effectiveness of perioperative antiepileptic drug

LITERATURE REVIEWJ Neurosurg 130:1274–1282, 2019

ApproximAtely 75,000 primary brain tumors32 and 170,000 cerebral metastases22 are diagnosed each year in the US. Many types of intracranial tumors

predispose patients to seizures. By the time of diagnosis, 20%–40% of patients with brain tumors have already had seizures, and significantly more will develop them after diagnosis depending upon tumor location, pathology, and treatment.2–4,10,11,13,24,28,36,41 Neurosurgical biopsy or resec-tion can, at least transiently, further increase that risk.9

Prophylactic use of postoperative AEDs in seizure-naïve patients is controversial. Seizures in the immedi-ate postoperative period impede clinical assessment and can result in hypoxemia, cardiovascular instability, and transient increases in intracranial pressure.5,20,21,23,29 Long-term consequences of postoperative seizures may include chronic AED therapy, cognitive decline, and death. Even in the absence of overt complications, a single seizure may have a profoundly negative impact on quality of life, for

ABBREVIATIONS AAN = American Association of Neurology; AED = antiepileptic drug; AMSTAR = A Measurement Tool to Assess Systematic Reviews; CI = confidence interval; PRISMA = Preferred Reporting Items for Systematic Review and Meta-Analysis; RCT = randomized controlled trial; RR = risk ratio; SIGLE = System for Information on Gray Literature in Europe.SUBMITTED September 15, 2017. ACCEPTED October 30, 2017.INCLUDE WHEN CITING Published online April 27, 2018; DOI: 10.3171/2017.10.JNS172236.

Effectiveness of perioperative antiepileptic drug prophylaxis for early and late seizures following oncologic neurosurgery: a meta-analysisEvan F. Joiner, BA,1 Brett E. Youngerman, MD,1 Taylor S. Hudson, BA,1 Jingyan Yang, MHS,2 Mary R. Welch, MD,3,4 Guy M. McKhann II, MD,1,4 Alfred I. Neugut, MD, PhD,2,4,5 and Jeffrey N. Bruce, MD1,4

1Department of Neurological Surgery, 2Department of Epidemiology, Mailman School of Public Health, and 3Department of Neurology, Columbia University; 4Herbert Irving Comprehensive Cancer Center, and 5Department of Medicine, Columbia University College of Physicians and Surgeons, New York, New York

OBJECTIVE The purpose of this meta-analysis was to evaluate the impact of perioperative antiepileptic drug (AED) prophylaxis on short- and long-term seizure incidence among patients undergoing brain tumor surgery. It is the first meta-analysis to focus exclusively on perioperative AED prophylaxis among patients undergoing brain tumor surgery.METHODS The authors searched PubMed/MEDLINE, Embase, Cochrane Central Register of Controlled Trials, clinicaltrials.gov, and the System for Information on Gray Literature in Europe for records related to perioperative AED prophylaxis for patients with brain tumors. Risk of bias in the included studies was assessed using the Cochrane risk of bias tool. Incidence rates for early seizures (within the first postoperative week) and total seizures were estimated based on data from randomized controlled trials. A Mantel-Haenszel random-effects model was used to analyze pooled rela-tive risk (RR) of early seizures (within the first postoperative week) and total seizures associated with perioperative AED prophylaxis versus control.RESULTS Four RCTs involving 352 patients met the criteria of inclusion. The results demonstrated that perioperative AED prophylaxis for patients undergoing brain tumor surgery provides a statistically significant reduction in risk of early postoperative seizures compared with control (RR = 0.352, 95% confidence interval 0.130–0.949, p = 0.039). AED pro-phylaxis had no statistically significant effect on the total (combined short- and long-term) incidence of seizures.CONCLUSIONS This meta-analysis demonstrates for the first time that perioperative AED prophylaxis for brain tumor surgery provides a statistically significant reduction in early postoperative seizure risk.https://thejns.org/doi/abs/10.3171/2017.10.JNS172236KEYWORDS brain tumor; seizure prophylaxis; antiepileptic drugs; perioperative seizures; glioblastoma; meningioma; oncology

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example, by precluding a patient’s ability to drive and thus limiting independence.1,7–9,11,16,19,34,40 Conversely, prophy-lactic AEDs can cause serious adverse effects, interfere with the metabolisms of chemotherapies and corticoste-roids,11,34 and, if ineffective, are a wasted expenditure. Guidelines remain unclear. The American Association of Neurology (AAN) recommends against routine prophy-laxis for newly diagnosed tumors in seizure-naïve patients but leaves prophylaxis in the first postoperative week up to surgeon discretion. The AANS recommends against rou-tine prophylaxis in the case of cerebral metastases but is notably silent on prophylaxis for other tumors.11,25,30,31 Sur-vey data suggest that between 63% and 81% of US neuro-surgeons prescribe AEDs postoperatively to seizure-naïve patients with brain tumors.6,12,37

Multiple trials and meta-analyses have evaluated AED prophylaxis for patients with brain tumors and found no benefit of prophylaxis over control in the prevention of seizures.11,18,33,38,39 However, these studies have typically failed to address the efficacy of perioperative AED pro-phylaxis due to the inclusion of both surgical and nonsur-gical patients. Furthermore, most of these meta-analyses have combined data from widely different periods of treat-ment and follow up (from 3 days to 12 months), making it difficult to assess the true efficacy of common clinical practices.

The objective of this meta-analysis was to evaluate the impact of perioperative AED prophylaxis on short- and long-term seizure incidence among patients undergoing brain tumor surgery. It is the first meta-analysis to focus exclusively on AED prophylaxis among patients undergo-ing brain tumor surgery.

MethodsStudy Design

In accordance with PRISMA (Preferred Reporting Items for Systematic Review and Meta-Analysis) and AMSTAR (A Measurement Tool to Assess Systematic Reviews) guidelines, a protocol for this meta-analysis was developed and submitted to the PROSPERO international prospective registry of systematic reviews prior to imple-mentation of the literature review.17,27,35 The defined goal of the meta-analysis was to pool data from randomized controlled trials (RCTs) to evaluate the efficacy of AED prophylaxis in the prevention of seizures among seizure-naïve brain tumor patients undergoing craniotomy. Prior meta-analyses pooled short- and long-term seizure out-comes.38,39 To address this methodological issue, the decision was made in the present study to pool data on short-term seizure incidence (within the first postoperative week) and long-term (total) seizure incidence separately.

Search StrategyA systematic literature search of PubMed/MEDLINE,

Embase, and Cochrane Central Register of Controlled Trials was conducted using the following terms: “brain tumor,” “brain tumour,” “craniotomy,” “craniotomies,” “neurosurgery,” “neurosurgeries,” “cerebral tumor,” “cere-bral tumour,” “brain neoplasm,” “brain cancer,” “glioma,” “glioblastoma,” “GBM,” “cerebral metastasis,” “cerebral

metastases,” “meningioma,” “prophylactic,” “antiepilep-tic,” “anticonvulsant,” “prophylaxis,” “AED,” “phenytoin,” “phenobarbital,” “divalproex,” “valproic acid,” “carba-mazepine,” “levetiracetam,” “etiracetam,” “gabapentin,” “lamotrigine,” and “topiramate.” Terms were combined using appropriate Boolean operators. No limitations in language, publication type, or publication period were ap-plied. Gray literature (print and electronic works not pub-lished by commercial publishers, including but not limited to doctoral dissertations, research reports, and conference proceedings) was further queried by performing similar searches in clinicaltrials.gov and the System for Informa-tion on Gray Literature in Europe (SIGLE).

Selection CriteriaFollowing elimination of duplicates, records were

screened using titles and abstracts to identify publications that potentially addressed the subject of AED prophylaxis for patients with brain tumors undergoing craniotomy. Successfully screened studies were subsequently evalu-ated on the basis of prespecified inclusion and exclusion criteria. Only RCTs (with a control group consisting of either a placebo or no treatment arm) were included. At least a portion of patients had to have undergone cranioto-my, at least a portion had to have been seizure-naïve prior to surgery (no preoperative seizure history), and seizure incidence had to be an outcome. Studies were excluded if craniotomy patient data were not extractable (in stud-ies with patients who underwent craniotomy and patients who did not undergo craniotomy), if tumor patient data were not extractable (in studies with patients undergoing craniotomy for a wide range of indications), or if seizure-naïve patient data were not extractable (in studies with a combination of seizure-naïve and nonseizure-naïve pa-tients). Two reviewers (E.F.J. and T.S.H.) independently performed literature searches and decided which records were eligible for inclusion. A third reviewer (B.E.Y.) medi-ated any disagreements.

Data ExtractionTwo reviewers (E.F.J. and T.S.H.) independently ex-

tracted previously specified study data (study setting, pa-tient population demographics, participant demographics and characteristics, dose/frequency and duration of AED prophylaxis, conditions of control arm, duration of follow up, seizure incidence within the first postoperative week, seizure incidence following first postoperative week, inci-dence of adverse effects) and evaluated the quality of each study using the Cochrane Collaboration’s tool for assess-ing risk of bias in randomized trials.14

Statistical AnalysisRelative risk (risk ratios, RR) for early seizures and to-

tal seizures associated with AED prophylaxis compared with control were calculated with 95% confidence inter-vals (CIs) for each included RCT. Data from included tri-als were combined using the Mantel-Haenszel random-effects model to assess the pooled relative risk of seizures within the first postoperative week (short-term) and over-all (short- and long-term). For each outcome, 95% CIs and


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2-sided p values were calculated. A prespecified p value < 0.05 was considered statistically significant. Heterogene-ity was evaluated using the I2 statistic. An I2 value > 40% was prespecified to be indicative of substantial heteroge-neity. Publication bias was evaluated using funnel plots and Egger’s test. All analyses were conducted using Stata (version 14.0 SE). Forest plots and funnel plots were refor-matted using Cochrane Review Manager.

ResultsSearch Results

Four thousand eight hundred thirty-three nondupli-cate records were identified by an electronic search of PubMed/MEDLINE, Embase, Cochrane Central Regis-ter of Controlled Trials, SIGLE, and clinicaltrials.gov, as well as a manual reference search (Fig. 1). Four thousand five hundred eighty-six records were excluded on the ba-sis of title and abstract because they were not relevant to the subject of AED prophylaxis for brain tumor surgery (see Appendix A for a full list of negatively screened re-cords). The 247 remaining full-text articles were reviewed according to inclusion/exclusion criteria. Two hundred

twenty-four records were excluded because they were not RCTs, 7 because they reported preliminary data that were subsequently published in another included study, 1 be-cause data on patients with brain tumors could not be ex-tracted, 1 because data on seizure-naïve patients could not be extracted, 2 because data on patients who underwent craniotomy could not be extracted, and 8 because full-text articles were not available (an attempt was made to contact each corresponding author; see Appendix B for the full list of excluded articles and rationale for exclusion). Four studies ultimately met criteria for qualitative and quantita-tive synthesis (Table 1).10,23,29,40

Description of Included StudiesTwo studies (North et al. and Lee et al.) included pa-

tients undergoing supratentorial craniotomy for a range of indications from which the data on patients with brain tumors could be extracted. One study (Franceschetti et al.) included patients with and without prior seizures, but data on seizure-naïve patients were readily extractable because these patients had been randomized separately. The final study (Wu et al.) included only seizure-naïve patients with brain tumors.

FIG. 1. Flow diagram of our systematic literature search (adapted from PRISMA).27 Figure is available in color online only.


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E. F. Joiner et al.

Two of the studies (Lee et al. and Franceschetti et al.) included patients with gliomas, meningiomas, and metas-tases, while one study (North et al.) also included patients with sellar tumors, and the last (Wu et al.) included only patients with gliomas and metastases. Two of the studies (North et al. and Lee et al.) were placebo controlled, while the control group in the other two (Franceschetti et al. and Wu et al.) received no treatment. The AED arm in three of the studies (North et al., Lee et al., and Wu et al.) re-ceived comparable doses of phenytoin; in the fourth study (Franceschetti et al.), a portion of the AED arm received phenytoin, and a portion received phenobarbital. The du-ration of treatment and follow up varied considerably: 1) 3 days of prophylaxis and 3 days follow up (Lee et al.); 2) 7 days of prophylaxis plus AED taper and 12 months of follow up (Wu et al.); 3) 12 months of prophylaxis and 12 months of follow up (North et al.); and 4) variable duration of prophylaxis and follow up from approximately 6 to 18 months (Franceschetti et al.). Patient characteristics were roughly equivalent across studies and between both arms of each study (detailed patient characteristics of both arms were available for all studies except Franceschetti et al.; Table 2).

Assessment of Study QualityStudy quality was assessed using the Cochrane Col-

laboration’s tool for assessing risk of bias (Fig. 2).14

In the allocation category (randomization and alloca-tion concealment), all four studies were at unclear risk of bias because methods of randomization and allocation concealment were not reported in detail.

For blinding, two studies (North et al. and Lee et al.) were at low risk of bias because satisfactory methods of blinding were reported. One study (Wu et al.) was at high risk of performance bias because participants and person-nel were unblinded but at low risk of detection bias be-cause seizure assessors were blinded. One study (France-schetti et al.) was at unclear risk of bias because methods of blinding were not reported in detail.

Regarding incomplete outcome data, two studies (North et al. and Wu et al.) were at low risk of bias because of no missing data. Two studies (Lee et al. and Franceschetti et al.) were at unclear risk of bias because they provided lim-ited information on the analysis of 26 excluded patients who died during randomization and 24 patients lost to fol-low up, respectively.

In the selective reporting category, all four studies were at unclear risk of bias because no study protocol was avail-able for comparison.

Finally, regarding other potential sources of bias, three studies were at low risk of bias (North et al., Lee et al., and Franceschetti et al.), whereas one study (Wu et al.) was at unclear risk of bias because of early termination after futility analysis showing no effect.

TABLE 1. Summary of 4 studies that met inclusion criteria

Authors & Year Comparison, Tx Duration, & FU Total No. of Patients

No. Undergoing Op For Tumor w/o

Prior Seizures Study Setting

Method of Seizure

Determination

North et al., 1983

Randomized to phenytoin (250 mg IV b.i.d. started in recovery room, then 100 mg p.o. t.i.d.) vs identical placebo; Tx & FU 12 mos

281 seizure-naïve patients undergoing supraten-torial op for trauma, aneurysm, tumor, or VA shunt

81 patients w/ glioma, meningioma, metastasis, or sellar tumor

1 tertiary care hospital

Not specified

Lee et al., 1989

Randomized to phenytoin (15 mg/kg IV started 15–20 min before wound closure, then 5–6 mg/kg/day IV) vs identical normal saline placebo; FU 3 days; Tx & FU 3 days

374 seizure-naïve patients undergoing intracranial, supratentorial op for trauma, aneurysm, hemorrhage, tumor, etc.

85 patients w/ glioma, me-ningioma, or metastasis


Not specified

Franceschetti et al., 1990

Randomized to phenytoin (10 mg/kg p.o. q.d. for 5 days, then 5 mg/kg q.d. p.o. thereafter) or phe-nobarbital (4 mg/kg q.d. p.o. for 5 days, then 2 mg/kg q.d. p.o. thereafter) vs no Tx; AEDs were started perioperatively, & plasma levels were monitored prior to op; prophylaxis duration & FU period were variable (up to >1 yr)

128 patients (w/ & w/o history of prior seizures) undergoing craniotomy for supratentorial tumor resection

63 patients w/ meningiomas, malignant glial tumors, or metastases

1 tertiary care neurological institute

Not specified

Wu et al., 2013

Randomized to phenytoin (15 mg/kg IV in OR, then 100 mg IV or p.o. t.i.d. for 7 days postopera-tively for goal phenytoin level 10–20 mg/L, then taper starting postop day 8 w/ 100-mg dosage decrease every 2 days until discontinuation) vs no Tx; Tx 7 days followed by taper, FU 12 mos

123 seizure-naïve patients undergoing craniotomy for glioma or metastasis

123 patients w/ glioma or metastasis


Clinical or EEG diagnosis by independent, blinded neurologist

b.i.d. = twice a day; EEG = electroencephalography; FU = follow-up; IV = intravenous; OR = operating room; p.o. = orally; q.d. = every day; t.i.d. = three times a day; Tx = treatment; VA = ventriculoatrial.


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Effectiveness of AED Prophylaxis in the Prevention of Early Postoperative Seizures

Two hundred seventy-one patients were evaluated for the outcome of early postoperative seizures, includ-ing 147 who received AED prophylaxis and 124 who did not (Fig. 3). In pooled meta-analysis, AED prophylaxis with phenytoin or phenobarbital provided a statistically significant reduction in risk of early seizure compared with control (Mantel-Haenszel random-effects model: RR 0.352, 95% CI 0.130–0.949, p = 0.039). There was minimal heterogeneity (I2 = 0%, p value for heterogene-ity = 0.782).

Effectiveness of AED Prophylaxis in Prevention of Early or Late (Total) Postoperative Seizures

Two hundred sixty-seven patients were evaluated for the outcome of early or late (total) postoperative seizures, 145 who received AED prophylaxis and 122 who did not (Fig. 4). In pooled meta-analysis, AED prophylaxis with phenytoin or phenobarbital showed no statistically signifi-cant benefit over control in the prevention of early and late

(total) postoperative seizures (Mantel-Haenszel random-effects model: RR 1.033, 95% CI 0.498–2.141, p = 0.931). There was moderate heterogeneity (I2 = 51.8%, p value for heterogeneity = 0.125).

Adverse Effects From AED ProphylaxisIt was not possible to pool adverse effects data (Table

3) because one study did not report them (Lee et al.), two studies reported them at markedly different time points (Franceschetti et al. at 1 week and Wu et al. at 1 month), and data from tumor patients could not be extracted from the fourth study (North et al.). The study of Wu et al. pro-vided the clearest account of adverse events, noting 20 ad-verse effects of phenytoin among 62 patients in the AED prophylaxis arm within 30 days of surgery. Adverse ef-fects included rash, dry skin, elevated liver function test values, thrombocytopenia, confusion, aphasia, altered consciousness, nausea, vomiting, and ataxia. There were 5 major adverse events (National Cancer Institute Common Toxicity Criteria grades 3, 4, or 5), including 2 gastroin-testinal and 3 neurological events. There were no adverse events in the control arm.

TABLE 2. Patient characteristics of 4 included studies

Authors & YearTotal

NSex Ratio

(M:F) Age (yrs)Seizure-Naïve Tumor Patients Glioma Metastasis Meningioma

Sellar Tumor

North et al., 1983 AED 140 1.37:1 Mean 46.7 ± 17.7 (SD) 42 16 6 10 10 Control 141 1.47:1 Mean 50.1 ± 17.5 (SD) 39 16 7 9 7Lee et al., 1989 AED 189 1.9:1 Mean 39.86 ± 2.92 (SE) 44 15 3 26 0 Control 185 2.1:1 Mean 37.49 ± 2.67 (SE) 41 15 2 24 1Franceschetti et al., 1990 AED 106 1.2:1

(entire study)Mean 55 ± 11 (SE) (entire

study)41 23

(entire study)13

(entire study)27

(entire study)0

Control 22 22Wu et al., 2013 AED 62 1.5:1 Median 56 (range 16–80) 62 23 39 0 0 Control 61 1.0:1.0 Median 61 (range 35–84) 61 23 38 0 0

SD = standard deviation; SE = standard error.

FIG. 2. Risk of bias assessment (adapted from the Cochrane Handbook for Systematic Reviews of Interventions).15 Figure is avail-able in color online only.



E. F. Joiner et al.

Assessment of Publication BiasStudies included in the early seizure analysis and stud-

ies included in the total seizure analysis were evaluated in separate funnel plots (Fig. 5). The absence of obvious asymmetry in either funnel plot suggests an absence of publication bias. For early seizure data, Egger’s test re-vealed a coefficient for bias of -1.540, a standard error of 0.227, and p value of 0.093, suggesting little evidence of small-study effects. For total seizure data, Egger’s test revealed a coefficient for bias of -3.678, a standard error of 6.136, and a p value of 0.656, again suggesting little evidence of small-study effects. However, it should be not-ed that funnel plots and Egger’s test have limited power to detect publication bias when fewer than 10 studies are evaluated.15

DiscussionOur meta-analysis demonstrates that AED prophylaxis

provides a statistically and clinically significant reduc-tion in early seizures (within the first week) following brain tumor surgery in seizure-naïve patients. It is the first meta-analysis to evaluate exclusively perioperative AED prophylaxis for brain tumors and the first meta-analysis to demonstrate a statistically significant benefit of AED pro-phylaxis in patients with brain tumors. Our meta-analysis showed no statistically significant effect of AED prophy-laxis on total (combined short- and long-term) incidence of seizures.

Prior meta-analyses have sought to evaluate the effi-cacy of AED prophylaxis for patients with brain tumors by pooling operative and nonoperative patients. In this manner, Glantz et al. 200011 and Perry et al. 200633 con-

cluded that AED prophylaxis had no effect on incidence of seizures among patients with brain tumors. Additional meta-analyses have pooled RCTs that reported exclusively short- or long-term postoperative seizure incidence. Sirven et al. 200438 and Tremont-Lukats et al. 2008,39 a Cochrane Review, thus combined short- and long-term outcome data from surgical and nonsurgical patients to conclude that AED prophylaxis provided no benefit.

Separate evaluation of the effect of AED prophylaxis on short-term seizure rates has important implications for current postoperative management. First, according to neurosurgeon survey data, a week of postoperative AED prophylaxis is the most common duration of prophylaxis prescribed.6 Second, for seizure-naïve patients with brain tumors, AAN guidelines recommend tapering and dis-continuing perioperative AED prophylaxis after the first week.11 Thus, it is reasonable to evaluate whether this com-mon practice, supported by AAN guidelines, is effective. Third, the highest risk of postoperative seizures occurs within the first the week of surgery.9,10,29,40 Early postoper-ative seizure reduction should therefore be a priority, but there was previously no clear evidence that AEDs mitigate the risk.

Our study suggests that postoperative AED prophylax-is has benefit for short-term seizure outcomes but not for long-term outcomes. There are several potential mecha-nisms to explain the different effect of AED prophylaxis on short- and long-term seizure rates. First, AED prophy-laxis may be effective in reducing seizure incidence in the immediate perioperative period when seizure risk is acutely elevated due to surgical manipulation. The effect of AED prophylaxis may subside as this acutely elevated

FIG. 3. Forest plot for pooled meta-analysis of effect of AED prophylaxis on incidence of early seizures (Mantel-Haenszel [M-H] random-effects model). Point estimates of relative risks are indicated with boxes, the areas of which are proportional to the weight afforded each study. Ninety-five percent CIs are indicated by horizontal lines and a diamond. Figure is available in color online only.

FIG. 4. Forest plot for pooled meta-analysis of effect of AED prophylaxis on incidence of early and late (total) seizures (Mantel-Haenszel random-effects model). Point estimates of relative risks are indicated with boxes, the areas of which are proportional to the weight afforded each study. Ninety-five percent CIs are indicated by horizontal lines and a diamond. Figure is available in color online only.


E. F. Joiner et al.


risk passes. Second, long-term postoperative seizures are more likely to be associated with radiographic evidence of tumor progression.10,40 Given that seizures related to tu-mor progression are not effectively prevented by AEDs,11 it is thus possible that tumor growth gradually dilutes any difference in seizure incidence between AED prophylaxis arms and control arms over time. Furthermore, the results of the long-term analysis do not support the so-called “kin-dling hypothesis,” the notion that prevention of early sei-zures can reduce the formation of a scarred epileptogenic focus and thus reduce the risk of later seizures. Indeed, the lack of long-term benefit of AED prophylaxis seen in our meta-analysis argues against this hypothesis.29,34

There are several limitations to this study. First, be-cause there are relatively few RCTs of AED prophylaxis with extractable data from brain tumor patients undergo-ing craniotomy, the sample sizes for our pooled analyses are somewhat small. In particular, sample sizes were not large enough to stratify seizure risk or AED benefit by type of tumor, which may be an important variable. Sec-ond, although the interventions in the selected short-term analysis were fairly comparable, there was greater varia-tion in interventions included in the analysis of long-term outcomes. Among the studies that reported long-term fol-low up, Wu et al. provided 7 days of AED prophylaxis plus a taper, while North et al. provided 12 months of pro-phylaxis; in the study of Franceschetti et al., prophylaxis

duration ranged from approximately 6–18 months. Given the differences between these interventions, our conclu-sions about the long-term effect of AED prophylaxis are more limited. At most, these data suggest that prevention of early postoperative seizures with AED prophylaxis does not appear to affect the incidence of late postopera-tive seizures. A third limitation of this meta-analysis was our inability to pool adverse effects data from the included studies. The lack of adverse effects data makes it difficult to assess the extent to which the observed benefit from AED prophylaxis outweighs the associated risk of side effects. Furthermore, because the included studies used older AEDs (phenytoin and phenobarbital) for prophylaxis instead of newer AEDs such as levetiracetam (which are known to be more tolerable), a risk-benefit analysis from the included studies would have been largely obsolete even if pooling of adverse effects had been possible.26 Finally, the studies included in this meta-analysis are at uncertain risk of bias because of certain limitations in the details published about each study design. Particularly because such norms of design reporting have evolved over time, the results of these older studies should not be discarded be-cause of this uncertainty. However, the uncertain quality of these studies nonetheless must be factored into the con-fidence with which the conclusions of this meta-analysis are made.

FIG. 5. Funnel plots for early seizure incidence (left) and total seizure incidence (right). Each dashed vertical line indicates the point estimate of pooled relative risk. Ninety-five percent of studies would be expected to fall within the diagonal dashed lines in the absence of heterogeneity or biases. Figure is available in color online only.

TABLE 3. Incidence of adverse effects in 4 included studies

Authors & YearIncidence of Adverse Effects

AED Control Arm

North et al., 1983 Tumor patient data not extractableLee et al., 1989 Not reportedFranceschetti et al., 1990 4/41 “adverse effects” in first wk 0/22 in first 1 wkWu et al., 2013 5 major (grade 3, 4, or 5) & 15 minor (grade 1 or 2) adverse

events among 62 patients w/in 30 days of op*0 adverse events among 61 patients w/in 30 days of op

* According to the National Cancer Institute Common Toxicity Criteria: 1) mild, 2) moderate, 3) severe, 4) life-threatening, and 5) death.



E. F. Joiner et al.

ConclusionsThis meta-analysis demonstrates for the first time that

perioperative AED prophylaxis for brain tumor surgery provides a statistically significant reduction in early post-operative seizure risk within the first week. While this analysis supports the use of AED prophylaxis for the first postoperative week, we are unable to make any conclu-sions about the maximally effective duration of AED pro-phylaxis. A well-powered RCT may help to determine the ideal duration of prophylaxis and to evaluate the benefit-to-risk profile of newer AEDs. However, given the contem-porary practice of AED prophylaxis as well as the findings of this meta-analysis, the question of equipoise deserves careful consideration.

AcknowledgmentsWe would like to thank Jimmy Duong, MPH, and Walter Pal-

mas, MD, MS, for additional statistical consultation, and Vivien Wong, PhD, for translation of a study published in Chinese.

References 1. Beenen LF, Lindeboom J, Kasteleijn-Nolst Trenité DG, Hei-

mans JJ, Snoek FJ, Touw DJ, et al: Comparative double blind clinical trial of phenytoin and sodium valproate as anticon-vulsant prophylaxis after craniotomy: efficacy, tolerability, and cognitive effects. J Neurol Neurosurg Psychiatry 67:474–480, 1999

2. Boarini DJ, Beck DW, VanGilder JC: Postoperative prophy-lactic anticonvulsant therapy in cerebral gliomas. Neurosur-gery 16:290–292, 1985

3. Byrne TN, Cascino TL, Posner JB: Brain metastasis from melanoma. J Neurooncol 1:313–317, 1983

4. Cohen N, Strauss G, Lew R, Silver D, Recht L: Should pro-phylactic anticonvulsants be administered to patients with newly-diagnosed cerebral metastases? A retrospective analy-sis. J Clin Oncol 6:1621–1624, 1988

5. De Santis A, Villani R, Sinisi M, Stocchetti N, Perucca E: Add-on phenytoin fails to prevent early seizures after surgery for supratentorial brain tumors: a randomized controlled study. Epilepsia 43:175–182, 2002

6. Dewan MC, Thompson RC, Kalkanis SN, Barker FG II, Had-jipanayis CG: Prophylactic antiepileptic drug administration following brain tumor resection: results of a recent AANS/CNS Section on Tumors survey. J Neurosurg 126:1772–1778, 2017

7. Drazkowski J: An overview of epilepsy and driving. Epilep-sia 48 (Suppl 9):10–12, 2007

8. Forsyth PA, Weaver S, Fulton D, Brasher PM, Sutherland G, Stewart D, et al: Prophylactic anticonvulsants in patients with brain tumour. Can J Neurol Sci 30:106–112, 2003

9. Foy PM, Copeland GP, Shaw MD: The incidence of postop-erative seizures. Acta Neurochir (Wien) 55:253–264, 1981

10. Franceschetti S, Binelli S, Casazza M, Lodrini S, Panzica F, Pluchino F, et al: Influence of surgery and antiepileptic drugs on seizures symptomatic of cerebral tumours. Acta Neuro-chir (Wien) 103:47–51, 1990

11. Glantz MJ, Cole BF, Forsyth PA, Recht LD, Wen PY, Cham-berlain MC, et al: Practice parameter: anticonvulsant prophy-laxis in patients with newly diagnosed brain tumors. Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 54:1886–1893, 2000

12. Glantz MJ, Cole BF, Friedberg MH, Lathi E, Choy H, Furie K, et al: A randomized, blinded, placebo-controlled trial of divalproex sodium prophylaxis in adults with newly diag-nosed brain tumors. Neurology 46:985–991, 1996

13. Hagen NA, Cirrincione C, Thaler HT, DeAngelis LM: The role of radiation therapy following resection of single brain metastasis from melanoma. Neurology 40:158–160, 1990

14. Higgins JPT, Altman DG, Gøtzsche PC, Jüni P, Moher D, Oxman AD, et al: The Cochrane Collaboration’s tool for as-sessing risk of bias in randomised trials. BMJ 343:d5928, 2011

15. Higgins JPT, Green S (eds): Cochrane Handbook for Systematic Reviews of Interventions, Version 5.1.0. Lon-don: The Cochrane Collaboration, 2011 (http://handbook.cochrane.org) [Accessed January 5, 2018]

16. Jacoby A, Gamble C, Doughty J, Marson A, Chadwick D: Quality of life outcomes of immediate or delayed treatment of early epilepsy and single seizures. Neurology 68:1188–1196, 2007

17. Klimo P Jr, Thompson CJ, Ragel BT, Boop FA: Methodology and reporting of meta-analyses in the neurosurgical litera-ture. J Neurosurg 120:796–810, 2014

18. Kong X, Guan J, Yang Y, Li Y, Ma W, Wang R: A meta-analysis: do prophylactic antiepileptic drugs in patients with brain tumors decrease the incidence of seizures? Clin Neurol Neurosurg 134:98–103, 2015

19. Krumholz A: Driving issues in epilepsy: past, present, and future. Epilepsy Curr 9:31–35, 2009

20. Kuijlen JM, Teernstra OP, Kessels AG, Herpers MJ, Beuls EA: Effectiveness of antiepileptic prophylaxis used with supratentorial craniotomies: a meta-analysis. Seizure 5:291–298, 1996

21. Kvam DA, Loftus CM, Copeland B, Quest DO: Seizures during the immediate postoperative period. Neurosurgery 12:14–17, 1983

22. Langer CJ, Mehta MP: Current management of brain me-tastases, with a focus on systemic options. J Clin Oncol 23:6207–6219, 2005

23. Lee ST, Lui TN, Chang CN, Cheng WC, Wang DJ, Heim-burger RF, et al: Prophylactic anticonvulsants for prevention of immediate and early postcraniotomy seizures. Surg Neu-rol 31:361–364, 1989

24. Mahaley MS Jr, Dudka L: The role of anticonvulsant medica-tions in the management of patients with anaplastic gliomas. Surg Neurol 16:399–401, 1981

25. Mikkelsen T, Paleologos NA, Robinson PD, Ammirati M, Andrews DW, Asher AL, et al: The role of prophylactic anticonvulsants in the management of brain metastases: a systematic review and evidence-based clinical practice guide-line. J Neurooncol 96:97–102, 2010

26. Milligan TA, Hurwitz S, Bromfield EB: Efficacy and toler-ability of levetiracetam versus phenytoin after supratentorial neurosurgery. Neurology 71:665–669, 2008

27. Moher D, Shamseer L, Clarke M, Ghersi D, Liberati A, Petti-crew M, et al: Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement. Syst Rev 4:1, 2015

28. Moots PL, Maciunas RJ, Eisert DR, Parker RA, Laporte K, Abou-Khalil B: The course of seizure disorders in patients with malignant gliomas. Arch Neurol 52:717–724, 1995

29. North JB, Penhall RK, Hanieh A, Frewin DB, Taylor WB: Phenytoin and postoperative epilepsy. A double-blind study. J Neurosurg 58:672–677, 1983

30. Olson JJ, Kalkanis SN, Ryken TC: Evidence-based clinical practice parameter guidelines for the treatment of adults with diffuse low grade glioma: introduction and methods. J Neu-rooncol 125:449–456, 2015

31. Olson JJ, Ryken T: Guidelines for the treatment of newly diagnosed glioblastoma: introduction. J Neurooncol 89:255–258, 2008

32. Ostrom QT, Gittleman H, Xu J, Kromer C, Wolinsky Y, Kruchko C, et al: CBTRUS Statistical Report: Primary Brain and Other Central Nervous System Tumors Diagnosed in the


E. F. Joiner et al.


United States in 2009–2013. Neuro Oncol 18 (Suppl 5):v1–v75, 2016

33. Perry J, Zinman L, Chambers A, Spithoff K, Lloyd N, La-perriere N: The use of prophylactic anticonvulsants in pa-tients with brain tumours-a systematic review. Curr Oncol 13:222–229, 2006

34. Sayegh ET, Fakurnejad S, Oh T, Bloch O, Parsa AT: Anticon-vulsant prophylaxis for brain tumor surgery: determining the current best available evidence. J Neurosurg 121:1139–1147, 2014

35. Shea BJ, Grimshaw JM, Wells GA, Boers M, Andersson N, Hamel C, et al: Development of AMSTAR: a measurement tool to assess the methodological quality of systematic re-views. BMC Med Res Methodol 7:10, 2007

36. Simionescu MD: Metastatic tumors of the brain: a follow-up study of 195 patients with neurosurgical considerations. J Neurosurg 17:361–373, 1960

37. Siomin V, Angelov L, Li L, Vogelbaum MA: Results of a survey of neurosurgical practice patterns regarding the pro-phylactic use of anti-epilepsy drugs in patients with brain tumors. J Neurooncol 74:211–215, 2005

38. Sirven JI, Wingerchuk DM, Drazkowski JF, Lyons MK, Zim-merman RS: Seizure prophylaxis in patients with brain tu-mors: a meta-analysis. Mayo Clin Proc 79:1489–1494, 2004

39. Tremont-Lukats IW, Ratilal BO, Armstrong T, Gilbert MR: Antiepileptic drugs for preventing seizures in people with brain tumors. Cochrane Database Syst Rev (2):CD004424, 2008

40. Wu AS, Trinh VT, Suki D, Graham S, Forman A, Weinberg JS, et al: A prospective randomized trial of perioperative seizure prophylaxis in patients with intraparenchymal brain tumors. J Neurosurg 118:873–883, 2013

41. Zimm S, Wampler GL, Stablein D, Hazra T, Young HF: In-

tracerebral metastases in solid-tumor patients: natural history and results of treatment. Cancer 48:384–394, 1981

DisclosuresThe authors report no conflict of interest concerning the materi-als or methods used in this study or the findings specified in this paper.

Author ContributionsConception and design: Bruce, Joiner, Youngerman. Acquisition of data: Joiner, Hudson. Analysis and interpretation of data: Join-er, Youngerman. Drafting the article: Joiner. Critically revising the article: Bruce, Joiner, Youngerman. Reviewed submitted ver-sion of manuscript: Bruce, Joiner, Youngerman, Hudson, Welch, McKhann, Neugut. Approved the final version of the manuscript on behalf of all authors: Bruce. Statistical analysis: Joiner, Yang. Administrative/technical/material support: Joiner, Hudson. Study supervision: Bruce, Joiner, Youngerman.

Supplemental InformationOnline-Only ContentSupplemental material is available with the online version of the article.

Appendices A and B. https://thejns.org/doi/suppl/10.3171/2017. 10.JNS172236.

CorrespondenceJeffrey Bruce: The Neurological Institute of New York, New York, NY. [email protected].




effectiveness of perioperative antiepileptic drug

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