Advertisement

Epilepsy-related brain tumors

Open ArchivePublished:December 22, 2016DOI:https://doi.org/10.1016/j.seizure.2016.12.012

      Highlights

      • Neuroglial tumors and the gliomas are the most common tumor types related with seizures.
      • Epileptogenesis in brain tumor-related epilepsy is influenced by several factors.
      • Identification of molecular markers may guide future therapeutic approaches.

      Abstract

      Seizures are among the most common presentations of brain tumors. Several tumor types can cause seizures in varying rates; neuroglial tumors and the gliomas are the most common ones. Brain tumors are the second most common cause of focal intractable epilepsy in epilepsy surgery series, with the highest frequency being dysembryoplastic neuroepithelial tumors and gangliogliomas. Seizure management is an important part of the treatment of patients with brain tumors. This review discusses clinical features and management of seizures in patients with brain tumors, including, neuroglial tumors, gliomas, meningioma and metastases; with the help of recent literature data. Tumor-related seizures are focal seizures with or without secondary generalization. Seizures may occur either as initial symptom or during the course of the disease. Brain tumors related epilepsy tends to be resistant to antiepileptic drugs and treatment of tumor is main step also for the seizure treatment. Early surgery and extent of the tumor removal are important factors for achieving seizure freedom particularly in neuroglial tumors and low grade gliomas. During selection of the appropriate antiepileptic drug, the general approach to partial epilepsies can be followed. There are several factors influencing epileptogenesis in brain tumor-related epilepsy which also explains clinical heterogeneity of epilepsy among tumor types. Identification of molecular markers may guide future therapeutic approaches and further studies are needed to prove antitumor effects of different antiepileptic drugs.

      Keywords

      1. Introduction

      Seizures are among the most common presentations of brain tumors. The frequency of epilepsy in patients with brain tumors ranges from 30 to 100% depending on tumor type [
      • van Breemen M.S.
      • Wilms E.B.
      • Vecht C.J.
      Epilepsy in patients with brain tumours: epidemiology, mechanisms, and management.
      ]. Although any type of tumor can cause a seizure, neuroglial tumors, and gliomas are the most common ones. Dysembryoplastic neuroepithelial tumors (DNETs), gangliogliomas (GGs), low-grade glial tumors, glioblastomas, metastases, leptomeningeal tumors and primary CNS lymphomas are associated with seizures in varying rates [
      • van Breemen M.S.
      • Wilms E.B.
      • Vecht C.J.
      Epilepsy in patients with brain tumours: epidemiology, mechanisms, and management.
      ]. Tumor-related seizures are symptomatic by nature; they are focal with or without secondary generalization [
      • Rudà R.
      • Trevisan E.
      • Soffietti R.
      Epilepsy and brain tumors.
      ]. Semiologic characteristics depend on the localization of the tumor. The course of the clinical picture of epilepsy may differ according to the tumor type.
      Seizures may occur either as an initial symptom, that leads to the diagnosis of the tumor (seen in about 30–50% of patients); or during the course of the disease (seen in 10–30% of patients) [
      • van Breemen M.S.
      • Wilms E.B.
      • Vecht C.J.
      Epilepsy in patients with brain tumours: epidemiology, mechanisms, and management.
      ]. The seizure risk is influenced by type and location of tumor and the number of the lesions [
      • Sperling M.R.
      • Ko J.
      Seizures and brain tumors.
      ]. Slow growing tumors, particularly DNETs and gangliogliomas, are particularly epileptogenic and associated with the highest risk for seizures [
      • Rudà R.
      • Trevisan E.
      • Soffietti R.
      Epilepsy and brain tumors.
      ,
      • Englot D.J.
      • Chang E.F.
      Rates and predictors of seizure freedom in resective epilepsy surgery: an update.
      ,
      • Thom M.
      • Blümcke I.
      • Aronica E.
      Long-term epilepsy-associated tumors.
      ]. High-grade tumors have relatively lower rates of seizures. The location of the tumor is also important, for instance, cortical tumors are associated with a higher risk of causing seizures. Additionally, frontal, temporal and parietal tumors are associated with a higher risk of causing epilepsy than occipital tumors [
      • Rudà R.
      • Trevisan E.
      • Soffietti R.
      Epilepsy and brain tumors.
      ]. Multiple lesions are associated with a higher risk compared to a solitary lesions [
      • Sperling M.R.
      • Ko J.
      Seizures and brain tumors.
      ]. Infratentorial tumors are rarely associated with epilepsy [
      • van Breemen M.S.
      • Wilms E.B.
      • Vecht C.J.
      Epilepsy in patients with brain tumours: epidemiology, mechanisms, and management.
      ].
      The treatment of patients with brain tumors requires a multidisciplinary approach and clinical management varies according to the type of tumor. Brain tumors related epilepsy is usually refractory to medical treatment, and surgical or radiological treatment of the underlying tumor (when possible) is the mainstay of the treatment for the seizures [
      • Michelucci R.
      • Pasini E.
      • Meletti S.
      • Fallica E.
      • Rizzi R.
      • Florindo I.
      • et al.
      Epilepsy in primary cerebral tumors: the characteristics of epilepsy at the onset (results from the PERNO study-Project of Emilia Romagna Region on Neuro-Oncology).
      ]. Brain tumors are the second most common cause of focal intractable epilepsy in epilepsy surgery series, with the greatest proportion related to DNETs and GGs [
      • Englot D.J.
      • Chang E.F.
      Rates and predictors of seizure freedom in resective epilepsy surgery: an update.
      ].
      In this paper, we will review the clinical features and management of seizures in patients with brain tumors.

      2. Epidemiology and clinical characteristics

      2.1 Neuroglial developmental tumors

      DNETs and gangliogliomas compose a specific group of tumors since they are highly epileptogenic developmental lesions clinically characterized by early onset seizures [
      • Blumcke I.
      • Aronica E.
      • Urbach H.
      • Alexopoulos A.
      • Gonzalez-Martinez J.A.
      A neuropathology-based approach to epilepsy surgery in brain tumors and proposal for a new terminology use for long-term epilepsy-associated brain tumors.
      ]. Although the population prevalence of DNETs and GGs is not high, they are among the most common causes of intractable focal epilepsy [
      • Englot D.J.
      • Chang E.F.
      Rates and predictors of seizure freedom in resective epilepsy surgery: an update.
      ,
      • Blumcke I.
      • Aronica E.
      • Urbach H.
      • Alexopoulos A.
      • Gonzalez-Martinez J.A.
      A neuropathology-based approach to epilepsy surgery in brain tumors and proposal for a new terminology use for long-term epilepsy-associated brain tumors.
      ]. Seizures are usually the first and the only symptom of the patients with developmental tumors. The frequency of seizures reaches to almost 100% with DNETs and 80–90% with GGs [
      • van Breemen M.S.
      • Wilms E.B.
      • Vecht C.J.
      Epilepsy in patients with brain tumours: epidemiology, mechanisms, and management.
      ]. They are benign tumors of neuroglial origin with a broad histopathological spectrum [
      • Blumcke I.
      • Aronica E.
      • Urbach H.
      • Alexopoulos A.
      • Gonzalez-Martinez J.A.
      A neuropathology-based approach to epilepsy surgery in brain tumors and proposal for a new terminology use for long-term epilepsy-associated brain tumors.
      ]. Eighty percent of DNETs are located in the temporal lobe, while extratemporal tumors constituting only about 20% of all DNETs. The most frequent extratemporal location is frontal [
      • Thom M.
      • Toma A.
      • An S.
      • Martinian L.
      • Hadjivassiliou G.
      • Ratilal B.
      • et al.
      One hundred and one dysembryoplastic neuroepithelial tumors: an adult epilepsy series with immunohistochemical, molecular genetic, and clinical correlations and a review of the literature.
      ]. GGs are also mostly located in the temporal lobes [
      • Blumcke I.
      • Aronica E.
      • Urbach H.
      • Alexopoulos A.
      • Gonzalez-Martinez J.A.
      A neuropathology-based approach to epilepsy surgery in brain tumors and proposal for a new terminology use for long-term epilepsy-associated brain tumors.
      ,
      • Kerkhof M.
      • Vecht C.J.
      Seizure characteristics and prognostic factors of gliomas.
      ,
      • Sommer B.
      • Wimmer C.
      • Coras R.
      • Blumcke I.
      • Lorber B.
      • Hamer H.M.
      • et al.
      Resection of cerebral gangliogliomas causing drug-resistant epilepsy: short- and long-term outcomes using intraoperative MRI and neuronavigation.
      ]. Both tumors have a benign course, therefore relapse and malignant progression are very rare [
      • Blumcke I.
      • Aronica E.
      • Urbach H.
      • Alexopoulos A.
      • Gonzalez-Martinez J.A.
      A neuropathology-based approach to epilepsy surgery in brain tumors and proposal for a new terminology use for long-term epilepsy-associated brain tumors.
      ]. They are classified in the group of ‘low-grade epilepsy-associated tumors’ (LEAT) [
      • Blümcke I.
      • Aronica E.
      • Becker A.
      • Capper D.
      • Coras R.
      • Honavar M.
      • et al.
      Low-grade epilepsy-associated neuroepithelial tumours - the 2016 WHO classification.
      ]. LEATs are a specific group of tumors strongly associated with epilepsy. Their characteristics include a slow growth rate, early-onset drug-resistant epilepsy, neocortical localization and temporal lobe predominance [
      • Thom M.
      • Blümcke I.
      • Aronica E.
      Long-term epilepsy-associated tumors.
      ,
      • Blümcke I.
      • Aronica E.
      • Becker A.
      • Capper D.
      • Coras R.
      • Honavar M.
      • et al.
      Low-grade epilepsy-associated neuroepithelial tumours - the 2016 WHO classification.
      ]. There are various tumors in this group, however, the most common are DNETs and GGs. Following the developments in the molecular genetics, the WHO introduced a new classification based on a molecular genetic approach for some tumor entities [
      • Louis D.N.
      • Perry A.
      • Reifenberger G.
      • von Deimling A.
      • Figarella-Branger D.
      • Cavenee W.K.
      • et al.
      The 2016 World Health Organization Classification of tumors of the central nervous system: a summary.
      ]. However, LEAT’s are still difficult to classify because they lack a clear clinicopathological and molecular genetic profile [
      • Blümcke I.
      • Aronica E.
      • Becker A.
      • Capper D.
      • Coras R.
      • Honavar M.
      • et al.
      Low-grade epilepsy-associated neuroepithelial tumours - the 2016 WHO classification.
      ]. What is more, the MRI lesion may not match up with the epileptogenic zone, which may lead to a need for complex investigations with invasive EEG in some cases [
      • Blumcke I.
      • Aronica E.
      • Urbach H.
      • Alexopoulos A.
      • Gonzalez-Martinez J.A.
      A neuropathology-based approach to epilepsy surgery in brain tumors and proposal for a new terminology use for long-term epilepsy-associated brain tumors.
      ]. The mean age of onset of DNET is about 15 years [
      • Thom M.
      • Toma A.
      • An S.
      • Martinian L.
      • Hadjivassiliou G.
      • Ratilal B.
      • et al.
      One hundred and one dysembryoplastic neuroepithelial tumors: an adult epilepsy series with immunohistochemical, molecular genetic, and clinical correlations and a review of the literature.
      ], of GGs it is 16–19 [
      • Sommer B.
      • Wimmer C.
      • Coras R.
      • Blumcke I.
      • Lorber B.
      • Hamer H.M.
      • et al.
      Resection of cerebral gangliogliomas causing drug-resistant epilepsy: short- and long-term outcomes using intraoperative MRI and neuronavigation.
      ,
      • Compton J.J.
      • Laack N.N.
      • Eckel L.J.
      • Schomas D.A.
      • Giannini C.
      • Meyer F.B.
      Long-term outcomes for low-grade intracranial ganglioglioma: 30-year experience from the Mayo Clinic.
      ]; however, they may manifest also in young adults. The mean age at surgery is around 30 for both types of the tumors [
      • Thom M.
      • Toma A.
      • An S.
      • Martinian L.
      • Hadjivassiliou G.
      • Ratilal B.
      • et al.
      One hundred and one dysembryoplastic neuroepithelial tumors: an adult epilepsy series with immunohistochemical, molecular genetic, and clinical correlations and a review of the literature.
      ,
      • Sommer B.
      • Wimmer C.
      • Coras R.
      • Blumcke I.
      • Lorber B.
      • Hamer H.M.
      • et al.
      Resection of cerebral gangliogliomas causing drug-resistant epilepsy: short- and long-term outcomes using intraoperative MRI and neuronavigation.
      ]. Tumors can be associated with focal cortical dysplasia, however, the impact of focal cortical dysplasia on the epileptogenicity is still not clear. Focal seizures with loss of awareness are the most common seizure type associated with DNETs and GGs (seen in about 80% of cases) [
      • Thom M.
      • Toma A.
      • An S.
      • Martinian L.
      • Hadjivassiliou G.
      • Ratilal B.
      • et al.
      One hundred and one dysembryoplastic neuroepithelial tumors: an adult epilepsy series with immunohistochemical, molecular genetic, and clinical correlations and a review of the literature.
      ,
      • Sommer B.
      • Wimmer C.
      • Coras R.
      • Blumcke I.
      • Lorber B.
      • Hamer H.M.
      • et al.
      Resection of cerebral gangliogliomas causing drug-resistant epilepsy: short- and long-term outcomes using intraoperative MRI and neuronavigation.
      ]. Secondary generalized tonic–clonic seizures are seen in about 50% of patients. One exception to the preponderance of focal seizures is the histologically simple subtype of DNET, in which secondarily generalized seizures are most common [
      • Thom M.
      • Toma A.
      • An S.
      • Martinian L.
      • Hadjivassiliou G.
      • Ratilal B.
      • et al.
      One hundred and one dysembryoplastic neuroepithelial tumors: an adult epilepsy series with immunohistochemical, molecular genetic, and clinical correlations and a review of the literature.
      ].

      2.2 Low-grade gliomas (WHO grade II tumors)

      Low-grade gliomas (astrocytoma, oligodendroglioma, oligoastrocytoma) are also associated with a high incidence of seizures. The overall proportion of patients with these tumors who develop seizures varies between 65–90% [
      • Kerkhof M.
      • Vecht C.J.
      Seizure characteristics and prognostic factors of gliomas.
      ,
      • Iuchi T.
      • Hasegawa Y.
      • Kawasaki K.
      • Sakaida T.
      Epilepsy in patients with gliomas: incidence and control of seizures.
      ,
      • Pallud J.
      • Audureau E.
      • Blonski M.
      • Sanai N.
      • Bauchet L.
      • Fontaine D.
      • et al.
      Epileptic seizures in diffuse low-grade gliomas in adults.
      ,
      • You G.
      • Sha Z.
      • Yan W.
      • Zhang W.
      • Wang Y.
      • Li S.
      • et al.
      Seizure characteristics and outcomes in 508 Chinese adult patients undergoing primary resection of low-grade gliomas:a clinicaopathological study.
      ]. A seizure is the most common presenting symptom, however, patients may also begin to develop seizures later in the course of the disease [
      • van Breemen M.S.
      • Wilms E.B.
      • Vecht C.J.
      Epilepsy in patients with brain tumours: epidemiology, mechanisms, and management.
      ,
      • Kerkhof M.
      • Vecht C.J.
      Seizure characteristics and prognostic factors of gliomas.
      ]. These tumors are usually diagnosed between the ages 30–45 [
      • Pallud J.
      • Audureau E.
      • Blonski M.
      • Sanai N.
      • Bauchet L.
      • Fontaine D.
      • et al.
      Epileptic seizures in diffuse low-grade gliomas in adults.
      ,
      • You G.
      • Sha Z.
      • Yan W.
      • Zhang W.
      • Wang Y.
      • Li S.
      • et al.
      Seizure characteristics and outcomes in 508 Chinese adult patients undergoing primary resection of low-grade gliomas:a clinicaopathological study.
      ]. An age of under 38 years and cortical involvement by these tumors have been identified as risk factors for seizures in patients with these tumors [
      • You G.
      • Sha Z.
      • Yan W.
      • Zhang W.
      • Wang Y.
      • Li S.
      • et al.
      Seizure characteristics and outcomes in 508 Chinese adult patients undergoing primary resection of low-grade gliomas:a clinicaopathological study.
      ]. A location of the tumor close to functional areas makes it more likely to seizures to be present at diagnosis [
      • Pallud J.
      • Audureau E.
      • Blonski M.
      • Sanai N.
      • Bauchet L.
      • Fontaine D.
      • et al.
      Epileptic seizures in diffuse low-grade gliomas in adults.
      ]. Contrary to neuroglial tumors, low-grade glial tumors more frequently involve extratemporal lobes with the highest frequency in frontal lobes. If the tumor involves the temporal lobe, it usually extends into the insula [
      • Kerkhof M.
      • Vecht C.J.
      Seizure characteristics and prognostic factors of gliomas.
      ,
      • Pallud J.
      • Audureau E.
      • Blonski M.
      • Sanai N.
      • Bauchet L.
      • Fontaine D.
      • et al.
      Epileptic seizures in diffuse low-grade gliomas in adults.
      ,
      • You G.
      • Sha Z.
      • Yan W.
      • Zhang W.
      • Wang Y.
      • Li S.
      • et al.
      Seizure characteristics and outcomes in 508 Chinese adult patients undergoing primary resection of low-grade gliomas:a clinicaopathological study.
      ,
      • Smits A.
      • Duffau H.
      Seizures and the natural history of world health organization grade II gliomas: a review.
      ]. Seizures are mostly secondarily generalized [
      • You G.
      • Sha Z.
      • Yan W.
      • Zhang W.
      • Wang Y.
      • Li S.
      • et al.
      Seizure characteristics and outcomes in 508 Chinese adult patients undergoing primary resection of low-grade gliomas:a clinicaopathological study.
      ]. Seizures as the only presenting symptom of the tumor suggest a favorable prognosis [
      • Smits A.
      • Duffau H.
      Seizures and the natural history of world health organization grade II gliomas: a review.
      ,
      • Vecht C.J.
      • Kerkhof M.
      • Duran-Pena A.
      Seizure prognosis in brain tumors: new insights and evidence-based management.
      ]. They may allow tumors to be diagnosed in at an earlier stage when the tumor is small enough and there is a higher chance of complete resection. Despite AEDs, 50% of the patients may be drug-resistant preoperatively. Insular location, prolonged time to diagnosis, and tumor within functional areas are factors associated with medically refractory seizures [
      • Pallud J.
      • Audureau E.
      • Blonski M.
      • Sanai N.
      • Bauchet L.
      • Fontaine D.
      • et al.
      Epileptic seizures in diffuse low-grade gliomas in adults.
      ,
      • Smits A.
      • Duffau H.
      Seizures and the natural history of world health organization grade II gliomas: a review.
      ].

      2.3 High-grade gliomas (WHO grade III–IV)

      High-grade gliomas include anaplastic astrocytomas (AAs) and glioblastomas. Glioblastoma is the most common primary brain tumor in adults. The mean age at diagnosis is 60 years [
      • Kerkhof M.
      • Dielemans J.C.
      • van Breemen M.S.
      • Zwinkels H.
      • Walchenbach R.
      • Taphoorn M.J.
      • et al.
      Effect of valproic acid on seizure control and on survival in patients with glioblastoma multiforme.
      ]. The overall proportion of patients with these tumors in which seizures are diagnosed has been reported as ranging from 40 to 62% [
      • van Breemen M.S.
      • Wilms E.B.
      • Vecht C.J.
      Epilepsy in patients with brain tumours: epidemiology, mechanisms, and management.
      ,
      • Kerkhof M.
      • Dielemans J.C.
      • van Breemen M.S.
      • Zwinkels H.
      • Walchenbach R.
      • Taphoorn M.J.
      • et al.
      Effect of valproic acid on seizure control and on survival in patients with glioblastoma multiforme.
      ,
      • Wychowski T.
      • Wang H.
      • Buniak L.
      • Henry J.C.
      • Mohile N.
      Considerations in prophylaxis for tumor-associated epilepsy: prevention of status epilepticus and tolerability of newer generation AEDs.
      ]. Twenty-two percent of patients with these tumors had their first seizures after surgery [
      • Wychowski T.
      • Wang H.
      • Buniak L.
      • Henry J.C.
      • Mohile N.
      Considerations in prophylaxis for tumor-associated epilepsy: prevention of status epilepticus and tolerability of newer generation AEDs.
      ]. Both focal and generalized seizures are observed during the course of glioblastoma. About 38% of patients have partial seizures, whereas 41% develop partial seizures with secondary generalization. Status epilepticus (SE) may also be observed in 12% of patients [
      • Kerkhof M.
      • Dielemans J.C.
      • van Breemen M.S.
      • Zwinkels H.
      • Walchenbach R.
      • Taphoorn M.J.
      • et al.
      Effect of valproic acid on seizure control and on survival in patients with glioblastoma multiforme.
      ]. A frontal and temporal location are more frequent in glioblastoma and more commonly associated with seizures [
      • Wychowski T.
      • Wang H.
      • Buniak L.
      • Henry J.C.
      • Mohile N.
      Considerations in prophylaxis for tumor-associated epilepsy: prevention of status epilepticus and tolerability of newer generation AEDs.
      ]. Another study reported status epilepticus (SE) in 12% of their study group consisting of patients with primary tumors. SE was seen most commonly in those with glioblastoma, the most frequent tumor location in those with SE was frontal or fronto-temporal [
      • Michelucci R.
      • Pasini E.
      • Meletti S.
      • Fallica E.
      • Rizzi R.
      • Florindo I.
      • et al.
      Epilepsy in primary cerebral tumors: the characteristics of epilepsy at the onset (results from the PERNO study-Project of Emilia Romagna Region on Neuro-Oncology).
      ]. Prophylactic AEDs do not reduce the incidence of epilepsy postoperatively, however, patients not receiving AEDs after surgery had a higher incidence of SE [
      • Wychowski T.
      • Wang H.
      • Buniak L.
      • Henry J.C.
      • Mohile N.
      Considerations in prophylaxis for tumor-associated epilepsy: prevention of status epilepticus and tolerability of newer generation AEDs.
      ].

      2.4 Meningioma

      Although most meningiomas are silent and benign; meningiomas may become symptomatic depending on the size and location of the tumor. Seizures are one of the most common manifestations of symptomatic meningiomas apart from headache and neurological deficits [
      • Wirsching H.-G.
      • Morel C.
      • Gmür C.
      • Neidert M.C.
      • Baumann C.R.
      • Valavanis A.
      • et al.
      Predicting outcome of epilepsy after meningioma resection.
      ]. Surgical excision is the first choice of treatment for symptomatic intracranial meningiomas. The incidence of a preoperative seizure in patients with meningiomas is about 26–31% [
      • Wirsching H.-G.
      • Morel C.
      • Gmür C.
      • Neidert M.C.
      • Baumann C.R.
      • Valavanis A.
      • et al.
      Predicting outcome of epilepsy after meningioma resection.
      ,
      • Lieu A.S.
      • Howng S.L.
      Intracranial meningiomas and epilepsy: incidence, prognosis and influencing factors.
      ,
      • Englot D.J.
      • Magill S.T.
      • Han S.J.
      • Chang E.F.
      • Berger M.S.
      • McDermott M.W.
      Seizures in supratentorial meningioma: a systematic review and meta-analysis.
      ]. It is greater in older patients. The most common age at diagnosis of meningiomas subsequently treated with surgery is 50–60 years. The location of the tumor affects the seizure risk. Supratentorial meningiomas, mainly convexity and parasagittal, and peritumoral edema have been found to be associated with the greatest risk of seizures [
      • Lieu A.S.
      • Howng S.L.
      Intracranial meningiomas and epilepsy: incidence, prognosis and influencing factors.
      ,
      • Englot D.J.
      • Magill S.T.
      • Han S.J.
      • Chang E.F.
      • Berger M.S.
      • McDermott M.W.
      Seizures in supratentorial meningioma: a systematic review and meta-analysis.
      ]. Seizure freedom may be achieved in about 60–70% of meningioma patients with epilepsy [
      • Wirsching H.-G.
      • Morel C.
      • Gmür C.
      • Neidert M.C.
      • Baumann C.R.
      • Valavanis A.
      • et al.
      Predicting outcome of epilepsy after meningioma resection.
      ,
      • Englot D.J.
      • Magill S.T.
      • Han S.J.
      • Chang E.F.
      • Berger M.S.
      • McDermott M.W.
      Seizures in supratentorial meningioma: a systematic review and meta-analysis.
      ]. Risk factors for postoperative seizures include the presence of epilepsy before surgery, major surgical complications, epileptiform EEG activity, younger age and tumor progression. Therefore it has been suggested that EEG should be a part of the postoperative evaluation. This can contribute to a score based on the identified risk factors which may guide antiepileptic treatment postoperatively [
      • Wirsching H.-G.
      • Morel C.
      • Gmür C.
      • Neidert M.C.
      • Baumann C.R.
      • Valavanis A.
      • et al.
      Predicting outcome of epilepsy after meningioma resection.
      ]. About 12–19% of meningioma patients without preoperative seizures may suffer from seizures after surgery [
      • Wirsching H.-G.
      • Morel C.
      • Gmür C.
      • Neidert M.C.
      • Baumann C.R.
      • Valavanis A.
      • et al.
      Predicting outcome of epilepsy after meningioma resection.
      ].
      During the selection of an appropriate anticonvulsant drug for meningioma patients, general principles for focal epilepsy should be followed. In contrast to malignant tumors, drug interactions are rarely the case in meningiomas.

      2.5 Metastases

      Brain metastases develop about 20% of patients with systemic cancer [
      • Weller M.
      • Stupp R.
      • Wick W.
      Epilepsy meets cancer: when, why, and what to do about it?.
      ]. Parenchymal and leptomeningeal metastases may lead to seizures. About 35% of patients with metastases have seizures, 20% being as the initial symptom [
      • van Breemen M.S.
      • Wilms E.B.
      • Vecht C.J.
      Epilepsy in patients with brain tumours: epidemiology, mechanisms, and management.
      ,
      • Lynam L.M.
      • Lyons M.K.
      • Drazkowski J.F.
      • Sirven J.I.
      • Noe K.H.
      • Zimmerman R.S.
      • et al.
      Frequency of seizures in patients with newly diagnosed brain tumors: a retrospective review.
      ,
      • Skardelly M.
      • Brendle E.
      • Noell S.
      • Behling F.
      • Wuttke T.V.
      • Schittenhelm J.
      • et al.
      Predictors of preoperative and early postoperative seizures in patients with intra-axial primary and metastatic brain tumors: a retrospective observational single center study.
      ]. In some cases where the seizure is the first symptom, cancer is diagnosed subsequently. The mean age of patients with metastases is about 70 years [
      • Lynam L.M.
      • Lyons M.K.
      • Drazkowski J.F.
      • Sirven J.I.
      • Noe K.H.
      • Zimmerman R.S.
      • et al.
      Frequency of seizures in patients with newly diagnosed brain tumors: a retrospective review.
      ]. Although the commonest cause of seizures in patients with cancer is brain metastases; it should be born in mind that there may be other reasons for seizures associated with cancer such as electrolyte imbalances, chemotherapeutics, or paraneoplastic syndromes [
      • Weller M.
      • Stupp R.
      • Wick W.
      Epilepsy meets cancer: when, why, and what to do about it?.
      ]. A seizure as the initial symptom is significantly more common in patients with primary CNS neoplasms than metastases. This may be explained by the less infiltrative growth pattern of brain metastases as well as their inability biochemically to modulate neuronal excitability [
      • Weller M.
      • Stupp R.
      • Wick W.
      Epilepsy meets cancer: when, why, and what to do about it?.
      ]. Primary CNS lymphomas rarely cause seizures. They most commonly develop in the white matter and are usually not diagnosed because of an epileptic seizure [
      • van Breemen M.S.
      • Wilms E.B.
      • Vecht C.J.
      Epilepsy in patients with brain tumours: epidemiology, mechanisms, and management.
      ,
      • Weller M.
      • Stupp R.
      • Wick W.
      Epilepsy meets cancer: when, why, and what to do about it?.
      ].
      Although patients with brain metastases may be prone to seizures, prophylactic AED treatment is not recommended in those who have not experienced seizures. However, in many centers, physicians may prescribes AED even in the absence of a seizure history [
      • Dewan M.C.
      • Thompson R.C.
      • Kalkanis S.N.
      • Barker 2nd, F.G.
      • Hadjipanayis C.G.
      Prophylactic antiepileptic drug administration following brain tumor resection: results of a recent AANS/CNS Section on Tumors survey.
      ].

      3. Pathology and molecular markers

      The pathogenesis of tumor-related epilepsy is multifactorial and not fully understood [
      • Rudà R.
      • Trevisan E.
      • Soffietti R.
      Epilepsy and brain tumors.
      ,
      • Shamji M.F.
      • Fric-Shamji E.C.
      • Benoit B.G.
      Brain tumors and epilepsy: pathophysiology of peritumoral changes.
      ,
      • You G.
      • Sha Z.
      • Jiang T.
      The pathogenesis of tumor-related epilepsy and its implications for clinical treatment.
      ]. Epileptogenesis by brain tumors is influenced by many factors including tumor histology, location, genetic factors, the integrity of the blood brain barrier and changes in the peritumoral environment such as neurotransmitter changes, ion concentrations and hypoxia [
      • van Breemen M.S.
      • Wilms E.B.
      • Vecht C.J.
      Epilepsy in patients with brain tumours: epidemiology, mechanisms, and management.
      ,
      • Rudà R.
      • Trevisan E.
      • Soffietti R.
      Epilepsy and brain tumors.
      ,
      • Shamji M.F.
      • Fric-Shamji E.C.
      • Benoit B.G.
      Brain tumors and epilepsy: pathophysiology of peritumoral changes.
      ,
      • You G.
      • Sha Z.
      • Jiang T.
      The pathogenesis of tumor-related epilepsy and its implications for clinical treatment.
      ]. Greater levels of glutamate have been found in brain tumor samples of patients with epilepsy associated with tumors compared to those with nontumoral pathologies. Altered concentrations of GABA may also contribute to tumor-associated epilepsy [
      • Shamji M.F.
      • Fric-Shamji E.C.
      • Benoit B.G.
      Brain tumors and epilepsy: pathophysiology of peritumoral changes.
      ]. Among the molecular genetic factors, the PI3K- mTOR pathway seems to be involved in epileptogenesis in neuroglial tumors in addition to its role in tumor growth [
      • Rudà R.
      • Soffietti R.
      What is new in the management of epilepsy in gliomas?.
      ]. The mechanisms may vary among tumor types. This may explain the difference in the frequency with which particular tumors are associated with seizures [
      • Rudà R.
      • Trevisan E.
      • Soffietti R.
      Epilepsy and brain tumors.
      ].
      Several molecular markers have been identified in brain tumors in recent years. For instance, the clinical importance of isocitrate dehydrogenase 1/2 (IDH1/2) mutations, 1p/19q codeletion and MGMT promoter methylation for the patient’s prognosis have been confirmed in many studies [
      • Rudà R.
      • Pellerino A.
      • Magistrello M.
      • Franchino F.
      • Pinessi L.
      • Soffietti R.
      Molecularly based management of gliomas in clinical practice.
      ]. However, biological markers may also play a role in the development of seizures, and there are many studies looking for an association between biological markers and the risk of seizures in tumor-related epilepsies.
      IDH 1/2 mutations are common in diffuse low-grade gliomas and have been found to be associated with seizures as the initial symptom [
      • Rudà R.
      • Soffietti R.
      What is new in the management of epilepsy in gliomas?.
      ,
      • Stockhammer F.
      • Misch M.
      • Helms H.
      • Lengler U.
      • Prall F.
      • Von Deimling A.
      • et al.
      IDH1/2 mutations in WHO grade II astrocytomas associated with localization and seizure as the initial symptom.
      ]. Skardelly et al. also demonstrated that IDH mutation is a predictor of epileptogenicity and that different seizures rates within glioma subgroups are associated with differences in the prevalence of IDH mutations [
      • Skardelly M.
      • Brendle E.
      • Noell S.
      • Behling F.
      • Wuttke T.V.
      • Schittenhelm J.
      • et al.
      Predictors of preoperative and early postoperative seizures in patients with intra-axial primary and metastatic brain tumors: a retrospective observational single center study.
      ]. However, a recent large study did not confirm the relation between molecular markers (1p19q codeletion, p53 expression and isocitrate dehydrogenase 1 expression) and seizure in low-grade gliomas [
      • Pallud J.
      • Audureau E.
      • Blonski M.
      • Sanai N.
      • Bauchet L.
      • Fontaine D.
      • et al.
      Epileptic seizures in diffuse low-grade gliomas in adults.
      ].
      BRAF V600E mutations have been identified in glioneuronal tumors and their expression has been found to be associated with a worse postoperative seizure outcome [
      • Prabowo A.S.
      • Iyer A.M.
      • Veersema T.J.
      • Anink J.J.
      • Schouten-van Meeteren A.Y.
      • Spliet W.G.
      • et al.
      BRAF V600E mutation is associated with mTOR signaling activation in glioneuronal tumors.
      ].
      A number of molecular genetic markers has been identified as being associated with the seizure risk in patients with gliomas. The overexpression of nuclear protein Ki-67 was found to be a poor prognostic factor for seizure control in low-grade glioma patients [
      • Kerkhof M.
      • Vecht C.J.
      Seizure characteristics and prognostic factors of gliomas.
      ,
      • You G.
      • Sha Z.
      • Yan W.
      • Zhang W.
      • Wang Y.
      • Li S.
      • et al.
      Seizure characteristics and outcomes in 508 Chinese adult patients undergoing primary resection of low-grade gliomas:a clinicaopathological study.
      ]. Another study suggested that high RINT1 expression may represent a risk factor for low-grade glioma (LGG) -related seizures and may be associated with seizure outcomes [
      • Fan X.
      • Zhang Y.W.C.
      • You G.
      • Lei M.L.
      • Tao W.
      Expression of RINT1 predicts seizure occurrence and outcomes in patients with low-grade gliomas.
      ]. Low expression of very large G-protein-coupled receptor-1 (VLGR) 1 [
      • Wang Y.
      • Fan X.
      • Zhang W.
      • Wang L.
      Deficiency of very large G-protein-coupled receptor-1 is a risk factor of tumor-related epilepsy: a whole transcriptome sequencing analysis.
      ] and dysregulation of miR-128 expression has also been found to be associated with epilepsy in low-grade gliomas [
      • Yuan Y.
      • Xiang W.
      • Yanhui L.
      • Ruofei L.
      Dysregulation of microRNA-128 expression in WHO grades 2 glioma is associated with glioma-associated epilepsy: down-regulation of miR-128 induces glioma-associated seizure.
      ]. A recent study of patients with anaplastic gliomas found low Ki-67 expression and EGFR amplification to be correlated with preoperative seizures [
      • Yang P.
      • You G.
      • Zhang W.
      • Wang Y.
      Correlation of preoperative seizures with clinicopathological factors and prognosis in anaplastic gliomas: a report of 198 patients from China.
      ].

      4. The role of EEG

      All patients with a first seizure should undergo an MRI at the time of presentation which may show focal lesions such as tumors. Electroencephalography (EEG) also plays a role in the evaluation. EEG may help to localize the epileptogenic focus, to determine the patients who are at risk for recurrent seizures and guide decision regarding the need for antiepileptic drug therapy [
      • Lynam L.M.
      • Lyons M.K.
      • Drazkowski J.F.
      • Sirven J.I.
      • Noe K.H.
      • Zimmerman R.S.
      • et al.
      Frequency of seizures in patients with newly diagnosed brain tumors: a retrospective review.
      ].
      Intraoperative EEG is performed in some centers. However, in their review, Englot et al. found no significant difference in terms of seizure outcome between patients with glioneuronal tumors and LGG with and without intraoperative EEG [
      • Englot D.J.
      • Berger M.S.
      • Barbaro N.M.
      • Chang E.F.
      Predictors of seizure freedom after resection of supratentorial low-grade gliomas.
      ,
      • Englot D.J.
      • Berger M.S.
      • Barbaro N.M.
      • Chang E.F.
      Factors associated with seizure freedom in the surgical resection of glioneuronal tumors.
      ]. However, they emphasize that electrocorticography may have been carried out in more severe cases of epilepsy which may have confounded results.
      Invasive EEG recordings are used in about 10% of patients undergoing epilepsy surgery for tumor-related epilepsy. In extratemporal lobe epilepsy, invasive EEG is only needed when the lesion is close to eloquent cortex [
      • Rosenow F.
      • Menzler K.
      Invasive EEG studies in tumor-related epilepsy: when are they indicated and with what kind of electrodes?.
      ]. In this case it can help to confine the surgical resection by defining functional borders.
      In the case of lesions in the non-dominant temporal lobe with a long duration of epilepsy characterized by frequent and disabling seizures, mesial structures should also be resected if they are involved or in close relation with the tumor. If the lesions is located in the dominant temporal lobe, if the mesial structures are not involved and properly functioning they should not be included in resection. Otherwise mesial structures should also be resected to optimise seizure outcome. In patients with temporal lobe tumor-related epilepsy patients invasive EEG may only be carried out when the initial resection has failed to control seizures [
      • Rosenow F.
      • Menzler K.
      Invasive EEG studies in tumor-related epilepsy: when are they indicated and with what kind of electrodes?.
      ].
      Another study performed two stage surgery with intracranial EEG before tumor surgery to improve seizure outcomes in patients with primary brain tumors. They included 11 patients with glioneuronal, LGG and noninfiltrative tumors and found better seizure outcomes in patients with resection of the tumor and the seizure onset zone determined by intracranial EEG [
      • Mittal S.
      • Barkmeier D.
      • Hua J.
      • Pai D.S.
      • Fuerst D.
      • Basha M.
      • et al.
      Intracranial EEG analysis in tumor-related epilepsy: evidence of distant epileptic abnormalities.
      ]. This approach may be preferred for some developmental tumors and LGG. Prospective investigations are needed to determine the role of intraoperative or invasive EEG on seizure outcomes of tumor-related epilepsy.
      A recent study on meningiomas attributed a significant role to the EEG because it found that epileptiform abnormalities on postoperative EEG were associated with an increased risk of postoperative seizures [
      • Wirsching H.-G.
      • Morel C.
      • Gmür C.
      • Neidert M.C.
      • Baumann C.R.
      • Valavanis A.
      • et al.
      Predicting outcome of epilepsy after meningioma resection.
      ].

      5. Treatment of brain tumor-related epilepsy

      In brain tumor-related epilepsy, control of epilepsy depends on the successful treatment of the tumor [
      • Weller M.
      • Stupp R.
      • Wick W.
      Epilepsy meets cancer: when, why, and what to do about it?.
      ]. In addition to surgical resection and antiepileptic drugs, radiotherapy and chemotherapy may also play a role in the management of brain tumor-related epilepsy.

      5.1 Surgical treatment and prognostic factors

      Patients with glioneuronal tumors have long survivals and seizures tend to be refractory. Therefore seizure control is critical in the clinical management of glioneuronal tumors in terms of improving patients’ quality of life [
      • Englot D.J.
      • Berger M.S.
      • Barbaro N.M.
      • Chang E.F.
      Factors associated with seizure freedom in the surgical resection of glioneuronal tumors.
      ]. This means that surgery is the treatment of choice for DNETs and GGs. The rates of seizure freedom following DNET surgery differ between studies but usually range from 68 to 83% [
      • Thom M.
      • Toma A.
      • An S.
      • Martinian L.
      • Hadjivassiliou G.
      • Ratilal B.
      • et al.
      One hundred and one dysembryoplastic neuroepithelial tumors: an adult epilepsy series with immunohistochemical, molecular genetic, and clinical correlations and a review of the literature.
      ,
      • Englot D.J.
      • Berger M.S.
      • Barbaro N.M.
      • Chang E.F.
      Factors associated with seizure freedom in the surgical resection of glioneuronal tumors.
      ]. These rates are similar for GGs (70–85%) [
      • Sommer B.
      • Wimmer C.
      • Coras R.
      • Blumcke I.
      • Lorber B.
      • Hamer H.M.
      • et al.
      Resection of cerebral gangliogliomas causing drug-resistant epilepsy: short- and long-term outcomes using intraoperative MRI and neuronavigation.
      ,
      • Englot D.J.
      • Berger M.S.
      • Barbaro N.M.
      • Chang E.F.
      Factors associated with seizure freedom in the surgical resection of glioneuronal tumors.
      ,
      • Southwell D.G.
      • Garcia P.A.
      • Berger M.S.
      • Barbaro N.M.
      • Chang E.F.
      Long-term seizure control outcomes after resection of gangliogliomas.
      ]. A shorter duration of epilepsy (less than 1 year) and gross total resection are the most important factors for achieving seizure freedom [
      • Englot D.J.
      • Berger M.S.
      • Barbaro N.M.
      • Chang E.F.
      Factors associated with seizure freedom in the surgical resection of glioneuronal tumors.
      ]. In addition, preoperative secondarily generalized seizures have been found to be associated with less favorable outcomes. No significant difference was found in outcomes between temporal versus extratemporal tumors, medically controlled versus refractory seizures [
      • Englot D.J.
      • Berger M.S.
      • Barbaro N.M.
      • Chang E.F.
      Factors associated with seizure freedom in the surgical resection of glioneuronal tumors.
      ]. Early surgery can produce seizure freedom and, considering the younger age of these patients, has additional benefits in terms of avoidance of side effects of the drugs during the development of younger brains. Because malignant progression is rare in glioneuronal tumors; there is no role of chemotherapy and radiotherapy. Invasive EEG recordings may be helpful in some cases.
      Resection of the tumor improves seizure control also in LGG. Seizure freedom rates following LGG surgery range from 65 to 71% [
      • You G.
      • Sha Z.
      • Yan W.
      • Zhang W.
      • Wang Y.
      • Li S.
      • et al.
      Seizure characteristics and outcomes in 508 Chinese adult patients undergoing primary resection of low-grade gliomas:a clinicaopathological study.
      ,
      • Englot D.J.
      • Berger M.S.
      • Barbaro N.M.
      • Chang E.F.
      Predictors of seizure freedom after resection of supratentorial low-grade gliomas.
      ]. Additionally, radiotherapy and chemotherapy alone or in combination have beneficial effects on seizure control [
      • Smits A.
      • Duffau H.
      Seizures and the natural history of world health organization grade II gliomas: a review.
      ,
      • Vecht C.J.
      • Kerkhof M.
      • Duran-Pena A.
      Seizure prognosis in brain tumors: new insights and evidence-based management.
      ,
      • Rudà R.
      • Soffietti R.
      What is new in the management of epilepsy in gliomas?.
      ]. The most important predictor of seizure freedom is gross total resection [
      • Pallud J.
      • Audureau E.
      • Blonski M.
      • Sanai N.
      • Bauchet L.
      • Fontaine D.
      • et al.
      Epileptic seizures in diffuse low-grade gliomas in adults.
      ,
      • Englot D.J.
      • Berger M.S.
      • Barbaro N.M.
      • Chang E.F.
      Predictors of seizure freedom after resection of supratentorial low-grade gliomas.
      ]. Duration of seizures (less than 1 year), preoperative seizure control and control with antiepileptic medication are other influencing factors. Patients with simple partial seizures had a lower chance of achieving good seizure control [
      • Englot D.J.
      • Berger M.S.
      • Barbaro N.M.
      • Chang E.F.
      Predictors of seizure freedom after resection of supratentorial low-grade gliomas.
      ]. Patients with secondarily generalized seizures and calcification on MRI, with gross total resection have better outcomes [
      • You G.
      • Sha Z.
      • Yan W.
      • Zhang W.
      • Wang Y.
      • Li S.
      • et al.
      Seizure characteristics and outcomes in 508 Chinese adult patients undergoing primary resection of low-grade gliomas:a clinicaopathological study.
      ]. Following treatment of the tumor; a history of preoperative epilepsy and parietal and insular locations have been found to be associated with unfavorable seizure outcomes [
      • Pallud J.
      • Audureau E.
      • Blonski M.
      • Sanai N.
      • Bauchet L.
      • Fontaine D.
      • et al.
      Epileptic seizures in diffuse low-grade gliomas in adults.
      ].
      Glioblastoma is an aggressive tumor. Standard treatment involves tumor resection followed by external beam radiation therapy (RT) with concomitant and adjuvant chemotherapy [
      • Knudsen-Baas K.M.
      • Engeland A.
      • Gilhus N.E.
      • Storstein A.M.
      • Owe J.F.
      Does the choice of antiepileptic drug affect survival in glioblastoma patients?.
      ]. Seizure freedom rates following resection of glioblastoma are around 77% [
      • Vecht C.J.
      • Kerkhof M.
      • Duran-Pena A.
      Seizure prognosis in brain tumors: new insights and evidence-based management.
      ,
      • Wirsching H.-G.
      • Morel C.
      • Gmür C.
      • Neidert M.C.
      • Baumann C.R.
      • Valavanis A.
      • et al.
      Predicting outcome of epilepsy after meningioma resection.
      ]. Seizure recurrence is generally associated with progression of the glioblastoma, however, this association is not so clear for low-grade gliomas [
      • Vecht C.J.
      • Kerkhof M.
      • Duran-Pena A.
      Seizure prognosis in brain tumors: new insights and evidence-based management.
      ].

      5.2 Antiepileptic treatment

      Antiepileptic treatment is an essential part of the seizure control. Prophylactic use of an antiepileptic drug in patients with brain tumors with no history of seizures is not recommended [
      • Glantz M.J.
      • Cole B.F.
      • Forsyth P.A.
      • Recht L.D.
      • Wen P.Y.
      • Chamberlain M.C.
      • et al.
      Practice parameter: anticonvulsant prophylaxis in patients with newly diagnosed brain tumors. Report of the Quality Standards Subcommittee of the American Academy of Neurology.
      ]. However, AEDs may be initiated following a first seizure related to a tumor. Seizures in brain tumors are partial onset seizures with or without secondary generalization. The general approach to partial epilepsies can be followed during decision of the appropriate drug. However, enzyme-inducing drugs such as carbamazepine and phenytoin should be avoided particularly in glioblastoma patients because of the risk of interaction with chemotherapeutics [
      • Kerkhof M.
      • Dielemans J.C.
      • van Breemen M.S.
      • Zwinkels H.
      • Walchenbach R.
      • Taphoorn M.J.
      • et al.
      Effect of valproic acid on seizure control and on survival in patients with glioblastoma multiforme.
      ,
      • Rudà R.
      • Soffietti R.
      What is new in the management of epilepsy in gliomas?.
      ].
      The potential antitumor effects of antiepileptic drugs have attracted considerable attention in recent years. Valproic acid (VPA) is most commonly discussed in this context. VPA has long been used for seizures. This has led to an accumulation of experience with this drug. Apart from providing seizure control, VPA has been shown to improve the survival of patients with glioblastoma in several studies and is therefore considered a good option as a first line treatment for epilepsy in patients with glioblastomas [
      • Kerkhof M.
      • Dielemans J.C.
      • van Breemen M.S.
      • Zwinkels H.
      • Walchenbach R.
      • Taphoorn M.J.
      • et al.
      Effect of valproic acid on seizure control and on survival in patients with glioblastoma multiforme.
      ]. The risk of thrombocytopenia should be considered during VPA use in combination with chemotherapy [
      • Vecht C.J.
      • Kerkhof M.
      • Duran-Pena A.
      Seizure prognosis in brain tumors: new insights and evidence-based management.
      ]. However, a recent study which compared the effects of six different AEDs on survival in glioblastoma patients found no significant survival benefit either from treatment with AEDs for epilepsy in general nor from the use of any particular drug [
      • Knudsen-Baas K.M.
      • Engeland A.
      • Gilhus N.E.
      • Storstein A.M.
      • Owe J.F.
      Does the choice of antiepileptic drug affect survival in glioblastoma patients?.
      ]. Some studies highlight the importance of the dosing schedule and target serum level of VPA while preferring it because of its potential additional effects on survival [
      • Tsai H.-C.
      • Wei K.-C.
      • Tsai C.-N.
      • Huang Y.-C.
      • Chen P.-Y.
      • Chen S.-M.
      • et al.
      Effect of valproic acid on the outcome of glioblastoma multiforme.
      ].
      Levetiracetam (LEV) is an efficient and well-tolerated AED [
      • Vecht C.J.
      • Kerkhof M.
      • Duran-Pena A.
      Seizure prognosis in brain tumors: new insights and evidence-based management.
      ]. An antitumor effect of LEV through O-6 methylguanine-DNA methyltransferase (MGMT) has been suggested. Therefore a beneficial effect of LEV on the survival of patients with glioblastoma who receive temozolomide-based chemotherapy has been hypothesized [
      • Kim Y.
      • Kim T.
      • Joo J.
      • Han J.H.
      • Kim Y.J.
      Survival benefit of levetiracetam in patients treated with concomitant chemoradiotherapy and adjuvant chemotherapy with temozolomide for glioblastoma multiforme.
      ].
      Recently, several centers also reported their good experience with lacosamide [
      • Vecht C.J.
      • Kerkhof M.
      • Duran-Pena A.
      Seizure prognosis in brain tumors: new insights and evidence-based management.
      ,
      • Rudà R.
      • Soffietti R.
      What is new in the management of epilepsy in gliomas?.
      ].
      Although there are several drug options, about 10–35% of patients remain refractory [
      • Vecht C.J.
      • Kerkhof M.
      • Duran-Pena A.
      Seizure prognosis in brain tumors: new insights and evidence-based management.
      ].
      In patients with no preoperative seizures who underwent surgery, there is no evidence to suggest that one should continue AEDs administered perioperatively to prevent acute symptomatic seizures. They should be discontinued after the first postoperative week [
      • Glantz M.J.
      • Cole B.F.
      • Forsyth P.A.
      • Recht L.D.
      • Wen P.Y.
      • Chamberlain M.C.
      • et al.
      Practice parameter: anticonvulsant prophylaxis in patients with newly diagnosed brain tumors. Report of the Quality Standards Subcommittee of the American Academy of Neurology.
      ]. However, clinical practices may differ among different centers related to physicians preferences [
      • Dewan M.C.
      • Thompson R.C.
      • Kalkanis S.N.
      • Barker 2nd, F.G.
      • Hadjipanayis C.G.
      Prophylactic antiepileptic drug administration following brain tumor resection: results of a recent AANS/CNS Section on Tumors survey.
      ].
      Patients with developmental tumors usually have a history of seizures preoperatively. Following successful surgery AED withdrawal can be considered. However, there is no consensus among different centers about the timing of AED withdrawal [
      • Boshuisen K.
      • Arzimanoglou A.
      • Cross J.H.
      • Uiterwaal C.S.
      • Polster T.
      • van Nieuwenhuizen O.
      • et al.
      Timing of antiepileptic drug withdrawal and long-term seizure outcome after paediatric epilepsy surgery (TimeToStop): a retrospective observational study.
      ], and physicians’ practices vary in terms of AED withdrawal after successful epilepsy surgery [
      • Swisher C.B.
      • Sinha S.R.
      Survey of current practices among US epileptologists of antiepileptic drug withdrawal after epilepsy surgery.
      ].

      6. Conclusion

      Seizures are among the common symptoms of brain tumors and seizure control is an important part of the clinical management of patients with brain tumors. Brain tumor-related epilepsy tends to be resistant to antiepileptic drugs and the treatment of tumor is an important means of achieving seizure control. There are several factors influencing epileptogenesis in brain tumor-related epilepsy which also explain the clinical heterogeneity of the epilepsies associated with different tumor types. Identification of molecular markers may guide future therapeutic approaches and further studies are needed to prove the possible antitumor effects of different antiepileptic drugs.

      Conflict of interest statement

      The authors declare that they have no conflict of interest associated with the manuscript ‘Epilepsy-related brain tumors’.

      References

        • van Breemen M.S.
        • Wilms E.B.
        • Vecht C.J.
        Epilepsy in patients with brain tumours: epidemiology, mechanisms, and management.
        Lancet Neurol. 2007; 6: 421-430
        • Rudà R.
        • Trevisan E.
        • Soffietti R.
        Epilepsy and brain tumors.
        Curr Opin Oncol. 2010; 22: 611-620https://doi.org/10.1097/CCO.0b013e32833de99d
        • Sperling M.R.
        • Ko J.
        Seizures and brain tumors.
        Semin Oncol. 2006; 33: 333-341https://doi.org/10.1053/j.seminoncol.2006.03.009
        • Englot D.J.
        • Chang E.F.
        Rates and predictors of seizure freedom in resective epilepsy surgery: an update.
        Neurosurg Rev. 2014; 37: 389-404https://doi.org/10.1007/s10143-014-0527-9
        • Thom M.
        • Blümcke I.
        • Aronica E.
        Long-term epilepsy-associated tumors.
        Brain Pathol. 2012; 22: 350-379https://doi.org/10.1111/j.1750-3639.2012.00582.x
        • Michelucci R.
        • Pasini E.
        • Meletti S.
        • Fallica E.
        • Rizzi R.
        • Florindo I.
        • et al.
        Epilepsy in primary cerebral tumors: the characteristics of epilepsy at the onset (results from the PERNO study-Project of Emilia Romagna Region on Neuro-Oncology).
        Epilepsia. 2013; 54: 86-91https://doi.org/10.1111/epi.12314
        • Blumcke I.
        • Aronica E.
        • Urbach H.
        • Alexopoulos A.
        • Gonzalez-Martinez J.A.
        A neuropathology-based approach to epilepsy surgery in brain tumors and proposal for a new terminology use for long-term epilepsy-associated brain tumors.
        Acta Neuropathol. 2014; 128: 39-54https://doi.org/10.1007/s00401-014-1288-9
        • Thom M.
        • Toma A.
        • An S.
        • Martinian L.
        • Hadjivassiliou G.
        • Ratilal B.
        • et al.
        One hundred and one dysembryoplastic neuroepithelial tumors: an adult epilepsy series with immunohistochemical, molecular genetic, and clinical correlations and a review of the literature.
        J Neuropathol Exp Neurol. 2011; 70: 859-878
        • Kerkhof M.
        • Vecht C.J.
        Seizure characteristics and prognostic factors of gliomas.
        Epilepsia. 2013; 54: 12-17https://doi.org/10.1111/epi.12437
        • Sommer B.
        • Wimmer C.
        • Coras R.
        • Blumcke I.
        • Lorber B.
        • Hamer H.M.
        • et al.
        Resection of cerebral gangliogliomas causing drug-resistant epilepsy: short- and long-term outcomes using intraoperative MRI and neuronavigation.
        Neurosurg Focus. 2015; 38: E5https://doi.org/10.3171/2014.10.FOCUS14616
        • Blümcke I.
        • Aronica E.
        • Becker A.
        • Capper D.
        • Coras R.
        • Honavar M.
        • et al.
        Low-grade epilepsy-associated neuroepithelial tumours - the 2016 WHO classification.
        Nat Rev Neurol. 2016; 12: 732-740https://doi.org/10.1038/nrneurol.2016.173
        • Louis D.N.
        • Perry A.
        • Reifenberger G.
        • von Deimling A.
        • Figarella-Branger D.
        • Cavenee W.K.
        • et al.
        The 2016 World Health Organization Classification of tumors of the central nervous system: a summary.
        Acta Neuropathol. 2016; 131: 803-820https://doi.org/10.1007/s00401-016-1545-1
        • Compton J.J.
        • Laack N.N.
        • Eckel L.J.
        • Schomas D.A.
        • Giannini C.
        • Meyer F.B.
        Long-term outcomes for low-grade intracranial ganglioglioma: 30-year experience from the Mayo Clinic.
        J Neurosurg. 2012; 117: 825-830https://doi.org/10.3171/2012.7.jns111260
        • Iuchi T.
        • Hasegawa Y.
        • Kawasaki K.
        • Sakaida T.
        Epilepsy in patients with gliomas: incidence and control of seizures.
        J Clin Neurosci. 2015; 22: 87-91https://doi.org/10.1016/j.jocn.2014.05.036
        • Pallud J.
        • Audureau E.
        • Blonski M.
        • Sanai N.
        • Bauchet L.
        • Fontaine D.
        • et al.
        Epileptic seizures in diffuse low-grade gliomas in adults.
        Brain. 2014; 137: 449-462https://doi.org/10.1093/brain/awt345
        • You G.
        • Sha Z.
        • Yan W.
        • Zhang W.
        • Wang Y.
        • Li S.
        • et al.
        Seizure characteristics and outcomes in 508 Chinese adult patients undergoing primary resection of low-grade gliomas:a clinicaopathological study.
        Neuro Oncol. 2012; 14: 230-241https://doi.org/10.1093/neuonc/nor205
        • Smits A.
        • Duffau H.
        Seizures and the natural history of world health organization grade II gliomas: a review.
        Neurosurgery. 2011; 68: 1326-1333https://doi.org/10.1227/NEU.0b013e31820c3419
        • Vecht C.J.
        • Kerkhof M.
        • Duran-Pena A.
        Seizure prognosis in brain tumors: new insights and evidence-based management.
        Oncologist. 2014; 19: 751-759https://doi.org/10.1634/theoncologist.2014-0060
        • Kerkhof M.
        • Dielemans J.C.
        • van Breemen M.S.
        • Zwinkels H.
        • Walchenbach R.
        • Taphoorn M.J.
        • et al.
        Effect of valproic acid on seizure control and on survival in patients with glioblastoma multiforme.
        Neuro Oncol. 2013; 15: 961-967https://doi.org/10.1093/neuonc/not057
        • Wychowski T.
        • Wang H.
        • Buniak L.
        • Henry J.C.
        • Mohile N.
        Considerations in prophylaxis for tumor-associated epilepsy: prevention of status epilepticus and tolerability of newer generation AEDs.
        Clin Neurol Neurosurg. 2013; 115: 2365-2369https://doi.org/10.1016/j.clineuro.2013.08.023
        • Wirsching H.-G.
        • Morel C.
        • Gmür C.
        • Neidert M.C.
        • Baumann C.R.
        • Valavanis A.
        • et al.
        Predicting outcome of epilepsy after meningioma resection.
        Neuro Oncol. 2015; 18: 1002-1010https://doi.org/10.1093/neuonc/nov303
        • Lieu A.S.
        • Howng S.L.
        Intracranial meningiomas and epilepsy: incidence, prognosis and influencing factors.
        Epilepsy Res. 1999; 38: 45-52https://doi.org/10.1016/S0920-1211(99)00066-2
        • Englot D.J.
        • Magill S.T.
        • Han S.J.
        • Chang E.F.
        • Berger M.S.
        • McDermott M.W.
        Seizures in supratentorial meningioma: a systematic review and meta-analysis.
        J Neurosurg. 2016; 124: 1552-1561https://doi.org/10.3171/2015.4.JNS142742
        • Weller M.
        • Stupp R.
        • Wick W.
        Epilepsy meets cancer: when, why, and what to do about it?.
        Lancet Oncol. 2012; 13: e375-e382https://doi.org/10.1016/S1470-2045(12)70266-8
        • Lynam L.M.
        • Lyons M.K.
        • Drazkowski J.F.
        • Sirven J.I.
        • Noe K.H.
        • Zimmerman R.S.
        • et al.
        Frequency of seizures in patients with newly diagnosed brain tumors: a retrospective review.
        Clin Neurol Neurosurg. 2007; 109: 634-638https://doi.org/10.1016/j.clineuro.2007.05.017
        • Skardelly M.
        • Brendle E.
        • Noell S.
        • Behling F.
        • Wuttke T.V.
        • Schittenhelm J.
        • et al.
        Predictors of preoperative and early postoperative seizures in patients with intra-axial primary and metastatic brain tumors: a retrospective observational single center study.
        Ann Neurol. 2015; 78: 917-928https://doi.org/10.1002/ana.24522
        • Dewan M.C.
        • Thompson R.C.
        • Kalkanis S.N.
        • Barker 2nd, F.G.
        • Hadjipanayis C.G.
        Prophylactic antiepileptic drug administration following brain tumor resection: results of a recent AANS/CNS Section on Tumors survey.
        J Neurosurg. 2016; 24: 1-7
        • Shamji M.F.
        • Fric-Shamji E.C.
        • Benoit B.G.
        Brain tumors and epilepsy: pathophysiology of peritumoral changes.
        Neurosurg Rev. 2009; 32: 274-284https://doi.org/10.1007/s10143-009-0191-7
        • You G.
        • Sha Z.
        • Jiang T.
        The pathogenesis of tumor-related epilepsy and its implications for clinical treatment.
        Seizure. 2012; 21: 153-159https://doi.org/10.1016/j.seizure.2011.12.016
        • Rudà R.
        • Soffietti R.
        What is new in the management of epilepsy in gliomas?.
        Curr Treat Options Neurol. 2015; 17https://doi.org/10.1007/s11940-015-0351-8
        • Rudà R.
        • Pellerino A.
        • Magistrello M.
        • Franchino F.
        • Pinessi L.
        • Soffietti R.
        Molecularly based management of gliomas in clinical practice.
        Neurol Sci. 2015; 36: 1551-1557https://doi.org/10.1007/s10072-015-2332-9
        • Stockhammer F.
        • Misch M.
        • Helms H.
        • Lengler U.
        • Prall F.
        • Von Deimling A.
        • et al.
        IDH1/2 mutations in WHO grade II astrocytomas associated with localization and seizure as the initial symptom.
        Seizure. 2012; 21: 194-197https://doi.org/10.1016/j.seizure.2011.12.007
        • Prabowo A.S.
        • Iyer A.M.
        • Veersema T.J.
        • Anink J.J.
        • Schouten-van Meeteren A.Y.
        • Spliet W.G.
        • et al.
        BRAF V600E mutation is associated with mTOR signaling activation in glioneuronal tumors.
        Brain Pathol. 2014; 24: 52-66https://doi.org/10.1111/bpa.12081
        • Fan X.
        • Zhang Y.W.C.
        • You G.
        • Lei M.L.
        • Tao W.
        Expression of RINT1 predicts seizure occurrence and outcomes in patients with low-grade gliomas.
        J Cancer Res Clin Oncol. 2015; : 729-734https://doi.org/10.1007/s00432-014-1827-8
        • Wang Y.
        • Fan X.
        • Zhang W.
        • Wang L.
        Deficiency of very large G-protein-coupled receptor-1 is a risk factor of tumor-related epilepsy: a whole transcriptome sequencing analysis.
        J Neurooncol. 2015; : 609-616https://doi.org/10.1007/s11060-014-1674-0
        • Yuan Y.
        • Xiang W.
        • Yanhui L.
        • Ruofei L.
        Dysregulation of microRNA-128 expression in WHO grades 2 glioma is associated with glioma-associated epilepsy: down-regulation of miR-128 induces glioma-associated seizure.
        Epilepsy Res. 2016; 127: 6-11https://doi.org/10.1016/j.eplepsyres.2016.08.005
        • Yang P.
        • You G.
        • Zhang W.
        • Wang Y.
        Correlation of preoperative seizures with clinicopathological factors and prognosis in anaplastic gliomas: a report of 198 patients from China.
        Seizure. 2014; 23: 844-851https://doi.org/10.1016/j.seizure.2014.07.003
        • Englot D.J.
        • Berger M.S.
        • Barbaro N.M.
        • Chang E.F.
        Predictors of seizure freedom after resection of supratentorial low-grade gliomas.
        J Neurosurg. 2011; 115: 240-244https://doi.org/10.3171/2011.3.JNS1153
        • Englot D.J.
        • Berger M.S.
        • Barbaro N.M.
        • Chang E.F.
        Factors associated with seizure freedom in the surgical resection of glioneuronal tumors.
        Epilepsia. 2012; 53: 51-57https://doi.org/10.1111/j.1528-1167.2011.03269.x
        • Rosenow F.
        • Menzler K.
        Invasive EEG studies in tumor-related epilepsy: when are they indicated and with what kind of electrodes?.
        Epilepsia. 2013; 54: 61-65https://doi.org/10.1111/epi.12446
        • Mittal S.
        • Barkmeier D.
        • Hua J.
        • Pai D.S.
        • Fuerst D.
        • Basha M.
        • et al.
        Intracranial EEG analysis in tumor-related epilepsy: evidence of distant epileptic abnormalities.
        Clin Neurophysiol. 2016; 127: 238-244https://doi.org/10.1016/j.clinph.2015.06.028
        • Southwell D.G.
        • Garcia P.A.
        • Berger M.S.
        • Barbaro N.M.
        • Chang E.F.
        Long-term seizure control outcomes after resection of gangliogliomas.
        Neurosurgery. 2012; 70: 1406-1413https://doi.org/10.1227/NEU.0b013e3182500a4c
        • Knudsen-Baas K.M.
        • Engeland A.
        • Gilhus N.E.
        • Storstein A.M.
        • Owe J.F.
        Does the choice of antiepileptic drug affect survival in glioblastoma patients?.
        J Neurooncol. 2016; 129: 461-469https://doi.org/10.1007/s11060-016-2191-0
        • Glantz M.J.
        • Cole B.F.
        • Forsyth P.A.
        • Recht L.D.
        • Wen P.Y.
        • Chamberlain M.C.
        • et al.
        Practice parameter: anticonvulsant prophylaxis in patients with newly diagnosed brain tumors. Report of the Quality Standards Subcommittee of the American Academy of Neurology.
        Neurology. 2000; 54: 1886-1893https://doi.org/10.1212/WNL.54.10.1886
        • Tsai H.-C.
        • Wei K.-C.
        • Tsai C.-N.
        • Huang Y.-C.
        • Chen P.-Y.
        • Chen S.-M.
        • et al.
        Effect of valproic acid on the outcome of glioblastoma multiforme.
        Br J Neurosurg. 2012; 26: 347-354https://doi.org/10.3109/02688697.2011.638996
        • Kim Y.
        • Kim T.
        • Joo J.
        • Han J.H.
        • Kim Y.J.
        Survival benefit of levetiracetam in patients treated with concomitant chemoradiotherapy and adjuvant chemotherapy with temozolomide for glioblastoma multiforme.
        Cancer. 2015; 121: 2926-2932https://doi.org/10.1002/cncr.29439
        • Boshuisen K.
        • Arzimanoglou A.
        • Cross J.H.
        • Uiterwaal C.S.
        • Polster T.
        • van Nieuwenhuizen O.
        • et al.
        Timing of antiepileptic drug withdrawal and long-term seizure outcome after paediatric epilepsy surgery (TimeToStop): a retrospective observational study.
        Lancet Neurol. 2012; 11: 784-791
        • Swisher C.B.
        • Sinha S.R.
        Survey of current practices among US epileptologists of antiepileptic drug withdrawal after epilepsy surgery.
        Epilepsy Behav. 2013; 26: 203-206https://doi.org/10.1016/j.yebeh.2012.11.053