A systematic review of perioperative seizure prophylaxis during brain tumor resection: the case for a multicenter randomized clinical trial

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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. Consequently, the authors conducted a systematic review of prospective randomized controlled trials (RCTs) that have evaluated 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 investigating 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 difference 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 multicenter randomized clinical trial would be required to assess whether perioperative seizure prophylaxis provides benefit for patients undergoing brain tumor resection.

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

Abstract

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. Consequently, the authors conducted a systematic review of prospective randomized controlled trials (RCTs) that have evaluated 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 investigating 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 difference 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 multicenter randomized clinical trial would be required to assess whether perioperative seizure prophylaxis provides benefit for patients undergoing brain tumor resection.

Seizures are debilitating and burdensome for the health care system. Patients with seizures have higher medical expenses, lower employment rates, and barriers to social participation.11 Seizures lead to longer hospital stays and increased health care costs. The risk of new-onset seizure for a patient with a brain tumor is reported to be 20%–90%.7,12,20 Postcraniotomy seizure rates for patients with no prior history of seizure range from 7% to 18%.4,5 Antiepileptic drugs (AEDs) have been used to decrease the rate of postoperative seizures. This practice was first studied in the 1980s, with investigators in a double-blind trial concluding that preoperative phenytoin administration decreased seizure rates by 50%;20 however, the study included craniotomies for a variety of pathologies, and there was no significant difference in seizure rates between the AED-treated and untreated supratentorial tumor resection groups.

A 2015 survey of surgeons revealed that more than 63% of them administer seizure prophylaxis after tumor resection in patients without a history of seizures.3 Eighty-five percent of the surgeons who practice prophylaxis reported that they use the antiepileptic levetiracetam. The duration of prophylaxis varied from 1 week to more than 6 weeks. This suggests that a significant minority of tumor surgeons do not endorse the perioperative use of AEDs in seizure-naïve patients. This survey also revealed that 82% of the respondents would guide their future practice in this area based on the results of a well-designed randomized controlled trial (RCT).

There is no Class I evidence to support the widespread practice of administering prophylactic AEDs in patients undergoing tumor resection. Further, pharmaceuticals are not benign. Levetiracetam can cause behavioral problems (anger, apathy, irritability, neurosis), headache, drowsiness, suicidal ideation, increased blood pressure, and gastrointestinal disturbances. Phenytoin has a larger set of side effects, such as atrial conduction depression, arrhythmias, cerebral atrophy, cerebral dysfunction, peripheral neuropathy, dermatological issues, and various immunological issues. The total direct cost of a 7-day seizure prophylaxis with intravenous levetiracetam is $8784.63 and with intravenous phenytoin $8743.78. The cost-effectiveness ratio per successful seizure prophylaxis regimen (SSPR) was shown to be $10,044.91 for intravenous levetiracetam, compared with $11,525.63 for intravenous phenytoin.12

Given that the perioperative administration of AEDs is one of the most common practices encountered in neurological intensive care patients, we conducted a systematic review of relevant studies of perioperative seizure prophylaxis in patients undergoing tumor resection. Additionally, we provide an outline of the trial that would be necessary to provide Class I evidence. This is both a knowledge update and a blueprint for moving forward.

Methods

Literature Search and Inclusion Criteria

This systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses for Protocols (PRISMA-P) guidelines.18 Five databases were searched between May 10 and May 13, 2017. The databases included PubMed/MEDLINE, Cochrane Central Register of Controlled Trials (CENTRAL), CINAHL/Academic Search Complete, Web of Science, and ScienceDirect. Searches used combinations of specific terms related to neurosurgery, brain neoplasm, anticonvulsants, and prophylaxis (details of search strategies are provided in the Appendix). Only original peer-reviewed randomized clinical trials in humans whose results were published in the English language were considered for inclusion. In addition, the references of previous systematic reviews, meta-analyses, and selected studies were evaluated for the inclusion of additional studies.

Data Extraction and Outcome Measures

One reviewer (A.K.R.) evaluated and selected articles by title, abstract, and full-text review for data abstraction. Abstracted data included first author, year, location, study design, sample size, sample characteristics, tumor type, AED type, control group, timing of intervention, duration of intervention, follow-up interval, outcome definition, seizure incidence, risk estimate, and conclusions. The risk of bias (low, high, uncertain) of included trials was assessed using the Cochrane Handbook for Systematic Reviews of Interventions10 and the following 6 domains: random sequence generation, allocation concealment, blinding, incomplete outcome data, selective reporting, and other bias. The weighted average seizure rate of untreated controls was calculated based on reported values from the included studies. Power analyses were conducted using the weighted average seizure rate to estimate the number of patients required to demonstrate noninferiority within an RCT. All power analyses were based on the Farrington-Manning noninferiority test performed at the 0.05 level using a noninferiority difference of 5%.

Results

Study Selection

A total of 496 unique articles were identified through the database searches and underwent title, abstract, and full-text review (Fig. 1). After screening by title, there were 84 articles that underwent abstract review. Sixty-eight articles were subsequently excluded, and 16 articles were considered eligible for full-text review. Following the full-text review, 13 articles were excluded. Reasons for exclusion comprised a lack of perioperative seizure outcomes,15,16 a heterogeneous sample of neurosurgery patients,9 non-English language,19,23 absent assessment of seizure prophylaxis for brain tumor resection,7,22,28 and study design other than RCT.13,14,21,24,25 One additional study was identified through a review of the reference lists. A total of 4 studies met inclusion criteria and were considered in this systematic review (Table 1). Of these trials, one compared prophylactic phenobarbital or phenytoin to no intervention,8 one compared prophylactic phenytoin to no intervention,27 one compared prophylactic gabapentin to phenytoin use,26 and one evaluated the addition of prophylactic phenytoin to current AED therapy.2

FIG. 1.
FIG. 1.

Flow diagram according to the PRISMA-P statement.

TABLE 1.

A comparison of RCTs assessing perioperative AED prophylaxis in patients undergoing brain tumor resection

ParameterFranceschetti et al., 1990De Santis et al., 2002Türe et al., 2009*Wu et al., 2013
LocationItalyItalyTurkeyUSA
Study designRCTOpen-label RCTRCTRCT
Sample size6320075123
Sample characteristics34 M, 29 F; mean age: 55 yrs103 M, 97 F; preop Szs: 67; preexisting AED therapy: 18536 M, 39 F67 M, 56 F
Tumor typeSupratentorial neoplasm location: frontal, 12; temporal, 18; central, 2; parietal, 16; occipital, 15; meningiomas: 27; malignant glial: 23; metastases: 13Supratentorial tumor location: frontal, 70; temporal, 47; parietal, 41; sellar, 17; occipital, 7; deep structures, 6; intraventricular, 6; tentorial, 6; glioma: 95; meningioma: 81; metastases: 10; other: 14Supratentorial tumor surgical route: frontal, 17; parietal, 6; temporal, 4; pterional, 48; meningioma: 32; glioma: 42; metastases: 1Intraparenchymal supratentorial tumor location: frontal, 48; temporal, 34; parietal, 17; occipital, 18; other, 6; metastases: 77; glioma: 46
AED typePB or PHTPHT plus current AED therapyGabapentinPHT
Control groupNo medicationCurrent AED therapyPHTNo medication
Timing of interventionNSIntraoperatively7 days before surgeryIntraoperatively
Duration of interventionNS7 days6–12 mos for meningiomas or indefinitely for glial tumorsTapered on POD 8
FU intervalMinimum of 6 mos7 days1 mo12 mos
Outcome definitionEarly (≤7 days) & late postop SzsEarly postop Szs (≤7 days)Sz activity at 0, 15, 30 mins, 1, 2, 4, 6, 12, 24, 48 hrs, & 1 mo postoperativelyEarly Sz (≤30 days) or clinically significant Sz w/ neurological deficits assessed daily for 3 days after surgery, on POD 8, & every 2–3 mos for up to 12 mos
Sz incidenceEarly Szs in 18% untreated & 7% PB- or PHT-treated; late Szs in 21% untreated & 12% PB- or PHT-treatedEarly Szs in 13% PHT-treated & 11% controls1 patient in PHT group had partial Sz on POD 3; all patients Sz free at 1-mo FUSzs in 18% controls & 24% prophylaxis group (p = 0.51); early Szs (≤30 days) in 8% controls & 10% prophylaxis group (p = 1.00); late Szs (>30 days) in 10% controls & 14% prophylaxis group (p = 1.00); clinically significant Szs in 2% controls & 3% prophylaxis group (p = 0.62)
Risk estimateNSNSNSOdds of early Sz in prophylaxis vs control was 1.4 (95% CI 0.425–4.763)
Statistical significanceNoNoNoNo
Authors support prophylactic AED useYesNo§NoNo

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.

Assessment of Risk of Bias for the Included Studies

Details from the assessment of risk of bias for included studies are presented in Fig. 2. Despite claims of being RCTs, only 1 study reported methodology in support of random sequence generation when allocating participants to AED and control groups. Although 2 of the studies blinded researchers for outcome assessment, none of the studies had allocation concealment or blinded participants and personnel to allocated interventions. One study had incomplete data for outcomes because the trial was terminated after interim futility analysis had demonstrated that the power would be too low to show superiority between the AED and control groups.

FIG. 2.
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.

Seizure Outcomes

Four clinical trials assessed perioperative AED prophylaxis for preventing seizures in patients undergoing resection of brain tumors (Table 1).2,8,26,27 All of the studies included heterogeneous samples of patients with supratentorial tumors within a variety of anatomical locations. Two trials compared AED prophylaxis to no intervention,8,27 while the other 2 trials compared the addition of phenytoin to current AED therapy2 and gabapentin to treatment with phenytoin, respectively.26 There was significant diversity across studies in the timing of the intervention, duration of intervention, follow-up interval, and outcome definition. One study did not specify the timing and duration of the intervention.8 Two studies initiated AED therapy intraoperatively and continued treatment for 7 days,2,27 while 1 study initiated AED therapy 7 days prior to surgery and continued treatment for 6–12 months for meningiomas or indefinitely for glial tumors.26 The follow-up interval across studies ranged from 7 days to 12 months. Early postoperative seizures were defined by a cutoff of ≤ 7 days in 2 studies2,8 and ≤ 30 days in another study.27 Additional outcomes included late seizures (> 7 days) and a history of any new seizure activity. Only 1 study had a neurologist blinded to patient treatment who evaluated and confirmed the diagnosis of seizures on clinical grounds or electroencephalography.27 Across all of the studies, there was no significant reduction in the incidence of seizures among those in the intervention groups compared with controls.

Franceschetti et al. randomly assigned 63 patients without preoperative seizures to receive phenobarbital (n = 25), phenytoin (n = 16), or no medication (n = 22).8 Early postoperative seizures (≤ 7 days) occurred in 4 (18%) of 22 untreated patients and 3 (7%) of the 41 patients treated with phenobarbital or phenytoin, whereas late postoperative seizures (> 7 days) occurred in 3 (21%) of 14 untreated patients and 3 (12%) of 25 patients treated with phenobarbital or phenytoin. Seizure incidence did not significantly differ between groups. De Santis et al. conducted a prospective open-label RCT to determine the potential effectiveness of phenytoin in addition to a patient’s current AED therapy in preventing early postoperative seizures in those undergoing craniotomy for supratentorial brain tumor.2 Patients randomly assigned to the phenytoin group were treated intraoperatively with a loading dose of 18 mg/kg followed by 7 days of treatment adjusted according to serum concentrations. Early postoperative seizures occurred in 13% of patients in the phenytoin group and 11% of patients in the control group. The incidence of early postoperative seizures did not differ between prophylaxis and control groups. Türe et al. evaluated the postoperative effectiveness of gabapentin on acute postoperative pain as compared with phenytoin for AED prophylaxis in patients undergoing craniotomy for supratentorial tumor resection.26 Seizure activity was assessed at 0, 15, and 30 minutes; 1, 2, 4, 6, 12, 24, and 48 hours; and 1 month postoperatively. Only 1 patient in the phenytoin group had a seizure on postoperative Day 3.

Wu et al. pursued a prospective RCT examining the perioperative use of prophylactic AEDs (phenytoin) in patients without a history of seizures. Their study was designed to accrue 142 patients using an estimated seizure incidence of 30% in the control group and 10% in the prophylaxis group. After 6 years, the study was closed after 123 patients had been enrolled and an independent interim futility analysis had demonstrated a low likelihood that either the observation or phenytoin prophylaxis group would be superior using the full sample size. At the time, early seizures were observed in only 8% of the control group, and the true power to detect a two-thirds reduction in postsurgical 30-day seizure incidence using 123 patients was 19%. The probability that there would be insufficient evidence at the end of the trial to show superiority was 0.997, and calculations using the lower-than-expected incidence of seizures of 8% demonstrated that over 700 patients would be needed to detect the anticipated difference. Among the 123 patients who were enrolled, the incidence of overall, early (≤ 30 days), late (> 30 days), and clinically significant seizures was 24%, 10%, 14%, and 3% for the prophylaxis group and 18%, 8%, 10%, and 2% for controls, respectively. There was no significant difference in seizure incidence between the control and prophylaxis groups.27

The weighted average seizure rate was 10.65% based on reported values from control groups. Results from power analyses estimating the sample size for a noninferiority RCT are presented in Table 2.

TABLE 2.

Expected sample size required for a noninferiority study aimed at demonstrating similar seizure rates for prophylaxis and control groups

Sz RateTotal No.No. of Sites*
AED GroupControl Group
10%14%26,092131
10%13%6,32232
10%12%2,72014
10%11%1,4808
10%10.65%1,2587
10%10%9145
10%9%6124
10%8%4343

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.

Discussion

Clinical Implications

We conducted a systematic review of RCTs investigating perioperative seizure prophylaxis in patients without a history of seizures who were undergoing brain tumor resection, including data from 4 studies.2,8,26,27 Our review suggests that prophylactic AED administration may not be effective in preventing seizures in the perioperative period in patients without a history of seizures. Across all of the included studies, there was no significant difference in seizure incidence in the intervention groups compared with controls. Without clear evidence of improved seizure control, neurosurgeons must reconsider the routine perioperative administration of AEDs in patients without a history of seizures who are undergoing brain tumor resection. Apparently, a sizable minority of our colleagues has already done so.8

Limitations of Current Evidence

Current evidence has sizable limitations. Particularly striking is the lack of any trial evaluating levetiracetam. The reviewed trials investigated gabapentin, phenytoin, and phenobarbital. Levetiracetam is, by far, the AED most commonly used by tumor neurosurgeons, and its side-effect profile compares favorably to that for older AEDs. In addition, the reviewed studies did not consistently report tumor location and pathology, despite a strong belief among tumor surgeons about the varying degrees of epileptogenicity based on pathology. Nor was seizure timing or optimal length of prophylaxis consistently specified. These are major limitations within the existing RCTs that have investigated perioperative seizure prophylaxis for brain tumor resection.

Future Directions

There is widespread consensus that an RCT is needed to provide solid grounds for or against antiseizure prophylaxis in tumor surgery. Given the consistent lack of differences found between prophylaxis and control groups, the objective moving forward should not be to determine differences between these 2 groups (that is, superiority), but rather to show that these groups do not have different seizure profiles (that is, noninferiority). Table 2 shows the required sample size for a noninferiority study to achieve 80% power in comparing a prophylactic AED group to a control group in which the AED group has a 10% seizure rate and the control group has a seizure rate that varies from 8% to 14%. All power analyses were based on the Farrington-Manning noninferiority test performed at the 0.05 level using a noninferiority difference of 5%.6

To estimate possible enrollment, we extracted data on all of our institution’s first-time supratentorial craniotomies in adults for the period of 2014–2015. One hundred ninety-seven cases of first-time supratentorial tumor resection were performed during this period. The current literature suggests an enrollment rate slightly above 50% among eligible cancer patients approached for RCTs.17 Therefore, it is estimated that at our center, approximately 50 patients a year could be accrued to a possible AED RCT. This is clearly too few to expect a well-powered study conducted in a timely manner; therefore, such a trial would undoubtedly require multiple centers. To estimate the number needed, a guide is given but we assumed a 4-year accrual of 50 patients per site per year. These values should only be used as a guide as they do not incorporate any intersite variation. It is possible that including sites with larger patient volumes could significantly reduce the number of sites required for such a study.

We propose that such a trial would compare levetiracetam to placebo, with accrual occurring over a 4-year period. Levetiracetam would be chosen since its use reflects current practice; it is associated with similar efficacy and fewer adverse effects compared to other anticonvulsants. Outcome measures would include seizure incidence at 7 and 30 days postoperatively. Prophylaxis would be administered at the time of surgery and continued for 7 days postoperatively in accordance with the most commonly reported practice. Seizures would be assessed through patient, family, and practitioner reporting. All participants would be blinded to the patient treatment arm. Careful attention would be paid to monitoring and recording other adverse events in order to capture those related to AED administration. Costs of such a trial would be significant and would include the course of levetiracetam or placebo, as well as the staff for handling data and conducting follow-up. However, the cost would compare favorably with those for other RCTs since levetiracetam is now a generic drug, and the investigators could integrate existing clinical protocols and information gathering to reduce costs.

Conclusions

The question of whether to use perioperative seizure prophylaxis for patients undergoing brain tumor resection is unresolved. The use of AEDs postoperatively has become routine across major academic centers worldwide despite evidence indicating no significant reduction in the incidence of seizure among patients who receive prophylactic AEDs. Remarkably, the most commonly used AED, levetiracetam, has not been studied for this application in an RCT. There are significant limitations in the available evidence, as outlined above. To determine with any confidence and statistical significance that there is noninferiority in the seizure rate when giving or withholding AEDs, a large multicenter RCT should be performed.

Appendix

PubMed/MEDLINE Search Strategy

(“Neurosurgery”[Mesh] OR “Neurosurgical Procedures”[Mesh] OR “General Surgery”[Mesh] OR “Surgical Procedures, Operative”[Mesh] OR “surgery” [Subheading] OR brain surgery OR craniectomy OR neurological surgery OR craniotomy OR neurosurgery OR operation OR operative OR operative surgical procedure* OR procedure* OR resection OR surgery OR surgical OR surgical procedure* OR general surgery) AND (“Brain Neoplasms”[Mesh] OR brain tumor OR brain neoplasm*) AND (“Seizures”[Mesh] OR “Epilepsy, Partial, Sensory”[Mesh] OR “Epilepsy, Tonic-Clonic”[Mesh] OR “Epilepsy, Partial, Motor”[Mesh] OR “Epilepsy, Generalized”[Mesh] OR “Epilepsy, Post-Traumatic”[Mesh] OR “Epilepsies, Partial”[Mesh] OR “Epilepsy, Absence”[Mesh] OR “Epilepsies, Myoclonic”[Mesh] OR “Epilepsy”[Mesh] OR “Epilepsy, Complex Partial”[Mesh] OR “Anticonvulsants”[Mesh] OR “Anticonvulsants” [Pharmacological Action] OR “Barbiturates”[Mesh] OR “Propofol”[Mesh] OR “Hydantoins”[Mesh] OR “Carbamazepine”[Mesh] OR “brivaracetam” [Supplementary Concept] OR “clobazam” [Supplementary Concept] OR “Clonazepam”[Mesh] OR “Diazepam”[Mesh] OR “Valproic Acid”[Mesh] OR “eslicarbazepine acetate” [Supplementary Concept] OR “Ethosuximide”[Mesh] OR “ezogabine” [Supplementary Concept] OR “felbamate” [Supplementary Concept] OR “gabapentin” [Supplementary Concept] OR “etiracetam” [Supplementary Concept] OR “lamotrigine” [Supplementary Concept] OR “lacosamide” [Supplementary Concept] OR “Lorazepam”[Mesh] OR “oxcarbamazepine” [Supplementary Concept] OR “perampanel” [Supplementary Concept] OR “Phenobarbital”[Mesh] OR “Phenytoin”[Mesh] OR “Pregabalin”[Mesh] OR “Primidone”[Mesh] OR “rufinamide” [Supplementary Concept] OR “tiagabine” [Supplementary Concept] OR “topiramate” [Supplementary Concept] OR “Vigabatrin”[Mesh] OR “zonisamide” [Supplementary Concept] OR Seizures OR Epilepsy OR Anticonvulsants OR Barbiturates Propofol OR Hydantoins OR Carbamazepine OR brivaracetam OR clobazam OR Clonazepam OR Diazepam OR Valproic Acid OR eslicarbazepine acetate OR Ethosuximide OR ezogabine OR felbamate OR gabapentin OR etiracetam OR lamotrigine OR lacosamide OR Lorazepam OR oxcarbamazepine OR perampanel OR Phenobarbital OR Phenytoin OR Pregabalin OR Primidone OR rufinamide OR tiagabine OR topiramate OR Vigabatrin OR zonisamide) AND (“prevention and control” [Subheading] OR “Tertiary Prevention”[Mesh] OR “Secondary Prevention”[Mesh] OR “Primary Prevention”[Mesh] OR “Pre-Exposure Prophylaxis”[Mesh] OR “Post-Exposure Prophylaxis”[Mesh] OR prevention OR control OR prophylactic OR prophylaxis)

Cochrane Central Register of Controlled Trials (CENTRAL)

(Neurosurgery OR neurosurgical procedures OR general surgery OR operative surgical procedures OR surgery or brain surgery or craniectomy OR neurological surgery OR craniotomy OR operation OR operative OR procedure OR resection OR surgical or surgical procedure) AND (Brain Neoplasms OR brain tumor OR brain neoplasm) AND (Seizures OR Epilepsy OR Anticonvulsants OR Barbiturates OR Propofol OR Hydantoins OR Carbamazepine OR brivaracetam OR clobazam OR Clonazepam OR Diazepam OR Valproic Acid OR eslicarbazepine acetate OR Ethosuximide OR ezogabine OR felbamate OR gabapentin OR etiracetam OR lamotrigine OR lacosamide OR Lorazepam OR oxcarbamazepine OR perampanel OR Phenobarbital OR Phenytoin OR Pregabalin OR Primidone OR rufinamide OR tiagabine OR topiramate OR Vigabatrin OR zonisamide) AND (Prevention or control or prophylaxis or prophylactic)

CINAHL/Academic Search Complete

(Neurosurgery OR neurosurgical procedures OR general surgery OR operative surgical procedures OR surgery or brain surgery or craniectomy OR neurological surgery OR craniotomy OR operation OR operative OR procedure OR resection OR surgical or surgical procedure) AND (Brain Neoplasms OR brain tumor OR brain neoplasm) AND (Seizures OR Epilepsy OR Anticonvulsants OR Barbiturates OR Propofol OR Hydantoins OR Carbamazepine OR brivaracetam OR clobazam OR Clonazepam OR Diazepam OR Valproic Acid OR eslicarbazepine acetate OR Ethosuximide OR ezogabine OR felbamate OR gabapentin OR etiracetam OR lamotrigine OR lacosamide OR Lorazepam OR oxcarbamazepine OR perampanel OR Phenobarbital OR Phenytoin OR Pregabalin OR Primidone OR rufinamide OR tiagabine OR topiramate OR Vigabatrin OR zonisamide) AND (Prevention or control or prophylaxis or prophylactic)

Web of Science

(Neurosurgery OR neurosurgical procedures OR general surgery OR operative surgical procedures OR surgery or brain surgery or craniectomy OR neurological surgery OR craniotomy OR operation OR operative OR procedure OR resection OR surgical or surgical procedure) AND TOPIC: (Brain Neoplasms OR brain tumor OR brain neoplasm) AND TOPIC: (Seizures OR Epilepsy OR Anticonvulsants OR Barbiturates OR Propofol OR Hydantoins OR Carbamazepine OR brivaracetam OR clobazam OR Clonazepam OR Diazepam OR Valproic Acid OR eslicarbazepine acetate OR Ethosuximide OR ezogabine OR felbamate OR gabapentin OR etiracetam OR lamotrigine OR lacosamide OR Lorazepam OR oxcarbamazepine OR perampanel OR Phenobarbital OR Phenytoin OR Pregabalin OR Primidone OR rufinamide OR tiagabine OR topiramate OR Vigabatrin OR zonisamide) AND TOPIC: (Prevention or control or prophylaxis or prophylactic) AND TOPIC: (clinical trial OR comparative study OR multicenter study OR controlled clinical trial OR pragmatic clinical trial OR randomized controlled trial OR validation studies)

ScienceDirect

(neurosurgery or neurosurgical procedure or operative or surgery or craniectomy or neurological surgery or craniotomy or operation or operative or procedure or resection or surgical) and (brain neoplasm or brain tumor or brain neoplasm) and (brain neoplasm or brain tumor or brain neoplasm) and (seizure or epilepsy or anticonvulsant or antiepileptic) and (prevention or prophylaxis or prophylactic) and (clinical trial OR comparative study OR multicenter study OR controlled clinical trial OR pragmatic clinical trial OR randomized controlled trial OR validation studies) AND human AND English

Acknowledgments

Services in support of the research project were generated by the VCU Massey Cancer Center Biostatistics Shared Resource, supported, in part, with funding from NIH-NCI Cancer Center Support Grant P30 CA016059.

Disclosures

The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.

Author Contributions

Conception and design: Broaddus, Opalak, Stary. Acquisition of data: Rock, Carr. Analysis and interpretation of data: Rock, Sima. Drafting the article: Chandra, Rock, Opalak, Carr. Critically revising the article: Broaddus, Chandra, Opalak. Reviewed submitted version of manuscript: Broaddus, Opalak, Sima, Vega. Approved the final version of the manuscript on behalf of all authors: Broaddus. Statistical analysis: Rock. Administrative/technical/material support: Broaddus. Study supervision: Broaddus.

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    Levati ASavoia GZoppi FBoselli LTommasino C: Peri-operative prophylaxis with phenytoin: dosage and therapeutic plasma levels. Acta Neurochir (Wien) 138:2742791996

  • 16

    Lim DATarapore PChang EBurt MChakalian LBarbaro N: Safety and feasibility of switching from phenytoin to levetiracetam monotherapy for glioma-related seizure control following craniotomy: a randomized phase II pilot study. J Neurooncol 93:3493542009

  • 17

    Logan JKTang CLiao ZLee JJHeymach JVSwisher SG: Analysis of factors affecting successful clinical trial enrollment in the context of three prospective, randomized, controlled trials. Int J Radiat Oncol Biol Phys 97:7707772017

  • 18

    Moher DShamseer LClarke MGhersi DLiberati APetticrew M: Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement. Syst Rev 4:12015

  • 19

    Nakamura NIshijima BMayanagi YManaka S: A randomized controlled trial of zonisamide in postoperative epilepsy: a report of the cooperative group study. Jpn J Neurosurg 8:6476561999

  • 20

    North JBPenhall RKHanieh AFrewin DBTaylor WB: Phenytoin and postoperative epilepsy. A double-blind study. J Neurosurg 58:6726771983

  • 21

    Perucca E: Optimizing antiepileptic drug treatment in tumoral epilepsy. Epilepsia 54 (Suppl 9):971042013

  • 22

    Rosati ATomassini APollo BAmbrosi CSchwarz APadovani A: Epilepsy in cerebral glioma: timing of appearance and histological correlations. J Neurooncol 93:3954002009

  • 23

    Shershever ASBentsion DLLavrova SASorokova EV: [Use of Keppra during the radiotherapy in patients with brain tumors and epileptic seizures after surgical treatment.] Zh Nevrol Psikhiatr Im S S Korsakova 108:31362008 (Russian)

  • 24

    Sirven JIWingerchuk DMDrazkowski JFLyons MKZimmerman RS: Seizure prophylaxis in patients with brain tumors: a meta-analysis. Mayo Clin Proc 79:148914942004

  • 25

    Temkin NR: Antiepileptogenesis and seizure prevention trials with antiepileptic drugs: meta-analysis of controlled trials. Epilepsia 42:5155242001

  • 26

    Türe HSayin MKarlikaya GBingol CAAykac BTüre U: The analgesic effect of gabapentin as a prophylactic anticonvulsant drug on postcraniotomy pain: a prospective randomized study. Anesth Analg 109:162516312009

  • 27

    Wu ASTrinh VTSuki DGraham SForman AWeinberg JS: A prospective randomized trial of perioperative seizure prophylaxis in patients with intraparenchymal brain tumors. J Neurosurg 118:8738832013

  • 28

    Zadeghan SYSajedi PKhalili GR: Comparing ‘remifentanil-propofol’ and ‘fentanyl-propofol’ in patients undergoing craniotomy for supratentorial space-occupying lesions. Tehran Univ Med J 70:5485542012

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Article Information

Correspondence William C. Broaddus, Department of Neurosurgery, Virginia Commonwealth University Health System, PO Box 980631, Richmond, VA 23219. email: william.broaddus@vcuhealth.org.

INCLUDE WHEN CITING DOI: 10.3171/2017.8.FOCUS17442.

Disclosures The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.

© AANS, except where prohibited by US copyright law.

Headings

Figures

  • View in gallery

    Flow diagram according to the PRISMA-P statement.

  • View in gallery

    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.

References

1

Beenen LFLindeboom JKasteleijn-Nolst Trenité DGHeimans JJSnoek FJTouw DJ: Comparative double blind clinical trial of phenytoin and sodium valproate as anticonvulsant prophylaxis after craniotomy: efficacy, tolerability, and cognitive effects. J Neurol Neurosurg Psychiatry 67:4744801999

2

De Santis AVillani RSinisi MStocchetti NPerucca E: Add-on phenytoin fails to prevent early seizures after surgery for supratentorial brain tumors: a randomized controlled study. Epilepsia 43:1751822002

3

Dewan MCThompson RCKalkanis SNBarker FG IIHadjipanayis CG: Prophylactic antiepileptic drug administration following brain tumor resection: results of a recent AANS/CNS Section on Tumors survey. J Neurosurg 126:177217782017

4

Dewan MCWhite-Dzuro GABrinson PRThompson RCChambless LB: Perioperative seizure in patients with glioma is associated with longer hospitalization, higher readmission, and decreased overall survival. J Neurosurg 125:103310412016

5

Dewan MCWhite-Dzuro GABrinson PRZuckerman SLMorone PJThompson RC: The influence of perioperative seizure prophylaxis on seizure rate and hospital quality metrics following glioma resection. Neurosurgery 80:5635702017

6

Farrington CPManning G: Test statistics and sample size formulae for comparative binomial trials with null hypothesis of non-zero risk difference or non-unity relative risk. Stat Med 9:144714541990

7

Forsyth PAWeaver SFulton DBrasher PMSutherland GStewart D: Prophylactic anticonvulsants in patients with brain tumour. Can J Neurol Sci 30:1061122003

8

Franceschetti SBinelli SCasazza MLodrini SPanzica FPluchino F: Influence of surgery and antiepileptic drugs on seizures symptomatic of cerebral tumours. Acta Neurochir (Wien) 103:47511990

9

Fuller KLWang YYCook MJMurphy MAD’Souza WJ: Tolerability, safety, and side effects of levetiracetam versus phenytoin in intravenous and total prophylactic regimen among craniotomy patients: a prospective randomized study. Epilepsia 54:45572013

10

Higgins JPAltman DGGøtzsche PCJüni PMoher DOxman AD: The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. BMJ 343:d59282011

11

Jennum PGyllenborg JKjellberg J: The social and economic consequences of epilepsy: a controlled national study. Epilepsia 52:9499562011

12

Kazerooni RBounthavong M: Cost-effectiveness analysis of intravenous levetiracetam versus intravenous phenytoin for early onset seizure prophylaxis after neurosurgery and traumatic brain injury. Clinicoecon Outcomes Res 2:15232010

13

Kern KSchebesch KMSchlaier JHansen EFeigl GCBrawanski AT: Levetiracetam compared to phenytoin for the prevention of postoperative seizures after craniotomy for intracranial tumours in patients without epilepsy. J Clin Neurosci 19:991002012

14

Kuijlen JMTeernstra OPKessels AGHerpers MJBeuls EA: Effectiveness of antiepileptic prophylaxis used with supratentorial craniotomies: a meta-analysis. Seizure 5:2912981996

15

Levati ASavoia GZoppi FBoselli LTommasino C: Peri-operative prophylaxis with phenytoin: dosage and therapeutic plasma levels. Acta Neurochir (Wien) 138:2742791996

16

Lim DATarapore PChang EBurt MChakalian LBarbaro N: Safety and feasibility of switching from phenytoin to levetiracetam monotherapy for glioma-related seizure control following craniotomy: a randomized phase II pilot study. J Neurooncol 93:3493542009

17

Logan JKTang CLiao ZLee JJHeymach JVSwisher SG: Analysis of factors affecting successful clinical trial enrollment in the context of three prospective, randomized, controlled trials. Int J Radiat Oncol Biol Phys 97:7707772017

18

Moher DShamseer LClarke MGhersi DLiberati APetticrew M: Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement. Syst Rev 4:12015

19

Nakamura NIshijima BMayanagi YManaka S: A randomized controlled trial of zonisamide in postoperative epilepsy: a report of the cooperative group study. Jpn J Neurosurg 8:6476561999

20

North JBPenhall RKHanieh AFrewin DBTaylor WB: Phenytoin and postoperative epilepsy. A double-blind study. J Neurosurg 58:6726771983

21

Perucca E: Optimizing antiepileptic drug treatment in tumoral epilepsy. Epilepsia 54 (Suppl 9):971042013

22

Rosati ATomassini APollo BAmbrosi CSchwarz APadovani A: Epilepsy in cerebral glioma: timing of appearance and histological correlations. J Neurooncol 93:3954002009

23

Shershever ASBentsion DLLavrova SASorokova EV: [Use of Keppra during the radiotherapy in patients with brain tumors and epileptic seizures after surgical treatment.] Zh Nevrol Psikhiatr Im S S Korsakova 108:31362008 (Russian)

24

Sirven JIWingerchuk DMDrazkowski JFLyons MKZimmerman RS: Seizure prophylaxis in patients with brain tumors: a meta-analysis. Mayo Clin Proc 79:148914942004

25

Temkin NR: Antiepileptogenesis and seizure prevention trials with antiepileptic drugs: meta-analysis of controlled trials. Epilepsia 42:5155242001

26

Türe HSayin MKarlikaya GBingol CAAykac BTüre U: The analgesic effect of gabapentin as a prophylactic anticonvulsant drug on postcraniotomy pain: a prospective randomized study. Anesth Analg 109:162516312009

27

Wu ASTrinh VTSuki DGraham SForman AWeinberg JS: A prospective randomized trial of perioperative seizure prophylaxis in patients with intraparenchymal brain tumors. J Neurosurg 118:8738832013

28

Zadeghan SYSajedi PKhalili GR: Comparing ‘remifentanil-propofol’ and ‘fentanyl-propofol’ in patients undergoing craniotomy for supratentorial space-occupying lesions. Tehran Univ Med J 70:5485542012

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