Seizures are among the most common medical sequelae

J Neurosurg 121:1139–1147, 2014 ©AANS, 2014 Anticonvulsant prophylaxis for brain tumor surgery: determining the current best available evidence A rev...
Author: Marian Shepherd
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J Neurosurg 121:1139–1147, 2014 ©AANS, 2014

Anticonvulsant prophylaxis for brain tumor surgery: determining the current best available evidence A review Eli T. Sayegh, B.S., Shayan Fakurnejad, B.S., Taemin Oh, B.A., Orin Bloch, M.D., and Andrew T. Parsa, M.D., Ph.D. Department of Neurological Surgery, Northwestern University, Chicago, Illinois 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. (http://thejns.org/doi/abs/10.3171/2014.7.JNS132829)

Key Words      •      anticonvulsant      •      antiepileptic      •      prophylaxis      •      craniotomy      •   brain tumors      •      oncology      •      epilepsy

S

eizures 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

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

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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 1139

E. T. Sayegh et al. 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 crossreferencing 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 metaanalyses 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 system1140

atically 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 straightforwardly characterized as being broad-spectrum (e.g., valproic acid, lamotrigine, and levetiracetam), which refers to their suitability for all types of seizures, or narrowspectrum (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 postJ Neurosurg / Volume 121 / November 2014

Anticonvulsant prophylaxis for brain tumor surgery operative 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 J Neurosurg / Volume 121 / November 2014

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 Fur1141

1142

patients undergoing   supratentorial crani otomy patients diagnosed w/   brain tumors

Eligible Study Population

prospective controlled  trials

controlled trials meet   ing methodological   quality threshold RCTs

3 (19)‡

698

404

5

Mean Follow-Up Interval (range)

Pht, VPA, Cbz, 36.5 (1–12) mos   Lam, Lev   were most  common

Phb (2), Pht (4), 6.9 mos (3 days– VPA (1)   12 mos)

Phb (2), Pht (4), 6.9 mos (3 days– VPA (1)   12 mos)

Pht (5), Cbz (1), 9.4 mos (3 days–   VPA (1),   24 mos)   Phb (1)

Pht (1), Phb (2), 22.3 mos (3 days–   Pht (1), Cbz   48 mos)  (1) Pht (3), VPA (1), 9.7 (5.4–12) mos   Phb (1)

Agents (no.)

Duration of Intervention (no.)

Results of Pooled Analyses

3 days (1), 6 or no difference in overall   24 mos (1), 12   Sz risk   mos (1) ≤14 days after diagnosis 12 mos (2) no difference in overall   Sz risk or Sz-free   (1), preop (1), postop  survival  (1) day of surgery (1), preop 3 days (1), 7 days reduction of early Sz risk  or ≤24 hrs after diag-   (1), 6 or 24   by 44%; no difference   nosis, preop (1),   mos (1), 12   in late Sz risk   intraop (1), postop (2)   mos (2) ≤14 days after diagnosis 3 days (1), 12 no difference in early or   (1), preop (1), intraop   mos (2)   late Sz risk   (1), postop (1) ≤14 days after diagnosis 3 days (1), 12 no difference in overall   (1), preop. (1), intraop   mos (2)   Sz risk; significantly   (1), postop (1)   higher adverse event  rate intraop (1), postop (2) mean 4.2 (range no difference in early or   1–52) wks   late Sz risk, extent of   resection, recurrence,   or periop mortality

preop (1), intraop (1),   postop (1)

Timing of Intervention (no.)

*  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.

all studies presenting   original data w/   AED administration   & outcome data

403

1560

318

621

5

6

4

3

No. of No. of Eligible Study Designs Studies Patients

patients diagnosed w/ RCTs   brain tumors w/o prior  Szs patients diagnosed w/ RCTs   brain tumors

Komotar et al., patients undergoing  2011   resection of supraten  torial meningioma w/o   prior Szs

Tremont  Lukats et   al., 2008

Sirven et al.,  2004

Temkin, patients undergoing  2001/2002†  craniotomy

Glantz et al.,  2000

Kuijlen et al.,  1996

Meta-Analysis

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*

E. T. Sayegh et al.

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yes yes yes yes yes yes no yes *  Komotar et al. were the only authors whose study included non–Level I evidence in addition to the clinical trials referenced in the table.

yes yes yes no no yes no no no no no yes no yes no no yes no yes no no yes no no yes no yes no

no no no no

yes yes no yes no no no no no no no yes yes no no no no yes

Foy et al., 1992 Holland et al., 1995

Primary Study Included

Glantz et al., 1996 Beenen et al., 1999 De Santis et al., 2002 Forsyth et al., 2003

Search Methodology and Meta-Analysis Design. A total of 10 RCTs were included among the 6 metaanalyses (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

Meta-Analysis

Determining the Current Best Available Evidence

TABLE 2: Primary studies included in each of the meta-analyses

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 AEDrelated 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 shortversus 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 longterm treatment for 12 months,18,42 while the other 2 did not indicate the treatment duration.13,16

Shaw et al., 1991

Adverse Events

Komotar et al., 2011* Tremont-Lukats et al.,  2008 Sirven et al., 2004 Temkin, 2001/2002 Glantz et al., 2000 Kuijlen et al., 1996

Franceschetti et al., 1990

Lee et al., 1989

North et al., 1983

thermore, 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

yes yes

Anticonvulsant prophylaxis for brain tumor surgery

1143

1144

*  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.

3 6 4 2 3 3 15 15 15 7 15 9 no yes yes yes yes yes 3 (19)† 5 5 4 6 3 no yes yes no no no no yes yes no yes no Komotar et al., 2011 Tremont-Lukats et al., 2008 Sirven et al., 2004 Glantz et al., 2000 Temkin, 2001/2002 Kuijlen et al., 1996

yes yes yes yes yes yes

no yes yes no yes no

no no yes no no no

Primary Studies QUOROM Score Included Only RCTs (0–18) No. of Primary Studies Other CINAHL CENTRAL

Database Searched

EMBASE Meta-Analysis

PubMed/ MEDLINE

TABLE 3: Search methodology, study selection, methodological quality (QUOROM score), and scientific quality (Oxman-Guyatt score) of the meta-analyses*

Oxman-Guyatt Score (1–7)

E. T. Sayegh et al. risk, and/or adverse events (Table 4). Only 2 and 3 metaanalyses 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.

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 metaanalyses demonstrated an improvement in seizure control with the use of AED prophylaxis.

Discussion Implications for Clinical Practice

The current best available evidence, from the metaanalyses 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 latergeneration AEDs such as levetiracetam offer an improved safety profile over older AEDs, clinicians who wish to use prophylaxis should use these newer agents. J Neurosurg / Volume 121 / November 2014

no no yes yes yes no

J Neurosurg / Volume 121 / November 2014

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

no no yes no yes no no no no yes no no yes no no no no no yes no no no no no yes no no no no no yes no no no no no no no no yes no no no yes no yes yes yes Komotar et al., 2011 Tremont-Lukats et al., 2008 Sirven et al., 2004 Glantz et al., 2000 Temkin, 2001/2002 Kuijlen et al., 1996

yes no yes no yes no

yes no yes no yes no

no yes no yes no no

Statistical Heterogeneity Subgroup &/or Analysis Sensitivity Analyses OS Periop Mortality PFS Recurrence Extent of Resection Sz-Free Survival Overall Sz Risk

Early Sz Risk

Late Sz Risk

Adverse Events

Limitations of Current Evidence

Meta-Analysis

Outcome Reported

TABLE 4: Outcomes of interest, performance of statistical heterogeneity analysis, and performance of subgroup and/or sensitivity analyses in the meta-analyses*

Anticonvulsant prophylaxis for brain tumor surgery 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

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E. T. Sayegh et al. 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. References   1.  Baker CJ, Prestigiacomo CJ, Solomon RA: Short-term perioperative anticonvulsant prophylaxis for the surgical treatment of low-risk patients with intracranial aneurysms. Neurosurgery 37:863–871, 1995  2. Bauer J, Ben-Menachem E, Krämer G, Fryze W, Da Silva S, Kasteleijn-Nolst Trenité DG: Levetiracetam: a long-term follow-up study of efficacy and safety. Acta Neurol Scand 114:169–176, 2006   3.  Beenen LF, Lindeboom J, Kasteleijn-Nolst Trenité DG, Heimans JJ, Snoek FJ, Touw DJ, et al: Comparative double blind clinical trial of phenytoin and sodium valproate as anticonvulsant prophylaxis after craniotomy: efficacy, tolerability, and cognitive effects. J Neurol Neurosurg Psychiatry 67:474– 480, 1999   4.  Ben-Menachem E, Gilland E: Efficacy and tolerability of levetiracetam during 1-year follow-up in patients with refractory epilepsy. Seizure 12:131–135, 2003   5.  Bhandari M, Joensson A: Clinical Research for Surgeons. New York: Thieme, 2009   6.  Boarini DJ, Beck DW, VanGilder JC: Postoperative prophylactic anticonvulsant therapy in cerebral gliomas. Neurosurgery 16:290–292, 1985   7.  Calabresi P, Cupini LM, Centonze D, Pisani F, Bernardi G: Antiepileptic drugs as a possible neuroprotective strategy in brain ischemia. Ann Neurol 53:693–702, 2003   8.  Chalk JB, Ridgeway K, Brophy T, Yelland JD, Eadie MJ: Phenytoin impairs the bioavailability of dexamethasone in neurological and neurosurgical patients. J Neurol Neurosurg Psychiatry 47:1087–1090, 1984   9.  Curry WJ, Kulling DL: Newer antiepileptic drugs: gabapentin, lamotrigine, felbamate, topiramate and fosphenytoin. Am Fam Physician 57:513–520, 1998 10.  De Santis A, Villani R, Sinisi M, Stocchetti N, Perucca E: Add-on phenytoin fails to prevent early seizures after surgery for supratentorial brain tumors: a randomized controlled study. Epilepsia 43:175–182, 2002 11.  Deutschman CS, Haines SJ: Anticonvulsant prophylaxis in neurological surgery. Neurosurgery 17:510–517, 1985 12.  Dropcho EJ, Soong SJ: Steroid-induced weakness in patients with primary brain tumors. Neurology 41:1235–1239, 1991 13.  Forsyth PA, Weaver S, Fulton D, Brasher PM, Sutherland G, Stewart D, et al: Prophylactic anticonvulsants in patients with brain tumour. Can J Neurol Sci 30:106–112, 2003 14. Foy PM, Chadwick DW, Rajgopalan N, Johnson AL, Shaw MD: Do prophylactic anticonvulsant drugs alter the pattern of seizures after craniotomy? J Neurol Neurosurg Psychiatry 55:753–757, 1992 15.  Foy PM, Copeland GP, Shaw MD: The natural history of postoperative seizures. Acta Neurochir (Wien) 57:15–22, 1981 16.  Franceschetti S, Binelli S, Casazza M, Lodrini S, Panzica F, Pluchino F, et al: Influence of surgery and antiepileptic drugs on seizures symptomatic of cerebral tumours. Acta Neurochir (Wien) 103:47–51, 1990

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