Epilepsy is one of the most common neurological disorders with
a prevalence approaching 1% of the population [1]. There are
approximately 2,700,000 people with seizure disorders in the Uni-
ted States [1]. Factors that may increase seizure activity include:
withholding antiepileptic drugs (AEDs) while maintaining non
per os (NPO) status prior to surgery, sleep deprivation, and use of
proconvulsant medications [2]. These conditions may occur in pa-
tients receiving general anesthesia for diagnostic and therapeutic
procedures [2,3]. There are anecdotal observations and case reports
suggesting certain anesthetic medications may lower the seizure
threshold [3–10]. Medications implicated in this pathophysiologi-
cal response include: inhaled volatile anesthetics (e.g., enflurane,
sevoflurane), local anesthetics (e.g., lidocaine, bupivacaine), opi-
oids (e.g., fentanyl, alfentanil, sufentanil, meperidine), and some
sedative/hypnotic medications (e.g., propofol, etomidate, keta-
mine, methohexital) [3–21]. Considering these drugs are adminis-
tered to the majority of patients requiring general anesthesia, it is
imperative to elucidate whether patients with seizure disorders
are at increased risk for perioperative morbidity or mortality. The
rationale for the present study was to identify, in a population-
based cohort, the frequency of seizures and other anesthesia-
anesthesia for diagnostic studies or nonneurosurgical procedures.
2. Methods
A retrospective review of all patients with a seizure disorder
undergoing general anesthesia at Mayo Clinic, Rochester, MN,
USA, between 1995 and 2005 was performed. The patients were
identified through an anesthesia database containing information
regarding patients having undergone procedures requiring general
anesthesia between 1995 and 2005 at one institution (Mayo
Clinic). This database was cross-referenced with the ICD-9 codes
for epilepsy (345.0–345.9). The search produced 1262 procedures
being performed on patients with a diagnosis code of epilepsy.
Individuals undergoing a neurosurgical procedure or neurological
invasive diagnostic technique, for example, myelography or crani-
otomy, were excluded to avoid any inherent increased seizure ten-
dency associated with the examination or operation. A medical
record review of these patients was performed identifying the epi-
lepsy diagnosis, operative procedure or diagnostic investigation,
current AED medication, anesthetic medications received during
the procedure, and any complications recorded during the study
and in the postanesthetic period.

3. Results
* Corresponding author. Address: Department of Neurology, Mayo Clinic, 200
First Street SW, Rochester, MN 55905, USA. Fax: +1 507 266 4419.
E-mail address: gcascino@mayo.edu (G.D. Cascino). Two hundred thirty-six patients were identified who had
1
Present address: Minneapolis Clinic of Neurology, Edina, MN 55435, USA. undergone 297 anesthesia-related procedures. Ten procedures also

1525-5050/$ - see front matter Ó 2009 Published by Elsevier Inc.

doi:10.1016/j.yebeh.2009.10.015
88 S.M. Benish et al. / Epilepsy & Behavior 17 (2010) 87–89

Table 1 4. Discussion
Indications for general anesthesia.a

Indication Number of % of total Potential concerns associated with the use of general anesthesia
procedures procedures in individuals with seizure disorders include an increase in the fre-
MRI 118 35.7 quency or duration of seizure activity, development of status epi-
Surgical procedure 106 32.1 lepticus, pharmacokinetic and pharmacodynamic interactions
Diagnostic study 56 16.9
between AEDs and anesthetic medications, and delayed emergence
(other than MRI)
Biopsy 40 12.1 from anesthesia (i.e., difficulty awakening) following surgery [12–
Dental procedure 10 3.0 14,21]. The incidence of clinical seizure activity in individuals
a
without epilepsy in response to general anesthetic drugs is un-
Patients may have had more than one procedure, for example, diagnostic study
and surgical procedure, during the 297 general anesthetic exposures.
known [11]. EEG-identified epileptiform activity can be demon-
strated with anesthetic medications; however, observed seizures
are considered very rare [11]. The effect of anesthesia in patients
undergoing surgical treatment for intractable partial epilepsy has
Table 2 previously been evaluated [5]. However, the proconvulsant effect
Seizure types in the 236 patients. of general anesthesia in patients with seizure disorders not limited
to focal cortical resection is largely unknown. The present study
Seizure disorder Number of % of total
patients seizure disorders demonstrated that five of the six patients with observed seizures
were children. Two of these patients had symptomatic generalized
Partial 167 70.7
Tuberous sclerosis 5 2.1 epilepsy and the other three had intractable partial epilepsy and
Epilepsia partialis continua 3 1.3 were being considered for surgical treatment. The predominance
Landau–Kleffner syndrome 1 <1.0 of pediatric patients with seizures associated with general anes-
Generalized 64 27.1 thesia may have reflected the severity of their seizure disorders
Lennox–Gastaut syndrome 15 6.4
Mitochondrial disorder 2 <1.0
or frequency of seizure activity.
Pyridoxine dependent 1 <1.0
Neuronal ceroid lipofuscinosis 1 <1.0 4.1. General anesthetics, inhaled
Unknown 5 2.1
Inhalation agents (e.g., enflurane, sevoflurane) for general anes-
thesia have both pro- and anticonvulsant properties [7,8]. At low
involved local or regional anesthesia, and one procedure included doses, these drugs have the potential to induce EEG-identified epi-
spinal anesthesia. There were 121 males and 115 females. The leptiform activity (both clinically and electrographically) in individ-
mean age was 21 years (range: 1 month to 84 years). One hundred uals with or without a history of seizures [7,8]. Although the
thirty-two patients were 18 years of age or younger at the time of mechanism of action has yet to be fully elucidated, these changes
procedure and were considered pediatric for the purposes of this likely result from preferential inhibition of inhibitory central ner-
study. Reasons for the use of anesthesia in these patients are sum- vous system neurotransmission [7,8]. As a result, excitatory neuro-
marized in Table 1. The seizure disorder classification is given in transmission is left unchecked in cortical and subcortical brain
Table 2. Six of the 297 events (2%) were associated with clinical sei- regions. In contrast, with escalating doses, the EEG progresses
zure activity: during intubation (n = 1) or after the procedure prior through a continuum of increased beta EEG activity followed by
to recovery from general anesthesia (n = 5) (Table 3). Five of six pa- burst suppression and eventually isoelectricity. Volatile anesthetics
tients were pediatric patients with a mean age of 8 years (range: 1– can be administered to facilitate cortical mapping during epilepsy
13 years), and five of six had intractable seizure disorders and were surgery and also can be administered to terminate status epilepti-
receiving multiple AEDs. One of the six patients required acute cus in patients who are refractory to conventional therapy [17,18].
benzodiazepine therapy to terminate seizure activity. Seizures
associated with anesthesia occurred in 1 of 122 adult procedures 4.2. General anesthetics, intravenous
(0.8%) and 5 of 174 pediatric procedures (3%) (P 6 1.0). None of
the 11 patients who also received local or spinal anesthesia expe- It is well established that opioid medications have the potential
rienced seizure activity. to induce epileptiform activity in both laboratory animals and

Table 3
Patients who had seizure activity associated with anesthesia.

Patient Age Epilepsy Antiepileptic Procedure Anesthesia Seizure description

(years) drug therapy
1 5 Lennox–Gastaut Nitrazepam Status post MRI head Cisatracurium Generalized tonic–clonic seizure
syndrome corpus callosotomy Sevoflurane
Nitrous oxide
2 10 Partial Topiramate, phenytoin, SPECT scan Lidocaine 20 min after extubation clonic arm
(frontal lobe) valproic acid Propofol Sevoflurane twitching; required intravenous
nitrous oxide lorazepam
3 1 Generalized Lamotrigine, Laparoscopic nissen Thiopental atracurium Rhythmic twitching of legs and
clonazepam, carnitor fundoplication fentanyl left upper extremity
4 31 Partial Lamotrigine MRI head Propofol Generalized tonic–clonic seizure
(temporal lobe) Sodium pentothal
Vecuronium nitrous
Oxide isoflurane
5 13 Generalized Lamotrigine, Muscle biopsy Fentanyl Bupivacaine Generalized tonic–clonic seizure
valproic acid (Regional) ketamine
6 11 Partial Topiramate, MRI head Vecuronium No description
(unknown) lamotrigine
 S.M. Benish et al. / Epilepsy & Behavior 17 (2010) 87–89
humans [15,16]. Opioid-induced epileptiform activity may be used
to localize the epileptogenic zone activity in patients undergoing
epilepsy surgery [5,12]. Alfentanil, sufentanil, and remifentanil
(i.e., short-acting opioids) may be currently used to ‘‘activate” po-
tential epileptiform activity during intraoperative electrocorticog-
raphy (ECoG) at the time of focal cortical resection [5,12,13]. The
etiology of opioid-induced limbic system seizures has not been
fully determined. Proposed mechanisms include: selective activa-
tion of limbic opioid receptors, augmented release of excitatory
amino acids (e.g., glutamate), and facilitation of coupling between
excitatory postsynaptic potentials and somatic spike-generating
sites, or suppression of inhibitory interneurons (i.e., the disinhibi-
tion hypothesis) [14–18]. According to the disinhibition hypothe-
sis, opioids indirectly excite limbic system structures by
inhibiting neighboring c-aminobutyric acid-secreting inhibitory
interneurons [16].
4.3. Study limitations
The method of patient selection for general anesthesia for out-
patient diagnostic and surgical procedures may have increased the
inclusion of pediatric patients and adults with chronic global static
encephalopathy with medically refractory epilepsy. The observed
seizure activity in the six patients may have been incidental to
anesthesia and related to an intractable seizure disorder. The ‘‘ac-
tual” incidence of seizures in response to general anesthetic drugs
may be lower in all patients with epilepsy.
The lack of concomitant EEG monitoring in this patient series
during anesthesia may also have resulted in an underestimate of
seizure activity. However, all individuals were carefully monitored
by trained personnel until fully awakened from anesthesia; there-
fore, clinically evident seizures were unlikely to have been missed.
Anesthesia can be administered at various levels, such as sedation,
deep sedation, and unconsciousness. The current study design did
not permit the determination of safety of anesthesia at different
plasma concentrations. Finally, routine monitoring of AED levels
prior to and after anesthesia was not performed. Any alteration
in the concentration of AED levels would not have been detected.
Conflict of interest statement
The authors report no biomedical financial interests or potential
conflicts of interest.
89
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