Seizure 44 (2017) 93–97

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Seizure
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Review

Epilepsy-related brain tumors

Özdem Ertürk Çetina, Cihan _Işlerb, Mustafa Uzanb, Çiğdem Özkaraa,*
a
Istanbul University, Cerrahpasa Faculty of Medicine, Department of Neurology, 34098, Fatih, Istanbul, Turkey
b
Istanbul University, Cerrahpasa Faculty of Medicine, Department of Neurosurgery, Istanbul, Turkey

ARTICLEINFO ABSTRACT

Article history:
Received 15 September 2016 Seizures are among the most common presentations of brain tumors. Several tumor types can cause
Received in revised form 16 December 2016 seizures in varying rates; neuroglial tumors and the gliomas are the most common ones. Brain tumors are
Accepted 16 December 2016 the second most common cause of focal intractable epilepsy in epilepsy surgery series, with the highest
frequency being dysembryoplastic neuroepithelial tumors and gangliogliomas. Seizure management is
Keywords: an important part of the treatment of patients with brain tumors. This review discusses clinical features
Epilepsy and management of seizures in patients with brain tumors, including, neuroglial tumors, gliomas,
Brain tumors
meningioma and metastases; with the help of recent literature data. Tumor -related seizures are focal
Neuroglial tumors
seizures with or without secondary generalization. Seizures may occur either as initial symptom or
Gliomas
Glioblastoma
during the course of the disease. Brain tumors related epilepsy tends to be resistant to antiepileptic drugs
Meningioma and treatment of tumor is main step also for the seizure treatment. Early surgery and extent of the tumor
Surgery removal are important factors for achieving seizure freedom particularly in neuroglial tumors and low
grade gliomas. During selection of the appropriate antiepileptic drug, the general approach to partial
epilepsies can be followed. There are several factors influencing epileptogenesis in brain tumor-related
epilepsy which also explains clinical heterogeneity of epilepsy among tumor types. Identification of
molecular markers may guide future therapeutic approaches and further studies are needed to prove
antitumor effects of different antiepileptic drugs.
© 2016 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.

1. Introduction
Seizures are among the most common presentations of brain
tumors. The frequency of epilepsy in patients with brain tumors
ranges from 30 to 100% depending on tumor type [1]. Although any
type of tumor can cause a seizure, neuroglial tumors, and gliomas
are the most common ones. Dysembryoplastic neuroepithelial
tumors (DNETs), gangliogliomas (GGs), low-grade glial tumors,
glioblastomas, metastases, leptomeningeal tumors and primary
CNS lymphomas are associated with seizures in varying rates [1].
Tumor-related seizures are symptomatic by nature; they are focal
with or without secondary generalization [2]. Semiologic charac-
teristics depend on the localization of the tumor. The course of the
clinical picture of epilepsy may differ according to the tumor type.
Seizures may occur either as an initial symptom, that leads to the
diagnosis of the tumor (seen in about 30–50% of patients); or
during the course of the disease (seen in 10–30% of patients) [1].
* Corresponding author. Tel.: +90 533 4685665; fax: +90 212 6330176.
E-mail addresses: cigdemoz@istanbul.edu.tr, cigdem.ozkara@gmail.com
(Ç. Özkara).
The seizure risk is influenced by type and location of tumor and the
number of the lesions [3]. Slow growing tumors, particularly
DNETs and gangliogliomas, are particularly epileptogenic and
associated with the highest risk for seizures [2,4,5]. High-grade
tumors have relatively lower rates of seizures. The location of the
tumor is also important, for instance, cortical tumors are
associated with a higher risk of causing seizures. Additionally,
frontal, temporal and parietal tumors are associated with a higher
risk of causing epilepsy than occipital tumors [2]. Multiple lesions
are associated with a higher risk compared to a solitary lesions [3].
Infratentorial tumors are rarely associated with epilepsy [1].
The treatment of patients with brain tumors requires a
multidisciplinary approach and clinical management varies
according to the type of tumor. Brain tumors related epilepsy is
usually refractory to medical treatment, and surgical or radiologi-
cal treatment of the underlying tumor (when possible) is the
mainstay of the treatment for the seizures [6]. Brain tumors are the
second most common cause of focal intractable epilepsy in
epilepsy surgery series, with the greatest proportion related to
DNETs and GGs [4].
In this paper, we will review the clinical features and
management of seizures in patients with brain tumors.

http://dx.doi.org/10.1016/j.seizure.2016.12.012
1059-1311/© 2016 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.
94 O. Ertürk Çetin et al. / Seizure 44 (2017) 93–97
2. Epidemiology and clinical characteristics
2.1. Neuroglial developmental tumors
DNETs and gangliogliomas compose a specific group of tumors
since they are highly epileptogenic developmental lesions
clinically characterized by early onset seizures [7]. Although the
population prevalence of DNETs and GGs is not high, they are
among the most common causes of intractable focal epilepsy [4,7].
Seizures are usually the first and the only symptom of the patients
with developmental tumors. The frequency of seizures reaches to
almost 100% with DNETs and 80–90% with GGs [1]. They are benign
tumors of neuroglial origin with a broad histopathological
spectrum [7]. Eighty percent of DNETs are located in the temporal
lobe, while extratemporal tumors constituting only about 20% of
all DNETs. The most frequent extratemporal location is frontal [8].
GGs are also mostly located in the temporal lobes [7,9,10]. Both
tumors have a benign course, therefore relapse and malignant
progression are very rare [7]. They are classified in the group of
‘low-grade epilepsy-associated tumors’ (LEAT) [11]. LEATs are a
specific group of tumors strongly associated with epilepsy. Their
characteristics include a slow growth rate, early-onset drug-
resistant epilepsy, neocortical localization and temporal lobe
predominance [5,11]. There are various tumors in this group,
however, the most common are DNETs and GGs. Following the
developments in the molecular genetics, the WHO introduced a
new classification based on a molecular genetic approach for some
tumor entities [12]. However, LEAT’s are still difficult to classify
because they lack a clear clinicopathological and molecular genetic
profile [11]. What is more, the MRI lesion may not match up with
the epileptogenic zone, which may lead to a need for complex
investigations with invasive EEG in some cases [7]. The mean age of
onset of DNET is about 15 years [8], of GGs it is 16–19 [10,13];
however, they may manifest also in young adults. The mean age at
surgery is around 30 for both types of the tumors [8,10]. Tumors
can be associated with focal cortical dysplasia, however, the impact
of focal cortical dysplasia on the epileptogenicity is still not clear.
Focal seizures with loss of awareness are the most common seizure
type associated with DNETs and GGs (seen in about 80% of cases)
[8,10]. Secondary generalized tonic–clonic seizures are seen in
about 50% of patients. One exception to the preponderance of focal
seizures is the histologically simple subtype of DNET, in which
secondarily generalized seizures are most common [8].
2.2. Low-grade gliomas (WHO grade II tumors)
Low-grade gliomas (astrocytoma, oligodendroglioma, oligoas-
trocytoma) are also associated with a high incidence of seizures.
The overall proportion of patients with these tumors who develop
seizures varies between 65–90% [9,14–16]. A seizure is the most
common presenting symptom, however, patients may also begin to
develop seizures later in the course of the disease [1,9]. These
tumors are usually diagnosed between the ages 30–45 [15,16]. An
age of under 38 years and cortical involvement by these tumors
have been identified as risk factors for seizures in patients with
these tumors [16]. A location of the tumor close to functional areas
makes it more likely to seizures to be present at diagnosis [15].
Contrary to neuroglial tumors, low-grade glial tumors more
frequently involve extratemporal lobes with the highest frequency
in frontal lobes. If the tumor involves the temporal lobe, it usually
extends into the insula [9,15–17]. Seizures are mostly secondarily
generalized [16]. Seizures as the only presenting symptom of the
tumor suggest a favorable prognosis [17,18]. They may allow
tumors to be diagnosed in at an earlier stage when the tumor is
small enough and there is a higher chance of complete resection.
Despite AEDs, 50% of the patients may be drug-resistant
preoperatively. Insular location, prolonged time to diagnosis,
and tumor within functional areas are factors associated with
medically refractory seizures [15,17].
2.3. High-grade gliomas (WHO grade III–IV)
High-grade gliomas include anaplastic astrocytomas (AAs) and
glioblastomas. Glioblastoma is the most common primary brain
tumor in adults. The mean age at diagnosis is 60 years [19]. The
overall proportion of patients with these tumors in which seizures
are diagnosed has been reported as ranging from 40 to 62%
[1,19,20]. Twenty-two percent of patients with these tumors had
their first seizures after surgery [20]. Both focal and generalized
seizures are observed during the course of glioblastoma. About 38%
of patients have partial seizures, whereas 41% develop partial
seizures with secondary generalization. Status epilepticus (SE)
may also be observed in 12% of patients [19]. A frontal and
temporal location are more frequent in glioblastoma and more
commonly associated with seizures [20]. Another study reported
status epilepticus (SE) in 12% of their study group consisting of
patients with primary tumors. SE was seen most commonly in
those with glioblastoma, the most frequent tumor location in those
with SE was frontal or fronto-temporal [6]. Prophylactic AEDs do
not reduce the incidence of epilepsy postoperatively, however,
patients not receiving AEDs after surgery had a higher incidence of
SE [20].
2.4. Meningioma
Although most meningiomas are silent and benign; meningio-
mas may become symptomatic depending on the size and location
of the tumor. Seizures are one of the most common manifestations
of symptomatic meningiomas apart from headache and neurolog-
ical deficits [21]. Surgical excision is the first choice of treatment
for symptomatic intracranial meningiomas. The incidence of a
preoperative seizure in patients with meningiomas is about 26–
31% [21–23]. It is greater in older patients. The most common age
at diagnosis of meningiomas subsequently treated with surgery is
50–60 years. The location of the tumor affects the seizure risk.
Supratentorial meningiomas, mainly convexity and parasagittal,
and peritumoral edema have been found to be associated with the
greatest risk of seizures [22,23]. Seizure freedom may be
achieved in about 60–70% of meningioma patients with epilepsy
[21,23]. Risk factors for postoperative seizures include the
presence of epilepsy before surgery, major surgical
complications, epileptiform EEG activity, younger age and tumor
progression. Therefore it has been suggested that EEG should be a
part of the postoperative evaluation. This can contribute to a score
based on the identified risk factors which may guide antiepileptic
treatment postoperatively [21]. About 12–19% of meningioma
patients without preoperative seizures may suffer from seizures
after surgery [21].
During the selection of an appropriate anticonvulsant drug for
meningioma patients, general principles for focal epilepsy should
be followed. In contrast to malignant tumors, drug interactions are
rarely the case in meningiomas.
2.5. Metastases
Brain metastases develop about 20% of patients with systemic
cancer [24]. Parenchymal and leptomeningeal metastases may
lead to seizures. About 35% of patients with metastases have
seizures, 20% being as the initial symptom [1,25,26]. In some cases
where the seizure is the first symptom, cancer is diagnosed
subsequently. The mean age of patients with metastases is about
70 years [25]. Although the commonest cause of seizures in
 O. Ertürk Çetin et al. / Seizure 44 (2017) 93–97
patients with cancer is brain metastases; it should be born in mind
that there may be other reasons for seizures associated with cancer
such as electrolyte imbalances, chemotherapeutics, or paraneo-
plastic syndromes [24]. A seizure as the initial symptom is
significantly more common in patients with primary CNS neo-
plasms than metastases. This may be explained by the less
infiltrative growth pattern of brain metastases as well as their
inability biochemically to modulate neuronal excitability [24].
Primary CNS lymphomas rarely cause seizures. They most
commonly develop in the white matter and are usually not
diagnosed because of an epileptic seizure [1,24].
Although patients with brain metastases may be prone to
seizures, prophylactic AED treatment is not recommended in those
who have not experienced seizures. However, in many centers,
physicians may prescribes AED even in the absence of a seizure
history [27].
3. Pathology and molecular markers
The pathogenesis of tumor-related epilepsy is multifactorial
and not fully understood [2,28,29]. Epileptogenesis by brain
tumors is influenced by many factors including tumor histology,
location, genetic factors, the integrity of the blood brain barrier and
changes in the peritumoral environment such as neurotransmitter
changes, ion concentrations and hypoxia [1,2,28,29]. Greater levels
of glutamate have been found in brain tumor samples of patients
with epilepsy associated with tumors compared to those with
nontumoral pathologies. Altered concentrations of GABA may also
contribute to tumor-associated epilepsy [28]. Among the molecu-
lar genetic factors, the PI3K- mTOR pathway seems to be involved
in epileptogenesis in neuroglial tumors in addition to its role in
tumor growth [30]. The mechanisms may vary among tumor types.
This may explain the difference in the frequency with which
particular tumors are associated with seizures [2].
Several molecular markers have been identified in brain tumors
in recent years. For instance, the clinical importance of isocitrate
dehydrogenase 1/2 (IDH1/2) mutations, 1p/19q codeletion and
MGMT promoter methylation for the patient’s prognosis have been
confirmed in many studies [31]. However, biological markers may
also play a role in the development of seizures, and there are many
studies looking for an association between biological markers and
the risk of seizures in tumor-related epilepsies.
IDH 1/2 mutations are common in diffuse low-grade gliomas
and have been found to be associated with seizures as the initial
symptom [30,32]. Skardelly et al. also demonstrated that IDH
mutation is a predictor of epileptogenicity and that different
seizures rates within glioma subgroups are associated with
differences in the prevalence of IDH mutations [26]. However, a
recent large study did not confirm the relation between molecular
markers (1p19q codeletion, p53 expression and isocitrate dehy-
drogenase 1 expression) and seizure in low-grade gliomas [15].
BRAF V600E mutations have been identified in glioneuronal
tumors and their expression has been found to be associated with a
worse postoperative seizure outcome [33].
A number of molecular genetic markers has been identified as
being associated with the seizure risk in patients with gliomas. The
overexpression of nuclear protein Ki-67 was found to be a poor
prognostic factor for seizure control in low-grade glioma patients
[9,16]. Another study suggested that high RINT1 expression may
represent a risk factor for low-grade glioma (LGG) -related seizures
andmaybeassociatedwithseizureoutcomes[34]. Lowexpressionof
very large G-protein-coupled receptor-1 (VLGR) 1 [35] and
dysregulation of miR-128 expression has also been found to be
associated with epilepsy in low-gradegliomas[36]. A recent studyof
patients with anaplastic gliomas found low Ki-67 expression and
EGFR amplification to be correlated with preoperative seizures [37].
95
4. The role of EEG
All patients with a first seizure should undergo an MRI at the
time of presentation which may show focal lesions such as tumors.
Electroencephalography (EEG) also plays a role in the evaluation.
EEG may help to localize the epileptogenic focus, to determine the
patients who are at risk for recurrent seizures and guide decision
regarding the need for antiepileptic drug therapy [25].
Intraoperative EEG is performed in some centers. However, in
their review, Englot et al. found no significant difference in terms of
seizure outcome between patients with glioneuronal tumors and
LGG with and without intraoperative EEG [38,39]. However, they
emphasize that electrocorticography may have been carried out in
more severe cases of epilepsy which may have confounded results.
Invasive EEG recordings are used in about 10% of patients
undergoing epilepsy surgery for tumor-related epilepsy. In
extratemporal lobe epilepsy, invasive EEG is only needed when
the lesion is close to eloquent cortex [40]. In this case it can help to
confine the surgical resection by defining functional borders.
In the case of lesions in the non-dominant temporal lobe with a
long duration of epilepsy characterized by frequent and disabling
seizures, mesial structures should also be resected if they are
involved or in close relation with the tumor. If the lesions is located
in the dominant temporal lobe, if the mesial structures are not
involved and properly functioning they should not be included in
resection. Otherwise mesial structures should also be resected to
optimise seizure outcome. In patients with temporal lobe tumor-
related epilepsy patients invasive EEG may only be carried out
when the initial resection has failed to control seizures [40].
Another study performed two stage surgery with intracranial
EEG before tumor surgery to improve seizure outcomes in patients
with primary brain tumors. They included 11 patients with
glioneuronal, LGG and noninfiltrative tumors and found better
seizure outcomes in patients with resection of the tumor and the
seizure onset zone determined by intracranial EEG [41]. This
approach may be preferred for some developmental tumors and
LGG. Prospective investigations are needed to determine the role of
intraoperative or invasive EEG on seizure outcomes of tumor-
related epilepsy.
A recent study on meningiomas attributed a significant role to
the EEG because it found that epileptiform abnormalities on
postoperative EEG were associated with an increased risk of
postoperative seizures [21].
5. Treatment of brain tumor-related epilepsy
In brain tumor-related epilepsy, control of epilepsy depends on
the successful treatment of the tumor [24]. In addition to surgical
resection and antiepileptic drugs, radiotherapy and chemotherapy
may also play a role in the management of brain tumor-related
epilepsy.
5.1. Surgical treatment and prognostic factors
Patients with glioneuronal tumors have long survivals and
seizures tend to be refractory. Therefore seizure control is critical in
the clinical management of glioneuronal tumors in terms of
improving patients’ quality of life [39]. This means that surgery is
the treatment of choice for DNETs and GGs. The rates of seizure
freedom following DNET surgery differ between studies but
usually range from 68 to 83% [8,39]. These rates are similar for
GGs (70–85%) [10,39,42]. A shorter duration of epilepsy (less than
1 year) and gross total resection are the most important factors for
achieving seizure freedom [39]. In addition, preoperative second-
arily generalized seizures have been found to be associated with
less favorable outcomes. No significant difference was found in
96 O. Ertürk Çetin et al. / Seizure 44 (2017) 93–97
outcomes between temporal versus extratemporal tumors, medi-
cally controlled versus refractory seizures [39]. Early surgery can
produce seizure freedom and, considering the younger age of these
patients, has additional benefits in terms of avoidance of side
effects of the drugs during the development of younger brains.
Because malignant progression is rare in glioneuronal tumors;
there is no role of chemotherapy and radiotherapy. Invasive EEG
recordings may be helpful in some cases.
Resection of the tumor improves seizure control also in LGG.
Seizure freedom rates following LGG surgery range from 65 to 71%
[16,38]. Additionally, radiotherapy and chemotherapy alone or in
combination have beneficial effects on seizure control [17,18,30].
The most important predictor of seizure freedom is gross total
resection [15,38]. Duration of seizures (less than 1 year), preoper-
ative seizure control and control with antiepileptic medication are
other influencing factors. Patients with simple partial seizures had
a lower chance of achieving good seizure control [38]. Patients
with secondarily generalized seizures and calcification on MRI,
with gross total resection have better outcomes [16]. Following
treatment of the tumor; a history of preoperative epilepsy and
parietal and insular locations have been found to be associated
with unfavorable seizure outcomes [15].
Glioblastoma is an aggressive tumor. Standard treatment
involves tumor resection followed by external beam radiation
therapy (RT) with concomitant and adjuvant chemotherapy [43].
Seizure freedom rates following resection of glioblastoma are
around 77% [18,21]. Seizure recurrence is generally associated with
progression of the glioblastoma, however, this association is not so
clear for low-grade gliomas [18].
5.2. Antiepileptic treatment
Antiepileptic treatment is an essential part of the seizure
control. Prophylactic use of an antiepileptic drug in patients with
brain tumors with no history of seizures is not recommended [44].
However, AEDs may be initiated following a first seizure related to
a tumor. Seizures in brain tumors are partial onset seizures with or
without secondary generalization. The general approach to partial
epilepsies can be followed during decision of the appropriate drug.
However, enzyme-inducing drugs such as carbamazepine and
phenytoin should be avoided particularly in glioblastoma patients
because of the risk of interaction with chemotherapeutics [19,30].
The potential antitumor effects of antiepileptic drugs have
attracted considerable attention in recent years. Valproic acid
(VPA) is most commonly discussed in this context. VPA has long
been used for seizures. This has led to an accumulation of
experience with this drug. Apart from providing seizure control,
VPA has been shown to improve the survival of patients with
glioblastoma in several studies and is therefore considered a good
option as a first line treatment for epilepsy in patients with
glioblastomas [19]. The risk of thrombocytopenia should be
considered during VPA use in combination with chemotherapy
[18]. However, a recent study which compared the effects of six
different AEDs on survival in glioblastoma patients found no
significant survival benefit either from treatment with AEDs for
epilepsy in general nor from the use of any particular drug [43].
Some studies highlight the importance of the dosing schedule and
target serum level of VPA while preferring it because of its
potential additional effects on survival [45].
Levetiracetam (LEV) is an efficient and well-tolerated AED [18].
An antitumor effect of LEV through O-6 methylguanine-DNA
methyltransferase (MGMT) has been suggested. Therefore a
beneficial effect of LEV on the survival of patients with
glioblastoma who receive temozolomide-based chemotherapy
has been hypothesized [46].
Recently, several centers also reported their good experience
with lacosamide [18,30].
Although there are several drug options, about 10–35% of
patients remain refractory [18].
In patients with no preoperative seizures who underwent
surgery, there is no evidence to suggest that one should continue
AEDs administered perioperatively to prevent acute symptomatic
seizures. They should be discontinued after the first postoperative
week [44]. However, clinical practices may differ among different
centers related to physicians preferences [27].
Patients with developmental tumors usually have a history of
seizures preoperatively. Following successful surgery AED with-
drawal can be considered. However, there is no consensus among
different centers about the timing of AED withdrawal [47], and
physicians’ practices vary in terms of AED withdrawal after
successful epilepsy surgery [48].
6. Conclusion
Seizures are among the common symptoms of brain tumors and
seizure control is an important part of the clinical management of
patients with brain tumors. Brain tumor-related epilepsy tends to
be resistant to antiepileptic drugs and the treatment of tumor is an
important means of achieving seizure control. There are several
factors influencing epileptogenesis in brain tumor-related epilepsy
which also explain the clinical heterogeneity of the epilepsies
associated with different tumor types. Identification of molecular
markers may guide future therapeutic approaches and further
studies are needed to prove the possible antitumor effects of
different antiepileptic drugs.
Conflict of interest statement
The authors declare that they have no conflict of interest
associated with the manuscript ‘Epilepsy-related brain tumors’.
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