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Division of Epilepsy and Clinical Neurophysiology, Department of Neurology, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USADepartment of Child Neurology, Hospital Sant Joan de Déu, Universidad de Barcelona, Spain
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.
Pediatric brain tumors are the most common cause of death in pediatric cancer.
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Seizures are one of the most common symptoms in pediatric brain tumors.
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Supratentorial brain tumors that involve gray matter are more epileptogenic.
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Dysembryoplastic neuroepithelial tumor and ganglioglioma are particularly epileptogenic.
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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.
]. 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 [
]. 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 [
] 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 [
]. 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 [
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 [
]. 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 [
]. 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 [
]. 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 [
]. 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 [
]. 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 [
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 [
]. 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 [
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 [
]. 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 [
]. 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%) [
]. 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 [
]. 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 [
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% [
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%) [
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).
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).
]. Most seizures were generalized/secondarily generalized (35%) or focal with dyscognitive features (34%), followed by unclassified seizure type (21%), and focal (10%) [
]. 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 [
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 [
]. 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 [
]. 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 [
]. 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 [
]. 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 [
]. 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.
Frequency
Location
Pathology
5-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
] 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 [
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%) [
]. 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 [
]. 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 [
]. 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 [
]. Pathologically, they consist of a mixture of neoplastic glial and neuronal elements: clusters of large ganglion-like neurons mixed with neoplastic astrocytes [
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.
Dysembrioplastic neuroepitelial tumors (DNETs) (Fig. 2) are rare, represent approximately 1% of pediatric brain tumors, and appear most frequently in older children [
]. 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 [
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.
]. 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 [
]. They appear in the cerebral hemispheres as large, heterogeneous masses, often with necrosis, cystic degeneration, calcification, and osseous erosion [
]. Their histology is similar but the prognosis is worse to that of the most frequent infratentorial primitive neuroectodermal tumor: the medulloblastoma [
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%) [
]. 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%) [
]. 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 [
]. They appear as a large gadolinium-enhanced mass in the fourth ventricle, frequently obstructing the cerebrospinal fluid flow and causing hydrocephalus [
]. 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 [
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 [
], in these patients chronic seizures – which have been estimated to increase mortality by a factor of approximately 5 – may increase their overall mortality [
]. 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%) [
]. 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 [
]. Classic studies showed an inverse relationship between tumor grade and duration of symptoms: the longer the time to diagnosis, the lower the grade [
]. In general, low-grade and well-differentiated astrocytomas have the highest incidence of seizures while high-grade astrocytomas are less likely to present seizures [
]. 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 [
]. 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.
]. The interictal EEG findings in gangliogliomas can be normal or show unilateral, bilaterally independent, bilaterally synchronous, or multifocal discharges [
]. 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 [
]. 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 [
]. Headache, papilledema, and other signs or symptoms of increased intracranial pressure are rare at presentation or later in the course of the disease [
]. The most common electro-clinical seizure type is focal with dyscognitive features, although secondarily generalized and primary generalized tonic–clonic seizures are also common [
]. 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 [
]. 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 [
]. In a series that included seven children with oligodendroglioma presenting with seizures all seven became seizure free after treatment and four discontinued antiepileptic medication [
]. 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 [
]. 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 [
]. 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 [
], 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 [
]. Over time other seizure types may appear: focal seizures with dyscognitive features, tonic seizures, atonic seizures, and generalized tonic–clonic seizures [
]. 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 [
]. 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 [
]. 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 [
]. When seizures are captured on EEG, the correlate is variable and includes focal or diffuse attenuation, fast activity, slow activity, or spike-wave complexes [
]. 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 [
]. 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 [
]. In particular, more common presenting symptoms for infratentorial tumors are headache, nausea and vomiting, abnormal gait, and abnormal ocular movements [
]. 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%) [
]. Among a series of 1135 pediatric brain tumors, only 26 (2.3%) were solid metastases, and most metastases were solitary (65%) and supratentorial (89%) [
]. 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 [
]. 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 [
]. 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 [
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 [
]. 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 [
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 [
]. 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 [
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 [
]. 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 [
]. 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 [
]. 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 [
The brain tissue around brain tumors – especially in gangliogliomas and DNETs – is characterized by cortical disorganization and, sometimes, frank focal cortical dysplasia [
]. Abnormal neuronal morphology, aberrant neuronal migration, and abnormal pattern of synapses may explain epileptogenicity in the peritumoral tissue [
]. If their buffering and support function is disrupted by brain tissue or peritumoral edema, the resultant dysfunction in neuronal excitability may lead to seizures [
]. 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 [
]. 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 [
]. 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 [
]. 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 [
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 [
]. 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 [
]. 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 [
] 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 [
], 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 [
Brain tumors in eloquent areas: a European multicenter survey of intraoperative mapping techniques, intraoperative seizures occurrence, and antiepileptic drug prophylaxis.
Neurosurg Rev.2016; ([Epub ahead of print] PMID: 27481498)
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 [
Practice parameter: anticonvulsant prophylaxis in patients with newly diagnosed brain tumors. Report of the Quality Standards Subcommittee of the American Academy of Neurology.
]: 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 [
] 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 [
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 [
]. 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 [
]. Classical antiepileptic drugs such as phenobarbital, phenytoin, or carbamazepine should be avoided as they may alter the metabolism of chemotherapeutic agents [
]. 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 [
]. Apart from the modifications that antiepileptic drugs cause on chemotherapeutic agents levels, several chemotherapeutic agents can modify the levels of antiepileptic drugs (Table 2) [
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.
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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).
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