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Seizures in low-grade gliomas: naturalhistory, pathogenesis, and outcome after treatmentsRoberta Ruda `, Lorenzo Bello, Hugues Duffau, and Riccardo Sofetti

Department of Neuro-Oncology, University of Turin and San Giovanni Battista Hospital, Turin, Italy(R.R., R.S.); Department of Neurosurgery, University of Milan and Istituto Clinico Humanitas, Via Manzoni 56,20089 Rozzano (MI), Italy (L.B.); Department of Neurosurgery, University of Montpellier and Gui de Chauliac Hospital, Montpellier, France (H.D.)

Seizures represent a common symptom in low-gradegliomas; when uncontrolled, they signicantly contrib-ute to patient morbidity and negatively impact qualityof life. Tumor location and histology inuence the riskfor epilepsy. The pathogenesis of tumor-related epilepsyis multifactorial and may differ among tumor histologies(glioneuronal tumors vs diffuse grade II gliomas). Grosstotal resection is the strongest predictor of seizurefreedom in addition to clinical factors, such as preoper-ative seizure duration, type, and control with antiepilep-tic drugs (AEDs). Epilepsy surgery may improve seizure

control. Radiotherapy and chemotherapy with alkylat-ing agents (procarbazine 1 CCNU 1 vincristine, temo-zolomide) are effective in reducing the frequency of seizures in patients with pharmacoresistant epilepsy.Newer AEDs (levetiracetam, topiramate, lacosamide)seem to be better tolerated than the old AEDs (pheno-barbital, phenytoin, carbamazepine), but there is lackof evidence regarding their superiority in terms of efcacy.

Keywords: antiepileptic drugs, chemotherapy, diffusegliomas, epileptogenesis, glioneuronal tumors,radiotherapy, seizures, surgery.

M ost patients with low-grade gliomas (LGGs)experienc e epileptic seizures as a presentingsymptom. 1 4 Clinically, tumor-related sei-zures manifest as simple or complex partial seizureswith or without secondary generalization and, in morethan 50% of cases, are pharmacoresistant. When uncon-trolled, tumor-related epilepsy affectspatients quality of life, causes cognitive deterioration, and may result in

signicant morbidity. 5 ,6 Preope rative seizures couldreect intrinsic glioma properties 7 and are the most im-portant factor associated with continued seizures aftertumor surgery. 8 Seizures and their sequelae can mimictumor progression and prompt unwarranted interven-tions. A number of studies have suggested an associationbetween epilep tic seizures at disease onset and a favor-able prognosis. 9 11 The management of seizures re pre-sents an important part of the management of LGG 4 ,12

and increasingly needs specic and multidisciplinaryapproaches.

Factors Predisposing to Seizures

Tumor location inuences the risk for epilepsy. 13

Tumors involving the frontal, temporal, and parietallobes are more commonly associated with seizures thanare occipital lesions. Infratentorial tumors rarely causeseizures. Intractable epilepsy is particularly frequent intumors that involve the mesiotemporal and insular (par-alimbic) structures. 14 ,15 This is linked to the high epilep-togenicity of the temporal and insular cortex. Corticaltumors have a higher incidence of associated epilepsy

than nonco rtical deeper lesions regardless of the in-volved lobe. 15 ,16 Proximity to the rolandic ssure andthe central sulcus also increases seizure frequency.

The frequency of seizures differs widely according totumor type. Glioneuronal tumors, such as ganglio-gliomas (GGs) and disembryoplastic neuroepithelialtumors (DNTs), are typically associated with a chronicpharmac oresistant epilepsy in up to 90% 100% of patients. 17 They occur predominantly in children andyoung adults and in the temporal lobe. These tumorsare designat ed by World Health Organization (WHO)classication 18 as grade I tumors, thus most patientshave a favorable outcome after surgical resection

Corresponding Author: Roberta Ruda`, MD, Dept Neuro-Oncology,University of Turin and San Giovanni Battista Hospital, Via Cherasco15, 10126 Torino, Italy ([email protected]).

Neuro-Oncology 14:iv55iv64, 2012.doi:10.1093 / neuonc / nos199 N E U R O - O N C O L O G Y

# The Author(s) 2012. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.All rights reserved. For permissions, please e-mail: [email protected].


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alone, with only rare cases of GG s that recur and / orundergo malignant transformation. 19 ,20 Among DNTs,2 histolog ical variants, simple and complex, have beenidentied. 21 Sometimes the differential diagnosisbetween these grade I tumors and the most commongrade II gliomas is challenging due to sampling prob-lems. The brain tissue adjacent to a GG or a DNT mayfrequently show an atypical cortical architecture due toa mal form ation of cortical development or cortical dys-plasia 17 ,22 ; conversely, the presence of adjacent corticalmaldevelopment is distinctly uncommon in grade IIgliomas. Moreover, a dual pathology, such as hippocam-pal sclerosis in conjunction with the epileptogenictumor, may occur. Other rare grade I gliomas, such assupratentorial pilocytic astrocytomas, pleomorphicxanthoastrocytomas, and angiocentric gliomas, whichprevail in children and young adults, frequently causeseizures. 17

Diffuse LGGs (WHO grade II astrocytomas, oligo-dendrogliomas, and oligo astrocytomas) present seizuresin 60% 88% of patients. 4 ,11 Among LGGs, seizures are

much less frequent (47% vs 85% ) in patients

60 yearscompared with younger patients. 23 Patients with oligo-dendrogliomas and oligoastrocytomas, which moreoften involve the cortex, are more prone to seizuresthan those with astr ocytomas, which tend to be situatedin the white matter. 15 The rare protoplasmic astrocyto-ma, which is predominantly cortically based, can belinked to chronic epilepsy. Among grade II astrocyto-mas, a subtype characterized by long-term epilepsy,longer survival, and lower recurrence rate have been de-scribed. 24 This subtype, called isomorphic astrocytoma,is characterized by low cellularity, lack of mitotic activ-ity, highly differentiated astrocytic cells, absence of nuclear p53 accumulation, and expression of glialmicrotubule-associated protein 2 and cluster of differen-tiation molecule 34.

No correlation has been found between seizure activ-ity and metaboli c rate of the tumor measured by PETwith methionine. 11

Unlike high-grade gliomas, LGGs presenting with sei-zures have been reported to be larger on MRI t han thosepresenting with other neurological symptoms. 25

Mechanisms of Epileptogenesis

The pathogenesis of tumor-related seizures is multifacto-rial and still not fully understood. 26 ,27 The mechanisms

of epileptogenesis differ among tumor types.Intrinsic epileptogenicity of glioneuronal tumors issupported by electrocorticography and surgical and im-munocytochemical studies, suggesting the presence of ahyperexcitable neuronal component. 28 The cells of these developmental tumors can overexpress neurotrans-mitter receptors and neuropeptides, com promising thebalance between excitation and inhibition. 29 The associ-ated dysplastic disorganization of the adjacent cortexcontributes to the mechanism of seizure generation. Anextensive inammatory reaction with accumulation of microglial cells in the perilesional areas has also beensuggested. 30

Slow-growing tumors could produce an epileptogenicmilieu by partial deafferentation of cor tical regions, thuscausing a denervation hypersensitivity. 13

Studies using magnetoencephalographic recordingshave shown that functional connectivity and network to-pology are signicantly altered in diffuse LGG casescompared low-frequency connectivity (in particular thetheta band) is pathologically increased, and the n ormalsmall-world network conguration is alte red,31 33thus leading to a lower threshold for seizures. 34 Thesedifferences not only implicate the area around thetumor, but involve brainwide networks and are relatedto cognitive decits.

The role of change s in peritumoral tissue is being in-creasingly recognized. 35 Neuronal density in the hippo-campus of patients with mesial temporal lobe epilepsyand gliomas is normal; however, peritumoral cells mayhave an anomalous phenotype. Morphologic changesinclude aberrant migration with persistent neuronsin the white matter, and pyramidal neurons with fewerinhibitory and more excitatory synapses. Intercellular

connections between adjacent glial cells occur viaconnexin transmembrane gap junction proteins,and immunohistochemical studies have found alteredexpression of connexins in tumor cells and reactive as-trocytes of the pe rilesional cortex of patients withLGGs and epilepsy. 36

Modern neuroimaging techniques have provided newevidence that the peritumoral microenvironment inbrain tumors is substantially different from that of normal brain tissue: MR spectroscopy has demonstrateddecreased levels of N -acetylaspartate, a marker of neuro-nal viab ility and function, in lesional epileptogeniccortex. 37 Several alterations predispose to seizure gener-ation. The tumor can mechanically compress the sur-rounding normal tissue because of mass effect,inducing ischemia, hypoxia, and acidosis, which inturn induce glial cell swelling and damage. A functionalconsequence of acidic pH is the deregulation of sodiumand calcium inux across cell membranes. Further, theinuence of pH on the activity of antiepileptic drugs(AEDs) is uncertain. Changes in ionic concentrationscan also contribute to neuronal excitability, and afocal disruption of the bloodb rain barrier leads to thedevelopment of a seizure focus. 38

Brain tumors and peritumoral tissue have an alteredexpression of neurotransmitters and their receptors. Agreater concentration of glutamate, the major excitatory

amino acid neurotransmitter in the brain, has beenfound in brai n tumor samples from patients withactive epilepsy. 39 When invading the normal tissue,glioma cells could react to spatial constraints by releas-ing high levels of glutamate into the extracellularspace, which induces seizures and later causes excito-toxic neuronal cell death, thereby facilitating invasionand migration. 40 43 Ionotropic and metabotropic gluta-mate receptors have been shown to be overexpr essedboth in glioma cells and in peritumoral astrocytes. 44 46

Activation of these receptors by glutamate coulddownregulate gamma-aminobutyric acid (GABA)mediated inhibitory stimuli as a second mechanism of

Ruda et al.: Seizures in low-grade gliomas

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epileptogenesis. Alterations in levels of GABA, the maininhibitory neurotransmitter, may also contribute totumor-associated seizures, but it remains unclearwhether decreased inhibition or new excitatory activity,together with altered receptor subtype expression, isresponsible for neuronal hyperexcitability. 35

Recent molecular genetic ndings have been de-scribed in glioneuronal tumors. A common role hasbeen suggested for the phosphatidylinositol 3 kinasemammalian target of rapamycin pathway in the patho-genesis of glioneuronal tum ors, focal cortical dysplasiastype IIB, and cortical tubers. 47 Gene expression prolingof epilepsy-associated GGs has revealed alterations inthe expression of genes involved in the immu ne system,synaptic transmission, and cell cycle control. 48 Overall,it remains to be demonstrated that tumor-associatedepilepsy and glioma growth have common geneticpathways. 49

Regarding diffuse LGGs, susceptibility candidategenes associated with tumor-related seizures have notyet been identied. In this regard, it has been reported

that LGGs without LOH19q were more likely topresent with seizures of secondary generalized typethan those with LOH19q, thus suggesting tha t candidategenes could be located on chromosome 19q. 50

An actively discharging epileptic focus has the capa-bility to induce a paroxysmal activity in areas of thebrain distal to the original site and lead to a secondaryepileptic focus, as occurs in cases of slow-growingtumors of the temporal lobe and long history of seizures.Both animal and human studies have demonstratedchanges in synaptic plas ticity and cerebral blood owwith prolonged epilepsy. 51

Factors Inuencing Preoperative Seizure Control

There is a lack of information on factors associated withpreoperative seizure control in diffuse LGGs in the con-temporary MRI era. In a recent large single-instituti onstudy, about half of patients had uncontrolled seizures. 15

Associated with uncontrolled preoperative seizures werethe presence of simple partial seizures, a longer durationfrom seizure onset, and temporal lobe involvement.Conversely, the presence of generalized seizures wasassociated with better seizure control.

Outcome after surgerySurgery allows seizure control in a signicant proportionof cases of diffuse LGGs, including pharmacoresistantepilepsy. 52 58 A recent study performed a systematicreview of the published literature involving 773 patientsin order to identify factors associated with seizureoutcome after surgery. 59 Overall, gross total resectionwas the strongest predictor of seizure freedom at aminimum follow-up of 6 months postsurgery: 71% of patients were seizure free (Engel class I), whereas 29%continued to have seizures (Engel classes II IV).Interestingly, in one of the major series, 15 the benet in

terms of seizure control was maintained at 12 months,and conversely only 9% of patients had no improvementor worsened. These results have improved dramaticallyover time as a result of the increased use of preoperativeneuroimaging modalities (functional MRI, diffusiontensor imaging), intraoperative brain mapping tech-niques, and awake surgery, which allow more aggressiveresections while preserving normal eloquent areas. Thus,in the modern era, resection can be accomplishedaccording to functional boundaries, 60 ,61 and grosstotal resection means resection of abnormalities of uid attenuated inversion recovery (FLAIR) on MRI.Unfortunately, as the majority of L GGs tend to growclose to or within eloquent areas, 62 a total or neartotal resection is feasible in no more than 45% of pa-tients. 61 Recently the concept of supratotal resection(ie, removal of a margin around FLAIR abnor malities)for better seizure control has been put forward. 63 In ad-dition to gross total resection, pr eoperative seizurehistory may also predict outcome. 59 Patients whoseseizures were well controlled by AEDs preoperatively

and whose seizures were

1 year in duration achievedbetter seizure control postsurgery. The presence of nongeneralizing partial seizures was associated withpoorer outcome. No signicant difference in epilepsyoutcome was found between temporal and extratempo-ral tumors and between adults and children. Second-linesurgery can be useful for seizure control. In this settin g,preoperative chemotherapy is being investigated. 64 ,65

Regarding glioneuronal tumors, similarly to diffusegliomas, gross total resection has emerged as the stron-gest predictor of seizure freedom. At a minimumfollow-up of 6 months after surgery 80% of patientswere seizure free (Engel class I), wher eas 20% continuedto have seizures (Engel classes II IV). 66 Moreover, earlysurgical intervention ( , 3 years from onset of seizure s)was associated with improved seizure outcome. 67

Other factors positively associated with seizure controlwere 1 year duration of epilepsy and the absenceof secondarily generalized seizures preoperatively.Outcome did not differ signicantly between patientswith temporal lobe versus extratemporal tumors, histo-logic diagnosis of GG versus DNT, and medically co n-trolled versus refractory seizures before surgery. 66

Favorable seizure control has also been associated withfactors such as younger age at surgery, presence of large nerve cells in the tumor specime n, and absence of postoperative epileptic discharges. 19 ,68 ,69 Overall,

among patients with temporal lobe epilepsy, long-termseizure control seems better in cases of glioneuronaltumors (94%) than o f diffuse gliomas (79%) and corti-cal dysplasias (68%). 70

A major issue related to surgery, especially in tempo-ral and paralimbic tumors, is that the epileptogenic zonecan include signicant extratumoral cortical areas.Thus, 15%20% of patients still suffe r f rom refractoryseizures after total tumor resection. 55, 57 In this settingthe identication and removal of the epileptogeniczone beyond the tumor (ie, epilepsy surgery) could leadto an improved seizure outcome. Seizure outcome afterlesionectomy versus lesionectomy + hippocampectomy,


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corticectomy, or both in patients with medically intrac-table seizures has been compared in several series, andimproved s eizure control after epilepsy surgery hasbeen found. 14 ,59 ,66 ,71 74 An open question remains re-garding the use of intraoperative electrocorticographyto identify the epileptogenic areas in epilepsy surgery.A series of studies t ried to addr ess this issue, leading toinconclusive results. 14 ,15 ,59 ,66 ,75 77 It is generally recog-nized that the cases in which electrocorticography wasused were associated with more severe and refractoryepilepsy.

Role of Radiotherapy, Chemotherapy, and Targeted Therapy

Limited data are available regarding the impact of radio-therapy on tumor-related seizures. Stereotactic intersti-tial irradiation improves sei zure control in 40%100% of unresectable LGGs, 78 ,79 and this could bedue to an increased benzodiazepine receptor density. 79

Gamma-knife radiosu rgery is active in mesiotemporaltumor-related epilepsy 80 and in patients with gelasticor generalized seizures from hypothalamic hamarto-mas. 81 ,82 Conventional radiotherapy has been reportedto be effective in seizure control in 72%100% of pa-tients with medically intractable epilepsy andLGGs. 83 ,84 Patients may become seizure free (27%55%), and the median duration of seizure control is

12 months but can be as long as 8 years. An indirectsuggestion of the efcacy of radiotherapy on epilepticseizures comes from the EORTC (European Organisationfor Research and Treatment of Cancer) 22845 phaseIII trial, which compared adjuvant postoperative radio-therapy versus observation in LGGs. At 1 year, 25%of patients who were irradiated had seizures, co mparedwith 41% of patients who were not irradiated. 85 Afterboth interstitial and conventional radiotherapy, seizurereduction may begin early during radiotherapy and isnot always associated with a tumor shrinkage on MRI.In fact, among patients who had a signicant reductionof seizures after r adio therapy, 50% had stabledisease on CT / MRI. 83 ,84 Thus, in addition to a directantitumor effect, ionizing radiation may decreaseseizure activity by damaging epileptogenic neuronsor inducing changes of the microenvironment in theperitumoral tissue.

The efcacy of chemotherapy with alkylating agents

(procarbazine + CCNU + vincristine, temozolomide)in treating LGGs, either as salvage treatment aftersurgery and radiotherapy or as initial treatment aftersurgery in symptomatic / progressive patients, is well es-tablished. 12 Seizure improvement has been obtained in48% 100% o f patients, with 20%40% becomingseizure free. 86 96 Clinical improvement is more frequentthan objective response on MRI. The majority of pa-tients have hyperintense lesions on T2 / FLAIR imageswith ill-dened margins and display a minor responseor stable disease. Decreased seizure frequency seemsto be better correlated with decrease of uptake of methionine on PET, whereas no signicant correlation

between seizure res ponse and 1p / 19q codeletion hasbeen reported so far. 96

A signicant decrease of epileptic seizures, in associa-tion with volume reduction on MRI, has been reportedin subependymal giant-cell astrocytomas of tuberoussclerosis a fter treatment with the mTOR inhibitoreverolimus. 97 ,98

Efcacy and Side Effects of Antiepileptic Drugs

Studies regarding the impact of old AEDs (phenobarbi-tal, phenytoin, carbamazepine) on tumor-related sei-zures are scarce. Overall, up to 70% of p at ients treatedwith these agents have recurrent seizures. 99

In the last 10 years there have been an increasednumber of papers focusing on the efcacy and t olerabil-ity of new AEDs in patients with brain tumors 100 107 ;however, they are all small series, either retrospectiveor prospective, that group together different histologies(high-grade gliomas and LGGs, metastases, meningio-

mas, etc). No papers have evaluated this issue in LGGsonly.From a methodological point of view, when consider-

ing the efcacy of an AED, one should take into accountthe frequency of seizures, the phase of the disease (atdiagnosis or at the time of progression), and the concom-itant antineoplastic treatment (radiotherapy, chemo-therapy) that may contribute to the control of seizures.Unfortunately in the published studies these issueshave not been addressed adequately. Thus, lack of studies in homogeneous subgroups of patients probablyexplains the wide range of seizure response that has beenreported.

In this review of the different series, we have tried toextrapolate the data regarding the efcacy of AEDs inLGGs. Table 1 summarizes the series in which thesedata are provided.

Most reports are on levetiracetam. 102 104 ,107 Thisdrug, employed either as an add-on or as monotherapy,has displayed a high rate of seizure response (75%100%) with a good tolerance (mild drowsiness and diz-ziness in a few patients). Thus, levetiracetam may be areasonable choice for the treatment of seizures inadults with brain tumors, particularly if concerns areraised about potential interactions with other medi ca-tions, such as steroids or chemotherapeutic drugs. 108

Two series have studied topiramate. Maschio et al. 105

reported promising data in 13 cases of LGGs treated asadd-on or monotherapy. The rate of response was85% (with 7 of 13 patients seizure free), but 11 of 13 pa-tients had received concomitant antineoplastic therapies(7 chemotherapy, 4 chemoradiotherapy), and the poten-tial contribution of these treatments was not analyzed.In our series (R. Ruda`, unpublished data), the settingwas different: topiramate was employed as an add-onin patients with low-grade tumors and an active epilepsywith poor seizure control despite 1 AED. Good seizurecontrol was obtained in 8% of patients only. Tiagabinewas investigated as an add-on in 10 pat ients withLGG and drug-resistant partial epilepsy. 101 A seizure




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reduction . 50% was observed in 7 of 10 patients, with3 patients becoming seizure free. Adverse events wereseldom observed and did not lead to a discontinuationof the drug. More recently a small series was publishedon the use of lacosamide. 109 In this prospective study,14 patients were enrolled, including only 3 with LGGs.With a median follow-up of 6 months, the authorsreported improved seizure control in all patients, with2 of 3 being seizure free and 1 with a signicant reduc-tion of seizures. No side effects were reported. Overall,these studies suggest that side effects are less intensewhen newer, non-enzyme-inducing AEDs are adminis-tered in cases of brain tumors. Merrel et al. 110 reporteda retrospective comparative series of 76 cases of gliomatreated with levetiracetam or phenytoin. There was nodifference in seizure outcome between the phenytoinand levetiracetam groups, while patients treated withlevetiracetam experienced fewer side effects and re-quired fewer non-seizure-related dose adjustments thanpatients treated with phenytoin. Switching from phenyt-oin to levetiracetam monotherapy for seizure control fol-

lowing surgery of gliomas was reported to be safe andfeasible in a randomized phase II study. 111

In conclusion, the available data on the efcacy andtolerability of AEDs in tumor-related epilepsy arescarce and heterogeneous due to the different histolo-gies, the pathophysiology of seizures, the naturalhistory of the tumor, and concomitant treatments.Needed are prospective trials focused on specic drugsin specic tumor categories. In current clinical practice,non-enzyme-inducing AEDs should be the rst choicein the treatment of LGG due to a lesser incidence of side effects and lack of potential interactions withothe r drugs (especially steroids and chemotherapeu-tics). 99 ,112 ,113 Seizure control together with a reductionof side effects should be the primary goals of therapyin cases of LGG where tumors are compatible withlong survival.

Interactions between Antiepileptic and AnticancerAgents

Interactions have been reported between AEDs and che-motherapeutic dr ugs, based on shared cytochrome P450drug metabolism. 114 Potent inducers such as phenobar-bital, phenytoin, primidone, and carbamazepine maysignicantly reduce serum levels of nitrosoureas, procar-bazine, vincristine, cyclophosphamide, ifosfamide, pac-

litaxel, irinotecan, topotecan, 9-aminocampthotecin,doxorubi cin, teniposide, thiotepa, methotrexate, andbusulfan. 115 ,116 AED levels may also be affected bysome chemotherapeutic agents, such as methotrexate,doxorubicin, adriamycin, and cisplatin, which decreasethe serum levels of valproic acid, carbamazepine, andphenytoin. Demonstrating that temozolomide hasminimal hepatic metabolism, one study documentedno effect of temozolomide on levels of topi ram ate oroxcarbazepine in chronically treated patients. 117

Among targeted agents, bevacizumab, a monoclonalantibody against vascular endothelial growth factorthat is under investigation in recurrent grade II gliomas T a

b l e 1

. E f c a c y o f n o v e l A E D s i n l o w - g r a d e g l i o m a s

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after standard treatments (EORTC 26091: TAVAREC),has a low potential for drugdrug interactions, whereassmall tyrosine kinase inhibitor molecules (being investi-gated in clinical trials in malignant gliomas) such asimatinib, getinib, erlotinib, tipifarnib, and sorafenibare metabolized by the P450 system, thus leadin g topotential interactions with enzyme-inducing AEDs. 118

Valproic acid has distinct enzyme-inhibiting proper-ties and might reduce the metabolism of a seconddrug, thereby raising plasma concentrations andpotentially increasing the bone marrow toxic effectsof concomi tan t chemotherapeutic drugs such asnitrosoureas. 119

Also, metabolism of corticosteroids is highly sensitiveto enzyme induction. 114 Enzyme-inducing AEDs in-crease the metabolism of various steroids, including dex-amethasone, possibly resulting in inadequate control of peritumoral edema.

Mechanisms of Resistance to Antiepileptic Drugs

The major cause of resistance of epilepsy to AEDsis overexpression of proteins belonging to theATP-binding cassette transporter family (in particularP-glycoprotein [P-gp]), which actively transport avariety of lypophilic drugs out of the brain capillary en-dothelium at the level of the bloodbrain barrier (theso-called multidrug-resistant proteins [MRPs]). An over-expression of these proteins has been reported in tumorcells of patients with glioma 120 and in samples of braintissue from patients with GG 121 and could lead to dimin-ished drug transport into the brain parenchyma.Moreove r, t he release of glutamate upregulates P-gp ex-pression. 122 A number of AEDs, including phenytoin,phenobarbital, carbamazepine, lamotrigine, and felba-mate, are substrates for P-gp. 123 Levetiracetam andvalpr oic acid do not seem to represent a substrate forP-gp,123 ,124 making these drugs attractive in braintumor associated epilepsy. Valproic acid might evenreduce the expression of MRP1 via its histonedeacetylase-inhibiting effects. 125

AEDs may also fail to control seizures because of lossof receptor sensitivity. 13

The Problem of Prophylaxis

Antiepileptic therapy in cases of brain tumor is recom-mended after a rst seizure. 12 ,13 Two meta-analyses

found no evidence to support prophylaxis with pheno-barbital, phenytoin, or valproic acid in patients with

no history of seizures. 126 ,127 A recent Cochranereview 128 pointed out several pitfalls of both meta-analyses and trials reviewed. The strength of evidenceand recommendations are weakened by clinical hetero-geneity among and within trials, misclassication of levels of evidence, and selection bias in the reporting of outcomes (especially adverse events). Hence, theauthors prefer to state that the evidence for seizure pro-phylaxis is inconclusive, at best. Nonetheless, regardingimplications for practice, they agree wi th the AmericanAcademy of Neurology subcommittee 126 that recom-mended against routine use of AEDs as prophylaxis incases of brain tumors and advised discontinuance of AEDs . 1 week postsurgery when used as perioperativeprophylaxis. However, many physicians still prescribeprophylactic AE Ds, especially for prophylaxis of periop-erative seizures. 129

It is unclear whether newer AEDs may have anybenet in preventing seizures. Only 2 retrospectivetrials are available. The rst trial 130 evaluated oxcarba-zepine for prevention of early postoperative seizures,

which occurred in ,

3% of patients, and found similardata to those reported for old drugs; moreover, oxcarba-zepine was well tolerated with rapid titration. Thesecond study 131 compared levetiracetam with phenytoinafter supratentorial neurosurgery and found that the in-cidence of early and late seizures was similar in bothgroups but that signicantly fewer adverse eventsoccurred with the use of levetiracetam, resulting in ahigher retention rate after 1 year.

Conclusion

LGGs are the most epileptogenic brain tumors. Total ornear total surgical resection predicts better seizureoutcome for most low-grade histologies. This supportsearly operation not only based on oncological consider-ations, but also to avoid the risk of chronic epilepsy andoptimize patients quality of life. However, no high-quality evidence, neither from randomized controlledtrials nor from large registry studies, is available that ad-dresses this question. Radiation and chemotherapy canbe proposed when pharmacoresistant seizures stillpersist even if a true tumor progression is not evident.Newer AEDs seem to be better tolerated than the olddrugs. Lastly, seizure control should always be a second-ary endpoint in clinical trials in LGGs.

Conict of interest statement . None declared.

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