NEUROSURGICAL

  FOCUS Neurosurg Focus 43 (5):E18, 2017

A systematic review of perioperative seizure prophylaxis

during brain tumor resection: the case for a multicenter
randomized clinical trial
Vyshak Chandra, MS,1 Andrew K. Rock, MHS, MS,1 Charles Opalak, MD, MPH,1
Joel M. Stary, MD, PhD,1 Adam P. Sima, PhD,2 Matthew Carr, BS,1 Rafael A. Vega, MD, PhD,1 and
William C. Broaddus, MD, PhD1
1
Department of Neurosurgery, Virginia Commonwealth University Health System, Medical College of Virginia; and 2Department
of Biostatistics, Virginia Commonwealth University, Richmond, Virginia

OBJECTIVE  The majority of neurosurgeons administer antiepileptic drugs (AEDs) prophylactically for supratentorial
tumor resection without clear evidence to support this practice. The putative benefit of perioperative seizure prophylaxis
must be weighed against the risks of adverse effects and drug interactions in patients without a history of seizures. Con-
sequently, the authors conducted a systematic review of prospective randomized controlled trials (RCTs) that have evalu-
ated the efficacy of perioperative seizure prophylaxis among patients without a history of seizures.
METHODS  Five databases (PubMed/MEDLINE, Cochrane Central Register of Controlled Trials, CINAHL/Academic
Search Complete, Web of Science, and ScienceDirect) were searched for RCTs published before May 2017 and investi-
gating perioperative seizure prophylaxis in brain tumor resection. Of the 496 unique research articles identified, 4 were
selected for inclusion in this review.
RESULTS  This systematic review revealed a weighted average seizure rate of 10.65% for the control groups. There
was no significant difference in seizure rates among the groups that received seizure prophylaxis and those that did not.
Further, this expected incidence of new-onset postoperative seizures would require a total of 1258 patients to enroll in a
RCT, as determined by a Farrington-Manning noninferiority test performed at the 0.05 level using a noninferiority differ-
ence of 5%.
CONCLUSIONS  According to a systematic review of major RCTs, the administration of prophylactic AEDs after brain
tumor resection shows no significant reduction in the incidence of seizures compared with that in controls. A large mul-
ticenter randomized clinical trial would be required to assess whether perioperative seizure prophylaxis provides benefit
for patients undergoing brain tumor resection.
https://thejns.org/doi/abs/10.3171/2017.8.FOCUS17442
KEY WORDS  brain neoplasms; neurosurgery; seizures; anticonvulsants; prevention and control; systematic review

S
eizures are debilitating and burdensome for the tice was first studied in the 1980s, with investigators in a
health care system. Patients with seizures have high- double-blind trial concluding that preoperative phenytoin
er medical expenses, lower employment rates, and administration decreased seizure rates by 50%;20 however,
barriers to social participation.11 Seizures lead to longer the study included craniotomies for a variety of patholo-
hospital stays and increased health care costs. The risk of gies, and there was no significant difference in seizure
new-onset seizure for a patient with a brain tumor is re- rates between the AED-treated and untreated supratento-
ported to be 20%–90%.7,12,20 Postcraniotomy seizure rates rial tumor resection groups.
for patients with no prior history of seizure range from A 2015 survey of surgeons revealed that more than 63%
7% to 18%.4,5 Antiepileptic drugs (AEDs) have been used of them administer seizure prophylaxis after tumor resec-
to decrease the rate of postoperative seizures. This prac- tion in patients without a history of seizures.3 Eighty-five

ABBREVIATIONS  AED = antiepileptic drug; RCT = randomized controlled trial.

SUBMITTED  July 1, 2017.  ACCEPTED  August 21, 2017.
INCLUDE WHEN CITING  DOI: 10.3171/2017.8.FOCUS17442.

©AANS, 2017 Neurosurg Focus  Volume 43 • November 2017 1

V. Chandra et al.

percent of the surgeons who practice prophylaxis reported of intervention, follow-up interval, outcome definition, sei-
that they use the antiepileptic levetiracetam. The dura- zure incidence, risk estimate, and conclusions. The risk of
tion of prophylaxis varied from 1 week to more than 6 bias (low, high, uncertain) of included trials was assessed
weeks. This suggests that a significant minority of tumor using the Cochrane Handbook for Systematic Reviews
surgeons do not endorse the perioperative use of AEDs in of Interventions10 and the following 6 domains: random
seizure-naïve patients. This survey also revealed that 82% sequence generation, allocation concealment, blinding,
of the respondents would guide their future practice in this incomplete outcome data, selective reporting, and other
area based on the results of a well-designed randomized bias. The weighted average seizure rate of untreated con-
controlled trial (RCT). trols was calculated based on reported values from the in-
There is no Class I evidence to support the widespread cluded studies. Power analyses were conducted using the
practice of administering prophylactic AEDs in patients weighted average seizure rate to estimate the number of
undergoing tumor resection. Further, pharmaceuticals are patients required to demonstrate noninferiority within an
not benign. Levetiracetam can cause behavioral problems RCT. All power analyses were based on the Farrington-
(anger, apathy, irritability, neurosis), headache, drowsi- Manning noninferiority test performed at the 0.05 level
ness, suicidal ideation, increased blood pressure, and gas- using a noninferiority difference of 5%.
trointestinal disturbances. Phenytoin has a larger set of
side effects, such as atrial conduction depression, arrhyth- Results
mias, cerebral atrophy, cerebral dysfunction, peripheral
neuropathy, dermatological issues, and various immu- Study Selection
nological issues. The total direct cost of a 7-day seizure A total of 496 unique articles were identified through
prophylaxis with intravenous levetiracetam is $8784.63 the database searches and underwent title, abstract, and
and with intravenous phenytoin $8743.78. The cost-ef- full-text review (Fig. 1). After screening by title, there
fectiveness ratio per successful seizure prophylaxis regi- were 84 articles that underwent abstract review. Sixty-
men (SSPR) was shown to be $10,044.91 for intravenous eight articles were subsequently excluded, and 16 articles
levetiracetam, compared with $11,525.63 for intravenous were considered eligible for full-text review. Following
phenytoin.12 the full-text review, 13 articles were excluded. Reasons
Given that the perioperative administration of AEDs is for exclusion comprised a lack of perioperative seizure
one of the most common practices encountered in neuro- outcomes,15,16 a heterogeneous sample of neurosurgery pa-
logical intensive care patients, we conducted a systematic tients,9 non-English language,19,23 absent assessment of sei-
review of relevant studies of perioperative seizure prophy- zure prophylaxis for brain tumor resection,7,22,28 and study
laxis in patients undergoing tumor resection. Additionally, design other than RCT.13,14,21,24,25 One additional study was
we provide an outline of the trial that would be necessary identified through a review of the reference lists. A total
to provide Class I evidence. This is both a knowledge up- of 4 studies met inclusion criteria and were considered in
date and a blueprint for moving forward. this systematic review (Table 1). Of these trials, one com-
pared prophylactic phenobarbital or phenytoin to no in-
tervention,8 one compared prophylactic phenytoin to no
Methods intervention,27 one compared prophylactic gabapentin to
Literature Search and Inclusion Criteria phenytoin use,26 and one evaluated the addition of prophy-
This systematic review was conducted according to the lactic phenytoin to current AED therapy.2
Preferred Reporting Items for Systematic Reviews and
Meta-Analyses for Protocols (PRISMA-P) guidelines.18 Assessment of Risk of Bias for the Included Studies
Five databases were searched between May 10 and May Details from the assessment of risk of bias for included
13, 2017. The databases included PubMed/MEDLINE, Co- studies are presented in Fig. 2. Despite claims of being
chrane Central Register of Controlled Trials (CENTRAL), RCTs, only 1 study reported methodology in support of
CINAHL/Academic Search Complete, Web of Science, random sequence generation when allocating participants
and ScienceDirect. Searches used combinations of specific to AED and control groups. Although 2 of the studies
terms related to neurosurgery, brain neoplasm, anticon- blinded researchers for outcome assessment, none of the
vulsants, and prophylaxis (details of search strategies are studies had allocation concealment or blinded participants
provided in the Appendix). Only original peer-reviewed and personnel to allocated interventions. One study had
randomized clinical trials in humans whose results were incomplete data for outcomes because the trial was termi-
published in the English language were considered for in- nated after interim futility analysis had demonstrated that
clusion. In addition, the references of previous systematic the power would be too low to show superiority between
reviews, meta-analyses, and selected studies were evalu- the AED and control groups.
ated for the inclusion of additional studies.
Seizure Outcomes
Data Extraction and Outcome Measures Four clinical trials assessed perioperative AED pro-
One reviewer (A.K.R.) evaluated and selected articles phylaxis for preventing seizures in patients undergoing re-
by title, abstract, and full-text review for data abstraction. section of brain tumors (Table 1).2,8,26,27 All of the studies
Abstracted data included first author, year, location, study included heterogeneous samples of patients with supraten-
design, sample size, sample characteristics, tumor type, torial tumors within a variety of anatomical locations. Two
AED type, control group, timing of intervention, duration trials compared AED prophylaxis to no intervention,8,27

2 Neurosurg Focus  Volume 43 • November 2017

 Perioperative seizure prophylaxis during brain tumor resection

FIG. 1. Flow diagram according to the PRISMA-P statement.

while the other 2 trials compared the addition of phenytoin patients and 3 (12%) of 25 patients treated with pheno-
to current AED therapy2 and gabapentin to treatment with barbital or phenytoin. Seizure incidence did not signifi-
phenytoin, respectively.26 There was significant diversity cantly differ between groups. De Santis et al. conducted
across studies in the timing of the intervention, duration of a prospective open-label RCT to determine the potential
intervention, follow-up interval, and outcome definition. effectiveness of phenytoin in addition to a patient’s current
One study did not specify the timing and duration of the AED therapy in preventing early postoperative seizures
intervention.8 Two studies initiated AED therapy intraop- in those undergoing craniotomy for supratentorial brain
eratively and continued treatment for 7 days,2,27 while 1 tumor.2 Patients randomly assigned to the phenytoin group
study initiated AED therapy 7 days prior to surgery and were treated intraoperatively with a loading dose of 18
continued treatment for 6–12 months for meningiomas mg/kg followed by 7 days of treatment adjusted according
or indefinitely for glial tumors.26 The follow-up interval to serum concentrations. Early postoperative seizures oc-
across studies ranged from 7 days to 12 months. Early curred in 13% of patients in the phenytoin group and 11%
postoperative seizures were defined by a cutoff of ≤ 7 days of patients in the control group. The incidence of early
in 2 studies2,8 and ≤ 30 days in another study.27 Additional postoperative seizures did not differ between prophylaxis
outcomes included late seizures (> 7 days) and a history of and control groups. Türe et al. evaluated the postopera-
any new seizure activity. Only 1 study had a neurologist tive effectiveness of gabapentin on acute postoperative
blinded to patient treatment who evaluated and confirmed pain as compared with phenytoin for AED prophylaxis in
the diagnosis of seizures on clinical grounds or electro- patients undergoing craniotomy for supratentorial tumor
encephalography.27 Across all of the studies, there was no resection.26 Seizure activity was assessed at 0, 15, and 30
significant reduction in the incidence of seizures among minutes; 1, 2, 4, 6, 12, 24, and 48 hours; and 1 month post-
those in the intervention groups compared with controls. operatively. Only 1 patient in the phenytoin group had a
Franceschetti et al. randomly assigned 63 patients with- seizure on postoperative Day 3.
out preoperative seizures to receive phenobarbital (n = 25), Wu et al. pursued a prospective RCT examining the
phenytoin (n = 16), or no medication (n = 22).8 Early post- perioperative use of prophylactic AEDs (phenytoin) in pa-
operative seizures (≤ 7 days) occurred in 4 (18%) of 22 tients without a history of seizures. Their study was de-
untreated patients and 3 (7%) of the 41 patients treated signed to accrue 142 patients using an estimated seizure
with phenobarbital or phenytoin, whereas late postopera- incidence of 30% in the control group and 10% in the pro-
tive seizures (> 7 days) occurred in 3 (21%) of 14 untreated phylaxis group. After 6 years, the study was closed after

Neurosurg Focus  Volume 43 • November 2017 3

V. Chandra et al.

123 patients had been enrolled and an independent interim be needed to detect the anticipated difference. Among the
futility analysis had demonstrated a low likelihood that ei- 123 patients who were enrolled, the incidence of overall,
ther the observation or phenytoin prophylaxis group would early (≤ 30 days), late (> 30 days), and clinically significant
be superior using the full sample size. At the time, early sei- seizures was 24%, 10%, 14%, and 3% for the prophylaxis
zures were observed in only 8% of the control group, and group and 18%, 8%, 10%, and 2% for controls, respectively.
the true power to detect a two-thirds reduction in postsur- There was no significant difference in seizure incidence
gical 30-day seizure incidence using 123 patients was 19%. between the control and prophylaxis groups.27
The probability that there would be insufficient evidence The weighted average seizure rate was 10.65% based on
at the end of the trial to show superiority was 0.997, and reported values from control groups. Results from power
calculations using the lower-than-expected incidence of analyses estimating the sample size for a noninferiority
seizures of 8% demonstrated that over 700 patients would RCT are presented in Table 2.

TABLE 1. A comparison of RCTs assessing perioperative AED prophylaxis in patients undergoing brain tumor resection
Parameter Franceschetti et al., 1990 De Santis et al., 2002 Türe et al., 2009* Wu et al., 2013†
Location Italy Italy Turkey USA
Study design RCT Open-label RCT RCT RCT
Sample size 63‡ 200 75 123
Sample charac- 34 M, 29 F; mean age: 103 M, 97 F; preop Szs: 67; 36 M, 39 F 67 M, 56 F
teristics 55 yrs preexisting AED therapy: 185
Tumor type Supratentorial neoplasm Supratentorial tumor location: Supratentorial tumor Intraparenchymal supratentorial tumor loca-
location: frontal, 12; frontal, 70; temporal, 47; surgical route: fron- tion: frontal, 48; temporal, 34; parietal,
temporal, 18; central, parietal, 41; sellar, 17; oc- tal, 17; parietal, 17; occipital, 18; other, 6; metastases: 77;
2; parietal, 16; occipi- cipital, 7; deep structures, 6; 6; temporal, 4; glioma: 46
tal, 15; meningiomas: intraventricular, 6; tentorial, 6; pterional, 48; menin-
27; malignant glial: 23; glioma: 95; meningioma: 81; gioma: 32; glioma:
metastases: 13 metastases: 10; other: 14 42; metastases: 1
AED type PB or PHT PHT plus current AED therapy Gabapentin PHT
Control group No medication Current AED therapy PHT No medication
Timing of NS Intraoperatively 7 days before surgery Intraoperatively
intervention
Duration of NS 7 days 6–12 mos for meningio- Tapered on POD 8
intervention mas or indefinitely
for glial tumors
FU interval Minimum of 6 mos 7 days 1 mo 12 mos
Outcome Early (≤7 days) & late Early postop Szs (≤7 days) Sz activity at 0, 15, 30 Early Sz (≤30 days) or clinically significant
definition postop Szs mins, 1, 2, 4, 6, 12, Sz w/ neurological deficits assessed
24, 48 hrs, & 1 mo daily for 3 days after surgery, on POD 8,
postoperatively & every 2–3 mos for up to 12 mos
Sz incidence Early Szs in 18% un­treat­ Early Szs in 13% PHT-treated & 1 patient in PHT group Szs in 18% controls & 24% prophylaxis
ed & 7% PB- or PHT- 11% controls had partial Sz on group (p = 0.51); early Szs (≤30 days) in
treated; late Szs in POD 3; all patients 8% controls & 10% prophylaxis group (p
21% untreated & 12% Sz free at 1-mo FU = 1.00); late Szs (>30 days) in 10% con-
PB- or PHT-treated trols & 14% prophylaxis group (p = 1.00);
clinically significant Szs in 2% controls &
3% prophylaxis group (p = 0.62)
Risk estimate NS NS NS Odds of early Sz in prophylaxis vs control
was 1.4 (95% CI 0.425–4.763)
Statistical No No No No
significance
Authors support Yes No§ No No
prophylactic
AED use
FU = follow-up; NS = not specified; PB = phenobarbital; PHT = phenytoin; POD = postoperative day; Sz = seizure; USA = United States of America.
*  Study designed to assess postoperative analgesic efficacy of gabapentin compared to phenytoin.
†  Trial closed early due to limited power to observe significant differences between groups.
‡  After removing patients with preoperative seizures.
§  Conclusions only extend to short-term PHT prophylaxis plus current AED therapy.

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 Perioperative seizure prophylaxis during brain tumor resection

TABLE 2. Expected sample size required for a noninferiority

study aimed at demonstrating similar seizure rates for
prophylaxis and control groups
Sz Rate
AED Group Control Group Total No. No. of Sites*
10% 14% 26,092 131
10% 13% 6,322 32
10% 12% 2,720 14
10% 11% 1,480 8
10% 10.65% 1,258 7
10% 10% 914 5
10% 9% 612 4
10% 8% 434 3
This information is based on a Type I error = 0.05, power = 80%, difference =
5%.
*  Number of sites calculated from an accrual rate of 50 per site each year for
4 years.
FIG. 2. Risk of bias summary for each included study. Green plus sign
indicates low risk; red minus sign, high risk; and yellow question mark,
not reported. to provide solid grounds for or against antiseizure prophy-
laxis in tumor surgery. Given the consistent lack of dif-
ferences found between prophylaxis and control groups,
Discussion the objective moving forward should not be to determine
Clinical Implications differences between these 2 groups (that is, superiority),
but rather to show that these groups do not have different
We conducted a systematic review of RCTs investigat- seizure profiles (that is, noninferiority). Table 2 shows the
ing perioperative seizure prophylaxis in patients without required sample size for a noninferiority study to achieve
a history of seizures who were undergoing brain tumor 80% power in comparing a prophylactic AED group to a
resection, including data from 4 studies.2,8,26,27 Our review control group in which the AED group has a 10% seizure
suggests that prophylactic AED administration may not rate and the control group has a seizure rate that varies
be effective in preventing seizures in the perioperative pe- from 8% to 14%. All power analyses were based on the
riod in patients without a history of seizures. Across all of Farrington-Manning noninferiority test performed at the
the included studies, there was no significant difference 0.05 level using a noninferiority difference of 5%.6
in seizure incidence in the intervention groups compared To estimate possible enrollment, we extracted data on
with controls. Without clear evidence of improved seizure all of our institution’s first-time supratentorial cranioto-
control, neurosurgeons must reconsider the routine peri- mies in adults for the period of 2014–2015. One hundred
operative administration of AEDs in patients without a ninety-seven cases of first-time supratentorial tumor re-
history of seizures who are undergoing brain tumor resec- section were performed during this period. The current
tion. Apparently, a sizable minority of our colleagues has literature suggests an enrollment rate slightly above 50%
already done so.8 among eligible cancer patients approached for RCTs.17
Therefore, it is estimated that at our center, approximately
Limitations of Current Evidence 50 patients a year could be accrued to a possible AED
Current evidence has sizable limitations. Particularly RCT. This is clearly too few to expect a well-powered
striking is the lack of any trial evaluating levetiracetam. study conducted in a timely manner; therefore, such a trial
The reviewed trials investigated gabapentin, phenytoin, would undoubtedly require multiple centers. To estimate
and phenobarbital. Levetiracetam is, by far, the AED most the number needed, a guide is given but we assumed a
commonly used by tumor neurosurgeons, and its side- 4-year accrual of 50 patients per site per year. These values
effect profile compares favorably to that for older AEDs. should only be used as a guide as they do not incorporate
In addition, the reviewed studies did not consistently re- any intersite variation. It is possible that including sites
port tumor location and pathology, despite a strong belief with larger patient volumes could significantly reduce the
among tumor surgeons about the varying degrees of epi- number of sites required for such a study.
leptogenicity based on pathology. Nor was seizure timing We propose that such a trial would compare levetirace-
or optimal length of prophylaxis consistently specified. tam to placebo, with accrual occurring over a 4-year pe-
These are major limitations within the existing RCTs that riod. Levetiracetam would be chosen since its use reflects
have investigated perioperative seizure prophylaxis for current practice; it is associated with similar efficacy and
brain tumor resection. fewer adverse effects compared to other anticonvulsants.
Outcome measures would include seizure incidence at 7
Future Directions and 30 days postoperatively. Prophylaxis would be admin-
There is widespread consensus that an RCT is needed istered at the time of surgery and continued for 7 days

Neurosurg Focus  Volume 43 • November 2017 5

V. Chandra et al.

postoperatively in accordance with the most commonly OR Seizures OR Epilepsy OR Anticonvulsants OR Barbiturates
reported practice. Seizures would be assessed through pa- Propofol OR Hydantoins OR Carbamazepine OR brivaracetam
tient, family, and practitioner reporting. All participants OR clobazam OR Clonazepam OR Diazepam OR Valproic Acid
OR eslicarbazepine acetate OR Ethosuximide OR ezogabine OR
would be blinded to the patient treatment arm. Careful at- felbamate OR gabapentin OR etiracetam OR lamotrigine OR
tention would be paid to monitoring and recording other lacosamide OR Lorazepam OR oxcarbamazepine OR perampanel
adverse events in order to capture those related to AED OR Phenobarbital OR Phenytoin OR Pregabalin OR Primidone
administration. Costs of such a trial would be significant OR rufinamide OR tiagabine OR topiramate OR Vigabatrin OR
and would include the course of levetiracetam or placebo, zonisamide) AND (“prevention and control” [Subheading] OR
as well as the staff for handling data and conducting fol- “Tertiary Prevention”[Mesh] OR “Secondary Prevention”[Mesh]
low-up. However, the cost would compare favorably with OR “Primary Prevention”[Mesh] OR “Pre-Exposure
those for other RCTs since levetiracetam is now a generic Prophylaxis”[Mesh] OR “Post-Exposure Prophylaxis”[Mesh] OR
prevention OR control OR prophylactic OR prophylaxis)
drug, and the investigators could integrate existing clinical
protocols and information gathering to reduce costs.
Cochrane Central Register of Controlled Trials (CENTRAL)
(Neurosurgery OR neurosurgical procedures OR general sur-
Conclusions gery OR operative surgical procedures OR surgery or brain sur-
The question of whether to use perioperative seizure gery or craniectomy OR neurological surgery OR craniotomy OR
prophylaxis for patients undergoing brain tumor resec- operation OR operative OR procedure OR resection OR surgical or
surgical procedure) AND (Brain Neoplasms OR brain tumor OR
tion is unresolved. The use of AEDs postoperatively has brain neoplasm) AND (Seizures OR Epilepsy OR Anticonvulsants
become routine across major academic centers worldwide OR Barbiturates OR Propofol OR Hydantoins OR Carbamazepine
despite evidence indicating no significant reduction in the OR brivaracetam OR clobazam OR Clonazepam OR Diazepam
incidence of seizure among patients who receive prophy- OR Valproic Acid OR eslicarbazepine acetate OR Ethosuximide
lactic AEDs. Remarkably, the most commonly used AED, OR ezogabine OR felbamate OR gabapentin OR etiracetam OR
levetiracetam, has not been studied for this application in lamotrigine OR lacosamide OR Lorazepam OR oxcarbamazepine
an RCT. There are significant limitations in the available OR perampanel OR Phenobarbital OR Phenytoin OR Pregabalin
evidence, as outlined above. To determine with any confi- OR Primidone OR rufinamide OR tiagabine OR topiramate OR
Vigabatrin OR zonisamide) AND (Prevention or control or pro-
dence and statistical significance that there is noninferior- phylaxis or prophylactic)
ity in the seizure rate when giving or withholding AEDs, a
large multicenter RCT should be performed.
CINAHL/Academic Search Complete
(Neurosurgery OR neurosurgical procedures OR general sur-
Appendix gery OR operative surgical procedures OR surgery or brain sur-
PubMed/MEDLINE Search Strategy gery or craniectomy OR neurological surgery OR craniotomy OR
operation OR operative OR procedure OR resection OR surgical or
(“Neurosurgery”[Mesh] OR “Neurosurgical Procedures”[Mesh] surgical procedure) AND (Brain Neoplasms OR brain tumor OR
OR “General Surgery”[Mesh] OR “Surgical Procedures, brain neoplasm) AND (Seizures OR Epilepsy OR Anticonvulsants
Operative”[Mesh] OR “surgery” [Subheading] OR brain surgery OR Barbiturates OR Propofol OR Hydantoins OR Carbamazepine
OR craniectomy OR neurological surgery OR craniotomy OR OR brivaracetam OR clobazam OR Clonazepam OR Diazepam
neurosurgery OR operation OR operative OR operative surgi- OR Valproic Acid OR eslicarbazepine acetate OR Ethosuximide
cal procedure* OR procedure* OR resection OR surgery OR OR ezogabine OR felbamate OR gabapentin OR etiracetam OR
surgical OR surgical procedure* OR general surgery) AND lamotrigine OR lacosamide OR Lorazepam OR oxcarbamazepine
(“Brain Neoplasms”[Mesh] OR brain tumor OR brain neoplasm*) OR perampanel OR Phenobarbital OR Phenytoin OR Pregabalin
AND (“Seizures”[Mesh] OR “Epilepsy, Partial, Sensory”[Mesh] OR Primidone OR rufinamide OR tiagabine OR topiramate OR
OR “Epilepsy, Tonic-Clonic”[Mesh] OR “Epilepsy, Partial, Vigabatrin OR zonisamide) AND (Prevention or control or pro-
Motor”[Mesh] OR “Epilepsy, Generalized”[Mesh] OR “Epilepsy, phylaxis or prophylactic)
Post-Traumatic”[Mesh] OR “Epilepsies, Partial”[Mesh] OR
“Epilepsy, Absence”[Mesh] OR “Epilepsies, Myoclonic”[Mesh]
OR “Epilepsy”[Mesh] OR “Epilepsy, Complex Partial”[Mesh] OR Web of Science
“Anticonvulsants”[Mesh] OR “Anticonvulsants” [Pharmacological (Neurosurgery OR neurosurgical procedures OR general sur-
Action] OR “Barbiturates”[Mesh] OR “Propofol”[Mesh] OR gery OR operative surgical procedures OR surgery or brain surgery
“Hydantoins”[Mesh] OR “Carbamazepine”[Mesh] OR “brivarace- or craniectomy OR neurological surgery OR craniotomy OR opera-
tam” [Supplementary Concept] OR “clobazam” [Supplementary tion OR operative OR procedure OR resection OR surgical or sur-
Concept] OR “Clonazepam”[Mesh] OR “Diazepam”[Mesh] gical procedure) AND TOPIC: (Brain Neoplasms OR brain tumor
OR “Valproic Acid”[Mesh] OR “eslicarbazepine acetate” OR brain neoplasm) AND TOPIC: (Seizures OR Epilepsy OR
[Supplementary Concept] OR “Ethosuximide”[Mesh] OR “ezo- Anticonvulsants OR Barbiturates OR Propofol OR Hydantoins OR
gabine” [Supplementary Concept] OR “felbamate” [Supplementary Carbamazepine OR brivaracetam OR clobazam OR Clonazepam
Concept] OR “gabapentin” [Supplementary Concept] OR OR Diazepam OR Valproic Acid OR eslicarbazepine acetate OR
“etiracetam” [Supplementary Concept] OR “lamotrigine” Ethosuximide OR ezogabine OR felbamate OR gabapentin OR eti-
[Supplementary Concept] OR “lacosamide” [Supplementary racetam OR lamotrigine OR lacosamide OR Lorazepam OR oxcar-
Concept] OR “Lorazepam”[Mesh] OR “oxcarbamazepine” bamazepine OR perampanel OR Phenobarbital OR Phenytoin OR
[Supplementary Concept] OR “perampanel” [Supplementary Pregabalin OR Primidone OR rufinamide OR tiagabine OR topi-
Concept] OR “Phenobarbital”[Mesh] OR “Phenytoin”[Mesh] OR ramate OR Vigabatrin OR zonisamide) AND TOPIC: (Prevention
“Pregabalin”[Mesh] OR “Primidone”[Mesh] OR “rufinamide” or control or prophylaxis or prophylactic) AND TOPIC: (clinical
[Supplementary Concept] OR “tiagabine” [Supplementary trial OR comparative study OR multicenter study OR controlled
Concept] OR “topiramate” [Supplementary Concept] OR clinical trial OR pragmatic clinical trial OR randomized controlled
“Vigabatrin”[Mesh] OR “zonisamide” [Supplementary Concept] trial OR validation studies)

6 Neurosurg Focus  Volume 43 • November 2017

 Perioperative seizure prophylaxis during brain tumor resection

ScienceDirect 12. Kazerooni R, Bounthavong M: Cost-effectiveness analysis

(neurosurgery or neurosurgical procedure or operative or of intravenous levetiracetam versus intravenous phenytoin
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ticenter study OR controlled clinical trial OR pragmatic clinical for intracranial tumours in patients without epilepsy. J Clin
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human AND English 14. Kuijlen JM, Teernstra OP, Kessels AG, Herpers MJ, Beuls
EA: Effectiveness of antiepileptic prophylaxis used with
supratentorial craniotomies: a meta-analysis. Seizure 5:291–
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Neurosurg Focus  Volume 43 • November 2017 7

V. Chandra et al.

Sima. Drafting the article: Chandra, Rock, Opalak, Carr. Criti-

cally revising the article: Broaddus, Chandra, Opalak. Reviewed
submitted version of manuscript: Broaddus, Opalak, Sima, Vega.
Disclosures Approved the final version of the manuscript on behalf of all
The authors report no conflict of interest concerning the materi- authors: Broaddus. Statistical analysis: Rock. Administrative/tech-
als or methods used in this study or the findings specified in this nical/material support: Broaddus. Study supervision: Broaddus.
paper.
Correspondence
Author Contributions William C. Broaddus, Department of Neurosurgery, Virginia
Conception and design: Broaddus, Opalak, Stary. Acquisition Commonwealth University Health System, PO Box 980631, Rich-
of data: Rock, Carr. Analysis and interpretation of data: Rock, mond, VA 23219. email: william.broaddus@vcuhealth.org.

8 Neurosurg Focus  Volume 43 • November 2017