Advertisement

Seizures caused by brain tumors in children

  • Iván Sánchez Fernández
    Affiliations
    Division of Epilepsy and Clinical Neurophysiology, Department of Neurology, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA

    Department of Child Neurology, Hospital Sant Joan de Déu, Universidad de Barcelona, Spain
    Search for articles by this author
  • Tobias Loddenkemper
    Correspondence
    Corresponding author at: Harvard Medical School, Division of Epilepsy and Clinical Neurophysiology, Fegan 9, Boston Children’s Hospital, 300 Longwood Avenue, Boston, MA 02115, USA. Fax: +1 617 730 0463.
    Affiliations
    Division of Epilepsy and Clinical Neurophysiology, Department of Neurology, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA
    Search for articles by this author
Open ArchivePublished:December 07, 2016DOI:https://doi.org/10.1016/j.seizure.2016.11.028

      Highlights

      • Pediatric brain tumors are the most common cause of death in pediatric cancer.
      • Seizures are one of the most common symptoms in pediatric brain tumors.
      • Supratentorial brain tumors that involve gray matter are more epileptogenic.
      • Dysembryoplastic neuroepithelial tumor and ganglioglioma are particularly epileptogenic.
      • Newer drugs with less interactions are preferred for seizures caused by tumors.

      Abstract

      Purpose

      To review the epidemiology, clinical features, and treatment of seizures secondary to pediatric brain tumors.

      Method

      Literature review.

      Results

      Pediatric brain tumors are the most common solid pediatric tumor and the most common cause of death in pediatric cancer. Seizures are one of the most common symptoms of pediatric brain tumors. Factors associated with increased risk of seizures include supratentorial location, gray matter involvement, low-grade, and certain histological features—especially dysembryoplastic neuroepithelial tumor, ganglioglioma, and oligodendroglioma. Leukemic infiltration of the brain, brain metastases of solid tumors, and brain injury secondary to chemotherapy or radiotherapy can also cause seizures. Mechanisms by which brain tumors cause seizures include metabolic, and neurotransmitter changes in peritumoral brain, morphologic changes – including malformation of cortical development – in peritumoral brain, and presence of peritumoral blood products, gliosis, and necrosis. As there is a high degree of uncertainty on how effective different antiepileptic drugs are for seizures caused by brain tumors, choices are often driven by the interaction and side effect profile. Classic antiepileptic drugs – phenobarbital, phenytoin, or carbamazepine – should be avoided as they may alter the metabolism of chemotherapeutic agents. Newer drugs – valproate, lamotrigine, topiramate, zonisamide, and levetiracetam – may be the preferred option in patients with tumors because of their very limited interaction with chemotherapy.

      Conclusion

      Seizures are a common presentation of pediatric brain tumors, especially in supratentorial tumors with gray matter involvement. Antiepileptic drug therapy is usually driven by the interaction and side effect profile and newer drugs with few interactions are generally preferred.

      Keywords

      1. Introduction

      Pediatric brain tumors are the second cause of pediatric cancer [
      • A.W. Group
      • CCM
      • A.W. Group
      Italian cancer figures, report 2012: cancer in children and adolescents.
      ,
      • Karim-Kos H.E.
      • Hackl M.
      • Mann G.
      • Urban C.
      • Woehrer A.
      • Slavc I.
      • et al.
      Trends in incidence, survival and mortality of childhood and adolescent cancer in Austria, 1994-2011.
      ,
      • Ostrom Q.T.
      • Gittleman H.
      • Fulop J.
      • Liu M.
      • Blanda R.
      • Kromer C.
      • et al.
      CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2008-2012.
      ,
      • Ward E.
      • DeSantis C.
      • Robbins A.
      • Kohler B.
      • Jemal A.
      Childhood and adolescent cancer statistics, 2014.
      ] and the leading cause of cancer mortality in children [
      • de Blank P.M.
      • Ostrom Q.T.
      • Rouse C.
      • Wolinsky Y.
      • Kruchko C.
      • Salcido J.
      • et al.
      Years of life lived with disease and years of potential life lost in children who die of cancer in the United States, 2009.
      ,
      • Pollack I.F.
      • Jakacki R.I.
      Childhood brain tumors: epidemiology, current management and future directions.
      ]. Seizures are one of the most common symptoms of pediatric brain tumors, both as presenting symptom or appearing during the course of the disease [
      • Ullrich N.J.
      • Pomeroy S.L.
      • Kapur K.
      • Manley P.E.
      • Goumnerova L.C.
      • Loddenkemper T.
      Incidence, risk factors, and longitudinal outcome of seizures in long-term survivors of pediatric brain tumors.
      ,
      • Wilne S.
      • Collier J.
      • Kennedy C.
      • Koller K.
      • Grundy R.
      • Walker D.
      Presentation of childhood CNS tumours: a systematic review and meta-analysis.
      ]. In this review of the literature, we summarize the main epidemiology, clinical features, and treatment of seizures caused by pediatric brain tumors. We also provide a brief summary on the current understanding of the pathophysiology that may contribute to seizures in patients with brain tumors.

      2. Epidemiology

      Approximately 1 in 285 children will be diagnosed with cancer before age 20 years, and approximately 1 in 530 young adults between the ages of 20 and 39 years is a childhood cancer survivor [
      • Ward E.
      • DeSantis C.
      • Robbins A.
      • Kohler B.
      • Jemal A.
      Childhood and adolescent cancer statistics, 2014.
      ]. Brain cancers are the second most common cancer in children (after leukemias) accounting for 20–25% of cases in this age range and the third most common in adolescents accounting for approximately 10% of cases in this age range [
      • Karim-Kos H.E.
      • Hackl M.
      • Mann G.
      • Urban C.
      • Woehrer A.
      • Slavc I.
      • et al.
      Trends in incidence, survival and mortality of childhood and adolescent cancer in Austria, 1994-2011.
      ,
      • Ward E.
      • DeSantis C.
      • Robbins A.
      • Kohler B.
      • Jemal A.
      Childhood and adolescent cancer statistics, 2014.
      ]. Further, brain tumors are the leading cause of pediatric cancer-related mortality [
      • Pollack I.F.
      • Jakacki R.I.
      Childhood brain tumors: epidemiology, current management and future directions.
      ] and the largest cause of years of potential life lost in children accounting for 31% of potential life years lost among cancer and 1.4% among all causes [
      • de Blank P.M.
      • Ostrom Q.T.
      • Rouse C.
      • Wolinsky Y.
      • Kruchko C.
      • Salcido J.
      • et al.
      Years of life lived with disease and years of potential life lost in children who die of cancer in the United States, 2009.
      ]. Although pediatric brain tumors most frequently associated with seizures are typically low-grade and associated with low mortality, seizures are a common comorbidity in pediatric brain tumor of all types [
      • Ullrich N.J.
      • Pomeroy S.L.
      • Kapur K.
      • Manley P.E.
      • Goumnerova L.C.
      • Loddenkemper T.
      Incidence, risk factors, and longitudinal outcome of seizures in long-term survivors of pediatric brain tumors.
      ].
      With an standardized incidence rate of 25–35 cases/1,000,000 persons-years, primary brain tumors represent approximately 15–20% of all pediatric tumors [
      • A.W. Group
      • CCM
      • A.W. Group
      Italian cancer figures, report 2012: cancer in children and adolescents.
      ,
      • Karim-Kos H.E.
      • Hackl M.
      • Mann G.
      • Urban C.
      • Woehrer A.
      • Slavc I.
      • et al.
      Trends in incidence, survival and mortality of childhood and adolescent cancer in Austria, 1994-2011.
      ,
      • Ward E.
      • DeSantis C.
      • Robbins A.
      • Kohler B.
      • Jemal A.
      Childhood and adolescent cancer statistics, 2014.
      ,
      • Linabery A.M.
      • Ross J.A.
      Trends in childhood cancer incidence in the U.S. (1992-2004).
      ]. Astrocytomas are the most frequent type of solid brain tumor with a standardized incidence rate of 12–18 cases/1,000,000 persons-years and accounting for approximately 30–40% of pediatric brain tumors [
      • Karim-Kos H.E.
      • Hackl M.
      • Mann G.
      • Urban C.
      • Woehrer A.
      • Slavc I.
      • et al.
      Trends in incidence, survival and mortality of childhood and adolescent cancer in Austria, 1994-2011.
      ,
      • Ward E.
      • DeSantis C.
      • Robbins A.
      • Kohler B.
      • Jemal A.
      Childhood and adolescent cancer statistics, 2014.
      ,
      • Linabery A.M.
      • Ross J.A.
      Trends in childhood cancer incidence in the U.S. (1992-2004).
      ]. At a considerable distance, the second and third most frequent pediatric brain tumors are medulloblastomas—standardized incidence rate of 2–6 cases/1,000,000 persons-years—and ependymomas—standardized incidence rate of 2–4 cases/1,000,000 persons-years [
      • Karim-Kos H.E.
      • Hackl M.
      • Mann G.
      • Urban C.
      • Woehrer A.
      • Slavc I.
      • et al.
      Trends in incidence, survival and mortality of childhood and adolescent cancer in Austria, 1994-2011.
      ,
      • Ward E.
      • DeSantis C.
      • Robbins A.
      • Kohler B.
      • Jemal A.
      Childhood and adolescent cancer statistics, 2014.
      ,
      • Linabery A.M.
      • Ross J.A.
      Trends in childhood cancer incidence in the U.S. (1992-2004).
      ].
      Seizures are one of the most frequent presenting symptom of pediatric brain tumors occurring in 13% of patients [
      • Wilne S.
      • Collier J.
      • Kennedy C.
      • Koller K.
      • Grundy R.
      • Walker D.
      Presentation of childhood CNS tumours: a systematic review and meta-analysis.
      ]. Seizures are more frequent with certain tumor types, termed long-term epilepsy associated tumors (LEATs) [
      • Luyken C.
      • Blumcke I.
      • Fimmers R.
      • Urbach H.
      • Elger C.E.
      • Wiestler O.D.
      • et al.
      The spectrum of long-term epilepsy-associated tumors: long-term seizure and tumor outcome and neurosurgical aspects.
      ]: dysembryoplastic neuroepithelial tumors, gangliogliomas, and oligodendrogliomas. Typically, LEATs are low-grade supratentorial tumors associated with relatively low mortality [
      • Luyken C.
      • Blumcke I.
      • Fimmers R.
      • Urbach H.
      • Elger C.E.
      • Wiestler O.D.
      • et al.
      The spectrum of long-term epilepsy-associated tumors: long-term seizure and tumor outcome and neurosurgical aspects.
      ]. There is a smaller proportion of non-LEATs brain tumors associated with seizures [
      • van Breemen M.S.
      • Wilms E.B.
      • Vecht C.J.
      Epilepsy in patients with brain tumours: epidemiology, mechanisms, and management.
      ]. Because of non-LEATs relatively frequent association with seizures, these may also be relevant to epileptologists and neurologists caring for patients with seizures secondary to brain tumors [
      • Ullrich N.J.
      • Pomeroy S.L.
      • Kapur K.
      • Manley P.E.
      • Goumnerova L.C.
      • Loddenkemper T.
      Incidence, risk factors, and longitudinal outcome of seizures in long-term survivors of pediatric brain tumors.
      ]. In a series of 207 pediatric and adult patients with brain tumors, three fourths of seizures were secondary to “epilepsy-associated” tumors and one fourth of cases was related to other tumor types [
      • Luyken C.
      • Blumcke I.
      • Fimmers R.
      • Urbach H.
      • Elger C.E.
      • Wiestler O.D.
      • et al.
      The spectrum of long-term epilepsy-associated tumors: long-term seizure and tumor outcome and neurosurgical aspects.
      ]. Seizures affect 25–35% of patients during the course of a pediatric brain tumor, with most seizure onsets occurring at presentation or around tumor treatment and, more rarely, after treatment has been completed [
      • Ullrich N.J.
      • Pomeroy S.L.
      • Kapur K.
      • Manley P.E.
      • Goumnerova L.C.
      • Loddenkemper T.
      Incidence, risk factors, and longitudinal outcome of seizures in long-term survivors of pediatric brain tumors.
      ,
      • Baytan B.
      • Evim M.S.
      • Guler S.
      • Gunes A.M.
      • Okan M.
      Acute central nervous system complications in pediatric acute lymphoblastic leukemia.
      ].

      3. Characteristics of seizures in children with brain tumors

      In a meta-analysis of presenting signs and symptoms of pediatric brain tumor, seizures were the fifth more common clinical presentation only behind headache, nausea and vomiting, abnormal gait or coordination, and papilledema [
      • Wilne S.
      • Collier J.
      • Kennedy C.
      • Koller K.
      • Grundy R.
      • Walker D.
      Presentation of childhood CNS tumours: a systematic review and meta-analysis.
      ]. Further, considering only supra-tentorial tumors, seizures were the second more common clinical presentation – behind symptoms of increased intracranial pressure – occurring in 38% of cases [
      • Wilne S.
      • Collier J.
      • Kennedy C.
      • Koller K.
      • Grundy R.
      • Walker D.
      Presentation of childhood CNS tumours: a systematic review and meta-analysis.
      ].
      The probability of a tumor presenting with seizures depends on several factors such as tumor histology and tumor location in the brain. Low-grade tumors are more epileptogenic, probably reflecting longer survival and, therefore, a longer time period to develop epilepsy [
      • van Breemen M.S.
      • Wilms E.B.
      • Vecht C.J.
      Epilepsy in patients with brain tumours: epidemiology, mechanisms, and management.
      ]. In an adult series of 1028 gliomas, seizures occurred in 49% of patients with glioblastoma, in 69% of patients with anaplastic glioma, and in 85% of patients with low-grade glioma [
      • Lote K.
      • Stenwig A.E.
      • Skullerud K.
      • Hirschberg H.
      Prevalence and prognostic significance of epilepsy in patients with gliomas.
      ]. In a pediatric series of 298 children with brain tumors, seizures occurred in 81% of glioneuronal tumors, in 71% of high-grade gliomas, and in 80% of oligodendroglioma while they were rare in medulloblastoma (8%), germ cell tumor (11%), atypical teratoid rhabdoid tumor (0%), and pineocytoma or pineoblastoma (0%) [
      • Ullrich N.J.
      • Pomeroy S.L.
      • Kapur K.
      • Manley P.E.
      • Goumnerova L.C.
      • Loddenkemper T.
      Incidence, risk factors, and longitudinal outcome of seizures in long-term survivors of pediatric brain tumors.
      ]. In the same pediatric series, seizures were more frequent among tumors involving the cerebral cortex (53%) than in those with midline (18%) and infratentorial (9%) location [
      • Ullrich N.J.
      • Pomeroy S.L.
      • Kapur K.
      • Manley P.E.
      • Goumnerova L.C.
      • Loddenkemper T.
      Incidence, risk factors, and longitudinal outcome of seizures in long-term survivors of pediatric brain tumors.
      ]. Although infratentorial tumors are less frequently associated with seizures as compared to supratentorial tumors, seizures tend to occur through mass effect, hydrocephalus, or metastases, and their relative frequency makes them a relevant contributor to seizures in children with brain tumors [
      • Ullrich N.J.
      • Pomeroy S.L.
      • Kapur K.
      • Manley P.E.
      • Goumnerova L.C.
      • Loddenkemper T.
      Incidence, risk factors, and longitudinal outcome of seizures in long-term survivors of pediatric brain tumors.
      ].
      Despite tumors being focal, seizure semiology is often generalized and, when focal, it may or may not reflect the location of the brain tumor. In a series of 100 adult patients with primary cerebral tumors, the most frequent semiology was tonic–clonic (without focal signs in 26% of patients and with focal signs in 22% of patients), focal motor in 26% of patients, focal with dyscognitive symptoms in 10% of patients, somatosensory in 8% of patients, aphasic in 4%, and other in 4% [
      • 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).
      ]. The most frequent seizure sequence (43%) consisted of a primarily or secondarily generalized seizure as initial presentation followed after a few days or weeks by focal seizures, while the reverse sequence of focal seizures at initial presentation followed by secondarily generalized seizures was less frequent (33%) [
      • 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).
      ]. In this series, 42% of patients had an isolated seizure or less than 1 seizure per month, and 64% were on monotherapy [
      • 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).
      ]. In a large pediatric series of 298 children with brain tumors, 71 patients had seizures [
      • Ullrich N.J.
      • Pomeroy S.L.
      • Kapur K.
      • Manley P.E.
      • Goumnerova L.C.
      • Loddenkemper T.
      Incidence, risk factors, and longitudinal outcome of seizures in long-term survivors of pediatric brain tumors.
      ]. Most seizures were generalized/secondarily generalized (35%) or focal with dyscognitive features (34%), followed by unclassified seizure type (21%), and focal (10%) [
      • Ullrich N.J.
      • Pomeroy S.L.
      • Kapur K.
      • Manley P.E.
      • Goumnerova L.C.
      • Loddenkemper T.
      Incidence, risk factors, and longitudinal outcome of seizures in long-term survivors of pediatric brain tumors.
      ]. In this series, 44% of patients were on monotherapy and 38% were on no medications, reflecting the large proportion (28%) of patients with less than one seizure per month [
      • Ullrich N.J.
      • Pomeroy S.L.
      • Kapur K.
      • Manley P.E.
      • Goumnerova L.C.
      • Loddenkemper T.
      Incidence, risk factors, and longitudinal outcome of seizures in long-term survivors of pediatric brain tumors.
      ]. In both adults and pediatric series, most patients have a low seizure frequency and are controlled on monotherapy [
      • Ullrich N.J.
      • Pomeroy S.L.
      • Kapur K.
      • Manley P.E.
      • Goumnerova L.C.
      • Loddenkemper T.
      Incidence, risk factors, and longitudinal outcome of seizures in long-term survivors of pediatric brain tumors.
      ,
      • 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).
      ].

      4. Classification of brain tumors in children with approximate frequency

      The current classification of primary brain tumors – the classification of the World Health Organization (WHO) – is mainly based on the cell of origin as determined by histologic and molecular features [
      • 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.
      ]. The 2016 WHO classification represents a break with older schemes that classified tumors based mostly or exclusively on histology [
      • 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.
      ]. By adding molecular and genetic aspects to the classification, the 2016 WHO scheme adds a level of objectivity that may result in more homogeneous categories with more accurate determination of prognosis and treatment response [
      • 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.
      ]. Tumors of neuroepithelial tissue derive from glial cells – astrocytes, oligodendrocytes, and ependymal cells – and are termed gliomas. Gliomas account for approximately half of all primary brain tumors and for approximately two thirds of primary malignant brain tumors in children and adolescents [
      • A.W. Group
      • CCM
      • A.W. Group
      Italian cancer figures, report 2012: cancer in children and adolescents.
      ,
      • Ostrom Q.T.
      • Gittleman H.
      • Fulop J.
      • Liu M.
      • Blanda R.
      • Kromer C.
      • et al.
      CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2008-2012.
      ]. The main tumor of embryonal origin is the medulloblastoma. As the clinical presentation of brain tumors varies by location, a frequently used topographical classification further distinguishes between supratentorial and infratentorial tumors. Approximately 50–60% of primary pediatric brain tumors are supratentorial in location, most of which are of astrocytic origin [
      • A.W. Group
      • CCM
      • A.W. Group
      Italian cancer figures, report 2012: cancer in children and adolescents.
      ,
      • Ostrom Q.T.
      • Gittleman H.
      • Fulop J.
      • Liu M.
      • Blanda R.
      • Kromer C.
      • et al.
      CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2008-2012.
      ]. Approximately 35–45% of primary pediatric brain tumors are infratentorial, most of which are of neuronal or glial in origin [
      • A.W. Group
      • CCM
      • A.W. Group
      Italian cancer figures, report 2012: cancer in children and adolescents.
      ,
      • Ostrom Q.T.
      • Gittleman H.
      • Fulop J.
      • Liu M.
      • Blanda R.
      • Kromer C.
      • et al.
      CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2008-2012.
      ]. Prior to providing a detailed description on the characteristics of seizures in each tumor type, we will briefly summarize the most salient characteristics of the most frequent tumors. Detailed descriptions of the clinical presentation, the different tumor types, and the specialized details of the pathology classifications are beyond the scope of this manuscript and can be found elsewhere [
      • 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.
      ,
      • Crawford J.
      Childhood brain tumors.
      ,
      • Holthausen H.
      • Blumcke I.
      Epilepsy-associated tumours: what epileptologists should know about neuropathology, terminology, and classification systems.
      ]. Even if the histology is classified as supratentorial or infratentorial to reflect their most common locations, tumors of any histology can appear in either region (Table 1).
      Table 1Main characteristics of the most frequent pediatric brain tumors.
      FrequencyLocationPathology5-year survival
      Supratentorial brain tumors
       Diffuse astrocytoma (grade II)++Cerebral hemispheres: frontal and temporal lobes (less frequently, brainstem and spinal cord)Meningeal fibrils. No mitoses. No vascular proliferation+++
       Anaplastic astrocytoma (grade III)+SupratentorialIncreased cellularity, pleomorphism, mitoses
       Glioblastoma multiforme (grade IV)+SupratentorialIncreased cellularity, pleomorphism, mitoses. Vascular proliferation. Necrosis−−
       Ganglioglioma+Cerebral hemispheres: temporal > frontalMixture of neoplastic glial and neuronal elements++++
       Dysembryoplastic neuroepithelial tumor (DNET)Cerebral hemispheres: temporal > frontal > parietal lobes. Centered in the cerebral cortex, although it might extend to the white matterMultinodular microcystic lesions with floating neurons. Pleomorphism, glial-neural elements. May be surrounded by areas of dysplasia. Limited mitoses.++++
       Supratentorial primitive neuroectodermal tumor+Cerebral hemispheresUndifferentiated or poorly differentiated neuroepithelial cells. Pathology similar to neuroblastoma.+
      Variable depending on pathology and age. Higher risk of relapse than medulloblastoma
       OligodendrogliomaCerebral hemispheres (rarely medulla)Honeycomb appearance: repetitive pattern of similar rounded cells with perinuclear haloVariable depending on the other histologic components of the tumor
      Posterior fossa tumors
       Pilocytic astrocytoma++++Cerebellum (less frequently cerebral hemispheres, optic pathway, hypothalamus, and brain stem)Compact areas with Rosenthal fibers and spongy areas with microcysts++++
       Medulloblastoma++++Posterior fossaClassic variant: densely packed cells with hyperchromatic nuclei and scant cytoplasm+++
      Desmoplastic/nodular variant: nodular, reticular-free zones of neuronal maturation surrounded by densely-packed mitotically active cellsVariable depending on pathology and age
      Extensive nodularity variant: expanded lobular architecture
      Large cell variant: monomorphic cells with large, round, vesicular nuclei with prominent nucleoli
      Anaplastic variant: cells with marked nuclear pleomorphism and nuclear moulding
       Ependymoma+++2/3 infratentorial, 1/3 supratentorialRosettes and pseudorosettes. Histologic features predict degree of malignancy poorly++
      Hypothalamic tumors
       Hypothalamic hamartomaHypothalamusAbnormally distributed, but cytologically normal small neurons and glia++++
      The 2016 WHO classification of tumors of the central nervous system [
      • 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.
      ] highlights the need for classification schemes with more homogeneous groups and subgroups. Within broad histologic categories such as “low-grade gliomas” the included tumors vary greatly in terms of molecular and genetic features, response to treatment, and prognosis [
      • 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.
      ,
      • Holthausen H.
      • Blumcke I.
      Epilepsy-associated tumours: what epileptologists should know about neuropathology, terminology, and classification systems.
      ]. This more granular classification of tumors may lead to a more precise and reproducible staging [
      • Holthausen H.
      • Blumcke I.
      Epilepsy-associated tumours: what epileptologists should know about neuropathology, terminology, and classification systems.
      ].

      4.1 Supratentorial tumors

      The most common clinical presentation of supratentorial tumors is with unspecified symptoms of increased intracranial pressure (47%), seizures (38%), papilledema (21%), focal neurological signs (17%), headache (11%), hemiplegia (10%), nausea and vomiting (8%), and macrocephaly (6%) [
      • Wilne S.
      • Collier J.
      • Kennedy C.
      • Koller K.
      • Grundy R.
      • Walker D.
      Presentation of childhood CNS tumours: a systematic review and meta-analysis.
      ]. The most common supratentorial tumors are astrocytomas, gangliogliomas, dysembryoplastic neuroepithelial tumors, and oligodendrogliomas.
      • a)
        Astrocytomas represent approximately one third of all intracranial tumors and the most common histology in the supratentorial region [
        • A.W. Group
        • CCM
        • A.W. Group
        Italian cancer figures, report 2012: cancer in children and adolescents.
        ,
        • Ostrom Q.T.
        • Gittleman H.
        • Fulop J.
        • Liu M.
        • Blanda R.
        • Kromer C.
        • et al.
        CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2008-2012.
        ]. The World Health Organization classification grades tumors according to an increasing level of malignancy so that grade I is benign, grade II is low grade, grade III is anaplastic or moderately malignant, and grade IV is highly malignant [
        • 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.
        ]. Fortunately, most pediatric astrocytomas are low grade. The most common pediatric astrocytoma is pilocytic astrocytoma (grade I) which occurs most frequently in the cerebellum, hence we will discuss it under the infratentorial tumors. Grade II diffuse astrocytomas represent approximately 15% of pediatric astrocytomas and have a biphasic distribution with peaks at 2–4 years of age and in adolescence [
        • Dastgir J.
        • Dabscheck G.
        • Ullrich N.
        Neuro-oncology and neurocutaneous syndromes.
        ]. They appear most commonly in the frontal and temporal lobes as heterogeneous masses [
        • Dastgir J.
        • Dabscheck G.
        • Ullrich N.
        Neuro-oncology and neurocutaneous syndromes.
        ]. Pathologically, they consist of a fibrillary pattern that infiltrates neighboring brain structures [
        • Dastgir J.
        • Dabscheck G.
        • Ullrich N.
        Neuro-oncology and neurocutaneous syndromes.
        ]. Their 5-year survival rate varies between 50–100% depending on the extent of surgical resection [
        • Dastgir J.
        • Dabscheck G.
        • Ullrich N.
        Neuro-oncology and neurocutaneous syndromes.
        ]. Anaplastic astrocytoma (grade III) and glioblastoma multiforme (grade IV) peak at 9–10 years of age and appear most frequently as supratentorial masses with cystic components and necrosis being more frequent with increasing malignancy [
        • Dastgir J.
        • Dabscheck G.
        • Ullrich N.
        Neuro-oncology and neurocutaneous syndromes.
        ]. Pathologically, they consist of increased cellularity, pleomorphism, and in grade IV, vascular proliferation and areas of necrosis [
        • Dastgir J.
        • Dabscheck G.
        • Ullrich N.
        Neuro-oncology and neurocutaneous syndromes.
        ]. Their 5-year survival rates are approximately 15–30% [
        • Dastgir J.
        • Dabscheck G.
        • Ullrich N.
        Neuro-oncology and neurocutaneous syndromes.
        ].
      • b)
        Gangliogliomas (Fig. 1) represent approximately 3% of brain tumors and 6% of supratentorial pediatric brain tumors [
        • Dastgir J.
        • Dabscheck G.
        • Ullrich N.
        Neuro-oncology and neurocutaneous syndromes.
        ]. They peak in adolescence and the most common presenting sign is seizures [
        • Dastgir J.
        • Dabscheck G.
        • Ullrich N.
        Neuro-oncology and neurocutaneous syndromes.
        ]. They appear most frequently in the temporo-parieto-occipital regions followed by the frontal lobes and the posterior fossa [
        • Hu W.H.
        • Ge M.
        • Zhang K.
        • Meng F.G.
        • Zhang J.G.
        Seizure outcome with surgical management of epileptogenic ganglioglioma: a study of 55 patients.
        ,
        • Krouwer H.G.
        • Davis R.L.
        • McDermott M.W.
        • Hoshino T.
        • Prados M.D.
        Gangliogliomas: a clinicopathological study of 25 cases and review of the literature.
        ,
        • Ogiwara H.
        • Nordli D.R.
        • DiPatri A.J.
        • Alden T.D.
        • Bowman R.M.
        • Tomita T.
        Pediatric epileptogenic gangliogliomas: seizure outcome and surgical results.
        ]. They appear as an enhancing mass with partially cystic appearance in at least 40% of the cases [
        • Hu W.H.
        • Ge M.
        • Zhang K.
        • Meng F.G.
        • Zhang J.G.
        Seizure outcome with surgical management of epileptogenic ganglioglioma: a study of 55 patients.
        ]. Calcification can be found in 40–50% of cases [
        • Krouwer H.G.
        • Davis R.L.
        • McDermott M.W.
        • Hoshino T.
        • Prados M.D.
        Gangliogliomas: a clinicopathological study of 25 cases and review of the literature.
        ]. Pathologically, they consist of a mixture of neoplastic glial and neuronal elements: clusters of large ganglion-like neurons mixed with neoplastic astrocytes [
        • Hu W.H.
        • Ge M.
        • Zhang K.
        • Meng F.G.
        • Zhang J.G.
        Seizure outcome with surgical management of epileptogenic ganglioglioma: a study of 55 patients.
        ,
        • Ogiwara H.
        • Nordli D.R.
        • DiPatri A.J.
        • Alden T.D.
        • Bowman R.M.
        • Tomita T.
        Pediatric epileptogenic gangliogliomas: seizure outcome and surgical results.
        ]. Most pediatric gangliogliomas are benign (World Health Organization grade I) [
        • Hu W.H.
        • Ge M.
        • Zhang K.
        • Meng F.G.
        • Zhang J.G.
        Seizure outcome with surgical management of epileptogenic ganglioglioma: a study of 55 patients.
        ,
        • Ogiwara H.
        • Nordli D.R.
        • DiPatri A.J.
        • Alden T.D.
        • Bowman R.M.
        • Tomita T.
        Pediatric epileptogenic gangliogliomas: seizure outcome and surgical results.
        ]. The 5-year survival approaches 100%, but depending on the extent of the resection tumors may recur within 5-years of resection [
        • Haydon D.H.
        • Dahiya S.
        • Smyth M.D.
        • Limbrick D.D.
        • Leonard J.R.
        Greater extent of resection improves ganglioglioma recurrence-free survival in children: a volumetric analysis.
        ].
        Fig. 1
        Fig. 1Ganglioglioma in the left superior temporal gyrus. (A) Axial Fluid-attenuated inversion recovery T2 image showing a mildly T2 hyperintense lesion involving the gray and white matter of the left superior temporal gyrus. (B) Coronal T2 image showing partial mineralization and multiple cysts within the tumor.
        This male patient presented with right focal seizures with dyscognitive features at 9 years of age. During his epilepsy work-up a left superior temporal gyrus lesion was found and tentatively classified as malformation of cortical development versus tumor, which remained stable over time. At 16 years of age, he underwent resective epilepsy surgery. The pathology showed glioneuronal tissue with dyslamination, mild increased cellularity, and mild glial atypia consistent with ganglioglioma World Health Organization (classified in 2015 as) grade I. The specimens showed an infiltrating moderately cellular neoplasm composed of glial cells with slightly elongated nuclei, nuclear atypia, karyomegaly, hyperchromasia, and irregularity, admixed with occasional large cells with bizarre large nuclei with prominent nucleoli and abundant cytoplasm, most consistent with dysplastic neurons. Mitoses were difficult to find and there was no necrosis or microvascular proliferation. The glioneural tissue in the background showed mild neuronal crowding, dyslamination, and focal microcolumnar architecture, suggestive of focal cortical dysplasia type I. Immunohistochemistry showed that the GFAP immunostain highlighted moderate to marked subpial, cortical, and white matter reactive astrogliosis; the NeuN immunostain demonstrated the lack of lamination in some areas, and rare microcolumnar architecture; the SMI31 immunostain showed no definitive dysmorphic neurons; the Olig2 immunostain highlighted glial mild nuclear atypia; the Ki67 immunostain showed a low proliferation index; the BRAF V600e, IDH1 (R132H), and p53 immunostains were negative. The patient is seizure free after 3 months of follow-up.
      • c)
        Dysembrioplastic neuroepitelial tumors (DNETs) (Fig. 2) are rare, represent approximately 1% of pediatric brain tumors, and appear most frequently in older children [
        • Dastgir J.
        • Dabscheck G.
        • Ullrich N.
        Neuro-oncology and neurocutaneous syndromes.
        ,
        • Rickert C.H.
        • Paulus W.
        Epidemiology of central nervous system tumors in childhood and adolescence based on the new WHO classification.
        ]. They appear as a well-circumscribed cystic mass most commonly centered in the cerebral cortex, particularly frequent in the temporal lobe [
        • Dastgir J.
        • Dabscheck G.
        • Ullrich N.
        Neuro-oncology and neurocutaneous syndromes.
        ,
        • Nolan M.A.
        • Sakuta R.
        • Chuang N.
        • Otsubo H.
        • Rutka J.T.
        • Snead 3rd, O.C.
        • et al.
        Dysembryoplastic neuroepithelial tumors in childhood: long-term outcome and prognostic features.
        ]. Pathologically, they consist of columns of axon and oligodendroglial bundles that surround neurons floating in an eosinophilic matrix; DNETs are slow-growing and they are frequently associated with cortical dysplasias [
        • Dastgir J.
        • Dabscheck G.
        • Ullrich N.
        Neuro-oncology and neurocutaneous syndromes.
        ]. The 5-year survival approaches 100%, although they can recur after surgical resection [
        • Nolan M.A.
        • Sakuta R.
        • Chuang N.
        • Otsubo H.
        • Rutka J.T.
        • Snead 3rd, O.C.
        • et al.
        Dysembryoplastic neuroepithelial tumors in childhood: long-term outcome and prognostic features.
        ].
        Fig. 2
        Fig. 2Dysembryoplastic neuroepithelial tumor (DNET) in the left mesial temporal lobe. (A and B) Axial Fluid-attenuated inversion recovery T2 image showing a T2 hyperintense lesion centered within the left amygdala.
        This male patient presented with right focal seizures with dyscognitive features at 13 years of age. During his epilepsy work-up a left temporal lobe lesion was found and tentatively classified as DNET, which remained stable. At 15 years of age, he underwent resective epilepsy surgery. The pathology showed DNET World Health Organization (classified in 2015) grade I. The pathology report showed that the tumor was not infiltrating adjacent brain parenchyma, had mild cellularity, mild atypia, no mitoses detected, equivocal vascular proliferation, and equivocal necrosis. Immunohistochemistry was negative for BRAF V600e. The patient is seizure free after 18 months of follow-up.
      • d)
        Oligodendrogliomas are rare representing 1–2% of pediatric brain tumors [
        • Ostrom Q.T.
        • Gittleman H.
        • Fulop J.
        • Liu M.
        • Blanda R.
        • Kromer C.
        • et al.
        CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2008-2012.
        ,
        • Pollack I.F.
        Brain tumors in children.
        ]. They appear as a mass with nodular calcifications in the cerebral hemispheres [
        • Dastgir J.
        • Dabscheck G.
        • Ullrich N.
        Neuro-oncology and neurocutaneous syndromes.
        ]. Pathologically, they consist of a honeycomb structure with a monotonous collection of uniform rounded cells with clear cytoplasm. Oligodendrogliomas usually appear as a mixed glioma with different histologic components, so that the 5-year survival is variable depending on the other components of the tumor.
      • e)
        Supratentorial primitive neuroectodermal tumors represent approximately 5% of all pediatric supratentorial tumors [
        • Dastgir J.
        • Dabscheck G.
        • Ullrich N.
        Neuro-oncology and neurocutaneous syndromes.
        ]. They peak in the first 5 years of life, sometimes as a congenital tumor [
        • Dastgir J.
        • Dabscheck G.
        • Ullrich N.
        Neuro-oncology and neurocutaneous syndromes.
        ]. They appear in the cerebral hemispheres as large, heterogeneous masses, often with necrosis, cystic degeneration, calcification, and osseous erosion [
        • Dastgir J.
        • Dabscheck G.
        • Ullrich N.
        Neuro-oncology and neurocutaneous syndromes.
        ]. Their histology is similar but the prognosis is worse to that of the most frequent infratentorial primitive neuroectodermal tumor: the medulloblastoma [
        • Dastgir J.
        • Dabscheck G.
        • Ullrich N.
        Neuro-oncology and neurocutaneous syndromes.
        ].

      4.2 Infratentorial tumors

      The most common clinical presentation of posterior fossa tumors is with nausea and vomiting (75%), headache (67%), abnormal gait and coordination difficulties (60%), and papilledema (34%) [
      • Wilne S.
      • Collier J.
      • Kennedy C.
      • Koller K.
      • Grundy R.
      • Walker D.
      Presentation of childhood CNS tumours: a systematic review and meta-analysis.
      ]. The most common clinical presentation of brain stem tumors is with abnormal gait and coordination difficulties (78%), cranial nerve palsies (52%), pyramidal signs (33%), and headache (23%) [
      • Wilne S.
      • Collier J.
      • Kennedy C.
      • Koller K.
      • Grundy R.
      • Walker D.
      Presentation of childhood CNS tumours: a systematic review and meta-analysis.
      ].
      • a)
        Astrocytomas. Pilocytic astrocytomas represent approximately 20% of all pediatric astrocytomas and peak at 5–14 years of age [
        • Dastgir J.
        • Dabscheck G.
        • Ullrich N.
        Neuro-oncology and neurocutaneous syndromes.
        ,
        • Rickert C.H.
        • Paulus W.
        Epidemiology of central nervous system tumors in childhood and adolescence based on the new WHO classification.
        ]. They appear most commonly in the cerebellum [
        • Dastgir J.
        • Dabscheck G.
        • Ullrich N.
        Neuro-oncology and neurocutaneous syndromes.
        ,
        • Burkhard C.
        • Di Patre P.L.
        • Schuler D.
        • Schuler G.
        • Yasargil M.G.
        • Yonekawa Y.
        • et al.
        A population-based study of the incidence and survival rates in patients with pilocytic astrocytoma.
        ] as a well-defined mass or, more commonly, as a single large cyst with a mural node [
        • Dastgir J.
        • Dabscheck G.
        • Ullrich N.
        Neuro-oncology and neurocutaneous syndromes.
        ]. Pathologically, they consist of an alternation of compact areas with Rosenthal fibers and spongy areas with microcysts; calcification occurs in approximately one fifth of cases [
        • Sadighi Z.
        • Slopis J.
        Pilocytic astrocytoma: a disease with evolving molecular heterogeneity.
        ]. They can remain stable during prolonged periods and their 5-year survival exceeds 90% [
        • Dastgir J.
        • Dabscheck G.
        • Ullrich N.
        Neuro-oncology and neurocutaneous syndromes.
        ,
        • Burkhard C.
        • Di Patre P.L.
        • Schuler D.
        • Schuler G.
        • Yasargil M.G.
        • Yonekawa Y.
        • et al.
        A population-based study of the incidence and survival rates in patients with pilocytic astrocytoma.
        ].
      • b)
        Medulloblastomas represent 10–15% of all pediatric brain tumors [
        • A.W. Group
        • CCM
        • A.W. Group
        Italian cancer figures, report 2012: cancer in children and adolescents.
        ,
        • Ostrom Q.T.
        • Gittleman H.
        • Fulop J.
        • Liu M.
        • Blanda R.
        • Kromer C.
        • et al.
        CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2008-2012.
        ,
        • Rickert C.H.
        • Paulus W.
        Epidemiology of central nervous system tumors in childhood and adolescence based on the new WHO classification.
        ] and peak at 5–9 years of age [
        • Dastgir J.
        • Dabscheck G.
        • Ullrich N.
        Neuro-oncology and neurocutaneous syndromes.
        ]. In contrast with most other pediatric brain tumors where there is no gender differences, there is more than twofold preference for males [
        • Dastgir J.
        • Dabscheck G.
        • Ullrich N.
        Neuro-oncology and neurocutaneous syndromes.
        ]. They appear as a large gadolinium-enhanced mass in the fourth ventricle, frequently obstructing the cerebrospinal fluid flow and causing hydrocephalus [
        • Dastgir J.
        • Dabscheck G.
        • Ullrich N.
        Neuro-oncology and neurocutaneous syndromes.
        ]. Pathologically, they consist of densely packed cells with round to oval or carrot-shaped hyperchromatic nuclei surrounded by scant cytoplasm [
        • Massimino M.
        • Biassoni V.
        • Gandola L.
        • Garrè M.L.
        • Gatta G.
        • Giangaspero F.
        • et al.
        Childhood medulloblastoma.
        ]. Five-year survival rates in medulloblastoma have drastically improved in the last years and now are 50–70% depending on pathology and age [
        • Massimino M.
        • Biassoni V.
        • Gandola L.
        • Garrè M.L.
        • Gatta G.
        • Giangaspero F.
        • et al.
        Childhood medulloblastoma.
        ].
      • c)
        Ependymomas represent 2–14% of pediatric brain tumors [
        • A.W. Group
        • CCM
        • A.W. Group
        Italian cancer figures, report 2012: cancer in children and adolescents.
        ,
        • Ostrom Q.T.
        • Gittleman H.
        • Fulop J.
        • Liu M.
        • Blanda R.
        • Kromer C.
        • et al.
        CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2008-2012.
        ,
        • Rickert C.H.
        • Paulus W.
        Epidemiology of central nervous system tumors in childhood and adolescence based on the new WHO classification.
        ] with a peak at 0–5 years of age [
        • Dastgir J.
        • Dabscheck G.
        • Ullrich N.
        Neuro-oncology and neurocutaneous syndromes.
        ]. Approximately two thirds of ependymomas are infratentorial while one third is supratentorial: infratentorial location is more common in patients younger than 3 years of age and supratentorial location is more common in patients older than 3 years of age [
        • Perilongo G.
        • Massimino M.
        • Sotti G.
        • Belfontali T.
        • Masiero L.
        • Rigobello L.
        • et al.
        Analyses of prognostic factors in a retrospective review of 92 children with ependymoma: Italian Pediatric Neuro-oncology Group.
        ]. They appear as heterogeneous masses with frequent hemorrhage and necrosis [
        • Dastgir J.
        • Dabscheck G.
        • Ullrich N.
        Neuro-oncology and neurocutaneous syndromes.
        ]. Pathologically, they show ependymal rosettes with tumor cells lining a small central lumen [
        • Dastgir J.
        • Dabscheck G.
        • Ullrich N.
        Neuro-oncology and neurocutaneous syndromes.
        ]. 5-year survival is 20–80% and highly dependent on extent of surgical resection, age, and location [
        • Dastgir J.
        • Dabscheck G.
        • Ullrich N.
        Neuro-oncology and neurocutaneous syndromes.
        ].
      • d)
        Hypothalamic hamartomas are rare affecting approximately 1/200,000 children and adolescents [
        • Coons S.W.
        • Rekate H.L.
        • Prenger E.C.
        • Wang N.
        • Drees C.
        • Ng Y.T.
        • et al.
        The histopathology of hypothalamic hamartomas: study of 57 cases.
        ]. They are congenital, non-progressive masses that arise from the ventral hypothalamus and tuber cinereum [
        • Coons S.W.
        • Rekate H.L.
        • Prenger E.C.
        • Wang N.
        • Drees C.
        • Ng Y.T.
        • et al.
        The histopathology of hypothalamic hamartomas: study of 57 cases.
        ]. They appear as non-enhancing suprasellar masses of gray matter intensity [
        • Dastgir J.
        • Dabscheck G.
        • Ullrich N.
        Neuro-oncology and neurocutaneous syndromes.
        ]. Pathologically, they consist of abnormally distributed, but cytologically normal small neurons and glia [
        • Coons S.W.
        • Rekate H.L.
        • Prenger E.C.
        • Wang N.
        • Drees C.
        • Ng Y.T.
        • et al.
        The histopathology of hypothalamic hamartomas: study of 57 cases.
        ]. Five-year survival approaches 100% [
        • Dastgir J.
        • Dabscheck G.
        • Ullrich N.
        Neuro-oncology and neurocutaneous syndromes.
        ].

      5. Clinical presentation of the pediatric brain tumors most associated with seizures

      Seizures are more commonly seen in specific pediatric brain tumor types, often termed LEATs. Although LEATs are usually of low grade and have low mortality rates [
      • Luyken C.
      • Blumcke I.
      • Fimmers R.
      • Urbach H.
      • Elger C.E.
      • Wiestler O.D.
      • et al.
      The spectrum of long-term epilepsy-associated tumors: long-term seizure and tumor outcome and neurosurgical aspects.
      ], in these patients chronic seizures – which have been estimated to increase mortality by a factor of approximately 5 – may increase their overall mortality [
      • Bell G.S.
      • Sinha S.
      • Tisi J.
      • Stephani C.
      • Scott C.A.
      • Harkness W.F.
      • et al.
      Premature mortality in refractory partial epilepsy: does surgical treatment make a difference?.
      ,
      • Holst A.G.
      • Winkel B.G.
      • Risgaard B.
      • Nielsen J.B.
      • Rasmussen P.V.
      • Haunso S.
      • et al.
      Epilepsy and risk of death and sudden unexpected death in the young: a nationwide study.
      ,
      • Nashef L.
      • Fish D.R.
      • Sander J.W.
      • Shorvon S.D.
      Incidence of sudden unexpected death in an adult outpatient cohort with epilepsy at a tertiary referral centre.
      ]. In a series of 34 pediatric patients with refractory epilepsy and primary brain tumors, the most frequent tumor types were ganglioglioma (44%), low-grade astrocytoma (20.6%), dysembryoplastic neuroepithelial tumor (17.7%), and oligodendroglioma (11.8%) [
      • Khajavi K.
      • Comair Y.G.
      • Wyllie E.
      • Palmer J.
      • Morris H.H.
      • Hahn J.F.
      Surgical management of pediatric tumor-associated epilepsy.
      ]. Electroencephalographic (EEG) interictal findings in pediatric brain tumors are unspecific and can point to the location of the tumor, to other locations, or present normal EEG—even in patients with seizures [
      • Preuss M.
      • Preiss S.
      • Syrbe S.
      • Nestler U.
      • Fischer L.
      • Merkenschlager A.
      • et al.
      Signs and symptoms of pediatric brain tumors and diagnostic value of preoperative EEG.
      ]. In this section we summarize the characteristics of seizures most frequently associated with pediatric brain tumors.

      5.1 Astrocytomas

      Seizures are the presenting symptom in at least a third of pediatric patients with astrocytomas [

      MacDonald T, Packer R. Pediatric astrocytoma clinical presentation. Medscape. http://emedicine.medscape.com/article/985927-clinical [accessed 23.11.16].

      ]. Classic studies showed an inverse relationship between tumor grade and duration of symptoms: the longer the time to diagnosis, the lower the grade [
      • Walker M.D.
      • Green S.B.
      • Byar D.P.
      • Alexander Jr., E.
      • Batzdorf U.
      • Brooks W.H.
      • et al.
      Randomized comparisons of radiotherapy and nitrosoureas for the treatment of malignant glioma after surgery.
      ]. This may partially explain the classical association between longer duration of symptoms before diagnosis and better prognosis [
      • Walker M.D.
      • Green S.B.
      • Byar D.P.
      • Alexander Jr., E.
      • Batzdorf U.
      • Brooks W.H.
      • et al.
      Randomized comparisons of radiotherapy and nitrosoureas for the treatment of malignant glioma after surgery.
      ]. In general, low-grade and well-differentiated astrocytomas have the highest incidence of seizures while high-grade astrocytomas are less likely to present seizures [
      • Beaumont A.
      • Whittle I.R.
      The pathogenesis of tumour associated epilepsy.
      ,
      • Rossetti A.O.
      • Stupp R.
      Epilepsy in brain tumor patients.
      ]: seizures occur in approximately 75% of low-grade astrocytomas and in approximately 30% of high-grade astrocytomas [
      • van Breemen M.S.
      • Wilms E.B.
      • Vecht C.J.
      Epilepsy in patients with brain tumours: epidemiology, mechanisms, and management.
      ]. Seizure incidence and frequency also depends on tumor location: tumors in the cortex are more likely to be related to seizures than tumors in the white matter [
      • Gilles F.H.
      • Sobel E.
      • Leviton A.
      • Hedley-Whyte E.T.
      • Tavare C.J.
      • Adelman L.S.
      • et al.
      Epidemiology of seizures in children with brain tumors. The Childhood Brain Tumor Consortium.
      ]; similarly tumors in the temporal lobes and perirolandic regions are more likely to cause seizures than tumors in the occipital regions [
      • Beaumont A.
      • Whittle I.R.
      The pathogenesis of tumour associated epilepsy.
      ]. In general, astrocytomas are associated with seizures in 60–70% of cases at some point of their evolution [
      • Beaumont A.
      • Whittle I.R.
      The pathogenesis of tumour associated epilepsy.
      ]. The clinical presentation of seizures, related neurological deficits, and electroencephalographic findings are highly dependent on the location and grade of the tumor. Similarly, the degree of seizure control depends on the ability to resect the tumor and the epileptogenic zone.

      5.2 Ganglioglioma (Fig. 1)

      Seizures are the most common presenting symptom of gangliogliomas and occur at presentation in 60–70% of cases [
      • Krouwer H.G.
      • Davis R.L.
      • McDermott M.W.
      • Hoshino T.
      • Prados M.D.
      Gangliogliomas: a clinicopathological study of 25 cases and review of the literature.
      ,
      • Haydon D.H.
      • Dahiya S.
      • Smyth M.D.
      • Limbrick D.D.
      • Leonard J.R.
      Greater extent of resection improves ganglioglioma recurrence-free survival in children: a volumetric analysis.
      ]. The most common seizure type is focal with dyscognitive features followed by focal motor and focal with secondary generalization [
      • Hu W.H.
      • Ge M.
      • Zhang K.
      • Meng F.G.
      • Zhang J.G.
      Seizure outcome with surgical management of epileptogenic ganglioglioma: a study of 55 patients.
      ,
      • Ogiwara H.
      • Nordli D.R.
      • DiPatri A.J.
      • Alden T.D.
      • Bowman R.M.
      • Tomita T.
      Pediatric epileptogenic gangliogliomas: seizure outcome and surgical results.
      ]. Seizure frequency is variable from daily to monthly seizures [
      • Ogiwara H.
      • Nordli D.R.
      • DiPatri A.J.
      • Alden T.D.
      • Bowman R.M.
      • Tomita T.
      Pediatric epileptogenic gangliogliomas: seizure outcome and surgical results.
      ]. The interictal EEG findings in gangliogliomas can be normal or show unilateral, bilaterally independent, bilaterally synchronous, or multifocal discharges [
      • Hu W.H.
      • Ge M.
      • Zhang K.
      • Meng F.G.
      • Zhang J.G.
      Seizure outcome with surgical management of epileptogenic ganglioglioma: a study of 55 patients.
      ]. Seizure control in pediatric gangliogliomas is generally good, but can be challenging due to tumor recurrence. In a series of 55 patients with ganglioglioma, after a mean follow-up of 3.3 years, 48 (87%) patients were in Engel class I (1 patient required a reoperation) of whom 37 were not taking any antiepileptic drug [
      • Hu W.H.
      • Ge M.
      • Zhang K.
      • Meng F.G.
      • Zhang J.G.
      Seizure outcome with surgical management of epileptogenic ganglioglioma: a study of 55 patients.
      ]. In a series of 30 pediatric patients with ganglioglioma, after a mean follow-up of 3.4 years, 27 (90%) patients were in Engel class I of whom 22 were not taking any antiepileptic drug [
      • Ogiwara H.
      • Nordli D.R.
      • DiPatri A.J.
      • Alden T.D.
      • Bowman R.M.
      • Tomita T.
      Pediatric epileptogenic gangliogliomas: seizure outcome and surgical results.
      ].

      5.3 Dysembryoplastic neuroepithelial tumor (DNET) (Fig. 2)

      DNETs are rare and they often present with focal seizures with dyscognitive features at a peak age of 7–10 years [
      • Daumas-Duport C.
      • Scheithauer B.W.
      • Chodkiewicz J.P.
      • Laws Jr., E.R.
      • Vedrenne C.
      Dysembryoplastic neuroepithelial tumor: a surgically curable tumor of young patients with intractable partial seizures. Report of thirty-nine cases.
      ,
      • Honavar M.
      • Janota I.
      • Polkey C.E.
      Histological heterogeneity of dysembryoplastic neuroepithelial tumour: identification and differential diagnosis in a series of 74 cases.
      ,
      • Sharma M.C.
      • Jain D.
      • Gupta A.
      • Sarkar C.
      • Suri V.
      • Garg A.
      • et al.
      Dysembryoplastic neuroepithelial tumor: a clinicopathological study of 32 cases.
      ]. Among primary brain tumors, DNET is the most epileptogenic type with seizures in practically 100% of cases [
      • van Breemen M.S.
      • Wilms E.B.
      • Vecht C.J.
      Epilepsy in patients with brain tumours: epidemiology, mechanisms, and management.
      ]. Headache, papilledema, and other signs or symptoms of increased intracranial pressure are rare at presentation or later in the course of the disease [
      • Daumas-Duport C.
      • Scheithauer B.W.
      • Chodkiewicz J.P.
      • Laws Jr., E.R.
      • Vedrenne C.
      Dysembryoplastic neuroepithelial tumor: a surgically curable tumor of young patients with intractable partial seizures. Report of thirty-nine cases.
      ,
      • Honavar M.
      • Janota I.
      • Polkey C.E.
      Histological heterogeneity of dysembryoplastic neuroepithelial tumour: identification and differential diagnosis in a series of 74 cases.
      ,
      • Sharma M.C.
      • Jain D.
      • Gupta A.
      • Sarkar C.
      • Suri V.
      • Garg A.
      • et al.
      Dysembryoplastic neuroepithelial tumor: a clinicopathological study of 32 cases.
      ]. Epilepsy with DNET is typically disabling with frequent (daily to almost daily) seizures and highly refractory to antiepileptic drugs [
      • Daumas-Duport C.
      • Scheithauer B.W.
      • Chodkiewicz J.P.
      • Laws Jr., E.R.
      • Vedrenne C.
      Dysembryoplastic neuroepithelial tumor: a surgically curable tumor of young patients with intractable partial seizures. Report of thirty-nine cases.
      ,
      • Sharma M.C.
      • Jain D.
      • Gupta A.
      • Sarkar C.
      • Suri V.
      • Garg A.
      • et al.
      Dysembryoplastic neuroepithelial tumor: a clinicopathological study of 32 cases.
      ]. The most common electro-clinical seizure type is focal with dyscognitive features, although secondarily generalized and primary generalized tonic–clonic seizures are also common [
      • Daumas-Duport C.
      • Scheithauer B.W.
      • Chodkiewicz J.P.
      • Laws Jr., E.R.
      • Vedrenne C.
      Dysembryoplastic neuroepithelial tumor: a surgically curable tumor of young patients with intractable partial seizures. Report of thirty-nine cases.
      ,
      • Honavar M.
      • Janota I.
      • Polkey C.E.
      Histological heterogeneity of dysembryoplastic neuroepithelial tumour: identification and differential diagnosis in a series of 74 cases.
      ,
      • Sharma M.C.
      • Jain D.
      • Gupta A.
      • Sarkar C.
      • Suri V.
      • Garg A.
      • et al.
      Dysembryoplastic neuroepithelial tumor: a clinicopathological study of 32 cases.
      ]. Most patients with DNETs are highly resistant to antiepileptic drugs but surgical resection leads to seizure freedom in more than 85% of cases [
      • Ranger A.
      • Diosy D.
      Seizures in children with dysembryoplastic neuroepithelial tumors of the brain—a review of surgical outcomes across several studies.
      ]. DNETs are stable or slow-growing tumors in the borderline between tumor and cortical dysplasia; cortical dysplasia is actually found surrounding DNETs in at least one third of cases [
      • Sharma M.C.
      • Jain D.
      • Gupta A.
      • Sarkar C.
      • Suri V.
      • Garg A.
      • et al.
      Dysembryoplastic neuroepithelial tumor: a clinicopathological study of 32 cases.
      ]. The limit between DNET and cortical dysplasia can be difficult to delineate and patients who undergo lesionectomy have worse seizure outcome than patients who undergo a more extensive resection [
      • Chan C.H.
      • Bittar R.G.
      • Davis G.A.
      • Kalnins R.M.
      • Fabinyi G.C.
      Long-term seizure outcome following surgery for dysembryoplastic neuroepithelial tumor.
      ]. The question of whether intraoperative electrocorticography-guided resection improves outcome remains unanswered [
      • Fallah A.
      • Weil A.G.
      • Sur S.
      • Miller I.
      • Jayakar P.
      • Morrison G.
      • et al.
      Epilepsy surgery related to pediatric brain tumors: Miami Children’s Hospital experience.
      ,
      • Gelinas J.N.
      • Battison A.W.
      • Smith S.
      • Connolly M.B.
      • Steinbok P.
      Electrocorticography and seizure outcomes in children with lesional epilepsy.
      ,
      • Kameyama S.
      • Fukuda M.
      • Tomikawa M.
      • Morota N.
      • Oishi M.
      • Wachi M.
      • et al.
      Surgical strategy and outcomes for epileptic patients with focal cortical dysplasia or dysembryoplastic neuroepithelial tumor.
      ].

      5.4 Oligodendroglioma

      Seizures are the most common (40–70%) presenting symptom of oligodendrogliomas [
      • Creach K.M.
      • Rubin J.B.
      • Leonard J.R.
      • Limbrick D.D.
      • Smyth M.D.
      • Dacey R.
      • et al.
      Oligodendrogliomas in children.
      ,
      • Lebrun C.
      • Fontaine D.
      • Ramaioli A.
      • Vandenbos F.
      • Chanalet S.
      • Lonjon M.
      • et al.
      Long-term outcome of oligodendrogliomas.
      ,
      • Wu C.T.
      • Tsay P.K.
      • Jaing T.H.
      • Chen S.H.
      • Tseng C.K.
      • Jung S.M.
      Oligodendrogliomas in children: clinical experiences with 20 patients.
      ]. Seizures can be focal – most frequent type at onset – or secondarily generalized [
      • Lebrun C.
      • Fontaine D.
      • Ramaioli A.
      • Vandenbos F.
      • Chanalet S.
      • Lonjon M.
      • et al.
      Long-term outcome of oligodendrogliomas.
      ]. Even if pediatric oligodendrogliomas are relatively benign, a changing seizure pattern or clinical worsening can be a sign of tumor progression [
      • Lebrun C.
      • Fontaine D.
      • Ramaioli A.
      • Vandenbos F.
      • Chanalet S.
      • Lonjon M.
      • et al.
      Long-term outcome of oligodendrogliomas.
      ]. Limited data suggest that treatment of pediatric oligodendroglioma leads to seizure control in most patients [
      • Wang K.C.
      • Chi J.G.
      • Cho B.K.
      Oligodendroglioma in childhood.
      ]. In a series that included seven children with oligodendroglioma presenting with seizures all seven became seizure free after treatment and four discontinued antiepileptic medication [
      • Wang K.C.
      • Chi J.G.
      • Cho B.K.
      Oligodendroglioma in childhood.
      ]. However, the literature on seizure outcome of pediatric oligodendroglioma is very limited and, as in other tumors, the degree of seizure control depends on the extent to which the epileptogenic zone is resected.

      5.5 Hypothalamic harmartoma

      The syndrome of epilepsy with hypothalamic hamartoma is rare: a nationwide Swedish study estimated a prevalence of 0.5/100,000 [
      • Brandberg G.
      • Raininko R.
      • Eeg-Olofsson O.
      Hypothalamic hamartoma with gelastic seizures in Swedish children and adolescents.
      ]. The hallmark of epilepsy with hypothalamic hamartoma is gelastic seizures: bouts of vocalization with facial contraction [
      • Harvey A.S.
      • Freeman J.L.
      Epilepsy in hypothalamic hamartoma: clinical and EEG features.
      ]. Most frequently, vocalization resembles laughter and facial contraction resembles a smile, although the mechanical nature of the vocalization and facial contraction makes it sometimes appear the vocalization as crying and the facial contraction as grimace in episodes termed dacrystic seizures [
      • Harvey A.S.
      • Freeman J.L.
      Epilepsy in hypothalamic hamartoma: clinical and EEG features.
      ]. Laughter is most often described to occur without mirth. Gelastic and dacrystic semiologies frequently appear as different seizures in the same patient or even as mixed components during the same seizure [
      • Harvey A.S.
      • Freeman J.L.
      Epilepsy in hypothalamic hamartoma: clinical and EEG features.
      ,
      • Blumberg J.
      • Sánchez Fernández I.
      • Vendrame M.
      • Oehl B.
      • Tatum W.O.
      • Schuele S.
      • et al.
      Dacrystic seizures: demographic, semiologic, and etiologic insights from a multicenter study in long-term video-EEG monitoring units.
      ]. An abrupt sympathetic system activation often accompanies gelastic seizures [
      • Cerullo A.
      • Tinuper P.
      • Provini F.
      • Contin M.
      • Rosati A.
      • Marini C.
      • et al.
      Autonomic and hormonal ictal changes in gelastic seizures from hypothalamic hamartomas.
      ]. Gelastic seizures present within the first year of life in most cases [
      • Brandberg G.
      • Raininko R.
      • Eeg-Olofsson O.
      Hypothalamic hamartoma with gelastic seizures in Swedish children and adolescents.
      ,
      • Berkovic S.F.
      • Andermann F.
      • Melanson D.
      • Ethier R.E.
      • Feindel W.
      • Gloor P.
      Hypothalamic hamartomas and ictal laughter: evolution of a characteristic epileptic syndrome and diagnostic value of magnetic resonance imaging.
      ], but initially they are not necessarily recognized as abnormal, as illustrated by a patient who won a happy baby contest for having frequent laughter from the first day of life [
      • Berkovic S.F.
      • Andermann F.
      • Melanson D.
      • Ethier R.E.
      • Feindel W.
      • Gloor P.
      Hypothalamic hamartomas and ictal laughter: evolution of a characteristic epileptic syndrome and diagnostic value of magnetic resonance imaging.
      ]. Over time other seizure types may appear: focal seizures with dyscognitive features, tonic seizures, atonic seizures, and generalized tonic–clonic seizures [
      • Brandberg G.
      • Raininko R.
      • Eeg-Olofsson O.
      Hypothalamic hamartoma with gelastic seizures in Swedish children and adolescents.
      ,
      • Harvey A.S.
      • Freeman J.L.
      Epilepsy in hypothalamic hamartoma: clinical and EEG features.
      ,
      • Berkovic S.F.
      • Andermann F.
      • Melanson D.
      • Ethier R.E.
      • Feindel W.
      • Gloor P.
      Hypothalamic hamartomas and ictal laughter: evolution of a characteristic epileptic syndrome and diagnostic value of magnetic resonance imaging.
      ]. The reason why new seizure types develop is unknown because hypothalamic hamartomas are developmental, non-growing masses (technically, not tumors) which should not affect other brain regions over time [
      • Striano S.
      • Santulli L.
      • Ianniciello M.
      • Ferretti M.
      • Romanelli P.
      • Striano P.
      The gelastic seizures-hypothalamic hamartoma syndrome: facts, hypotheses, and perspectives.
      ]. It is speculated that frequent interictal epileptiform discharges and seizures from the hypothalamic hamartoma kindle other foci in the cerebral cortex; these secondary foci initially depend on the hypothalamic hamartoma to produce seizures, but might become completely independent if kindled for long-enough periods of time [
      • Harvey A.S.
      • Freeman J.L.
      Epilepsy in hypothalamic hamartoma: clinical and EEG features.
      ]. Patients with epilepsy with hypothalamic hamartoma often have a progressive cognitive and behavioral impairment [
      • Harvey A.S.
      • Freeman J.L.
      Epilepsy in hypothalamic hamartoma: clinical and EEG features.
      ,
      • Striano S.
      • Santulli L.
      • Ianniciello M.
      • Ferretti M.
      • Romanelli P.
      • Striano P.
      The gelastic seizures-hypothalamic hamartoma syndrome: facts, hypotheses, and perspectives.
      ]. Precocious puberty and other endocrine abnormalities are frequent [
      • Harvey A.S.
      • Freeman J.L.
      Epilepsy in hypothalamic hamartoma: clinical and EEG features.
      ,
      • Striano S.
      • Santulli L.
      • Ianniciello M.
      • Ferretti M.
      • Romanelli P.
      • Striano P.
      The gelastic seizures-hypothalamic hamartoma syndrome: facts, hypotheses, and perspectives.
      ]. EEGs are most frequently normal, although asymmetric background, focal slowing, and generalized or focal epileptiform discharges – often lateralized to the predominant side of the hypothalamic hamartoma – are common [
      • Brandberg G.
      • Raininko R.
      • Eeg-Olofsson O.
      Hypothalamic hamartoma with gelastic seizures in Swedish children and adolescents.
      ,
      • Harvey A.S.
      • Freeman J.L.
      Epilepsy in hypothalamic hamartoma: clinical and EEG features.
      ,
      • Berkovic S.F.
      • Andermann F.
      • Melanson D.
      • Ethier R.E.
      • Feindel W.
      • Gloor P.
      Hypothalamic hamartomas and ictal laughter: evolution of a characteristic epileptic syndrome and diagnostic value of magnetic resonance imaging.
      ,
      • Striano S.
      • Santulli L.
      • Ianniciello M.
      • Ferretti M.
      • Romanelli P.
      • Striano P.
      The gelastic seizures-hypothalamic hamartoma syndrome: facts, hypotheses, and perspectives.
      ]. When seizures are captured on EEG, the correlate is variable and includes focal or diffuse attenuation, fast activity, slow activity, or spike-wave complexes [
      • Harvey A.S.
      • Freeman J.L.
      Epilepsy in hypothalamic hamartoma: clinical and EEG features.
      ,
      • Berkovic S.F.
      • Andermann F.
      • Melanson D.
      • Ethier R.E.
      • Feindel W.
      • Gloor P.
      Hypothalamic hamartomas and ictal laughter: evolution of a characteristic epileptic syndrome and diagnostic value of magnetic resonance imaging.
      ,
      • Striano S.
      • Santulli L.
      • Ianniciello M.
      • Ferretti M.
      • Romanelli P.
      • Striano P.
      The gelastic seizures-hypothalamic hamartoma syndrome: facts, hypotheses, and perspectives.
      ]. The variable EEG patterns of gelastic seizures suggest that the surface EEG captures only seizure spread and not seizure onset [
      • Harvey A.S.
      • Freeman J.L.
      Epilepsy in hypothalamic hamartoma: clinical and EEG features.
      ,
      • Berkovic S.F.
      • Andermann F.
      • Melanson D.
      • Ethier R.E.
      • Feindel W.
      • Gloor P.
      Hypothalamic hamartomas and ictal laughter: evolution of a characteristic epileptic syndrome and diagnostic value of magnetic resonance imaging.
      ,
      • Striano S.
      • Santulli L.
      • Ianniciello M.
      • Ferretti M.
      • Romanelli P.
      • Striano P.
      The gelastic seizures-hypothalamic hamartoma syndrome: facts, hypotheses, and perspectives.
      ]. Most patients with epilepsy with hypothalamic hamartoma are highly resistant to antiepileptic drugs [
      • Brandberg G.
      • Raininko R.
      • Eeg-Olofsson O.
      Hypothalamic hamartoma with gelastic seizures in Swedish children and adolescents.
      ,
      • Berkovic S.F.
      • Andermann F.
      • Melanson D.
      • Ethier R.E.
      • Feindel W.
      • Gloor P.
      Hypothalamic hamartomas and ictal laughter: evolution of a characteristic epileptic syndrome and diagnostic value of magnetic resonance imaging.
      ,
      • Striano S.
      • Santulli L.
      • Ianniciello M.
      • Ferretti M.
      • Romanelli P.
      • Striano P.
      The gelastic seizures-hypothalamic hamartoma syndrome: facts, hypotheses, and perspectives.
      ]. The complete surgical removal or laser ablation of the hypothalamic hamartoma is effective in treating gelastic seizures as well as stop other seizure types (unless the secondary foci have become completely independent), and often halt or reverse the cognitive and behavioral impairment associated with this syndromic presentation [
      • Harvey A.S.
      • Freeman J.L.
      Epilepsy in hypothalamic hamartoma: clinical and EEG features.
      ,
      • Striano S.
      • Santulli L.
      • Ianniciello M.
      • Ferretti M.
      • Romanelli P.
      • Striano P.
      The gelastic seizures-hypothalamic hamartoma syndrome: facts, hypotheses, and perspectives.
      ].

      5.6 Seizures in infratententorial tumors

      Seizures occur in approximately 6% of pediatric patients with infratentorial tumors [
      • Gilles F.H.
      • Sobel E.
      • Leviton A.
      • Hedley-Whyte E.T.
      • Tavare C.J.
      • Adelman L.S.
      • et al.
      Epidemiology of seizures in children with brain tumors. The Childhood Brain Tumor Consortium.
      ]. However, seizures are not the most common presenting symptom of infratentorial tumor and typically appear when the tumor has spread or metastasized to the cerebral cortex or when it has caused increased intracranial pressure as illustrated by the fact that more than 95% of children with an infratentorial tumor and seizures have at least other tumor-related symptom [
      • Gilles F.H.
      • Sobel E.
      • Leviton A.
      • Hedley-Whyte E.T.
      • Tavare C.J.
      • Adelman L.S.
      • et al.
      Epidemiology of seizures in children with brain tumors. The Childhood Brain Tumor Consortium.
      ]. In particular, more common presenting symptoms for infratentorial tumors are headache, nausea and vomiting, abnormal gait, and abnormal ocular movements [
      • Wilne S.
      • Collier J.
      • Kennedy C.
      • Koller K.
      • Grundy R.
      • Walker D.
      Presentation of childhood CNS tumours: a systematic review and meta-analysis.
      ]. Among infratentorial tumors, the most frequent ones presenting with seizures are astrocytoma (5–10% of the cases), ependymoma (10% of the cases), and medulloblastoma (5%) [
      • Gilles F.H.
      • Sobel E.
      • Leviton A.
      • Hedley-Whyte E.T.
      • Tavare C.J.
      • Adelman L.S.
      • et al.
      Epidemiology of seizures in children with brain tumors. The Childhood Brain Tumor Consortium.
      ].

      6. Seizures secondary to brain metastases, leukemias, and treatment with chemotherapy and radiotherapy

      In contrast to adults where solid metastases represent the most frequent brain tumor, metastatic solid brain tumors are rare in pediatric patients [
      • Suki D.
      • Khoury Abdulla R.
      • Ding M.
      • Khatua S.
      • Sawaya R.
      Brain metastases in patients diagnosed with a solid primary cancer during childhood: experience from a single referral cancer center.
      ,
      • Wiens A.L.
      • Hattab E.M.
      The pathological spectrum of solid CNS metastases in the pediatric population.
      ]. Among a series of 1135 pediatric brain tumors, only 26 (2.3%) were solid metastases, and most metastases were solitary (65%) and supratentorial (89%) [
      • Wiens A.L.
      • Hattab E.M.
      The pathological spectrum of solid CNS metastases in the pediatric population.
      ]. In a series of 3950 pediatric patients with a solid primary cancer outside the brain, 54 (1.4%) had a solid brain metastasis or leptomeningeal disease [
      • Suki D.
      • Khoury Abdulla R.
      • Ding M.
      • Khatua S.
      • Sawaya R.
      Brain metastases in patients diagnosed with a solid primary cancer during childhood: experience from a single referral cancer center.
      ]. A simultaneous diagnosis of primary tumor and brain metastasis was rare (8/26 or 1/54 cases) and the median time between diagnosis of the primary tumor and diagnosis of the brain metastasis was 18–48 months [
      • Suki D.
      • Khoury Abdulla R.
      • Ding M.
      • Khatua S.
      • Sawaya R.
      Brain metastases in patients diagnosed with a solid primary cancer during childhood: experience from a single referral cancer center.
      ,
      • Wiens A.L.
      • Hattab E.M.
      The pathological spectrum of solid CNS metastases in the pediatric population.
      ]. The most frequent primary solid tumors were sarcomas (especially from bone and kidney) and melanomas [
      • Suki D.
      • Khoury Abdulla R.
      • Ding M.
      • Khatua S.
      • Sawaya R.
      Brain metastases in patients diagnosed with a solid primary cancer during childhood: experience from a single referral cancer center.
      ,
      • Wiens A.L.
      • Hattab E.M.
      The pathological spectrum of solid CNS metastases in the pediatric population.
      ]. The most common symptom of a brain metastasis is headache, which occurs in 30–40% of cases, but seizures are still one of the most common presenting symptoms occurring in 20–25% of the cases [
      • Suki D.
      • Khoury Abdulla R.
      • Ding M.
      • Khatua S.
      • Sawaya R.
      Brain metastases in patients diagnosed with a solid primary cancer during childhood: experience from a single referral cancer center.
      ,
      • Wiens A.L.
      • Hattab E.M.
      The pathological spectrum of solid CNS metastases in the pediatric population.
      ].
      More relevant for the pediatric population is the brain involvement in leukemias, as they represent the most frequent (approximately 30% of the total) pediatric cancer type [
      • A.W. Group
      • CCM
      • A.W. Group
      Italian cancer figures, report 2012: cancer in children and adolescents.
      ]. In children with acute lymphoblastic leukemia, seizures occur in approximately 10–15% of cases [
      • Maytal J.
      • Grossman R.
      • Yusuf F.H.
      • Shende A.C.
      • Karayalycin G.
      • Lanzkowsky P.
      • et al.
      Prognosis and treatment of seizures in children with acute lymphoblastic leukemia.
      ,
      • Ochs J.J.
      • Bowman W.P.
      • Pui C.H.
      • Abromowitch M.
      • Mason C.
      • Simone J.V.
      Seizures in childhood lymphoblastic leukaemia patients.
      ]. Seizure semiology can be either focal, generalized, or focal with secondary generalization [
      • Maytal J.
      • Grossman R.
      • Yusuf F.H.
      • Shende A.C.
      • Karayalycin G.
      • Lanzkowsky P.
      • et al.
      Prognosis and treatment of seizures in children with acute lymphoblastic leukemia.
      ]. Mechanisms by which leukemia leads to seizures include leukemic infiltration, thrombosis, and hemorrhage, among others [
      • Ochs J.J.
      • Bowman W.P.
      • Pui C.H.
      • Abromowitch M.
      • Mason C.
      • Simone J.V.
      Seizures in childhood lymphoblastic leukaemia patients.
      ]. Perhaps even more relevant is the neurotoxicity of prophylactic brain treatment in leukemia [
      • Ochs J.J.
      Neurotoxicity due to central nervous system therapy for childhood leukemia.
      ,
      • Packer R.J.
      • Meadows A.T.
      • Rorke L.B.
      • Goldwein J.L.
      • D’Angio G.
      Long-term sequelae of cancer treatment on the central nervous system in childhood.
      ]. In pediatric leukemias, especially in acute lymphoblastic leukemia, the brain is a reservoir for potential relapse. Therefore, prophylactic treatment reduces the risk for brain relapse but also increases the probability of severe neurologic side effects and the risk for developing seizures and epilepsy [
      • Baytan B.
      • Evim M.S.
      • Guler S.
      • Gunes A.M.
      • Okan M.
      Acute central nervous system complications in pediatric acute lymphoblastic leukemia.
      ]. In fact, in a series of pediatric patients with acute lymphoblastic leukemia, all seizures occurred during acute treatment [
      • Maytal J.
      • Grossman R.
      • Yusuf F.H.
      • Shende A.C.
      • Karayalycin G.
      • Lanzkowsky P.
      • et al.
      Prognosis and treatment of seizures in children with acute lymphoblastic leukemia.
      ].
      As survival for pediatric cancers increases, the long-term side-effects of cancer treatment on the brain are of increasing relevance. There are no definitive rules to assign a seizure to a specific treatment, but most chemotherapy-induced seizures occur within hours or days of treatment administration [
      • Singh G.
      • Rees J.H.
      • Sander J.W.
      Seizures and epilepsy in oncological practice: causes, course, mechanisms and treatment.
      ]. Drugs associated with seizures include cyclosporin A, cisplatin, and busulphan, but seizures represent one of the dose-limiting toxicity of cancer drugs and many cancer drugs can cause seizures at a high-enough dose typically tested in phases I and II clinical trials [
      • Singh G.
      • Rees J.H.
      • Sander J.W.
      Seizures and epilepsy in oncological practice: causes, course, mechanisms and treatment.
      ]. In contrast to seizures induced by chemotherapy, seizures secondary to radiotherapy tend to be persistent and sometimes refractory to treatment [
      • Reutens D.C.
      • Dubeau F.
      • Melanson D.
      • Remillard G.M.
      • Espinosa J.A.
      • King M.
      • et al.
      Intractable partial epilepsy following low-dose scalp irradiation in infancy.
      ]. Seizures are a well-described complication of radiotherapy involving the brain [
      • Bhansali A.
      • Banerjee A.K.
      • Chanda A.
      • Singh P.
      • Sharma S.C.
      • Mathuriya S.N.
      • et al.
      Radiation-induced brain disorders in patients with pituitary tumours.
      ] and can even occur at relatively low radiation doses for non-brain related pathology [
      • Reutens D.C.
      • Dubeau F.
      • Melanson D.
      • Remillard G.M.
      • Espinosa J.A.
      • King M.
      • et al.
      Intractable partial epilepsy following low-dose scalp irradiation in infancy.
      ]. In the long term, chemotherapy and radiotherapy can also cause secondary tumors in the brain with the potential for further seizures [
      • Chung C.K.
      • Stryker J.A.
      • Cruse R.
      • Vannuci R.
      • Towfighi J.
      Glioblastoma multiforme following prophylactic cranial irradiation and intrathecal methotrexate in a child with acute lymphocytic leukemia.
      ,
      • Pearl G.S.
      • Mirra S.S.
      • Miles M.L.
      Glioblastoma multiforme occurring 13 years after treatment of a medulloblastoma.
      ].

      7. Pathophysiological mechanisms by which brain tumors cause seizures

      The relationship between brain tumors and seizures can be explained as tumor epileptogenicity: the tumor may contain an abnormal distribution of cells or may excrete molecules that can make the tumor tissue itself epileptogenic; or as peritumoral epileptogenicity: the tumor may modify the peritumoral microenvironment into an epileptogenic zone [
      • You G.
      • Sha Z.
      • Jiang T.
      The pathogenesis of tumor-related epilepsy and its implications for clinical treatment.
      ]. The mechanisms through which brain tumors cause seizures are probably multifactorial and include a combination of: (1) metabolic changes in peritumoral brain, (2) morphologic changes in peritumoral brain, (3) secondary epileptogenesis, (4) neurotransmitter changes in peritumoral brain, (5) immunologic changes in peritumoral brain, and (6) presence of blood products, gliosis, and necrosis [
      • Dastgir J.
      • Dabscheck G.
      • Ullrich N.
      Neuro-oncology and neurocutaneous syndromes.
      ,
      • Beaumont A.
      • Whittle I.R.
      The pathogenesis of tumour associated epilepsy.
      ].
      Peritumoral brain tissue may be more alkaline because of peritumoral astrocytosis or infiltration by glial tumor cells [
      • Beaumont A.
      • Whittle I.R.
      The pathogenesis of tumour associated epilepsy.
      ]. Alkalosis leads to increased conductance to Ca2+ through the N-methyl-d-aspartate (NMDA) receptor [
      • Tang C.M.
      • Dichter M.
      • Morad M.
      Modulation of the N-methyl-d-aspartate channel by extracellular H+.
      ] and decreased conductance to Cl through the gamma-aminobutyric acid (GABA) receptor [
      • Pasternack M.
      • Bountra C.
      • Voipio J.
      • Kaila K.
      Influence of extracellular and intracellular pH on GABA-gated chloride conductance in crayfish muscle fibres.
      ]. On the other hand, insufficient vascular supply to meet the needs of elevated tumor metabolism or just mechanical compression of brain tissue leads to hypoxia and acidosis [
      • You G.
      • Sha Z.
      • Jiang T.
      The pathogenesis of tumor-related epilepsy and its implications for clinical treatment.
      ]. The acidic and hypoxic metabolic environment in the peritumoral tissue may disrupt neuronal and glial function, although the exact mechanisms leading to epileptogenesis are unclear [
      • You G.
      • Sha Z.
      • Jiang T.
      The pathogenesis of tumor-related epilepsy and its implications for clinical treatment.
      ].
      The brain tissue around brain tumors – especially in gangliogliomas and DNETs – is characterized by cortical disorganization and, sometimes, frank focal cortical dysplasia [
      • Ferrier C.H.
      • Aronica E.
      • Leijten F.S.
      • Spliet W.G.
      • van Huffelen A.C.
      • van Rijen P.C.
      • et al.
      Electrocorticographic discharge patterns in glioneuronal tumors and focal cortical dysplasia.
      ,
      • Morris H.H.
      • Matkovic Z.
      • Estes M.L.
      • Prayson R.A.
      • Comair Y.G.
      • Turnbull J.
      • et al.
      Ganglioglioma and intractable epilepsy: clinical and neurophysiologic features and predictors of outcome after surgery.
      ,
      • Pasquier B.
      • Peoc H.M.
      • Fabre-Bocquentin B.
      • Bensaadi L.
      • Pasquier D.
      • Hoffmann D.
      • et al.
      Surgical pathology of drug-resistant partial epilepsy. A 10-year-experience with a series of 327 consecutive resections.
      ]. The presence of continuous spiking related to a brain tumor is likely to be a marker of dysplasia [
      • Ferrier C.H.
      • Aronica E.
      • Leijten F.S.
      • Spliet W.G.
      • van Huffelen A.C.
      • van Rijen P.C.
      • et al.
      Electrocorticographic discharge patterns in glioneuronal tumors and focal cortical dysplasia.
      ]. Abnormal neuronal morphology, aberrant neuronal migration, and abnormal pattern of synapses may explain epileptogenicity in the peritumoral tissue [
      • van Breemen M.S.
      • Wilms E.B.
      • Vecht C.J.
      Epilepsy in patients with brain tumours: epidemiology, mechanisms, and management.
      ]. In addition, astrocytes play an important role in the regulation of neuronal function [
      • Seifert G.
      • Carmignoto G.
      • Steinhauser C.
      Astrocyte dysfunction in epilepsy.
      ]. If their buffering and support function is disrupted by brain tissue or peritumoral edema, the resultant dysfunction in neuronal excitability may lead to seizures [
      • Seifert G.
      • Carmignoto G.
      • Steinhauser C.
      Astrocyte dysfunction in epilepsy.
      ]. Kindling refers to the process by which an active focus of interictal epileptiform activity or seizures promotes abnormal neuronal networks that eventually are able to independently generate interictal epileptiform activity or seizures [
      • McIntyre D.C.
      • Poulter M.O.
      Kindling and the mirror focus.
      ]. This secondary focus can occur close to the primary focus or at a distant place [
      • McIntyre D.C.
      • Poulter M.O.
      Kindling and the mirror focus.
      ]. Brain tumors can be an active focus of interictal epileptiform activity and seizures and, therefore, are able to generate secondary epileptogenic foci around the tumor or distant to it [
      • Gilmore R.
      • Morris 3rd, H.
      • Van Ness P.C.
      • Gilmore-Pollak W.
      • Estes M.
      Mirror focus: function of seizure frequency and influence on outcome after surgery.
      ].
      An imbalance between excitatory and inhibitory synaptic transmission may further contribute to epileptogenesis in tumors [
      • Wolf H.K.
      • Roos D.
      • Blumcke I.
      • Pietsch T.
      • Wiestler O.D.
      Perilesional neurochemical changes in focal epilepsies.
      ]. Local concentrations of glutamate and GABA are variable in the peritumoral tissue [
      • van Breemen M.S.
      • Wilms E.B.
      • Vecht C.J.
      Epilepsy in patients with brain tumours: epidemiology, mechanisms, and management.
      ]. Further, the subunit composition of neurotransmitter receptors also changes around the tumor, potentially promoting excitability [
      • Wolf H.K.
      • Roos D.
      • Blumcke I.
      • Pietsch T.
      • Wiestler O.D.
      Perilesional neurochemical changes in focal epilepsies.
      ]. The immune response to the brain tumor fights its growth and spread but can also increase local excitability [
      • Beaumont A.
      • Whittle I.R.
      The pathogenesis of tumour associated epilepsy.
      ,
      • You G.
      • Sha Z.
      • Jiang T.
      The pathogenesis of tumor-related epilepsy and its implications for clinical treatment.
      ]. Physical destruction of parts of neuronal networks and an imbalance of inhibitory and excitatory cytokines may promote epileptogenicity [
      • Beaumont A.
      • Whittle I.R.
      The pathogenesis of tumour associated epilepsy.
      ,
      • You G.
      • Sha Z.
      • Jiang T.
      The pathogenesis of tumor-related epilepsy and its implications for clinical treatment.
      ]. Blood products, necrotic tissue, and gliosis in or around the tumor may promote the occurrence of interictal epileptiform activity and seizures by direct irritation or alteration of the microenvironment [
      • van Breemen M.S.
      • Wilms E.B.
      • Vecht C.J.
      Epilepsy in patients with brain tumours: epidemiology, mechanisms, and management.
      ,
      • Beaumont A.
      • Whittle I.R.
      The pathogenesis of tumour associated epilepsy.
      ,
      • You G.
      • Sha Z.
      • Jiang T.
      The pathogenesis of tumor-related epilepsy and its implications for clinical treatment.
      ]. Finally, different tumor histologies, different locations within the brain, and different genetic factors in the tumor and the patient may help explain differences in seizure frequency among different patients [
      • van Breemen M.S.
      • Wilms E.B.
      • Vecht C.J.
      Epilepsy in patients with brain tumours: epidemiology, mechanisms, and management.
      ,
      • Beaumont A.
      • Whittle I.R.
      The pathogenesis of tumour associated epilepsy.
      ,
      • You G.
      • Sha Z.
      • Jiang T.
      The pathogenesis of tumor-related epilepsy and its implications for clinical treatment.
      ].

      8. Treatment of seizures caused by pediatric brain tumors

      Both surgical and medical treatment of brain tumor addresses the primary cause of seizures and reduces seizure frequency in most cases. The extent of surgical resection in brain tumors and epilepsy is a debated topic [
      • Fallah A.
      • Weil A.G.
      • Sur S.
      • Miller I.
      • Jayakar P.
      • Morrison G.
      • et al.
      Epilepsy surgery related to pediatric brain tumors: Miami Children’s Hospital experience.
      ]. If the epileptogenic zone is peritumoral, then removing the tumor alone might not necessarily lead to seizure freedom [
      • You G.
      • Sha Z.
      • Jiang T.
      The pathogenesis of tumor-related epilepsy and its implications for clinical treatment.
      ]. It can also be argued that once the brain tumor is removed, the peritumoral tissue will tend to normalize [
      • You G.
      • Sha Z.
      • Jiang T.
      The pathogenesis of tumor-related epilepsy and its implications for clinical treatment.
      ]. In fact, pediatric brain tumor and epilepsy series show Engel class I outcome in more than 80% solely with total tumor resection, without further epilepsy surgery [
      • Giulioni M.
      • Galassi E.
      • Zucchelli M.
      • Volpi L.
      Seizure outcome of lesionectomy in glioneuronal tumors associated with epilepsy in children.
      ,
      • Kim S.K.
      • Wang K.C.
      • Hwang Y.S.
      • Kim K.J.
      • Cho B.K.
      Intractable epilepsy associated with brain tumors in children: surgical modality and outcome.
      ]. Additionally, in a series of 23 pediatric patients with intractable epilepsy associated with brain tumors, complete tumor resection led to better seizure outcome than incomplete tumor resection but there was no difference in seizure outcome between the 13 patients who underwent only lesionectomy and the 10 patients who underwent epilepsy surgery [
      • Kim S.K.
      • Wang K.C.
      • Hwang Y.S.
      • Kim K.J.
      • Cho B.K.
      Intractable epilepsy associated with brain tumors in children: surgical modality and outcome.
      ]. Certain tumors like gangliogliomas and DNETs are frequently associated with cortical dysplasia [
      • Ferrier C.H.
      • Aronica E.
      • Leijten F.S.
      • Spliet W.G.
      • van Huffelen A.C.
      • van Rijen P.C.
      • et al.
      Electrocorticographic discharge patterns in glioneuronal tumors and focal cortical dysplasia.
      ,
      • Morris H.H.
      • Matkovic Z.
      • Estes M.L.
      • Prayson R.A.
      • Comair Y.G.
      • Turnbull J.
      • et al.
      Ganglioglioma and intractable epilepsy: clinical and neurophysiologic features and predictors of outcome after surgery.
      ,
      • Pasquier B.
      • Peoc H.M.
      • Fabre-Bocquentin B.
      • Bensaadi L.
      • Pasquier D.
      • Hoffmann D.
      • et al.
      Surgical pathology of drug-resistant partial epilepsy. A 10-year-experience with a series of 327 consecutive resections.
      ] and may benefit more from a more extensive resection, possibly under electrocorticography guidance. In summary, the extent of surgical resection in brain tumors with epilepsy is not well established [
      • Fallah A.
      • Weil A.G.
      • Sur S.
      • Miller I.
      • Jayakar P.
      • Morrison G.
      • et al.
      Epilepsy surgery related to pediatric brain tumors: Miami Children’s Hospital experience.
      ], the correlation between resection of the irritative zone detected by intraoperative electrocorticography and outcome is variable [
      • Sánchez Fernández I.
      • Loddenkemper T.
      Electrocorticography for seizure foci mapping in epilepsy surgery.
      ], and tumor resection should be individualized case by case. Other strategies primarily targeted to tumor treatment may help control seizures: a meta-analysis of the treatment of low-grade glioma showed that both chemotherapy and radiotherapy improved seizure outcome even when the tumor size was not reduced [
      • Koekkoek J.A.
      • Kerkhof M.
      • Dirven L.
      • Heimans J.J.
      • Reijneveld J.C.
      • Taphoorn M.J.
      Seizure outcome after radiotherapy and chemotherapy in low-grade glioma patients: a systematic review.
      ]. On the other hand, seizure decompensation during tumor treatment can occur with both medical [
      • Leff R.S.
      • Thompson J.M.
      • Daly M.B.
      • Johnson D.B.
      • Harden E.A.
      • Mercier R.J.
      • et al.
      Acute neurologic dysfunction after high-dose etoposide therapy for malignant glioma.
      ] and surgical treatment [
      • Spena G.
      • Schucht P.
      • Seidel K.
      • Rutten G.J.
      • Freyschlag C.F.
      • D’Agata F.
      • et al.
      Brain tumors in eloquent areas: a European multicenter survey of intraoperative mapping techniques, intraoperative seizures occurrence, and antiepileptic drug prophylaxis.
      ].
      Apart from treating seizures targeting their etiology – the brain tumor – , symptomatic treatment of epilepsy involves the use of antiepileptic drugs. Despite the fact that seizures are frequent in patients with brain tumors, prolonged prophylactic use of antiepileptic drugs is not recommended regardless of tumor type because it does not provide substantial benefit – does not effectively prevent first seizures – but side effects from antiepileptic drugs in the context of chemotherapy are particularly common and occasionally life-threatening [
      • 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.
      ,
      • Sirven J.I.
      • Wingerchuk D.M.
      • Drazkowski J.F.
      • Lyons M.K.
      • Zimmerman R.S.
      Seizure prophylaxis in patients with brain tumors: a meta-analysis.
      ,
      • Tremont-Lukats I.W.
      • Ratilal B.O.
      • Armstrong T.
      • Gilbert M.R.
      Antiepileptic drugs for preventing seizures in people with brain tumors.
      ]: the risk-benefit ratio recommends watchful waiting. There is insufficient evidence for or against a short perioperative prophylactic treatment around the time of tumor resection [
      • Franceschetti S.
      • Binelli S.
      • Casazza M.
      • Lodrini S.
      • Panzica F.
      • Pluchino F.
      • et al.
      Influence of surgery and antiepileptic drugs on seizures symptomatic of cerebral tumours.
      ,
      • Mahaley Jr., M.S.
      • Dudka L.
      The role of anticonvulsant medications in the management of patients with anaplastic gliomas.
      ,
      • North J.B.
      • Penhall R.K.
      • Hanieh A.
      • Frewin D.B.
      • Taylor W.B.
      Phenytoin and postoperative epilepsy. A double-blind study.
      ,
      • Weston J.
      • Greenhalgh J.
      • Marson A.G.
      Antiepileptic drugs as prophylaxis for post-craniotomy seizures.
      ], although supportive results in some studies may justify its use on certain occasions [
      • Franceschetti S.
      • Binelli S.
      • Casazza M.
      • Lodrini S.
      • Panzica F.
      • Pluchino F.
      • et al.
      Influence of surgery and antiepileptic drugs on seizures symptomatic of cerebral tumours.
      ,
      • North J.B.
      • Penhall R.K.
      • Hanieh A.
      • Frewin D.B.
      • Taylor W.B.
      Phenytoin and postoperative epilepsy. A double-blind study.
      ]. In general, once a first seizure occurs, initiation of antiepileptic drugs is justified [
      • van Breemen M.S.
      • Wilms E.B.
      • Vecht C.J.
      Epilepsy in patients with brain tumours: epidemiology, mechanisms, and management.
      ] because the recurrence risk of seizures in patients with brain tumors is probably similar or higher than the risk of seizure recurrence after 2 unprovoked seizures [
      • Fisher R.S.
      • Acevedo C.
      • Arzimanoglou A.
      • Bogacz A.
      • Cross J.H.
      • Elger C.E.
      • et al.
      ILAE official report: a practical clinical definition of epilepsy.
      ].
      Brain tumors represent an heterogeneous group of etiologies causing seizures and, accordingly, the efficacy of antiepileptic drugs is variable depending not only on the drug efficacy but also on the underlying epilepsy severity [
      • van Breemen M.S.
      • Wilms E.B.
      • Vecht C.J.
      Epilepsy in patients with brain tumours: epidemiology, mechanisms, and management.
      ,
      • Beaumont A.
      • Whittle I.R.
      The pathogenesis of tumour associated epilepsy.
      ,
      • You G.
      • Sha Z.
      • Jiang T.
      The pathogenesis of tumor-related epilepsy and its implications for clinical treatment.
      ]. As there is a high degree of uncertainty on how effective antiepileptic drugs are for brain tumors, choices are often made based on the interaction and side effect profile [
      • van Breemen M.S.
      • Wilms E.B.
      • Vecht C.J.
      Epilepsy in patients with brain tumours: epidemiology, mechanisms, and management.
      ,
      • Beaumont A.
      • Whittle I.R.
      The pathogenesis of tumour associated epilepsy.
      ,
      • You G.
      • Sha Z.
      • Jiang T.
      The pathogenesis of tumor-related epilepsy and its implications for clinical treatment.
      ]. Classical antiepileptic drugs such as phenobarbital, phenytoin, or carbamazepine should be avoided as they may alter the metabolism of chemotherapeutic agents [
      • Dastgir J.
      • Dabscheck G.
      • Ullrich N.
      Neuro-oncology and neurocutaneous syndromes.
      ]. Newer drugs such as valproate, lamotrigine, topiramate, zonisamide, and levetiracetam may be the preferred drug treatment in patients with tumors because of their limited interaction with chemotherapy [
      • van Breemen M.S.
      • Wilms E.B.
      • Vecht C.J.
      Epilepsy in patients with brain tumours: epidemiology, mechanisms, and management.
      ,
      • Dastgir J.
      • Dabscheck G.
      • Ullrich N.
      Neuro-oncology and neurocutaneous syndromes.
      ]. In addition, valproate has some inherent antitumor effects through inhibition of histone deacetylase [
      • Eyal S.
      • Yagen B.
      • Sobol E.
      • Altschuler Y.
      • Shmuel M.
      • Bialer M.
      The activity of antiepileptic drugs as histone deacetylase inhibitors.
      ]. Apart from the modifications that antiepileptic drugs cause on chemotherapeutic agents levels, several chemotherapeutic agents can modify the levels of antiepileptic drugs (Table 2) [
      • Vecht C.J.
      • Wagner G.L.
      • Wilms E.B.
      Interactions between antiepileptic and chemotherapeutic drugs.
      ]. A practical approach to the treatment of seizures in brain tumor is suggested in Fig. 3 [
      • van Breemen M.S.
      • Wilms E.B.
      • Vecht C.J.
      Epilepsy in patients with brain tumours: epidemiology, mechanisms, and management.
      ,
      • Dastgir J.
      • Dabscheck G.
      • Ullrich N.
      Neuro-oncology and neurocutaneous syndromes.
      ,

      Drappatz J, Wen P, Avila E. Seizures in patients with primary and metastatic brain tumors. Uptodate. http://www.uptodate.com/contents/seizures-in-patients-with-primary-and-metastatic-brain-tumors [accessed 23.11.16].

      ].
      Table 2Main pharmacokinetic interaction between antiepileptic drugs and chemotherapeutic drugs
      • Vecht C.J.
      • Wagner G.L.
      • Wilms E.B.
      Interactions between antiepileptic and chemotherapeutic drugs.
      .
      Effect of antiepileptic drugs on chemotherapeutic agents
      Main AEDs that cause lower levels of chemotherapeutic agentsPhenobarbital, phenytoin, carbamazepine
      Main AEDs that cause increased levels of chemotherapeutic agentsValproate
      Effect of chemotherapeutic agents on antiepileptic drugs
      Main chemotherapeutic agents that lower levels of phenytoinNitrosureas, cisplatin, etoposide, carmustine, dacarbazine, carboplatin, vinblastine, methotrexate, bleomycin, dexamethasone
      Main chemotherapeutic agents that lower levels of carbamazepineCisplatin, adriamycine
      Main chemotherapeutic agents that lower levels of valproateMethotrexate, cisplatin, adriamycine
      Main chemotherapeutic agents that increase levels of phenytoinDexamethasone, 5-fluorouracil, tegafur, tamoxifen
      Fig. 3
      Fig. 3Suggested practical approach to the management of seizures in pediatric brain tumors [
      • van Breemen M.S.
      • Wilms E.B.
      • Vecht C.J.
      Epilepsy in patients with brain tumours: epidemiology, mechanisms, and management.
      ,
      • Dastgir J.
      • Dabscheck G.
      • Ullrich N.
      Neuro-oncology and neurocutaneous syndromes.
      ,

      Drappatz J, Wen P, Avila E. Seizures in patients with primary and metastatic brain tumors. Uptodate. http://www.uptodate.com/contents/seizures-in-patients-with-primary-and-metastatic-brain-tumors [accessed 23.11.16].

      ].

      9. Conclusions

      Seizures are a common presentation of pediatric brain tumors, especially in supratentorial tumors with involvement of the gray matter, and in certain histologies such as DNET, ganglioglioma, and oligodendroglioma. As there is a high degree of uncertainty on how effective antiepileptic drugs are for seizures caused by brain tumors, choices are often driven by interactions and side effect profile. Classic antiepileptic drugs – phenobarbital, phenytoin, or carbamazepine – should be avoided as they may alter the metabolism of chemotherapeutic agents. Newer drugs – valproate, lamotrigine, topiramate, zonisamide, and levetiracetam – may be the preferred option in patients with tumors because of their limited interaction with chemotherapy.

      Conflict of interest statement

      The authors report no potential conflicts of interest.

      Acknowledgments

      Iván Sánchez Fernández is funded by a grant for the study of Epileptic Encephalopathies from “Fundación Alfonso Martín Escudero” and by the HHV6 Foundation . Tobias Loddenkemper serves on the Laboratory Accreditation Board for Long Term (Epilepsy and Intensive Care Unit) Monitoring, on the Council (and as 2nd Vice President) of the American Clinical Neurophysiology Society, on the American Board of Clinical Neurophysiology, as an Associate Editor for Seizure, and as an Associate Editor for Wyllie’s Treatment of Epilepsy 6th edition. He is part of pending patent applications to detect and predict seizures and to diagnose epilepsy. He receives research support from the Epilepsy Research Fund, the American Epilepsy Society, the Epilepsy Foundation of America, the Epilepsy Therapy Project, PCORI, the Pediatric Epilepsy Research Foundation, CURE, HHV-6 Foundation, and received research grants from Lundbeck, Eisai, Upsher-Smith, Acorda, and Pfizer. He serves as a consultant for Zogenix, Upsher Smith and Lundbeck. He performs video electroencephalogram long-term and ICU monitoring, electroencephalograms, and other electrophysiological studies at Boston Children’s Hospital and affiliated hospitals and bills for these procedures and he evaluates pediatric neurology patients and bills for clinical care. He has received speaker honorariums from national societies including the AAN, AES and ACNS, and for grand rounds at various academic centers. His wife, Dr. Karen Stannard, is a pediatric neurologist and she performs video electroencephalogram long-term and ICU monitoring, electroencephalograms, and other electrophysiological studies and bills for these procedures and she evaluates pediatric neurology patients and bills for clinical care.

      References

        • A.W. Group
        • CCM
        • A.W. Group
        Italian cancer figures, report 2012: cancer in children and adolescents.
        Epidemiol Prev. 2013; 37: 1-225
        • Karim-Kos H.E.
        • Hackl M.
        • Mann G.
        • Urban C.
        • Woehrer A.
        • Slavc I.
        • et al.
        Trends in incidence, survival and mortality of childhood and adolescent cancer in Austria, 1994-2011.
        Cancer Epidemiol. 2016; 42: 72-81
        • Ostrom Q.T.
        • Gittleman H.
        • Fulop J.
        • Liu M.
        • Blanda R.
        • Kromer C.
        • et al.
        CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2008-2012.
        Neuro Oncol. 2015; 17: iv1-iv62
        • Ward E.
        • DeSantis C.
        • Robbins A.
        • Kohler B.
        • Jemal A.
        Childhood and adolescent cancer statistics, 2014.
        CA Cancer J Clin. 2014; 64: 83-103
        • de Blank P.M.
        • Ostrom Q.T.
        • Rouse C.
        • Wolinsky Y.
        • Kruchko C.
        • Salcido J.
        • et al.
        Years of life lived with disease and years of potential life lost in children who die of cancer in the United States, 2009.
        Cancer Med. 2015; 4: 608-619
        • Pollack I.F.
        • Jakacki R.I.
        Childhood brain tumors: epidemiology, current management and future directions.
        Nat Rev Neurol. 2011; 7: 495-506
        • Ullrich N.J.
        • Pomeroy S.L.
        • Kapur K.
        • Manley P.E.
        • Goumnerova L.C.
        • Loddenkemper T.
        Incidence, risk factors, and longitudinal outcome of seizures in long-term survivors of pediatric brain tumors.
        Epilepsia. 2015; 56: 1599-1604
        • Wilne S.
        • Collier J.
        • Kennedy C.
        • Koller K.
        • Grundy R.
        • Walker D.
        Presentation of childhood CNS tumours: a systematic review and meta-analysis.
        Lancet Oncol. 2007; 8: 685-695
        • Linabery A.M.
        • Ross J.A.
        Trends in childhood cancer incidence in the U.S. (1992-2004).
        Cancer. 2008; 112: 416-432
        • Baytan B.
        • Evim M.S.
        • Guler S.
        • Gunes A.M.
        • Okan M.
        Acute central nervous system complications in pediatric acute lymphoblastic leukemia.
        Pediatr Neurol. 2015; 53: 312-318
        • Luyken C.
        • Blumcke I.
        • Fimmers R.
        • Urbach H.
        • Elger C.E.
        • Wiestler O.D.
        • et al.
        The spectrum of long-term epilepsy-associated tumors: long-term seizure and tumor outcome and neurosurgical aspects.
        Epilepsia. 2003; 44: 822-830
        • 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
        • Lote K.
        • Stenwig A.E.
        • Skullerud K.
        • Hirschberg H.
        Prevalence and prognostic significance of epilepsy in patients with gliomas.
        Eur J Cancer. 1998; 34: 98-102
        • 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: 86-91
        • 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: 803-820
        • Crawford J.
        Childhood brain tumors.
        Pediatr Rev. 2013; 34: 63-78
        • Holthausen H.
        • Blumcke I.
        Epilepsy-associated tumours: what epileptologists should know about neuropathology, terminology, and classification systems.
        Epileptic Disord. 2016; 18: 240-251
        • Dastgir J.
        • Dabscheck G.
        • Ullrich N.
        Neuro-oncology and neurocutaneous syndromes.
        in: Sims K. Peters J. Musolino P. Zelime Elibol M. Handbook of pediatric neurology. Lippincott Williams & Wilkins, Wolters Kluwer, Philadelphia2014
        • Hu W.H.
        • Ge M.
        • Zhang K.
        • Meng F.G.
        • Zhang J.G.
        Seizure outcome with surgical management of epileptogenic ganglioglioma: a study of 55 patients.
        Acta Neurochir (Wien). 2012; 154: 855-861
        • Krouwer H.G.
        • Davis R.L.
        • McDermott M.W.
        • Hoshino T.
        • Prados M.D.
        Gangliogliomas: a clinicopathological study of 25 cases and review of the literature.
        J Neurooncol. 1993; 17: 139-154
        • Ogiwara H.
        • Nordli D.R.
        • DiPatri A.J.
        • Alden T.D.
        • Bowman R.M.
        • Tomita T.
        Pediatric epileptogenic gangliogliomas: seizure outcome and surgical results.
        J Neurosurg Pediatr. 2010; 5: 271-276
        • Haydon D.H.
        • Dahiya S.
        • Smyth M.D.
        • Limbrick D.D.
        • Leonard J.R.
        Greater extent of resection improves ganglioglioma recurrence-free survival in children: a volumetric analysis.
        Neurosurgery. 2014; 75: 37-42
        • Rickert C.H.
        • Paulus W.
        Epidemiology of central nervous system tumors in childhood and adolescence based on the new WHO classification.
        Childs Nerv Syst. 2001; 17: 503-511
        • Nolan M.A.
        • Sakuta R.
        • Chuang N.
        • Otsubo H.
        • Rutka J.T.
        • Snead 3rd, O.C.
        • et al.
        Dysembryoplastic neuroepithelial tumors in childhood: long-term outcome and prognostic features.
        Neurology. 2004; 62: 2270-2276
        • Pollack I.F.
        Brain tumors in children.
        N Engl J Med. 1994; 331: 1500-1507
        • Burkhard C.
        • Di Patre P.L.
        • Schuler D.
        • Schuler G.
        • Yasargil M.G.
        • Yonekawa Y.
        • et al.
        A population-based study of the incidence and survival rates in patients with pilocytic astrocytoma.
        J Neurosurg. 2003; 98: 1170-1174
        • Sadighi Z.
        • Slopis J.
        Pilocytic astrocytoma: a disease with evolving molecular heterogeneity.
        J Child Neurol. 2013; 28: 625-632
        • Massimino M.
        • Biassoni V.
        • Gandola L.
        • Garrè M.L.
        • Gatta G.
        • Giangaspero F.
        • et al.
        Childhood medulloblastoma.
        Crit Rev Oncol Hematol. 2016; 105 (Review. PMID: 27375228): 35-51https://doi.org/10.1016/j.critrevonc.2016.05.012
        • Perilongo G.
        • Massimino M.
        • Sotti G.
        • Belfontali T.
        • Masiero L.
        • Rigobello L.
        • et al.
        Analyses of prognostic factors in a retrospective review of 92 children with ependymoma: Italian Pediatric Neuro-oncology Group.
        Med Pediatr Oncol. 1997; 29: 79-85
        • Coons S.W.
        • Rekate H.L.
        • Prenger E.C.
        • Wang N.
        • Drees C.
        • Ng Y.T.
        • et al.
        The histopathology of hypothalamic hamartomas: study of 57 cases.
        J Neuropathol Exp Neurol. 2007; 66: 131-141
        • Bell G.S.
        • Sinha S.
        • Tisi J.
        • Stephani C.
        • Scott C.A.
        • Harkness W.F.
        • et al.
        Premature mortality in refractory partial epilepsy: does surgical treatment make a difference?.
        J Neurol Neurosurg Psychiatry. 2010; 81: 716-718
        • Holst A.G.
        • Winkel B.G.
        • Risgaard B.
        • Nielsen J.B.
        • Rasmussen P.V.
        • Haunso S.
        • et al.
        Epilepsy and risk of death and sudden unexpected death in the young: a nationwide study.
        Epilepsia. 2013; 54: 1613-1620
        • Nashef L.
        • Fish D.R.
        • Sander J.W.
        • Shorvon S.D.
        Incidence of sudden unexpected death in an adult outpatient cohort with epilepsy at a tertiary referral centre.
        J Neurol Neurosurg Psychiatry. 1995; 58: 462-464
        • Khajavi K.
        • Comair Y.G.
        • Wyllie E.
        • Palmer J.
        • Morris H.H.
        • Hahn J.F.
        Surgical management of pediatric tumor-associated epilepsy.
        J Child Neurol. 1999; 14: 15-25
        • Preuss M.
        • Preiss S.
        • Syrbe S.
        • Nestler U.
        • Fischer L.
        • Merkenschlager A.
        • et al.
        Signs and symptoms of pediatric brain tumors and diagnostic value of preoperative EEG.
        Childs Nerv Syst. 2015; 31: 2051-2054
      1. MacDonald T, Packer R. Pediatric astrocytoma clinical presentation. Medscape. http://emedicine.medscape.com/article/985927-clinical [accessed 23.11.16].

        • Walker M.D.
        • Green S.B.
        • Byar D.P.
        • Alexander Jr., E.
        • Batzdorf U.
        • Brooks W.H.
        • et al.
        Randomized comparisons of radiotherapy and nitrosoureas for the treatment of malignant glioma after surgery.
        N Engl J Med. 1980; 303: 1323-1329
        • Beaumont A.
        • Whittle I.R.
        The pathogenesis of tumour associated epilepsy.
        Acta Neurochir (Wien). 2000; 142: 1-15
        • Rossetti A.O.
        • Stupp R.
        Epilepsy in brain tumor patients.
        Curr Opin Neurol. 2010; 23: 603-609
        • Gilles F.H.
        • Sobel E.
        • Leviton A.
        • Hedley-Whyte E.T.
        • Tavare C.J.
        • Adelman L.S.
        • et al.
        Epidemiology of seizures in children with brain tumors. The Childhood Brain Tumor Consortium.
        J Neurooncol. 1992; 12: 53-68
        • Daumas-Duport C.
        • Scheithauer B.W.
        • Chodkiewicz J.P.
        • Laws Jr., E.R.
        • Vedrenne C.
        Dysembryoplastic neuroepithelial tumor: a surgically curable tumor of young patients with intractable partial seizures. Report of thirty-nine cases.
        Neurosurgery. 1988; 23: 545-556
        • Honavar M.
        • Janota I.
        • Polkey C.E.
        Histological heterogeneity of dysembryoplastic neuroepithelial tumour: identification and differential diagnosis in a series of 74 cases.
        Histopathology. 1999; 34: 342-356
        • Sharma M.C.
        • Jain D.
        • Gupta A.
        • Sarkar C.
        • Suri V.
        • Garg A.
        • et al.
        Dysembryoplastic neuroepithelial tumor: a clinicopathological study of 32 cases.
        Neurosurg Rev. 2009; 32 (Discussion 169-170): 161-169
        • Ranger A.
        • Diosy D.
        Seizures in children with dysembryoplastic neuroepithelial tumors of the brain—a review of surgical outcomes across several studies.
        Childs Nerv Syst. 2015; 31: 847-855
        • Chan C.H.
        • Bittar R.G.
        • Davis G.A.
        • Kalnins R.M.
        • Fabinyi G.C.
        Long-term seizure outcome following surgery for dysembryoplastic neuroepithelial tumor.
        J Neurosurg. 2006; 104: 62-69
        • Fallah A.
        • Weil A.G.
        • Sur S.
        • Miller I.
        • Jayakar P.
        • Morrison G.
        • et al.
        Epilepsy surgery related to pediatric brain tumors: Miami Children’s Hospital experience.
        J Neurosurg Pediatr. 2015; 16: 675-680
        • Gelinas J.N.
        • Battison A.W.
        • Smith S.
        • Connolly M.B.
        • Steinbok P.
        Electrocorticography and seizure outcomes in children with lesional epilepsy.
        Childs Nerv Syst. 2011; 27: 381-390
        • Kameyama S.
        • Fukuda M.
        • Tomikawa M.
        • Morota N.
        • Oishi M.
        • Wachi M.
        • et al.
        Surgical strategy and outcomes for epileptic patients with focal cortical dysplasia or dysembryoplastic neuroepithelial tumor.
        Epilepsia. 2001; 42: 37-41
        • Creach K.M.
        • Rubin J.B.
        • Leonard J.R.
        • Limbrick D.D.
        • Smyth M.D.
        • Dacey R.
        • et al.
        Oligodendrogliomas in children.
        J Neurooncol. 2012; 106: 377-382
        • Lebrun C.
        • Fontaine D.
        • Ramaioli A.
        • Vandenbos F.
        • Chanalet S.
        • Lonjon M.
        • et al.
        Long-term outcome of oligodendrogliomas.
        Neurology. 2004; 62: 1783-1787
        • Wu C.T.
        • Tsay P.K.
        • Jaing T.H.
        • Chen S.H.
        • Tseng C.K.
        • Jung S.M.
        Oligodendrogliomas in children: clinical experiences with 20 patients.
        J Pediatr Hematol Oncol. 2016; 8 (PMID: 27299589): 555-558https://doi.org/10.1097/MPH.0000000000000610
        • Wang K.C.
        • Chi J.G.
        • Cho B.K.
        Oligodendroglioma in childhood.
        J Korean Med Sci. 1993; 8: 110-116
        • Brandberg G.
        • Raininko R.
        • Eeg-Olofsson O.
        Hypothalamic hamartoma with gelastic seizures in Swedish children and adolescents.
        Eur J Paediatr Neurol. 2004; 8: 35-44
        • Harvey A.S.
        • Freeman J.L.
        Epilepsy in hypothalamic hamartoma: clinical and EEG features.
        Semin Pediatr Neurol. 2007; 14: 60-64
        • Blumberg J.
        • Sánchez Fernández I.
        • Vendrame M.
        • Oehl B.
        • Tatum W.O.
        • Schuele S.
        • et al.
        Dacrystic seizures: demographic, semiologic, and etiologic insights from a multicenter study in long-term video-EEG monitoring units.
        Epilepsia. 2012; 53: 1810-1819
        • Cerullo A.
        • Tinuper P.
        • Provini F.
        • Contin M.
        • Rosati A.
        • Marini C.
        • et al.
        Autonomic and hormonal ictal changes in gelastic seizures from hypothalamic hamartomas.
        Electroencephalogr Clin Neurophysiol. 1998; 107: 317-322
        • Berkovic S.F.
        • Andermann F.
        • Melanson D.
        • Ethier R.E.
        • Feindel W.
        • Gloor P.
        Hypothalamic hamartomas and ictal laughter: evolution of a characteristic epileptic syndrome and diagnostic value of magnetic resonance imaging.
        Ann Neurol. 1988; 23: 429-439
        • Striano S.
        • Santulli L.
        • Ianniciello M.
        • Ferretti M.
        • Romanelli P.
        • Striano P.
        The gelastic seizures-hypothalamic hamartoma syndrome: facts, hypotheses, and perspectives.
        Epilepsy Behav. 2012; 24: 7-13
        • Suki D.
        • Khoury Abdulla R.
        • Ding M.
        • Khatua S.
        • Sawaya R.
        Brain metastases in patients diagnosed with a solid primary cancer during childhood: experience from a single referral cancer center.
        J Neurosurg Pediatr. 2014; 14: 372-385
        • Wiens A.L.
        • Hattab E.M.
        The pathological spectrum of solid CNS metastases in the pediatric population.
        J Neurosurg Pediatr. 2014; 14: 129-135
        • Maytal J.
        • Grossman R.
        • Yusuf F.H.
        • Shende A.C.
        • Karayalycin G.
        • Lanzkowsky P.
        • et al.
        Prognosis and treatment of seizures in children with acute lymphoblastic leukemia.
        Epilepsia. 1995; 36: 831-836
        • Ochs J.J.
        • Bowman W.P.
        • Pui C.H.
        • Abromowitch M.
        • Mason C.
        • Simone J.V.
        Seizures in childhood lymphoblastic leukaemia patients.
        Lancet. 1984; 2: 1422-1424
        • Ochs J.J.
        Neurotoxicity due to central nervous system therapy for childhood leukemia.
        Am J Pediatr Hematol Oncol. 1989; 11: 93-105
        • Packer R.J.
        • Meadows A.T.
        • Rorke L.B.
        • Goldwein J.L.
        • D’Angio G.
        Long-term sequelae of cancer treatment on the central nervous system in childhood.
        Med Pediatr Oncol. 1987; 15: 241-253
        • Singh G.
        • Rees J.H.
        • Sander J.W.
        Seizures and epilepsy in oncological practice: causes, course, mechanisms and treatment.
        J Neurol Neurosurg Psychiatry. 2007; 78: 342-349