Anticonvulsant prophylaxis for brain tumor surgery: determining the current best available evidence

A review

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Patients who undergo craniotomy for brain tumor resection are prone to experiencing seizures, which can have debilitating medical, neurological, and psychosocial effects. A controversial issue in neurosurgery is the common practice of administering perioperative anticonvulsant prophylaxis to these patients despite a paucity of supporting data in the literature. The foreseeable benefits of this strategy must be balanced against potential adverse effects and interactions with critical medications such as chemotherapeutic agents and corticosteroids. Multiple disparate metaanalyses have been published on this topic but have not been applied into clinical practice, and, instead, personal preference frequently determines practice patterns in this area of management. Therefore, to select the current best available evidence to guide clinical decision making, the literature was evaluated to identify meta-analyses that investigated the efficacy and/or safety of anticonvulsant prophylaxis in this patient population. Six meta-analyses published between 1996 and 2011 were included in the present study. The Quality of Reporting of Meta-analyses and Oxman-Guyatt methodological quality assessment tools were used to score these meta-analyses, and the Jadad decision algorithm was applied to determine the highest-quality meta-analysis. According to this analysis, 2 metaanalyses were deemed to be the current best available evidence, both of which conclude that prophylactic treatment does not improve seizure control in these patients. Therefore, this management strategy should not be routinely used.

Abbreviations used in this paper:AED = antiepileptic drug; QUOROM = Quality of Reporting of Meta-analyses; RCT = randomized controlled trial.

Patients who undergo craniotomy for brain tumor resection are prone to experiencing seizures, which can have debilitating medical, neurological, and psychosocial effects. A controversial issue in neurosurgery is the common practice of administering perioperative anticonvulsant prophylaxis to these patients despite a paucity of supporting data in the literature. The foreseeable benefits of this strategy must be balanced against potential adverse effects and interactions with critical medications such as chemotherapeutic agents and corticosteroids. Multiple disparate metaanalyses have been published on this topic but have not been applied into clinical practice, and, instead, personal preference frequently determines practice patterns in this area of management. Therefore, to select the current best available evidence to guide clinical decision making, the literature was evaluated to identify meta-analyses that investigated the efficacy and/or safety of anticonvulsant prophylaxis in this patient population. Six meta-analyses published between 1996 and 2011 were included in the present study. The Quality of Reporting of Meta-analyses and Oxman-Guyatt methodological quality assessment tools were used to score these meta-analyses, and the Jadad decision algorithm was applied to determine the highest-quality meta-analysis. According to this analysis, 2 metaanalyses were deemed to be the current best available evidence, both of which conclude that prophylactic treatment does not improve seizure control in these patients. Therefore, this management strategy should not be routinely used.

Seizures are among the most common medical sequelae in patients with brain tumors, along with peritumoral edema, venous thromboembolism, fatigue, cognitive impairment, and treatment-related side effects.70 The mass lesion and eventual craniotomy predispose patients to seizures by causing numerous structural and metabolic derangements.26,27 Anticonvulsants, or antiepileptic drugs (AEDs), are frequently used for therapeutic or prophylactic purposes. While it is universally recognized that preoperative seizures must be controlled with AED administration,25 significant controversy surrounds the use of perioperative AED prophylaxis for patients undergoing brain tumor resection with no seizure history.58

A prophylactic drug should only be given if the risk of the adverse outcome (i.e., a seizure) is prominent and the medication is both effective at preventing it and poses an acceptable risk of toxicity.25 The American Academy of Neurology released practice parameters in 2000 advising against AED prophylaxis in newly diagnosed brain tumor patients due to a lack of efficacy and heightened adverse effects in their meta-analysis.18 The empirical administration of AED prophylaxis is also a contentious issue for other neurosurgical pathologies, such as traumatic brain injury62 and subarachnoid hemorrhage.53 However, this practice remains pervasive in neurosurgery.25 In 2005, 70% of polled neurosurgeons acknowledged routinely administering AED prophylaxis after craniotomy.56 Specifically, over 70% reported regular use of prophylactic AEDs for intraaxial gliomas or metastases, 53.8% for extraaxial benign tumors, and 21.4% for stereotactic biopsies.56

Seizures afflict 15%–50% of patients who undergo brain tumor surgery,10,42,54 including a sizable proportion without a prior seizure history.32,50 Postcraniotomy seizures are stratified by chronology: immediate (within 24 hours), early (within 1 week), and late (all subsequent events).15 Two-thirds of seizures occur in the first month after craniotomy,42 especially during the first 72 hours,27 although the seizure risk persists for several months postoperatively.50 In a systematic review of supratentorial craniotomies, the first postoperative seizure occurred at means of 2.3 days and 42 months for untreated and AED-treated patients, respectively.26 In another study, the type of epilepsy occurring after brain tumor surgery was generalized, focal, and mixed in 53%, 30%, and 17% of cases, respectively.15 While historical series demonstrated effective seizure prevention using AEDs following craniotomy,42,43 recent data suggest a low baseline incidence of postoperative seizures even in the absence of AED prophylaxis.26,58

The purpose of this study was to critically analyze the literature to select the current best available evidence. Personal preference heavily influences decision making on AED use following brain tumor surgery,58 perhaps an indication that the literature has not been translated into treatment recommendations for clinical practice. While high-quality meta-analyses of randomized controlled trials (RCTs) represent the highest level of evidence available to clinicians,21 methodological differences and discordant results across meta-analyses may complicate their interpretation and clinical application. Thus, published meta-analyses on this topic were assessed using validated methodological quality assessment tools and a decision algorithm, with the intent of selecting the highest-quality meta-analysis to guide clinical decision making.

Methods

In this study, the English-language literature was evaluated to appraise the scientific support for the use of perioperative AED prophylaxis. Published meta-analyses were identified following a PubMed search using the following search terms with Boolean operators: anticonvulsant, antiepileptic, prophylaxis, prophylactic, brain tumor, craniotomy, and neurosurgery. Manual citation cross-referencing of all reviewed articles was also performed. After reviewing study abstracts and procuring full-length papers for potentially eligible studies, the results of eligible meta-analyses were extracted. Meta-analyses were included if they assessed the efficacy and/or safety of AED prophylaxis in patients diagnosed with brain tumors, those undergoing craniotomy, or, optimally, those undergoing craniotomy for brain tumor resection. Systematic reviews that did not perform a meta-analysis using pooled outcome data were excluded. Data were extracted from the selected meta-analyses for the eligible study population and study design; the number of included studies and patients; the search methodology and study selection; follow-up interval; type, timing, and duration of intervention; outcome parameters; performance of statistical heterogeneity analysis and subgroup and/or sensitivity analyses; and results of pooled analyses with respect to overall, early, and/or late seizures, adverse events, and any secondary outcomes when available.

The methodological quality of the selected meta-analyses was analyzed using the Quality of Reporting of Meta-analyses (QUOROM)39 and Oxman-Guyatt45 scoring systems, which are validated quality assessment tools with increasing application in the broader surgical literature5 for weighing disparate meta-analyses and systematically determining which meta-analysis should guide clinical decision making. Subsequently, 2 lead authors independently used these scores and other extracted study characteristics to apply the Jadad decision algorithm,23 which aids in the interpretation of meta-analysis quality on the basis of parameters such as the clinical question of interest, inclusion and exclusion criteria, search strategies and study selection, validity assessment, data extraction and pooling, and statistical analysis.

Rationale for Anticonvulsant Prophylaxis

The occurrence of seizures after craniotomy obfuscates the postoperative evaluation of the patient's mental status, immediate postsurgical status, and possible evolving complications such as cerebral edema.10 In turn, the seizures can cause intracranial hypertension, leading to neurological deficits and delayed postoperative recovery.33 Seizures cause functional impairment, societal stigmatization (e.g., the ability to work and drive), and psychological distress to the patient and family. They are also associated with secondary morbidities such as aspiration, brain hypoxia and edema, consequent neurotoxicity, and falls.25,26 Strikingly, the seizure incidence has been associated with increased brain tumor progression and poorer overall survival.11 These patients are also predisposed to neurological impairment11 and higher rates of depression, anxiety, and suicidality.68 Rarely, seizure episodes can provoke potentially fatal status epilepticus or acute intracranial herniation syndromes.26,35 Speculative benefits of AED prophylaxis include not only the prevention of early postoperative seizures, but also long-term epilepsy.49 It is unclear whether AEDs have a disease-modifying effect by preventing postoperative epileptogenesis7,51,59 or merely suppress the clinical manifestations of seizures.1,26 Proponents of prophylactic treatment cite the kindling model of epilepsy, yet to be proven in humans, which suggests that postoperative seizures generate and/or sustain secondary epileptogenic foci in the brain.27,42

Overview and Pharmacology of Anticonvulsants in Use

The most commonly used AED for perioperative prophylaxis after brain tumor surgery is phenytoin.71 Other preferred AEDs include valproic acid, carbamazepine, lamotrigine, and levetiracetam.26 AEDs tend to have multiple mechanisms of action.24 AEDs can be straight-forwardly characterized as being broad-spectrum (e.g., valproic acid, lamotrigine, and levetiracetam), which refers to their suitability for all types of seizures, or narrow-spectrum (e.g., phenytoin, carbamazepine, phenobarbital, primidone, and gabapentin), indicating utility for simple partial, complex partial, and secondarily generalized seizures. Older AEDs such as phenytoin, carbamazepine, phenobarbital, and primidone are hepatically degraded by the cytochrome P450 (CYP450) system.38 The same is true for lamotrigine and topiramate, albeit to a lesser degree.66 Valproic acid exhibits hepatic metabolism but is not enzyme-inducing.70

When AEDs are used, it is critical to attain adequate serum levels, as subtherapeutic dosing may be the most commonly implicated factor in treatment-resistant postoperative seizures.6,28 With certain AEDs, especially phenytoin, clinicians should ensure timely quantitation and calibration of serum drug levels to avoid subtherapeutic levels or toxicities.3 Phenytoin has been historically favored in neurosurgery because it does not impair the level of consciousness29 and has a well-established therapeutic serum concentration range,10,20,42 although a disadvantage is its unpredictable nonlinear pharmacokinetics requiring up to 1 week before the steady-state serum concentration is achieved,6,16,27,36 which may be too late relative to the peak epileptic period.27 Newer AEDs generally allow for shorter loading periods,27 and later-generation AEDs such as levetiracetam have increasingly gained favor in neurosurgery. Another complicating factor with perioperative AED prophylaxis is that operative blood loss, which can be sizable with tumors such as meningiomas, can delay postoperative equilibration of the AED level with the neural tissue.27

Risks of Anticonvulsant Prophylaxis

Most early-generation AEDs are hepatically metabolized and thus either activate or inhibit cytochrome P450 enzymes. As a result, AEDs frequently interact with chemotherapeutic agents and corticosteroids, along with several other medications that patients admitted for brain tumor surgery may require, such as proton pump inhibitors, histamine H2-blockers, macrolide antibiotics, antidepressants, benzodiazepines, and typical antipsychotics.47,48 Interactions have been identified between enzyme-inducing AEDs and nitrosoureas, paclitaxel, 9-aminocamptothecin, thiotepa, topotecan, and irinotecan.18,65 Specifically, phenytoin, phenobarbital, and carbamazepine blunt the efficacy of corticosteroids.8,12,17,69 Strikingly, patients undergoing chemotherapy for glioblastoma exhibited significantly poorer overall survival when treated with enzyme-inducing versus non–enzyme inducing AEDs (10.8 vs 13.9 months), attributed to altered efficacy of chemotherapeutic agents.44 Importantly, AEDs such as phenytoin, carbamazepine, and valproic acid commonly interact with other AEDs, which may complicate the use of polytherapy, as can become necessary after tumor progression or increased brain edema.44 Lastly, patients with brain tumors have increased susceptibility to characteristic AED-related adverse effects.31

The New Generation of Antiepileptic Drugs: Levetiracetam

Later-generation AEDs, such as levetiracetam46 and gabapentin,9 are excreted without significant hepatic processing, lessening their risk of pharmacological interactions. As levetiracetam and gabapentin circulate in free form, they have a minimal effect on the protein binding and bioavailability of other drugs.46 Levetiracetam, a novel AED, is an increasingly favored agent with primarily renal metabolism and an improved risk profile relative to traditional AEDs.2,4 In 1 study, only 2.4% of 82 patients treated with this AED experienced adverse effects requiring treatment cessation, and no laboratory abnormalities were detected when given alongside chemotherapy.52 A large number of smaller studies have also shown levetiracetam to be well tolerated in brain tumor patients, with somnolence or other behavioral side effects being the most common adverse events,31,37,40,41,55,64 with adverse effects being mostly reversible with dose reduction or displacement.31,34,67

Levetiracetam demonstrated significantly fewer adverse effects than phenytoin when AED prophylaxis was given for supratentorial surgery, along with statistically equal efficacy (1% vs 4.3% early seizure incidence).37 In contrast, patients given phenytoin were more likely to experience adverse effects than a seizure (18% vs 4%), and were much less likely to remain on the medication 1 year after surgery than with levetiracetam (26% vs 64%).37 Usery et al. reported that 92 potential drug interactions were avoided by using levetiracetam instead of phenytoin, based on their analysis of the CYP450-processed medications their cohort of 17 patients had received.64 Lim et al. showed in their Phase II pilot study that conversion of phenytoin to levetiracetam following craniotomy was safe and feasible in glioma patients, along with a slightly higher rate of seizure control at 6 months with levetiracetam (87% vs 75%).31 Among 281 patients undergoing craniotomy for a supratentorial brain tumor, long-term complications were significantly less likely after perioperative prophylaxis with levetiracetam (9.8%) versus valproic acid (26.8%), as was the need for polytherapy (17.6% vs 38.5%).30

Results

Seizure Control

To date, 6 meta-analyses (Table 1),18,26,27,57,61,63 5 of which considered only Level I evidence from RCTs, have analyzed this management strategy. An additional study by Temkin60 presented results from the same meta-analysis,61 but it added information that was not provided in the original study. Five of 6 meta-analyses found no reduction in the overall, early, and/or late seizure risk after AED prophylaxis, while 1 found a reduction in the early seizure risk. There was significant heterogeneity across meta-analyses in the mean follow-up period, particular agents used, timing of the intervention, and duration of the intervention, as outlined in Table 1. Kuijlen et al., who studied AED prophylaxis for supratentorial craniotomy based on 3 trials that met the authors' threshold of methodological quality,27 found a nonsignificant trend toward reduced postoperative seizures using prophylactic AEDs. Glantz et al., whose meta-analysis was based on 4 RCTs, found that AED prophylaxis did not reduce the overall seizure risk in patients with gliomas, meningiomas, or brain metastases, although their focus was not specific to the perioperative setting.18 Temkin, who performed a meta-analysis of 6 trials of nontraumatic craniotomy, found that phenytoin decreased the risk of early postoperative seizures by 44%.61 Carbamazepine and valproic acid, each tested in one included study, had no significant effect on seizure incidence. Phenytoin, carbamazepine, and phenobarbital did not improve the late seizure risk.61 Sirven et al., who included 5 trials of patients with brain tumors and no history of epilepsy, concluded that AEDs did not reduce the early or late seizure risk.57 Furthermore, their subgroup analyses found no efficacy for AEDs used for individual tumor pathologies, namely primary glial tumors and cerebral metastases. Komotar et al., whose meta-analysis studied craniotomy for supratentorial meningioma, found no significant differences in seizure incidence prior to and following hospital discharge, perioperative mortality, and recurrence between those treated with and without AED prophylaxis.26 The treated and untreated groups, respectively, had equal rates of early and late postoperative seizures. Tremont-Lukats et al., who studied patients with brain tumors based on 5 trials, likewise found that prophylactic phenytoin, phenobarbital, or valproic acid did not decrease the incidence of first-time seizures.63

TABLE 1:

Clinical efficacy for early and late seizures and rate of adverse events associated with AED prophylaxis for brain tumors and/or after craniotomy according to published meta-analyses*

Meta-AnalysisEligible Study PopulationEligible Study DesignsNo. of StudiesNo. of PatientsAgents (no.)Mean Follow-Up Interval (range)Timing of Intervention (no.)Duration of Intervention (no.)Results of Pooled Analyses
Kuijlen et al., 1996patients undergoing supratentorial craniotomycontrolled trials meeting methodological quality threshold3621Pht (1), Phb (2), Pht (1), Cbz (1)22.3 mos (3 days–48 mos)preop (1), intraop (1), postop (1)3 days (1), 6 or 24 mos (1), 12 mos (1)no difference in overall Sz risk
Glantz et al., 2000patients diagnosed w/brain tumorsRCTs4318Pht (3), VPA (1), Phb (1)9.7 (5.4–12) mos≤14 days after diagnosis (1), preop (1), postop (1)12 mos (2)no difference in overall Sz risk or Sz-free survival
Temkin, 2001/2002patients undergoing craniotomyprospective controlled trials61560Pht (5), Cbz (1), VPA (1), Phb (1)9.4 mos (3 days–24 mos)day of surgery (1), preop or ≤24 hrs after diagnosis, preop (1), intraop (1), postop (2)3 days (1), 7 days (1), 6 or 24 mos (1), 12 mos (2)reduction of early Sz risk by 44%; no difference in late Sz risk
Sirven et al., 2004patients diagnosed w/brain tumors w/o prior SzsRCTs5403Phb (2), Pht (4), VPA (1)6.9 mos (3 days–12 mos)≤14 days after diagnosis (1), preop (1), intraop (1), postop (1)3 days (1), 12 mos (2)no difference in early or late Sz risk
Tremont-Lukats et al., 2008patients diagnosed w/ brain tumorsRCTs5404Phb (2), Pht (4), VPA (1)6.9 mos (3 days–12 mos)`3 days (1), 12 mos (2)no difference in overall Sz risk; significantly higher adverse event rate
Komotar et al., 2011patients undergoing resection of supratentorial meningioma w/o prior Szsall studies presenting original data w/AED administration & outcome data3 (19)698Pht, VPA, Cbz, Lam, Lev were most common36.5 (1–12) mosintraop (1), postop (2)mean 4.2 (range 1–52) wksno difference in early or late Sz risk, extent of resection, recurrence, or periop mortality

Cbz = carbamazepine; Lam = lamotrigine; Lev = levetiracetam; Phb = phenobarbital; Pht = phenytoin; Sz = seizure; VPA = valproate; Zon = zonisamide.

Both publications present results from the same meta-analysis, but each provides some unique information that the other did not provide.

Komotar et al. included an additional 16 uncontrolled studies in addition to the clinical trials referenced in the table.

Adverse Events

Two of the 6 meta-analyses performed a pooled analysis of adverse events associated with AED prophylaxis. The majority of reported adverse effects were not severe. The meta-analysis of Glantz et al. documented an AED-related adverse event rate of 23.8% using pooled data from 3 RCTs and 4 retrospective studies with historical controls.18 The most common adverse events were rash (14%), nausea or vomiting (5%), encephalopathy (5%), myelosuppression (3%), and ataxia, transaminitis, or gingival pain (5%). The meta-analysis of Tremont-Lukats et al.63 found an adverse event rate of 15% after AED prophylaxis, which was significantly higher than 0.9% in the control group, resulting in a number needed to harm of 3.13,19 The most common adverse events were rash and nausea, while tremor, vertigo and blurred vision, gait ataxia, gingival pain, myelosuppression, and increased lactate dehydrogenase were noted in 1 case each. The occurrence of these adverse events in relation to short-versus long-term AED use was not clearly indicated. In the meta-analysis of Glantz et al., adverse event data were derived from 2 RCTs, of which one employed long-term treatment for 12 months,19 while the other did not indicate the treatment duration,13 although data from an additional 4 uncontrolled studies were used for this analysis. In the meta-analysis of Tremont-Lukas et al., adverse event data were derived from 4 RCTs, of which 2 employed long-term treatment for 12 months,18,42 while the other 2 did not indicate the treatment duration.13,16

Determining the Current Best Available Evidence

Search Methodology and Meta-Analysis Design

A total of 10 RCTs were included among the 6 meta-analyses (Table 2), with each meta-analysis including between 3 and 6 of these primary studies. All but one meta- analysis limited the inclusion criteria for study design to RCTs. These meta-analyses differed in the comprehensiveness of their search strategies according to their use of the PubMed/Medline, Excerpta Medica Database (EMBASE), Cochrane Central Register of Controlled Trials (CENTRAL), Cumulative Index to Nursing and Allied Health Literature (CINAHL), and other databases (Table 3). Various outcome measures were analyzed for AED-treated versus untreated patients using pooled data, chiefly overall seizure risk, early seizure risk, late seizure risk, and/or adverse events (Table 4). Only 2 and 3 meta-analyses performed a statistical heterogeneity analysis and subgroup and/or sensitivity analyses, respectively, for specifically assessing variables such as the AED or the type of brain tumor pathology.

TABLE 2:

Primary studies included in each of the meta-analyses

Meta-AnalysisPrimary Study Included
Forsyth et al., 2003De Santis et al., 2002Beenen et al., 1999Glantz et al., 1996Holland et al., 1995 Foy et al., 1992Shaw et al., 1991Franceschetti et al., 1990Lee et al., 1989North et al., 1983
Komotar et al., 2011*nonoyesnononononoyesyes
Tremont-Lukats et al., 2008yesnonoyesnononoyesyesyes
Sirven et al., 2004yesnonoyesnononoyesyesyes
Temkin, 2001/2002noyesnonoyesnoyesyesyesyes
Glantz et al., 2000yesnonoyesnononoyesnoyes
Kuijlen et al., 1996nononononoyesnonoyesyes

Komotar et al. were the only authors whose study included non–Level I evidence in addition to the clinical trials referenced in the table.

TABLE 3:

Search methodology, study selection, methodological quality (QUOROM score), and scientific quality (Oxman-Guyatt score) of the meta-analyses*

Meta-AnalysisDatabase SearchedNo. of Primary StudiesPrimary Studies Included Only RCTsQUOROM Score (0–18)Oxman-Guyatt Score (1–7)
PubMed/MEDLINEEMBASECENTRALCINAHLOther
Komotar et al., 2011yesnononono3 (19)no153
Tremont-Lukats et al., 2008yesyesyesnoyes5yes156
Sirven et al., 2004yesyesyesyesyes5yes154
Glantz et al., 2000yesnononono4yes72
Temkin, 2001/2002yesyesyesnono6yes153
Kuijlen et al., 1996yesnononono3yes93

CENTRAL = Cochrane Central Register of Controlled Trials; CINAHL = Cumulative Index to Nursing and Allied Health Literature; EMBASE = Excerpta Medica Database; MEDLINE = Medical Literature Analysis and Retrieval System Online.

Komotar et al. included 16 uncontrolled studies in addition to 3 controlled trials.

TABLE 4:

Outcomes of interest, performance of statistical heterogeneity analysis, and performance of subgroup and/or sensitivity analyses in the meta-analyses*

Meta-AnalysisOutcome Reported
Overall Sz RiskEarly Sz RiskLate Sz RiskSz-Free SurvivalAdverse EventsExtent of ResectionRecurrence PFSPeriop MortalityOSStatistical Heterogeneity AnalysisSubgroup &/or Sensitivity Analyses
Komotar et al., 2011noyesyesnonoyesyesyesyesnonono
Tremont-Lukats et al., 2008yesnononoyesnonononononono
Sirven et al., 2004noyesyesnononononononoyesyes
Glantz et al., 2000yesnonoyesyesnonononoyesnoyes
Temkin, 2001/2002yesyesyesnononononononoyesyes
Kuijlen et al., 1996yesnonononononononononono

All outcomes pertain to the comparison of patients treated with AED prophylaxis versus without it. OS = overall survival; PFS = progression-free survival.

Validity Assessment

The QUOROM score varied widely across the 6 meta-analyses (range 7–15; maximum possible score, 18), with 3 achieving scores of 15 and thus exhibiting better methodological quality than the other 3. The Oxman-Guyatt score also varied widely across these meta-analyses (range 1–6; maximum possible score 7), with all meta-analyses demonstrating major flaws due to a score of 3 or lower, except for those of Sirven et al.57 and Tremont-Lukats et al.63

Application of Jadad Decision Algorithm

After scoring of these meta-analyses using these 2 indices was completed, the Jadad algorithm was applied. It was first noted that 3 of the meta-analyses are limited by the clinical question they ask (Steps A and B). Tremont-Lukats et al.63 and Glantz et al.18 studied prophylaxis for brain tumors in general, not necessarily in the perioperative setting, while Temkin61 analyzed prophylaxis for all craniotomies, including but not limited to brain tumors. The 2 meta-analyses by Sirven et al.57 and Tremont-Lukats et al.63 were favored over the other 4 meta-analyses due to clear differences in methodological and/or scientific quality according to the QUOROM and Oxmann and Guyatt indices (Step D). Furthermore, the selection criteria of the other 4 meta-analyses were less optimal (Step G), namely their use of narrower search strategies and/or inclusion of uncontrolled trials or respective studies subject to greater bias (Steps H and I). The meta-analysis of Temkin was eliminated from consideration due to the performance of data extraction by a single reviewer (Step E) and lack of validity assessment (Step I). With only the 2 meta-analyses of Sirven et al. and Tremont-Lukats et al. remaining, both were noted to include the same 5 RCTs (Step C), be of similar quality (Step D), and exercise appropriate data extraction, heterogeneity testing, and quantitative data synthesis (Step E). Therefore, application of the Jadad algorithm confirmed that the meta-analyses by Sirven et al. and Tremont-Lukats et al. represent the current best available evidence for clinicians considering whether to use this management strategy. Neither of these 2 meta-analyses demonstrated an improvement in seizure control with the use of AED prophylaxis.

Discussion

Implications for Clinical Practice

The current best available evidence, from the meta-analyses of RCTs conducted by Sirven et al.57 and Tremont-Lukats et al.,63 suggests that AED prophylaxis for brain tumor surgery should not be routinely used due to a lack of significant improvement in seizure control and a potential increase in adverse events. However, as later-generation AEDs such as levetiracetam offer an improved safety profile over older AEDs, clinicians who wish to use prophylaxis should use these newer agents.

Limitations of Current Evidence

Limitations of the existing literature include significant heterogeneity within and across cohorts in drug dosing, the route and timing of administration, the use of drug level monitoring, and outcome parameters.58 For instance, the trials included in the 6 meta-analyses treated patients with AEDs for as long as 3 days to 24 months. Further methodological variation was present in drug level monitoring and the route and timing of administration.49 Furthermore, many studies did not differentiate between early and late postoperative seizures or report auxiliary outcomes such as adverse events, functional disability (i.e., in relation to seizure severity), and mortality.49 Some studies also intermixed brain tumors with other nontraumatic and nontraumatic neurosurgical pathologies, such as traumatic brain injury, which is amenable to perioperative AED prophylaxis,62 and subarachnoid hemorrhage, for which such treatment strikingly impedes functional recovery.53

Future Directions

More research is needed to clarify how patient-specific factors, such as tumor location and histological type, tumor size, type of retraction and surgical technique required for resection, and residual tumor after craniotomy affect epileptic susceptibility and, perhaps, consideration of AED prophylaxis in selected, high-risk patients.58 In addition, further research should elucidate how the timing and duration of prophylactic AED administration, which varied significantly across the analyzed studies, influence its efficacy. Prophylaxis may be commenced preoperatively, intraoperatively, or postoperatively, and recommendations variably recommend treatment cessation after 1 week,18 as per the 2000 American Academy of Neurology guidelines, to 6 months after surgery.3,15 Future meta-analyses must consistently differentiate between early and postoperative seizures, as the former are of particular concern during neurosurgical care. Lastly, as newer-generation AEDs such as levetiracetam become increasingly favored by neurosurgeons in modern antiepileptic regimens, they should be the primary focus of any future RCTs and meta-analyses.

Conclusions

The management approach to seizures after brain tumor surgery is challenging. Although routinely employed at many neurosurgical centers, the current best available evidence on perioperative AED prophylaxis for brain tumor surgery, according to validated quality assessment indices and the Jadad decision algorithm for interpreting meta-analyses, indicates that this strategy should not be routinely employed due to a lack of improvement in seizure control and an appreciable adverse event rate. A limitation of the published literature is the predominant use of traditional AEDs in studies, which does not account for contemporary regimens that increasingly favor levetiracetam and other later-generation AEDs.

Disclosure

The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper. This work was supported by grants from the Howard Hughes Medical Institute (E.T.S.), the Reza and Georgianna Khatib Endowed Professor at Northwestern University (O.B.), and the Michael J. Marchese Professor and Chair at Northwestern University (A.T.P.).

Author contributions to the study and manuscript preparation include the following. Conception and design: Sayegh. Acquisition of data: Sayegh. Analysis and interpretation of data: Sayegh. Drafting the article: Sayegh, Fakurnejad. Critically revising the article: all authors. Reviewed submitted version of manuscript: all authors. Approved the final version of the manuscript on behalf of all authors: Parsa. Study supervision: Parsa.

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    • Export Citation
  • 14

    Foy PMChadwick DWRajgopalan NJohnson ALShaw MD: Do prophylactic anticonvulsant drugs alter the pattern of seizures after craniotomy?. J Neurol Neurosurg Psychiatry 55:7537571992

    • Search Google Scholar
    • Export Citation
  • 15

    Foy PMCopeland GPShaw MD: The natural history of postoperative seizures. Acta Neurochir (Wien) 57:15221981

  • 16

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

    • Search Google Scholar
    • Export Citation
  • 17

    Gambertoglio JGHolford NHKapusnik JENishikawa RSaltiel MStanik-Lizak P: Disposition of total and unbound prednisolone in renal transplant patients receiving anticonvulsants. Kidney Int 25:1191231984

    • Search Google Scholar
    • Export Citation
  • 18

    Glantz MJCole BFForsyth PARecht LDWen PYChamberlain MC: Practice parameter: anticonvulsant prophylaxis in patients with newly diagnosed brain tumors. Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 54:188618932000

    • Search Google Scholar
    • Export Citation
  • 19

    Glantz MJCole BFFriedberg MHLathi EChoy HFurie K: A randomized, blinded, placebo-controlled trial of divalproex sodium prophylaxis in adults with newly diagnosed brain tumors. Neurology 46:9859911996

    • Search Google Scholar
    • Export Citation
  • 20

    Glauser TAPippenger CE: Controversies in blood-level monitoring: reexamining its role in the treatment of epilepsy. Epilepsia 41:Suppl 8S6S152000

    • Search Google Scholar
    • Export Citation
  • 21

    Harbour RMiller J: A new system for grading recommendations in evidence based guidelines. BMJ 323:3343362001

  • 22

    Holland JPStapleton SRMoore AJMarsh HTUttley DBell BA: A randomized double blind study of sodium valproate for the prevention of seizures in neurosurgical patients. J Neurol Neurosurg Psychiatry 58:1161995

    • Search Google Scholar
    • Export Citation
  • 23

    Jadad ARCook DJBrowman GP: A guide to interpreting discordant systematic reviews. CMAJ 156:141114161997

  • 24

    Kerrigan SGrant R: Antiepileptic drugs for treating seizures in adults with brain tumours. Cochrane Database Syst Rev 8CD0085862011

  • 25

    Klimek MDammers R: Antiepileptic drug therapy in the perioperative course of neurosurgical patients. Curr Opin Anaesthesiol 23:5645672010

    • Search Google Scholar
    • Export Citation
  • 26

    Komotar RJRaper DMStarke RMIorgulescu JBGutin PH: Prophylactic antiepileptic drug therapy in patients undergoing supratentorial meningioma resection: a systematic analysis of efficacy. A review. J Neurosurg 115:4834902011

    • Search Google Scholar
    • Export Citation
  • 27

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

    • Search Google Scholar
    • Export Citation
  • 28

    Kvam DALoftus CMCopeland BQuest DO: Seizures during the immediate postoperative period. Neurosurgery 12:14171983

  • 29

    Lee STLui TNChang CNCheng WCWang DJHeimburger RF: Prophylactic anticonvulsants for prevention of immediate and early postcraniotomy seizures. Surg Neurol 31:3613641989

    • Search Google Scholar
    • Export Citation
  • 30

    Lee YJKim TBae SHKim YHHan JHYun CH: Levetiracetam compared with valproic acid for the prevention of postoperative seizures after supratentorial tumor surgery: a retrospective chart review. CNS Drugs 27:7537592013

    • Search Google Scholar
    • Export Citation
  • 31

    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

    • Search Google Scholar
    • Export Citation
  • 32

    Mahaley MS JrDudka L: The role of anticonvulsant medications in the management of patients with anaplastic gliomas. Surg Neurol 16:3994011981

    • Search Google Scholar
    • Export Citation
  • 33

    Manaka SIshijima BMayanagi Y: Postoperative seizures: epidemiology, pathology, and prophylaxis. Neurol Med Chir (Tokyo) 43:5896002003

    • Search Google Scholar
    • Export Citation
  • 34

    Maschio MAlbani FBaruzzi AZarabla ADinapoli LPace A: Levetiracetam therapy in patients with brain tumour and epilepsy. J Neurooncol 80:971002006

    • Search Google Scholar
    • Export Citation
  • 35

    Mason WP: Anticonvulsant prophylaxis for patients with brain tumours: insights from clinical trials. Can J Neurol Sci 30:89902003

  • 36

    Matthew ESherwin ALWelner SAOdusote KStratford JG: Seizures following intracranial surgery: incidence in the first post-operative week. Can J Neurol Sci 7:2852901980

    • Search Google Scholar
    • Export Citation
  • 37

    Milligan TAHurwitz SBromfield EB: Efficacy and toler ability of levetiracetam versus phenytoin after supratentorial neurosurgery. Neurology 71:6656692008

    • Search Google Scholar
    • Export Citation
  • 38

    Mintzer S: Metabolic consequences of antiepileptic drugs. Curr Opin Neurol 23:1641692010

  • 39

    Moher DCook DJEastwood SOlkin IRennie DStroup DF: Improving the quality of reports of meta-analyses of randomised controlled trials: the QUOROM statement. Quality of Reporting of Meta-analyses. Lancet 354:189619001999

    • Search Google Scholar
    • Export Citation
  • 40

    Newton HBDalton JGoldlust SPearl D: Retrospective analysis of the efficacy and tolerability of levetiracetam in patients with metastatic brain tumors. J Neurooncol 84:2932962007

    • Search Google Scholar
    • Export Citation
  • 41

    Newton HBGoldlust SAPearl D: Retrospective analysis of the efficacy and tolerability of levetiracetam in brain tumor patients. J Neurooncol 78:991022006

    • Search Google Scholar
    • Export Citation
  • 42

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

    • Search Google Scholar
    • Export Citation
  • 43

    North JBPenhall RKHanieh AHann CSChallen RGFrewin DB: Postoperative epilepsy: a double-blind trial of phenytoin after craniotomy. Lancet 1:3843861980

    • Search Google Scholar
    • Export Citation
  • 44

    Oberndorfer SPiribauer MMarosi CLahrmann HHitzenberger PGrisold W: P450 enzyme inducing and non-enzyme inducing antiepileptics in glioblastoma patients treated with standard chemotherapy. J Neurooncol 72:2552602005

    • Search Google Scholar
    • Export Citation
  • 45

    Oxman ADGuyatt GH: Validation of an index of the quality of review articles. J Clin Epidemiol 44:127112781991

  • 46

    Patsalos PN: Clinical pharmacokinetics of levetiracetam. Clin Pharmacokinet 43:7077242004

  • 47

    Patsalos PNPerucca E: Clinically important drug interactions in epilepsy: general features and interactions between antiepileptic drugs. Lancet Neurol 2:3473562003

    • Search Google Scholar
    • Export Citation
  • 48

    Patsalos PNPerucca E: Clinically important drug interactions in epilepsy: interactions between antiepileptic drugs and other drugs. Lancet Neurol 2:4734812003

    • Search Google Scholar
    • Export Citation
  • 49

    Pulman JGreenhalgh JMarson AG: Antiepileptic drugs as prophylaxis for post-craniotomy seizures. Cochrane Database Syst Rev 2:CD0072862013

    • Search Google Scholar
    • Export Citation
  • 50

    Ramamurthi BRavi BRamachandran V: Convulsions with meningiomas: incidence and significance. Surg Neurol 14:4154161980

  • 51

    Rekling JC: Neuroprotective effects of anticonvulsants in rat hippocampal slice cultures exposed to oxygen/glucose deprivation. Neurosci Lett 335:1671702003

    • Search Google Scholar
    • Export Citation
  • 52

    Rosati AButtolo LStefini RTodeschini ACenzato MPadovani A: Efficacy and safety of levetiracetam in patients with glioma: a clinical prospective study. Arch Neurol 67:3433462010

    • Search Google Scholar
    • Export Citation
  • 53

    Rosengart AJHuo DTolentino JNovakovic RLFrank JIGoldenberg FD: Outcome in patients with subarachnoid hemorrhage treated with antiepileptic drugs. J Neurosurg 107:2532602007

    • Search Google Scholar
    • Export Citation
  • 54

    Shaw MDFoy PM: Epilepsy after craniotomy and the place of prophylactic anticonvulsant drugs: discussion paper. J R Soc Med 84:2212231991

    • Search Google Scholar
    • Export Citation
  • 55

    Siddiqui FWen PDworetzky BCabello DBromfield EB: Use of levetiracetam in patients with brain tumors. Epilepsia 43:Suppl 72972002

    • Search Google Scholar
    • Export Citation
  • 56

    Siomin VAngelov LLi LVogelbaum MA: Results of a survey of neurosurgical practice patterns regarding the prophylactic use of anti-epilepsy drugs in patients with brain tumors. J Neurooncol 74:2112152005

    • Search Google Scholar
    • Export Citation
  • 57

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

    • Search Google Scholar
    • Export Citation
  • 58

    Sughrue MERutkowski MJChang EFShangari GKane AJMcDermott MW: Postoperative seizures following the resection of convexity meningiomas: are prophylactic anticonvulsants indicated? Clinical article. J Neurosurg 114:7057092011

    • Search Google Scholar
    • Export Citation
  • 59

    Tanabe MUmeda MHonda MOno H: Phenytoin and carbamazepine delay the initial depression of the population spike upon exposure to in vitro ischemia and promote its post-ischemic functional recovery in rat hippocampal slices. Eur J Pharmacol 553:1041082006

    • Search Google Scholar
    • Export Citation
  • 60

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

    • Search Google Scholar
    • Export Citation
  • 61

    Temkin NR: Prophylactic anticonvulsants after neurosurgery. Epilepsy Curr 2:1051072002

  • 62

    Temkin NRDikmen SSWilensky AJKeihm JChabal SWinn HR: A randomized, double-blind study of phenytoin for the prevention of post-traumatic seizures. N Engl J Med 323:4975021990

    • Search Google Scholar
    • Export Citation
  • 63

    Tremont-Lukats IWRatilal BOArmstrong TGilbert MR: Antiepileptic drugs for preventing seizures in people with brain tumors. Cochrane Database Syst Rev 2CD0044242008

    • Search Google Scholar
    • Export Citation
  • 64

    Usery JBMichael LM IISills AKFinch CK: A prospective evaluation and literature review of levetiracetam use in patients with brain tumors and seizures. J Neurooncol 99:2512602010

    • Search Google Scholar
    • Export Citation
  • 65

    van Breemen MSWilms EBVecht CJ: Epilepsy in patients with brain tumours: epidemiology, mechanisms, and management. Lancet Neurol 6:4214302007

    • Search Google Scholar
    • Export Citation
  • 66

    Vecht CJvan Breemen M: Optimizing therapy of seizures in patients with brain tumors. Neurology 67:12 Suppl 4S10S132006

  • 67

    Wagner GLWilms EBVan Donselaar CA: Vecht ChJ: Levetiracetam: preliminary experience in patients with primary brain tumours. Seizure 12:5855862003

    • Search Google Scholar
    • Export Citation
  • 68

    Wallace EMO'Reilly MTwomey M: A review of the use of antiepileptic drugs in high-grade central nervous system tumors. Am J Hosp Palliat Care 29:6186212012

    • Search Google Scholar
    • Export Citation
  • 69

    Wassner SJMalekzadeh MHPennisi AJEttenger RBUittenbogaart CHFine RN: Allograft survival in patients receiving anticonvulsant medications. Clin Nephrol 8:2932971977

    • Search Google Scholar
    • Export Citation
  • 70

    Wen PYSchiff DKesari SDrappatz JGigas DCDoherty L: Medical management of patients with brain tumors. J Neurooncol 80:3133322006

    • Search Google Scholar
    • Export Citation
  • 71

    Zachenhofer IDonat MOberndorfer SRoessler K: Perioperative levetiracetam for prevention of seizures in supratentorial brain tumor surgery. J Neurooncol 101:1011062011

    • Search Google Scholar
    • Export Citation

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Article Information

Address correspondence to: Andrew T. Parsa, M.D., Ph.D., Department of Neurological Surgery, Northwestern University Feinberg School of Medicine, 676 N. St. Clair St., Ste. 2210, Chicago, IL 60611. email: aparsa@nmff.org.

Please include this information when citing this paper: published online August 29, 2014; DOI: 10.3171/2014.7.JNS132829.

© AANS, except where prohibited by US copyright law.

Headings

References

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    Baker CJPrestigiacomo CJSolomon RA: Short-term perioperative anticonvulsant prophylaxis for the surgical treatment of low-risk patients with intracranial aneurysms. Neurosurgery 37:8638711995

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    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

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    Ben-Menachem EGilland E: Efficacy and tolerability of levetiracetam during 1-year follow-up in patients with refractory epilepsy. Seizure 12:1311352003

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    Calabresi PCupini LMCentonze DPisani FBernardi G: Antiepileptic drugs as a possible neuroprotective strategy in brain ischemia. Ann Neurol 53:6937022003

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    Chalk JBRidgeway KBrophy TYelland JDEadie MJ: Phenytoin impairs the bioavailability of dexamethasone in neurological and neurosurgical patients. J Neurol Neurosurg Psychiatry 47:108710901984

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    Curry WJKulling DL: Newer antiepileptic drugs: gabapentin, lamotrigine, felbamate, topiramate and fosphenytoin. Am Fam Physician 57:5135201998

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    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

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    Deutschman CSHaines SJ: Anticonvulsant prophylaxis in neurological surgery. Neurosurgery 17:5105171985

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    Dropcho EJSoong SJ: Steroid-induced weakness in patients with primary brain tumors. Neurology 41:123512391991

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

    • Search Google Scholar
    • Export Citation
  • 14

    Foy PMChadwick DWRajgopalan NJohnson ALShaw MD: Do prophylactic anticonvulsant drugs alter the pattern of seizures after craniotomy?. J Neurol Neurosurg Psychiatry 55:7537571992

    • Search Google Scholar
    • Export Citation
  • 15

    Foy PMCopeland GPShaw MD: The natural history of postoperative seizures. Acta Neurochir (Wien) 57:15221981

  • 16

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

    • Search Google Scholar
    • Export Citation
  • 17

    Gambertoglio JGHolford NHKapusnik JENishikawa RSaltiel MStanik-Lizak P: Disposition of total and unbound prednisolone in renal transplant patients receiving anticonvulsants. Kidney Int 25:1191231984

    • Search Google Scholar
    • Export Citation
  • 18

    Glantz MJCole BFForsyth PARecht LDWen PYChamberlain MC: Practice parameter: anticonvulsant prophylaxis in patients with newly diagnosed brain tumors. Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 54:188618932000

    • Search Google Scholar
    • Export Citation
  • 19

    Glantz MJCole BFFriedberg MHLathi EChoy HFurie K: A randomized, blinded, placebo-controlled trial of divalproex sodium prophylaxis in adults with newly diagnosed brain tumors. Neurology 46:9859911996

    • Search Google Scholar
    • Export Citation
  • 20

    Glauser TAPippenger CE: Controversies in blood-level monitoring: reexamining its role in the treatment of epilepsy. Epilepsia 41:Suppl 8S6S152000

    • Search Google Scholar
    • Export Citation
  • 21

    Harbour RMiller J: A new system for grading recommendations in evidence based guidelines. BMJ 323:3343362001

  • 22

    Holland JPStapleton SRMoore AJMarsh HTUttley DBell BA: A randomized double blind study of sodium valproate for the prevention of seizures in neurosurgical patients. J Neurol Neurosurg Psychiatry 58:1161995

    • Search Google Scholar
    • Export Citation
  • 23

    Jadad ARCook DJBrowman GP: A guide to interpreting discordant systematic reviews. CMAJ 156:141114161997

  • 24

    Kerrigan SGrant R: Antiepileptic drugs for treating seizures in adults with brain tumours. Cochrane Database Syst Rev 8CD0085862011

  • 25

    Klimek MDammers R: Antiepileptic drug therapy in the perioperative course of neurosurgical patients. Curr Opin Anaesthesiol 23:5645672010

    • Search Google Scholar
    • Export Citation
  • 26

    Komotar RJRaper DMStarke RMIorgulescu JBGutin PH: Prophylactic antiepileptic drug therapy in patients undergoing supratentorial meningioma resection: a systematic analysis of efficacy. A review. J Neurosurg 115:4834902011

    • Search Google Scholar
    • Export Citation
  • 27

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

    • Search Google Scholar
    • Export Citation
  • 28

    Kvam DALoftus CMCopeland BQuest DO: Seizures during the immediate postoperative period. Neurosurgery 12:14171983

  • 29

    Lee STLui TNChang CNCheng WCWang DJHeimburger RF: Prophylactic anticonvulsants for prevention of immediate and early postcraniotomy seizures. Surg Neurol 31:3613641989

    • Search Google Scholar
    • Export Citation
  • 30

    Lee YJKim TBae SHKim YHHan JHYun CH: Levetiracetam compared with valproic acid for the prevention of postoperative seizures after supratentorial tumor surgery: a retrospective chart review. CNS Drugs 27:7537592013

    • Search Google Scholar
    • Export Citation
  • 31

    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

    • Search Google Scholar
    • Export Citation
  • 32

    Mahaley MS JrDudka L: The role of anticonvulsant medications in the management of patients with anaplastic gliomas. Surg Neurol 16:3994011981

    • Search Google Scholar
    • Export Citation
  • 33

    Manaka SIshijima BMayanagi Y: Postoperative seizures: epidemiology, pathology, and prophylaxis. Neurol Med Chir (Tokyo) 43:5896002003

    • Search Google Scholar
    • Export Citation
  • 34

    Maschio MAlbani FBaruzzi AZarabla ADinapoli LPace A: Levetiracetam therapy in patients with brain tumour and epilepsy. J Neurooncol 80:971002006

    • Search Google Scholar
    • Export Citation
  • 35

    Mason WP: Anticonvulsant prophylaxis for patients with brain tumours: insights from clinical trials. Can J Neurol Sci 30:89902003

  • 36

    Matthew ESherwin ALWelner SAOdusote KStratford JG: Seizures following intracranial surgery: incidence in the first post-operative week. Can J Neurol Sci 7:2852901980

    • Search Google Scholar
    • Export Citation
  • 37

    Milligan TAHurwitz SBromfield EB: Efficacy and toler ability of levetiracetam versus phenytoin after supratentorial neurosurgery. Neurology 71:6656692008

    • Search Google Scholar
    • Export Citation
  • 38

    Mintzer S: Metabolic consequences of antiepileptic drugs. Curr Opin Neurol 23:1641692010

  • 39

    Moher DCook DJEastwood SOlkin IRennie DStroup DF: Improving the quality of reports of meta-analyses of randomised controlled trials: the QUOROM statement. Quality of Reporting of Meta-analyses. Lancet 354:189619001999

    • Search Google Scholar
    • Export Citation
  • 40

    Newton HBDalton JGoldlust SPearl D: Retrospective analysis of the efficacy and tolerability of levetiracetam in patients with metastatic brain tumors. J Neurooncol 84:2932962007

    • Search Google Scholar
    • Export Citation
  • 41

    Newton HBGoldlust SAPearl D: Retrospective analysis of the efficacy and tolerability of levetiracetam in brain tumor patients. J Neurooncol 78:991022006

    • Search Google Scholar
    • Export Citation
  • 42

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

    • Search Google Scholar
    • Export Citation
  • 43

    North JBPenhall RKHanieh AHann CSChallen RGFrewin DB: Postoperative epilepsy: a double-blind trial of phenytoin after craniotomy. Lancet 1:3843861980

    • Search Google Scholar
    • Export Citation
  • 44

    Oberndorfer SPiribauer MMarosi CLahrmann HHitzenberger PGrisold W: P450 enzyme inducing and non-enzyme inducing antiepileptics in glioblastoma patients treated with standard chemotherapy. J Neurooncol 72:2552602005

    • Search Google Scholar
    • Export Citation
  • 45

    Oxman ADGuyatt GH: Validation of an index of the quality of review articles. J Clin Epidemiol 44:127112781991

  • 46

    Patsalos PN: Clinical pharmacokinetics of levetiracetam. Clin Pharmacokinet 43:7077242004

  • 47

    Patsalos PNPerucca E: Clinically important drug interactions in epilepsy: general features and interactions between antiepileptic drugs. Lancet Neurol 2:3473562003

    • Search Google Scholar
    • Export Citation
  • 48

    Patsalos PNPerucca E: Clinically important drug interactions in epilepsy: interactions between antiepileptic drugs and other drugs. Lancet Neurol 2:4734812003

    • Search Google Scholar
    • Export Citation
  • 49

    Pulman JGreenhalgh JMarson AG: Antiepileptic drugs as prophylaxis for post-craniotomy seizures. Cochrane Database Syst Rev 2:CD0072862013

    • Search Google Scholar
    • Export Citation
  • 50

    Ramamurthi BRavi BRamachandran V: Convulsions with meningiomas: incidence and significance. Surg Neurol 14:4154161980

  • 51

    Rekling JC: Neuroprotective effects of anticonvulsants in rat hippocampal slice cultures exposed to oxygen/glucose deprivation. Neurosci Lett 335:1671702003

    • Search Google Scholar
    • Export Citation
  • 52

    Rosati AButtolo LStefini RTodeschini ACenzato MPadovani A: Efficacy and safety of levetiracetam in patients with glioma: a clinical prospective study. Arch Neurol 67:3433462010

    • Search Google Scholar
    • Export Citation
  • 53

    Rosengart AJHuo DTolentino JNovakovic RLFrank JIGoldenberg FD: Outcome in patients with subarachnoid hemorrhage treated with antiepileptic drugs. J Neurosurg 107:2532602007

    • Search Google Scholar
    • Export Citation
  • 54

    Shaw MDFoy PM: Epilepsy after craniotomy and the place of prophylactic anticonvulsant drugs: discussion paper. J R Soc Med 84:2212231991

    • Search Google Scholar
    • Export Citation
  • 55

    Siddiqui FWen PDworetzky BCabello DBromfield EB: Use of levetiracetam in patients with brain tumors. Epilepsia 43:Suppl 72972002

    • Search Google Scholar
    • Export Citation
  • 56

    Siomin VAngelov LLi LVogelbaum MA: Results of a survey of neurosurgical practice patterns regarding the prophylactic use of anti-epilepsy drugs in patients with brain tumors. J Neurooncol 74:2112152005

    • Search Google Scholar
    • Export Citation
  • 57

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

    • Search Google Scholar
    • Export Citation
  • 58

    Sughrue MERutkowski MJChang EFShangari GKane AJMcDermott MW: Postoperative seizures following the resection of convexity meningiomas: are prophylactic anticonvulsants indicated? Clinical article. J Neurosurg 114:7057092011

    • Search Google Scholar
    • Export Citation
  • 59

    Tanabe MUmeda MHonda MOno H: Phenytoin and carbamazepine delay the initial depression of the population spike upon exposure to in vitro ischemia and promote its post-ischemic functional recovery in rat hippocampal slices. Eur J Pharmacol 553:1041082006

    • Search Google Scholar
    • Export Citation
  • 60

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

    • Search Google Scholar
    • Export Citation
  • 61

    Temkin NR: Prophylactic anticonvulsants after neurosurgery. Epilepsy Curr 2:1051072002

  • 62

    Temkin NRDikmen SSWilensky AJKeihm JChabal SWinn HR: A randomized, double-blind study of phenytoin for the prevention of post-traumatic seizures. N Engl J Med 323:4975021990

    • Search Google Scholar
    • Export Citation
  • 63

    Tremont-Lukats IWRatilal BOArmstrong TGilbert MR: Antiepileptic drugs for preventing seizures in people with brain tumors. Cochrane Database Syst Rev 2CD0044242008

    • Search Google Scholar
    • Export Citation
  • 64

    Usery JBMichael LM IISills AKFinch CK: A prospective evaluation and literature review of levetiracetam use in patients with brain tumors and seizures. J Neurooncol 99:2512602010

    • Search Google Scholar
    • Export Citation
  • 65

    van Breemen MSWilms EBVecht CJ: Epilepsy in patients with brain tumours: epidemiology, mechanisms, and management. Lancet Neurol 6:4214302007

    • Search Google Scholar
    • Export Citation
  • 66

    Vecht CJvan Breemen M: Optimizing therapy of seizures in patients with brain tumors. Neurology 67:12 Suppl 4S10S132006

  • 67

    Wagner GLWilms EBVan Donselaar CA: Vecht ChJ: Levetiracetam: preliminary experience in patients with primary brain tumours. Seizure 12:5855862003

    • Search Google Scholar
    • Export Citation
  • 68

    Wallace EMO'Reilly MTwomey M: A review of the use of antiepileptic drugs in high-grade central nervous system tumors. Am J Hosp Palliat Care 29:6186212012

    • Search Google Scholar
    • Export Citation
  • 69

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