Neurosurg Rev (2014) 37:381–388 DOI 10.1007/s10143-014-0538-6
REVIEW
Treatment of epileptic seizures in brain tumors: a critical review R. Bauer & M. Ortler & M. Seiz-Rosenhagen & R. Maier & J. V. Anton & I. Unterberger
Received: 11 January 2013 / Revised: 24 October 2013 / Accepted: 26 January 2014 / Published online: 24 April 2014 # Springer-Verlag Berlin Heidelberg 2014
Abstract Epileptic seizures represent a common signal of intracranial tumors, frequently the presenting symptom and the main factor influencing quality of life. Treatment of tumors concentrates on survival; antiepileptic drug (AED) treatment frequently is prescribed in a stereotyped way. A differentiated approach according to epileptic syndromes can improve seizure control and minimize unwarranted AED effects. Prophylactic use of AEDs is to be discouraged in patients without seizures. Acutely provoked seizures do not need longterm medication except for patients with high recurrence risk indicated by distinct EEG patterns, auras, and several other parameters. With chronically repeated seizures (epilepsies), long-term AED treatment is indicated. Non-enzymeinducing AEDs might be preferred. Valproic acid exerts effects against progression of gliomatous tumors. In low-grade astrocytomas with epilepsy, a comprehensive presurgical epilepsy work-up including EEG-video monitoring is advisable; in static non-progressive tumors, it is mandatory. In these
R. Bauer (*) Neurosurgery, Landeskrankenhaus Feldkirch, Feldkirch, Austria e-mail: [email protected] M. Ortler Neurosurgery, Medical University Innsbruck, Innsbruck, Austria M. Seiz-Rosenhagen Neurosurgery, Medical University Mannheim, Mannheim, Germany R. Maier Radio-Oncology, Landeskrankenhaus Feldkirch, Feldkirch, Austria J. V. Anton Neurosurgery, University Hospital Salzburg, Salzburg, Austria I. Unterberger Neurology, Medical University Innsbruck, Innsbruck, Austria
cases, the neurosurgical approach has to include the removal of the seizure-onset zone frequently located outside the lesion. Keywords Supratentorial brain tumors . Epileptic seizures . Seizure syndromes . Antiepileptic drugs . Epilepsy surgery
Epileptic seizures and epilepsies/epileptic syndromes Epileptic seizures frequently represent the main symptom leading to the diagnosis of an underlying brain tumor. Incidence rates depend on the type of tumor, on patient’s age, on seizure type, and on localization of the tumor (Table 1). The likelihood of seizures is higher in supratentorial tumors [16, 18, 36, 54, 90]. Statistics proved an increased incidence of seizures in frontal low-grade astrocytomas [18] and in parietal meningiomas [20]. No correlation of seizure incidence with localization could be found in supratentorial astrocytic tumors [37]. Occipital tumors are less frequently complicated by seizures [36, 57]. Seizure types are generalized without focal signs in 32–40 % of patients [18, 36, 89]. The relation between focal and generalized seizures was 79 to 21 % in preoperative and 75 to 25 % in postoperative seizures [37]. Several types of focal seizures are observed; no one is specific for tumors. The correlation to tumor localization was not investigated by means of systematic EEG-video recordings. Status epilepticus was observed in 25 % of patients with primary brain tumors [15]. A syndromatic epileptological classification separates acutely provoked seizures from epilepsies with recurrent unprovoked seizures (see [35]). Recurring seizures in chronic cerebral lesions without acute additional triggers are termed remote symptomatic epilepsies. Table 2 proposes a classification of tumor-related seizure disorders based on this concept. Generalized tonic-clonic seizures can occur as an isolated single event. However, close history taking frequently reveals
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Table 1 Prevalence of seizures and tumor type Tumor type
Percentage of all seizures
Percentage of presenting symptom
Authors
Low-grade glioma Anaplastic glioma Glioblastoma multiforme Mixed glioma Oligodendroglioma Meningioma Brain metastases Cerebral lymphoma
41.4–95 43.3–69 24–49
81–85
[25, 50, 53, 89] [8, 47, 50, 53] [8, 16, 47, 50, 53] [47, 50] [8, 47, 50, 53] [8, 20, 50, 49] [8, 76, 85, 90] [50, 76]
57.1–62 53–90 26.6–41 20–40 10–16.7
24–50
20
Authors numbers according to “References”
the co-occurrence of minor seizures, especially auras (simple focal seizures). In these cases, epilepsy has to be diagnosed, and long-term antiepileptic drug (AED) treatment is justified. With well-differentiated tumors (Table 1) [37, 53, 54, 89], seizures occur more often as the presenting symptom and predate diagnosis for many years [33]. Medically resistant chronic epilepsy due to non-progressive static brain tumors have usually been diagnosed as cryptogenic focal epilepsies in the pre-CT or pre-MRI era. Preoperative histories were reported between 11 and 14 years [14, 69, 100]. Histological diagn o s e s i n c l u d e g a n g l i o g l i o m a , d y s e m b r yo p l a s t i c neuroepithelial tumor, pleomorphic xanthoastrocytoma, and pilocytic astrocytoma [14, 38, 59, 100]. In contrast to chronic epilepsies, early postoperative seizures are defined as occurring within the first week after surgery [24, 45, 48, 62]. Acute consequences of surgery act as provoking factors. After surgical removal of meningiomas, 18.4 % of patients developed new-onset seizures, 66.7 % of these patients within 48 h after operation, and 33.3 % as late seizures [49]. In a retrospective study of 180 meningioma patients without a preoperative history of seizures, one early postoperative seizure and no late seizures have been observed [83]. The incidence of acute postoperative seizures has not Table 2 Seizure manifestations/syndromes in patients with brain tumors Single seizures Seizures as the presenting symptom Chronic epilepsies in static brain tumors Epilepsies in slowly progressing tumors (low-grade astrocytoma) Postoperative acute symptomatic (early) seizures Acute symptomatic seizures due to other acute complications (bleeding, increased intracranial pressure, …) Postoperative epilepsy (late seizures) Postoperative epilepsy due to tumor progression/relapse Seizures not related to the tumor
been systematically investigated with other tumor types. Furthermore, the relation to the development of chronic epilepsies is largely unknown. Besides surgery, further etiologies for acute symptomatic seizures with brain tumors are intermittent hemorrhage, increased intracranial pressure, and edema among others. Late seizures can be considered postoperative epilepsies and are explained by scars after surgery, tumor rests, and/or neuronal network disruptions. In supratentorial astrocytic tumors, postoperative late seizures occurred in 18 % of patients [37]. Postoperative seizures are correlated with the presence of preoperative seizures [16, 37]. Recurrence after an initial postoperative seizure control or increased seizure frequency raises the suspicion of tumor relapse or progression [16, 17, 37]. In supratentorial brain tumors, seizures rarely are unrelated to the tumor. Several drugs like antidepressants or antibiotics (for summary see [6]) as well as withdrawal from AEDs or alcohol can provoke acute symptomatic seizures not related to the tumor. Furthermore, epilepsy can represent a second independent disorder. The pathophysiology of tumor-related seizures is poorly understood. The tumor itself is not identical with the seizureonset zone, mostly located in the tissue surrounding the tumor (for review see [8, 23, 79, 81]). Peritumoral amino acid disturbances, local metabolic imbalances, edema, disordered neurotransmitter and receptor balances, pH alterations, and several other factors play a role. A statistically elevated mean concentration of the main excitatory neurotransmitter glutamate was found in tumor and peritumoral brain specimens [98].
EEG in brain tumors Although neuroimaging methods have replaced EEG as a diagnostic and localizing tool, EEG is of relevance in seizure monitoring and detecting epileptiform discharges. Within the tumor itself, no electrical activity can be recorded in most tumor types. Slow waves signify loss-of-function disturbances of the surrounding region, and spikes or seizures are produced by areas more distant from the tumor (for summary see [34]). New aspects arise from magnetoencephalography (MEG) and EEG-video monitoring. Low-frequency magnetic activity is limited to the peritumoral tissue [3]. If this activity is recorded within the tumor area, it warns the neurosurgeon that the lesion comprises functioning neurons [3] related to cognitive deficits (Bartolomei [5]). Continuous spiking in long-term monitoring specifies glioneuronal tumors and focal cortical dysplasias [28]. In 28 % of cases, long-term-monitoring can detect unnoticed seizures and prompt changes of AED therapy [41]. Furthermore, EEG monitoring of seizures remains the golden standard for the delineation of the seizure-onset zone.
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Treatment of epileptogenic brain tumors Neurosurgery The surgical armamentarium includes lesion biopsy, subtotal lesionectomy, complete lesionectomy, extended lesionectomy, lesionectomy combined with corticotomy of the seizure-onset zone (epilepsy surgery), and several palliative measures. Standard neurosurgery per se has a significant impact on seizure frequency. However, numbers are difficult to interpret. Papers differ with respect to length of follow-up, concomitant AED therapy, mode of neurosurgical methods, presurgical work-up, and scrutiny of seizure counting among others. Table 3 gives an overview of postoperative seizure freedom in patients with preoperative epilepsies. Seizure control can be reached in more than 50 % of patients. As the most significant factor, gross-total tumor resection was uniformly reported. Standard neurosurgery of tumors aims to achieve complete lesionectomy when possible. In epileptogenic brain tumors, strategies of non-tumor-related epilepsy surgery might be added. In a recent review of the current treatment of low-grade astrocytoma [73], seizures are considered the most common presentation. Since the seizure-onset zone is located in neighboring or even remote areas (see pathophysiology), a close presurgical work-up is advisable in cases with long life expectancy and/or seizures as a significant factor for quality of life [40, 68]. In cases of slowly growing or static epileptogenic tumors, a thorough presurgical evaluation is considered state of the art [7, 21]. For epilepsy surgery in dysembryoplastic neuroepithelial tumors, an MRIbased scheme was developed [19]. Besides improved epileptological results, electrical stimulation via intracranial electrodes can indicate eloquent brain areas, avoid intraoperative testing, and govern surgical approach.
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not performed in tumor epilepsies. Treatment guidelines for persons with epilepsy in general leave open specific questions of tumor epilepsies (see [96]). A part of these questions can be solved by a close diagnosis of the epilepsy syndrome according to Table 2. In acute symptomatic seizures, chronic AEDs are generally not indicated. Several clinical parameters might indicate a high risk for the development of chronic epilepsies after an acute symptomatic seizure. Among these signs are specific seizure types, EEG signs, results of a prolonged EEGvideo recording [41], or detection of inconspicuous seizures by close history taking. In these cases and definite epilepsies principles of general epilepsy, treatment might be applied balancing the impact of seizures against unwarranted AED effects, discomfort, and expense of chronic AED intake [44]. Prophylactic AED treatment The high risk for development of seizures and epilepsies raised the question of prophylactic AED treatment in newly diagnosed brain tumors without seizures. Glantz et al. [32] summarize practice parameters of the American Academy of Neurology. Prophylactic AED treatment should not be used. A meta-analysis of relevant studies found no evidence for preventing first seizures. After the year 2000, further studies [24, 29] and meta-analyses [85, 88] confirmed these recommendations. However, frequent use of prophylactic AED— 57 % of patients after Lwu et al. [56]—contradicts published evidence [17, 84]. Perioperative AED treatment
Antiepileptic drugs
Prophylaxis can also be directed against acute symptomatic seizures in the postoperative phase. After brain trauma, the hallmark paper of Temkin et al. [87] found effectiveness of prophylactic treatment against acute symptomatic seizures, but not against the development of posttraumatic epilepsies. Comparable results were not reported with tumor-related seizures. Some hints can be found. Franceschetti et al. [30] reported an effect of prophylactic AEDs on early seizures, Shugrue et al. [83] a small benefit in meningioma patients, and Boarini et al. [12] a reduction of the severity of seizures. Many neurosurgeons administer AEDs in the perioperative phase in order to prevent acute symptomatic seizures. If this strategy is chosen on the basis of an argument of analogy with trauma, anticonvulsants should be tapered in the first postoperative week. An equivalent study to Temkin et al. [87] in brain tumors should solve the question whether the routine use of perioperative AED treatment is justified or not.
Continuous AED treatment
Withdrawal of AED treatment
Efficacies of AEDs have been investigated in controlled studies in the general epilepsy population. Corresponding trials are
After gaining seizure freedom in epilepsies, withdrawal of AEDs remains controversial. In the general epilepsy
Radiotherapy and chemotherapy De Groot et al. [23] review papers reporting the effect of radiotherapy or radiosurgery on seizure frequency. Observational studies reported an improvement in unoperated tumor patients. In a cohort study, Sherman et al. [82] compared operated low-grade glioma patients with consecutive temozolomide therapy and those under observation after operation. Of the temozolomide patients, 59 % exhibited a seizure reduction of >50 % compared with 13 % not using chemotherapy.
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Table 3 Seizure freedom after neurosurgery in general
structural abnormalities, the result of repeated prolonged EEG-video recording, and AED serum levels influence the individual decision.
Tumor type
Percentage of class I (Engel) seizure outcome after resection
Authors
Low-grade glioma
36–100, ∑ 71
[26] (review over 20 papers)
Meningioma Glioneural tumor
63.5–62.7 45–100, ∑ 80
Malignant astrocytoma Temporal tumor
77 26–64.7
[20, 49] [26] (review over 39 papers) [16] [38] (mixed tumor types in children) [99] (low grade glioma) [55]
Non-progressive and 82 slowly growing tumors
Choice of the drug
Authors numbers according to “References”
population, several papers analyze withdrawal trials (for summary see [42]). Predictors for successful withdrawal are length of seizure freedom, age, duration of uncontrolled epilepsy, seizure type, structural abnormalities, and EEG. However, controlled, prospective, randomized, double-blinded studies [52] are the exception. Seizure relapse at 12 months occurred in 15 % of the withdrawal group and 7 % of the nonwithdrawal group [52]. A number of observational and retrospective studies report successful AED withdrawal in 42– 75 % of patients [1, 9, 43, 46, 75, 80, 97]. However, Menon et al. [64] found complete AED-free status in only 20 % of patients after 4 years. No studies systematically examine AED withdrawal in tumor-related epilepsies. Therefore, the decision has to be made, transferring what is known in general. Patient’s attitude after careful information about the increased risk of seizure recurrence plays a key role. The number and severity of prior seizures, the development of EEG and
No single AED exhibits significant superiority with regard to efficacy, but new AEDs might be better tolerated [10]. With tumor-related epilepsies, some aspects have to be added to epilepsy guidelines. The role of enzyme-inducing AEDs was studied in several conflicting papers. Interactions between AEDs and chemotherapeutic agents have been reviewed by Vecht et al. [92]. Poor seizure and tumor control as well as increased unwarranted side effects can be observed with enzyme-inducing AEDs. Valproic acid (VPA) was considered the drug of first choice. This recommendation is confirmed by a retrospective study comparing valproic acid with enzyme-inducing AEDs in glioblastoma patients treated with standard chemotherapy [72]. An analysis in patients with glioblastoma reported contrasting results [39]. Paradoxically, use of enzyme-inducing AEDs correlated with a better outcome. However, the study was biased by a small number of patients receiving enzymeinducing AEDs. In a recent review, the use of enzymeinducing or enzyme-inhibiting AEDs is discouraged in patients with brain tumors [22]. Most AEDs of the second and third generation (“New AEDs”) are not enzyme-inducing. Therefore, their use should be preferred in tumor patients. Several studies investigated Levetiracetam (LEV). Table 4 summarizes results of nine studies. All studies report efficacy against seizures comparable to phenytoin but superior tolerability. Table 5 gives an overview of trials with other new AEDs. Data are far from being conclusive; no paper fulfills criteria demanded by
Table 4 Studies with levetiracetam (LEV) in brain tumors Authors Study design
Number of patients
Type of tumor
Results
Glioma Prim brain tumor
Effect similar to PHT, LEV better tolerated LEV “feasible in brain tumor”
[65] [93]
Retrospective comparison with PHT 76 Preliminary, observational 18
[70] [58] [67]
Retrospective chart review Observational, add-on Retrospective comp with PHT, prophylactic use Pilot study, switch PHT to LEV Prospective, uncontrolled
41 Prim brain tumor, metastases 19 Supratentorial glioma LEV 105 PHT 210 After craniotomy for different reasons, including tumors 29 Glioma 82 under LEV Glioma
Effective + well tolerated, 59 % seizure-free Reduced seizures refractory to other AEDs Similar effect preventing early and late seizures, better tolerated Switching to LEV is safe 91 % free of seizures at last control
Prospective, uncontrolled, laboratory Prospective, single-arm study
34
Glioma
SV2A correlates with clinical response
25
Suspected primary brain tumors Efficacy of LEV appears promising
[51] [77] [22] [4]
PHT phenytoin, Authors numbers according to “References”
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Table 5 Studies in tumor-related epilepsies with secondary and tertiary generation AEDs AED
Authors Study design
Number of patients
Tumor type
Pregabalin
[71]
Observational, retrospective
9
Primary brain tumors, mostly glioma
[91] [78] Tiagabine [86] Oxcarbazepine [63] [60]
Expert opinion Expert opinion Open-label, add-on Prophylactic against early seizures, uncontrolled Retrospective, observational
Topiramate
[61]
Prospective, observational
Lacosamide
[59]
Add-on
Results
6 seizure-free, all >50 % seizure reduction, 2 discontinuation due to side effects LEV or gabapentin … can be useful LEV and gabapentin seem promising 11 Glioma 3 seizure-free, 7>50 % reduction 150 Glioma 2.7 % (4 patients) early seizures, no comments on long-term use 35 mono 35 Primary and secondary Similar effect as traditional AEDs, better tolerated add-on brain tumors 14 mono 33 Primary and secondary 55.6 % seizure-free, 20 % reduction >50 % add-on brain tumors 14 Glioma, different 78.6 % reduction >50 % grades
Authors numbers according to “References”
regulatory authorities for licensing. Therefore, decisions are bound on lower levels of evidence. (2) AEDs and anti-tumor effects Cell line experiments report anti-tumor effects of topiramate and LEV [13, 27]. The most promising experimental and clinical results are reported for VPA (for reviews see [11, 65, 66]). Weller et al. [95] retrospectively analyzed a multicentre temozolamide trial for glioblastoma. Patients receiving VPA alone derived more survival benefit from a combined temozolamide/radiotherapy. For explanation, an increase of temozolamide bioavailability or sensitizing for radiochemotherapy due to inhibition of histone deacetylase is discussed. This study represents an argument to prefer VPA in glioma patients. Future studies are needed to establish VPA as the AED of first choice. Blood dyscrasias of VPA and neurosurgical interventions Thrombocytopenia and inhibition of platelet aggregation are the most common hematologic abnormalities associated with VPA (for summary see [31]). Therefore, some authors recommend routine discontinuation prior to surgery [74]. Others found no increase of blood loss during temporal lobectomy [94] or no bleeding complications in patients undergoing neurosurgery while receiving VPA [2]. Statistically conclusive investigations are not published.
Concluding pragmatic recommendations (1) Many questions cannot be answered evidence-based. Even if matched samples might not be possible for
(3) (4)
(5)
(6)
ethical reasons, adequate pragmatic trials should be performed in future. Prophylactic AED treatment is to be discouraged [32]. The effectiveness against acute symptomatic seizures [30, 83] has to be re-analyzed by well-designed studies. Chronically recurrent seizures (epilepsies) should be treated according to the guidelines for epilepsies in general. Withdrawal from chronic AED treatment depends on the length of seizure freedom, the adverse events with AEDs, and several other factors [42]. No guidelines exist for tumor epilepsies. In cases with seizures as the main problem, especially with low-grade astrocytomas, a comprehensive presurgical epilepsy monitoring can demonstrate the seizure-onset zone frequently outside the lesion. A lesionectomy combined with removal of the seizure focus can increase the percentage of seizure-free patients after operation [40, 68]. Static non-progressive tumors should be treated by epilepsy surgery per se in every case [7, 21].
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Comments Krasimir Minkin, Sofia, Bulgaria This review is focused on the epilepsy problems of oncological neurosurgery. The authors raised the question about the contradictions between evidence-based medicine and practical medicine regarding prophylactic antiepileptic drug treatment of patients with newly diagnosed brain tumors without history of seizures. The review of the risks for early and late acute postoperative seizures provides some insights for the perioperative and continuous AED treatment in patients with brain tumors. An important positive feature of this paper is the attempt to review all antiepileptic treatment options in patients with brain tumor-related epilepsy: drugs, surgery, radiotherapy, and chemotherapy. Bowen Jiang, Alfredo Quinones-Hinojosa, Baltimore, USA. Seizures represent a major symptomatology in the brain tumor population and have significant implications on a patient’s quality of life. The use of antiepileptic drugs (AED) for brain tumor patients is an area of ongoing controversy and debate. Bauer and colleagues are commended for their critical review of the existing literature on this topic. The authors suggest that prophylactic use of AEDs is unwarranted in patients without preoperative seizures. They provide evidence that acutely provoked seizures, for the most part, do not require long-term AED treatment. The authors are applauded for their attempt to summarize the vast literature on evidencedriven guidelines. Yet, the question of when an AED is indicated and for how long is nuanced and complex. The answer is likely dependent upon a combination of pre/intra/postoperative factors, with a patient’s unique tumor history paramount to sophisticated decision-making. For instance, the authors included meta-analysis from Sirven et al. [1] and Tremont-Lukats et al. [2] to support the conclusion that prophylactic AED treatment has no evidence in brain tumor patients without seizures. Within the benign brain tumor literature, Sughrue et al. evaluated 180 patients who underwent resection for convexity meningiomas. Although none of these patients had preoperative seizures, 129 were treated with AED postoperatively without any statistical difference in seizure control (0 vs 1.9 %) [3]. These data are confirmed by a meta-analysis from Komotar et al. [4] on 19 studies with a total of 689 supratentorial meningioma patients, which concluded no difference in the rate of early or late seizures between AED-treated and not treated groups. It would appear that the routine use of prophylactic AEDs for patients undergoing supratentorial meningioma resection provides no benefit, a sentiment many clinicians would be inclined to agree.
Neurosurg Rev (2014) 37:381–388 However, as we become more sophisticated and granular with our research, the neurosurgical community is now increasingly able to identify factors associated with higher seizure risk and thus better select patients ideal for AED management. Our institution has previously studied risk factors associated with seizures in WHO grade 1 meningiomas and found that patients with poor functional status, absence of signs of increased ICP, and MRI findings with significant cerebral edema are at higher risk for seizures [5]. Parasagittal and sphenoid wing meningioma are associated with continued seizures despite surgery and therapeutic AED. Likewise, for patients with high-grade gliomas (WHO III and IV), our institution previously found preoperative uncontrolled seizures and parietal lobe involvement to be negative predictors of seizure control [6]. In the era of individualized medicine, patient-specific disease characteristics should be factored into a potential AED therapeutic course. For these patients, a unified shotgun recommendation may not be appropriate, and in fact, many of these patients may benefit from AED therapy despite the guidelines. At our institution, the use of levetiracetam is routine in the postoperative period and often maintained until the patient returns for first followup visit at 14–21 days. Since levetiracetam is a newer AED, its efficacy and side effect profile is frequently debated with that of phenytoin. Lim et al. conducted a randomized phase II pilot study on 29 patients who received either levetiracetam or phenytoin for postoperative seizure control [7]. The authors report better seizure control (87 vs 75 %) and fewer side effects (dizziness, depression, lethargy, insomnia) with levetiracetam. Indeed, this has been our institutional experience as well. Finally, the authors astutely recognized that the initial data was from Temkin et al. [8] in the traumatic brain injury literature, in which phenytoin was utilized for the prevention of posttraumatic seizures. This literature has since then been extrapolated into the brain tumor armamentarium. Clearly, studies focused on seizure frequency, duration, and severity in the postoperative period will continue to advance the current literature. This study by Bauer et al. succinctly summarizes the vast literature on this topic and suggests treatment paradigms that will help neurosurgeons and neurologists alike in managing seizures for the brain tumor population. References 1. Sirven JI, Wingerchuk DM, Drazkowski JF et al. (2004) Seizure prophylaxis in patients with brain tumors: a meta-analysis. Mayo Clin Proc 79:1,489–1,494 2. Tremont-Lukats W, Ratilal BO, Armstrong T, Gilbert MR (2008) Antiepileptic drugs for preventing seizures in people with brain tumors. Cochrane Database Syst Rev 18:CD004424 3. Seghrue ME, Rutkowski MJ, Chang EF, Shangari G, Kane AJ, McDermott MW, Berger MS, Parsa AT (2011) Postoperative seizures following the resection of convexity meningiomas: are prophylactic anticonvulsants indicated? J Neurosurg 114: 705–709. 4. Komotar RJ, Raper DM, Starke RM, Iorgulescu JB, Gutin PH (2011) Prophylactic antiepileptic drug therapy in patients undergoing supratentorial meningioma resection: a systematic analysis of efficacy. J Neurosurg 115: 483–490 5. Chaichana KL, Pendleton C, Zaidi H, Olivi A, Weingart JD, Gallia GL, Lim M, Brem H, Quinones-Hinojosa A (2013) Seizure control for patients undergoing meningioma surgery. World Neurosurg 90(3– 4):512–524 6. Chaichana KL, Parker SL, Olivi A, Quinones-Hinojosa A (2009) Long-term seizure outcomes in adult patients undergoing primary resection of malignant brain astrocytoma. J Neurosurg 111(2):282–292 7. Lim DA, Tarapore P, Chang EF, Burt M, Chakalian L, Barbaro N, Chang S, Lamborn KR, McDermott MW (2009). Safety and feasibility of switching from phenytoin to levetiracetam monotherapy for gliomarelated seizure control following craniotomy: a randomized phase II pilot study. J Neurooncol 93:349–354. 8. Temkin NR, Dikmen SS, Wilensky AJ et al. (1990) A randomized, double-blind study of phenytoin for the prevention of post-traumatic seizures. NEJM 323:497–502
REVIEW
Treatment of epileptic seizures in brain tumors: a critical review R. Bauer & M. Ortler & M. Seiz-Rosenhagen & R. Maier & J. V. Anton & I. Unterberger
Received: 11 January 2013 / Revised: 24 October 2013 / Accepted: 26 January 2014 / Published online: 24 April 2014 # Springer-Verlag Berlin Heidelberg 2014
Abstract Epileptic seizures represent a common signal of intracranial tumors, frequently the presenting symptom and the main factor influencing quality of life. Treatment of tumors concentrates on survival; antiepileptic drug (AED) treatment frequently is prescribed in a stereotyped way. A differentiated approach according to epileptic syndromes can improve seizure control and minimize unwarranted AED effects. Prophylactic use of AEDs is to be discouraged in patients without seizures. Acutely provoked seizures do not need longterm medication except for patients with high recurrence risk indicated by distinct EEG patterns, auras, and several other parameters. With chronically repeated seizures (epilepsies), long-term AED treatment is indicated. Non-enzymeinducing AEDs might be preferred. Valproic acid exerts effects against progression of gliomatous tumors. In low-grade astrocytomas with epilepsy, a comprehensive presurgical epilepsy work-up including EEG-video monitoring is advisable; in static non-progressive tumors, it is mandatory. In these
R. Bauer (*) Neurosurgery, Landeskrankenhaus Feldkirch, Feldkirch, Austria e-mail: [email protected] M. Ortler Neurosurgery, Medical University Innsbruck, Innsbruck, Austria M. Seiz-Rosenhagen Neurosurgery, Medical University Mannheim, Mannheim, Germany R. Maier Radio-Oncology, Landeskrankenhaus Feldkirch, Feldkirch, Austria J. V. Anton Neurosurgery, University Hospital Salzburg, Salzburg, Austria I. Unterberger Neurology, Medical University Innsbruck, Innsbruck, Austria
cases, the neurosurgical approach has to include the removal of the seizure-onset zone frequently located outside the lesion. Keywords Supratentorial brain tumors . Epileptic seizures . Seizure syndromes . Antiepileptic drugs . Epilepsy surgery
Epileptic seizures and epilepsies/epileptic syndromes Epileptic seizures frequently represent the main symptom leading to the diagnosis of an underlying brain tumor. Incidence rates depend on the type of tumor, on patient’s age, on seizure type, and on localization of the tumor (Table 1). The likelihood of seizures is higher in supratentorial tumors [16, 18, 36, 54, 90]. Statistics proved an increased incidence of seizures in frontal low-grade astrocytomas [18] and in parietal meningiomas [20]. No correlation of seizure incidence with localization could be found in supratentorial astrocytic tumors [37]. Occipital tumors are less frequently complicated by seizures [36, 57]. Seizure types are generalized without focal signs in 32–40 % of patients [18, 36, 89]. The relation between focal and generalized seizures was 79 to 21 % in preoperative and 75 to 25 % in postoperative seizures [37]. Several types of focal seizures are observed; no one is specific for tumors. The correlation to tumor localization was not investigated by means of systematic EEG-video recordings. Status epilepticus was observed in 25 % of patients with primary brain tumors [15]. A syndromatic epileptological classification separates acutely provoked seizures from epilepsies with recurrent unprovoked seizures (see [35]). Recurring seizures in chronic cerebral lesions without acute additional triggers are termed remote symptomatic epilepsies. Table 2 proposes a classification of tumor-related seizure disorders based on this concept. Generalized tonic-clonic seizures can occur as an isolated single event. However, close history taking frequently reveals
382
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Table 1 Prevalence of seizures and tumor type Tumor type
Percentage of all seizures
Percentage of presenting symptom
Authors
Low-grade glioma Anaplastic glioma Glioblastoma multiforme Mixed glioma Oligodendroglioma Meningioma Brain metastases Cerebral lymphoma
41.4–95 43.3–69 24–49
81–85
[25, 50, 53, 89] [8, 47, 50, 53] [8, 16, 47, 50, 53] [47, 50] [8, 47, 50, 53] [8, 20, 50, 49] [8, 76, 85, 90] [50, 76]
57.1–62 53–90 26.6–41 20–40 10–16.7
24–50
20
Authors numbers according to “References”
the co-occurrence of minor seizures, especially auras (simple focal seizures). In these cases, epilepsy has to be diagnosed, and long-term antiepileptic drug (AED) treatment is justified. With well-differentiated tumors (Table 1) [37, 53, 54, 89], seizures occur more often as the presenting symptom and predate diagnosis for many years [33]. Medically resistant chronic epilepsy due to non-progressive static brain tumors have usually been diagnosed as cryptogenic focal epilepsies in the pre-CT or pre-MRI era. Preoperative histories were reported between 11 and 14 years [14, 69, 100]. Histological diagn o s e s i n c l u d e g a n g l i o g l i o m a , d y s e m b r yo p l a s t i c neuroepithelial tumor, pleomorphic xanthoastrocytoma, and pilocytic astrocytoma [14, 38, 59, 100]. In contrast to chronic epilepsies, early postoperative seizures are defined as occurring within the first week after surgery [24, 45, 48, 62]. Acute consequences of surgery act as provoking factors. After surgical removal of meningiomas, 18.4 % of patients developed new-onset seizures, 66.7 % of these patients within 48 h after operation, and 33.3 % as late seizures [49]. In a retrospective study of 180 meningioma patients without a preoperative history of seizures, one early postoperative seizure and no late seizures have been observed [83]. The incidence of acute postoperative seizures has not Table 2 Seizure manifestations/syndromes in patients with brain tumors Single seizures Seizures as the presenting symptom Chronic epilepsies in static brain tumors Epilepsies in slowly progressing tumors (low-grade astrocytoma) Postoperative acute symptomatic (early) seizures Acute symptomatic seizures due to other acute complications (bleeding, increased intracranial pressure, …) Postoperative epilepsy (late seizures) Postoperative epilepsy due to tumor progression/relapse Seizures not related to the tumor
been systematically investigated with other tumor types. Furthermore, the relation to the development of chronic epilepsies is largely unknown. Besides surgery, further etiologies for acute symptomatic seizures with brain tumors are intermittent hemorrhage, increased intracranial pressure, and edema among others. Late seizures can be considered postoperative epilepsies and are explained by scars after surgery, tumor rests, and/or neuronal network disruptions. In supratentorial astrocytic tumors, postoperative late seizures occurred in 18 % of patients [37]. Postoperative seizures are correlated with the presence of preoperative seizures [16, 37]. Recurrence after an initial postoperative seizure control or increased seizure frequency raises the suspicion of tumor relapse or progression [16, 17, 37]. In supratentorial brain tumors, seizures rarely are unrelated to the tumor. Several drugs like antidepressants or antibiotics (for summary see [6]) as well as withdrawal from AEDs or alcohol can provoke acute symptomatic seizures not related to the tumor. Furthermore, epilepsy can represent a second independent disorder. The pathophysiology of tumor-related seizures is poorly understood. The tumor itself is not identical with the seizureonset zone, mostly located in the tissue surrounding the tumor (for review see [8, 23, 79, 81]). Peritumoral amino acid disturbances, local metabolic imbalances, edema, disordered neurotransmitter and receptor balances, pH alterations, and several other factors play a role. A statistically elevated mean concentration of the main excitatory neurotransmitter glutamate was found in tumor and peritumoral brain specimens [98].
EEG in brain tumors Although neuroimaging methods have replaced EEG as a diagnostic and localizing tool, EEG is of relevance in seizure monitoring and detecting epileptiform discharges. Within the tumor itself, no electrical activity can be recorded in most tumor types. Slow waves signify loss-of-function disturbances of the surrounding region, and spikes or seizures are produced by areas more distant from the tumor (for summary see [34]). New aspects arise from magnetoencephalography (MEG) and EEG-video monitoring. Low-frequency magnetic activity is limited to the peritumoral tissue [3]. If this activity is recorded within the tumor area, it warns the neurosurgeon that the lesion comprises functioning neurons [3] related to cognitive deficits (Bartolomei [5]). Continuous spiking in long-term monitoring specifies glioneuronal tumors and focal cortical dysplasias [28]. In 28 % of cases, long-term-monitoring can detect unnoticed seizures and prompt changes of AED therapy [41]. Furthermore, EEG monitoring of seizures remains the golden standard for the delineation of the seizure-onset zone.
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Treatment of epileptogenic brain tumors Neurosurgery The surgical armamentarium includes lesion biopsy, subtotal lesionectomy, complete lesionectomy, extended lesionectomy, lesionectomy combined with corticotomy of the seizure-onset zone (epilepsy surgery), and several palliative measures. Standard neurosurgery per se has a significant impact on seizure frequency. However, numbers are difficult to interpret. Papers differ with respect to length of follow-up, concomitant AED therapy, mode of neurosurgical methods, presurgical work-up, and scrutiny of seizure counting among others. Table 3 gives an overview of postoperative seizure freedom in patients with preoperative epilepsies. Seizure control can be reached in more than 50 % of patients. As the most significant factor, gross-total tumor resection was uniformly reported. Standard neurosurgery of tumors aims to achieve complete lesionectomy when possible. In epileptogenic brain tumors, strategies of non-tumor-related epilepsy surgery might be added. In a recent review of the current treatment of low-grade astrocytoma [73], seizures are considered the most common presentation. Since the seizure-onset zone is located in neighboring or even remote areas (see pathophysiology), a close presurgical work-up is advisable in cases with long life expectancy and/or seizures as a significant factor for quality of life [40, 68]. In cases of slowly growing or static epileptogenic tumors, a thorough presurgical evaluation is considered state of the art [7, 21]. For epilepsy surgery in dysembryoplastic neuroepithelial tumors, an MRIbased scheme was developed [19]. Besides improved epileptological results, electrical stimulation via intracranial electrodes can indicate eloquent brain areas, avoid intraoperative testing, and govern surgical approach.
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not performed in tumor epilepsies. Treatment guidelines for persons with epilepsy in general leave open specific questions of tumor epilepsies (see [96]). A part of these questions can be solved by a close diagnosis of the epilepsy syndrome according to Table 2. In acute symptomatic seizures, chronic AEDs are generally not indicated. Several clinical parameters might indicate a high risk for the development of chronic epilepsies after an acute symptomatic seizure. Among these signs are specific seizure types, EEG signs, results of a prolonged EEGvideo recording [41], or detection of inconspicuous seizures by close history taking. In these cases and definite epilepsies principles of general epilepsy, treatment might be applied balancing the impact of seizures against unwarranted AED effects, discomfort, and expense of chronic AED intake [44]. Prophylactic AED treatment The high risk for development of seizures and epilepsies raised the question of prophylactic AED treatment in newly diagnosed brain tumors without seizures. Glantz et al. [32] summarize practice parameters of the American Academy of Neurology. Prophylactic AED treatment should not be used. A meta-analysis of relevant studies found no evidence for preventing first seizures. After the year 2000, further studies [24, 29] and meta-analyses [85, 88] confirmed these recommendations. However, frequent use of prophylactic AED— 57 % of patients after Lwu et al. [56]—contradicts published evidence [17, 84]. Perioperative AED treatment
Antiepileptic drugs
Prophylaxis can also be directed against acute symptomatic seizures in the postoperative phase. After brain trauma, the hallmark paper of Temkin et al. [87] found effectiveness of prophylactic treatment against acute symptomatic seizures, but not against the development of posttraumatic epilepsies. Comparable results were not reported with tumor-related seizures. Some hints can be found. Franceschetti et al. [30] reported an effect of prophylactic AEDs on early seizures, Shugrue et al. [83] a small benefit in meningioma patients, and Boarini et al. [12] a reduction of the severity of seizures. Many neurosurgeons administer AEDs in the perioperative phase in order to prevent acute symptomatic seizures. If this strategy is chosen on the basis of an argument of analogy with trauma, anticonvulsants should be tapered in the first postoperative week. An equivalent study to Temkin et al. [87] in brain tumors should solve the question whether the routine use of perioperative AED treatment is justified or not.
Continuous AED treatment
Withdrawal of AED treatment
Efficacies of AEDs have been investigated in controlled studies in the general epilepsy population. Corresponding trials are
After gaining seizure freedom in epilepsies, withdrawal of AEDs remains controversial. In the general epilepsy
Radiotherapy and chemotherapy De Groot et al. [23] review papers reporting the effect of radiotherapy or radiosurgery on seizure frequency. Observational studies reported an improvement in unoperated tumor patients. In a cohort study, Sherman et al. [82] compared operated low-grade glioma patients with consecutive temozolomide therapy and those under observation after operation. Of the temozolomide patients, 59 % exhibited a seizure reduction of >50 % compared with 13 % not using chemotherapy.
384
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Table 3 Seizure freedom after neurosurgery in general
structural abnormalities, the result of repeated prolonged EEG-video recording, and AED serum levels influence the individual decision.
Tumor type
Percentage of class I (Engel) seizure outcome after resection
Authors
Low-grade glioma
36–100, ∑ 71
[26] (review over 20 papers)
Meningioma Glioneural tumor
63.5–62.7 45–100, ∑ 80
Malignant astrocytoma Temporal tumor
77 26–64.7
[20, 49] [26] (review over 39 papers) [16] [38] (mixed tumor types in children) [99] (low grade glioma) [55]
Non-progressive and 82 slowly growing tumors
Choice of the drug
Authors numbers according to “References”
population, several papers analyze withdrawal trials (for summary see [42]). Predictors for successful withdrawal are length of seizure freedom, age, duration of uncontrolled epilepsy, seizure type, structural abnormalities, and EEG. However, controlled, prospective, randomized, double-blinded studies [52] are the exception. Seizure relapse at 12 months occurred in 15 % of the withdrawal group and 7 % of the nonwithdrawal group [52]. A number of observational and retrospective studies report successful AED withdrawal in 42– 75 % of patients [1, 9, 43, 46, 75, 80, 97]. However, Menon et al. [64] found complete AED-free status in only 20 % of patients after 4 years. No studies systematically examine AED withdrawal in tumor-related epilepsies. Therefore, the decision has to be made, transferring what is known in general. Patient’s attitude after careful information about the increased risk of seizure recurrence plays a key role. The number and severity of prior seizures, the development of EEG and
No single AED exhibits significant superiority with regard to efficacy, but new AEDs might be better tolerated [10]. With tumor-related epilepsies, some aspects have to be added to epilepsy guidelines. The role of enzyme-inducing AEDs was studied in several conflicting papers. Interactions between AEDs and chemotherapeutic agents have been reviewed by Vecht et al. [92]. Poor seizure and tumor control as well as increased unwarranted side effects can be observed with enzyme-inducing AEDs. Valproic acid (VPA) was considered the drug of first choice. This recommendation is confirmed by a retrospective study comparing valproic acid with enzyme-inducing AEDs in glioblastoma patients treated with standard chemotherapy [72]. An analysis in patients with glioblastoma reported contrasting results [39]. Paradoxically, use of enzyme-inducing AEDs correlated with a better outcome. However, the study was biased by a small number of patients receiving enzymeinducing AEDs. In a recent review, the use of enzymeinducing or enzyme-inhibiting AEDs is discouraged in patients with brain tumors [22]. Most AEDs of the second and third generation (“New AEDs”) are not enzyme-inducing. Therefore, their use should be preferred in tumor patients. Several studies investigated Levetiracetam (LEV). Table 4 summarizes results of nine studies. All studies report efficacy against seizures comparable to phenytoin but superior tolerability. Table 5 gives an overview of trials with other new AEDs. Data are far from being conclusive; no paper fulfills criteria demanded by
Table 4 Studies with levetiracetam (LEV) in brain tumors Authors Study design
Number of patients
Type of tumor
Results
Glioma Prim brain tumor
Effect similar to PHT, LEV better tolerated LEV “feasible in brain tumor”
[65] [93]
Retrospective comparison with PHT 76 Preliminary, observational 18
[70] [58] [67]
Retrospective chart review Observational, add-on Retrospective comp with PHT, prophylactic use Pilot study, switch PHT to LEV Prospective, uncontrolled
41 Prim brain tumor, metastases 19 Supratentorial glioma LEV 105 PHT 210 After craniotomy for different reasons, including tumors 29 Glioma 82 under LEV Glioma
Effective + well tolerated, 59 % seizure-free Reduced seizures refractory to other AEDs Similar effect preventing early and late seizures, better tolerated Switching to LEV is safe 91 % free of seizures at last control
Prospective, uncontrolled, laboratory Prospective, single-arm study
34
Glioma
SV2A correlates with clinical response
25
Suspected primary brain tumors Efficacy of LEV appears promising
[51] [77] [22] [4]
PHT phenytoin, Authors numbers according to “References”
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Table 5 Studies in tumor-related epilepsies with secondary and tertiary generation AEDs AED
Authors Study design
Number of patients
Tumor type
Pregabalin
[71]
Observational, retrospective
9
Primary brain tumors, mostly glioma
[91] [78] Tiagabine [86] Oxcarbazepine [63] [60]
Expert opinion Expert opinion Open-label, add-on Prophylactic against early seizures, uncontrolled Retrospective, observational
Topiramate
[61]
Prospective, observational
Lacosamide
[59]
Add-on
Results
6 seizure-free, all >50 % seizure reduction, 2 discontinuation due to side effects LEV or gabapentin … can be useful LEV and gabapentin seem promising 11 Glioma 3 seizure-free, 7>50 % reduction 150 Glioma 2.7 % (4 patients) early seizures, no comments on long-term use 35 mono 35 Primary and secondary Similar effect as traditional AEDs, better tolerated add-on brain tumors 14 mono 33 Primary and secondary 55.6 % seizure-free, 20 % reduction >50 % add-on brain tumors 14 Glioma, different 78.6 % reduction >50 % grades
Authors numbers according to “References”
regulatory authorities for licensing. Therefore, decisions are bound on lower levels of evidence. (2) AEDs and anti-tumor effects Cell line experiments report anti-tumor effects of topiramate and LEV [13, 27]. The most promising experimental and clinical results are reported for VPA (for reviews see [11, 65, 66]). Weller et al. [95] retrospectively analyzed a multicentre temozolamide trial for glioblastoma. Patients receiving VPA alone derived more survival benefit from a combined temozolamide/radiotherapy. For explanation, an increase of temozolamide bioavailability or sensitizing for radiochemotherapy due to inhibition of histone deacetylase is discussed. This study represents an argument to prefer VPA in glioma patients. Future studies are needed to establish VPA as the AED of first choice. Blood dyscrasias of VPA and neurosurgical interventions Thrombocytopenia and inhibition of platelet aggregation are the most common hematologic abnormalities associated with VPA (for summary see [31]). Therefore, some authors recommend routine discontinuation prior to surgery [74]. Others found no increase of blood loss during temporal lobectomy [94] or no bleeding complications in patients undergoing neurosurgery while receiving VPA [2]. Statistically conclusive investigations are not published.
Concluding pragmatic recommendations (1) Many questions cannot be answered evidence-based. Even if matched samples might not be possible for
(3) (4)
(5)
(6)
ethical reasons, adequate pragmatic trials should be performed in future. Prophylactic AED treatment is to be discouraged [32]. The effectiveness against acute symptomatic seizures [30, 83] has to be re-analyzed by well-designed studies. Chronically recurrent seizures (epilepsies) should be treated according to the guidelines for epilepsies in general. Withdrawal from chronic AED treatment depends on the length of seizure freedom, the adverse events with AEDs, and several other factors [42]. No guidelines exist for tumor epilepsies. In cases with seizures as the main problem, especially with low-grade astrocytomas, a comprehensive presurgical epilepsy monitoring can demonstrate the seizure-onset zone frequently outside the lesion. A lesionectomy combined with removal of the seizure focus can increase the percentage of seizure-free patients after operation [40, 68]. Static non-progressive tumors should be treated by epilepsy surgery per se in every case [7, 21].
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Comments Krasimir Minkin, Sofia, Bulgaria This review is focused on the epilepsy problems of oncological neurosurgery. The authors raised the question about the contradictions between evidence-based medicine and practical medicine regarding prophylactic antiepileptic drug treatment of patients with newly diagnosed brain tumors without history of seizures. The review of the risks for early and late acute postoperative seizures provides some insights for the perioperative and continuous AED treatment in patients with brain tumors. An important positive feature of this paper is the attempt to review all antiepileptic treatment options in patients with brain tumor-related epilepsy: drugs, surgery, radiotherapy, and chemotherapy. Bowen Jiang, Alfredo Quinones-Hinojosa, Baltimore, USA. Seizures represent a major symptomatology in the brain tumor population and have significant implications on a patient’s quality of life. The use of antiepileptic drugs (AED) for brain tumor patients is an area of ongoing controversy and debate. Bauer and colleagues are commended for their critical review of the existing literature on this topic. The authors suggest that prophylactic use of AEDs is unwarranted in patients without preoperative seizures. They provide evidence that acutely provoked seizures, for the most part, do not require long-term AED treatment. The authors are applauded for their attempt to summarize the vast literature on evidencedriven guidelines. Yet, the question of when an AED is indicated and for how long is nuanced and complex. The answer is likely dependent upon a combination of pre/intra/postoperative factors, with a patient’s unique tumor history paramount to sophisticated decision-making. For instance, the authors included meta-analysis from Sirven et al. [1] and Tremont-Lukats et al. [2] to support the conclusion that prophylactic AED treatment has no evidence in brain tumor patients without seizures. Within the benign brain tumor literature, Sughrue et al. evaluated 180 patients who underwent resection for convexity meningiomas. Although none of these patients had preoperative seizures, 129 were treated with AED postoperatively without any statistical difference in seizure control (0 vs 1.9 %) [3]. These data are confirmed by a meta-analysis from Komotar et al. [4] on 19 studies with a total of 689 supratentorial meningioma patients, which concluded no difference in the rate of early or late seizures between AED-treated and not treated groups. It would appear that the routine use of prophylactic AEDs for patients undergoing supratentorial meningioma resection provides no benefit, a sentiment many clinicians would be inclined to agree.
Neurosurg Rev (2014) 37:381–388 However, as we become more sophisticated and granular with our research, the neurosurgical community is now increasingly able to identify factors associated with higher seizure risk and thus better select patients ideal for AED management. Our institution has previously studied risk factors associated with seizures in WHO grade 1 meningiomas and found that patients with poor functional status, absence of signs of increased ICP, and MRI findings with significant cerebral edema are at higher risk for seizures [5]. Parasagittal and sphenoid wing meningioma are associated with continued seizures despite surgery and therapeutic AED. Likewise, for patients with high-grade gliomas (WHO III and IV), our institution previously found preoperative uncontrolled seizures and parietal lobe involvement to be negative predictors of seizure control [6]. In the era of individualized medicine, patient-specific disease characteristics should be factored into a potential AED therapeutic course. For these patients, a unified shotgun recommendation may not be appropriate, and in fact, many of these patients may benefit from AED therapy despite the guidelines. At our institution, the use of levetiracetam is routine in the postoperative period and often maintained until the patient returns for first followup visit at 14–21 days. Since levetiracetam is a newer AED, its efficacy and side effect profile is frequently debated with that of phenytoin. Lim et al. conducted a randomized phase II pilot study on 29 patients who received either levetiracetam or phenytoin for postoperative seizure control [7]. The authors report better seizure control (87 vs 75 %) and fewer side effects (dizziness, depression, lethargy, insomnia) with levetiracetam. Indeed, this has been our institutional experience as well. Finally, the authors astutely recognized that the initial data was from Temkin et al. [8] in the traumatic brain injury literature, in which phenytoin was utilized for the prevention of posttraumatic seizures. This literature has since then been extrapolated into the brain tumor armamentarium. Clearly, studies focused on seizure frequency, duration, and severity in the postoperative period will continue to advance the current literature. This study by Bauer et al. succinctly summarizes the vast literature on this topic and suggests treatment paradigms that will help neurosurgeons and neurologists alike in managing seizures for the brain tumor population. References 1. Sirven JI, Wingerchuk DM, Drazkowski JF et al. (2004) Seizure prophylaxis in patients with brain tumors: a meta-analysis. Mayo Clin Proc 79:1,489–1,494 2. Tremont-Lukats W, Ratilal BO, Armstrong T, Gilbert MR (2008) Antiepileptic drugs for preventing seizures in people with brain tumors. Cochrane Database Syst Rev 18:CD004424 3. Seghrue ME, Rutkowski MJ, Chang EF, Shangari G, Kane AJ, McDermott MW, Berger MS, Parsa AT (2011) Postoperative seizures following the resection of convexity meningiomas: are prophylactic anticonvulsants indicated? J Neurosurg 114: 705–709. 4. Komotar RJ, Raper DM, Starke RM, Iorgulescu JB, Gutin PH (2011) Prophylactic antiepileptic drug therapy in patients undergoing supratentorial meningioma resection: a systematic analysis of efficacy. J Neurosurg 115: 483–490 5. Chaichana KL, Pendleton C, Zaidi H, Olivi A, Weingart JD, Gallia GL, Lim M, Brem H, Quinones-Hinojosa A (2013) Seizure control for patients undergoing meningioma surgery. World Neurosurg 90(3– 4):512–524 6. Chaichana KL, Parker SL, Olivi A, Quinones-Hinojosa A (2009) Long-term seizure outcomes in adult patients undergoing primary resection of malignant brain astrocytoma. J Neurosurg 111(2):282–292 7. Lim DA, Tarapore P, Chang EF, Burt M, Chakalian L, Barbaro N, Chang S, Lamborn KR, McDermott MW (2009). Safety and feasibility of switching from phenytoin to levetiracetam monotherapy for gliomarelated seizure control following craniotomy: a randomized phase II pilot study. J Neurooncol 93:349–354. 8. Temkin NR, Dikmen SS, Wilensky AJ et al. (1990) A randomized, double-blind study of phenytoin for the prevention of post-traumatic seizures. NEJM 323:497–502
