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doi:10.
1093/brain/awr310
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BRAIN
A JOURNAL OF NEUROLOGY
REVIEW ARTICLE
Epilepsy in patients with a brain tumour: focal

epilepsy requires focused treatment
Marjolein de Groot,1,2 Jaap C. Reijneveld,1,3 Eleonora Aronica2,4 and Jan J. Heimans1
Department of Neurology, VU University Medical Center, PO Box 7057, 1007 MB Amsterdam, The Netherlands
Department of Neuropathology, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
Department of Neurology, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
Stichting Epilepsie Instellingen Nederland, Achterweg 5, 2103 SW Heemstede, The Netherlands
Correspondence to: Marjolein de Groot, MD,

Department of Neurology,
VU University Medical Center,
PO Box 7057, 1007 MB Amsterdam,
The Netherlands
E-mail: marjolein.degroot@vumc.nl
Brain tumours frequently cause epileptic seizures. Medical antiepileptic treatment is often met with limited success.
Pharmacoresistance, drug interactions and adverse events are common problems during treatment with antiepileptic drugs.
The unpredictability of epileptic seizures and the treatment-related problems deeply affect the quality of life of patients with
a brain tumour. In this review, we focus on both clinical and basic aspects of possible mechanisms in epileptogenesis in patients
with a brain tumour. We provide an overview of the factors that are involved in epileptogenesis, starting focally at the tumour
and the peritumoral tissue and eventually extending to alterations in functional connectivity throughout the brain. We correlate
this knowledge to the known mechanisms of antiepileptic drugs. We conclude that the underlying mechanisms of epileptogenesis in patients with a brain tumour are poorly understood. The currently available antiepileptic drugs have little to no influence
on the known epileptogenic mechanisms that could contribute to the poor efficacy. Better understanding of focal changes that
are involved in epileptogenesis may provide new tools for optimal treatment of both the seizures and the underlying tumour. In
our opinion, therapy for every patient with a brain tumour suffering from epilepsy should first and foremost aim at eliminating
the tumour as well as the epileptic focus through resection combined with postoperative treatment, and only if this strategy
does not result in adequate seizure control should medical antiepileptic treatment be intensified. If this strategy, however,
results in sustained seizure freedom, tapering of antiepileptic drugs should be considered in the long term.
Keywords: epilepsy; brain tumour; antiepileptic drugs; epileptogenesis

Abbreviation: GABA = -aminobutyric acid
Introduction
Brain tumours may arise from brain tissue (primary brain tumours,
e.g. astrocytic, oligodendroglial and glioneuronal tumours) or from
malignancies elsewhere in the body, e.g. lung cancer and melanoma (secondary brain tumours). Seizures are a frequent symptom
in patients with a brain tumour. The incidence varies between 30
and 100% and depends on the tumour type, with slow-growing

tumours being the most epileptogenic (van Breemen et al., 2007).
The impact of epilepsy on the total disease burden is high and
additionally, both epilepsy and the use of antiepileptic drugs predispose to deterioration of cognitive function (Klein et al., 2003),
already a major problem in patients with a brain tumour (Douw
et al., 2009; Hilverda et al., 2010).
Received June 23, 2011. Revised August 15, 2011. Accepted September 17, 2011. Advance Access publication December 13, 2011
The Author (2011). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved.
For Permissions, please email: journals.permissions@oup.com
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1
2
3
4
Epilepsy in patients with a brain tumour
Current state: treatment

of epilepsy
Efficacy of antiepileptic drugs in
patients with a brain tumour
Currently, the management of epilepsy in patients with a brain
tumour mainly relies on antiepileptic drug therapy. Antiepileptic
drugs can be divided into two groups: first generation drugs
(e.g. phenytoin, carbamazepine, valproic acid, ethosuximide,
benzodiazepines and barbiturates) and second generation drugs
(e.g. levetiracetam, felbamate, gabapentin, lamotrigine, pregabalin, tiagabin, zonisamide, oxcarbazepine and topiramate). The vast
majority of antiepileptic drugs are thought to modulate inhibitory
neurotransmission, in most cases voltage-gated ion channels.
These channels include sodium, calcium and potassium channels
(Table 1). Some antiepileptic drugs enable -aminobutyric acid
(GABA)ergic neurotransmission (e.g. benzodiazepines, barbiturates, felbamate and topiramate) and thereby enhance neuronal
inhibition. Other antiepileptic drugs enhance neuronal inhibition
by decreasing GABA metabolism (valproic acid), preventing
GABA reuptake (tiagabin) or increasing GABA synthesis (valproic
acid, gabapentin) (Meldrum and Rogawski, 2007; White et al.,
2007). Only two antiepileptic drugs (felbamate and topiramate)
modulate the excitatory neurotransmission by modulating glutamate receptors such as AMPA [(2-amino-3-(5-methyl-3-oxo-1,2oxazol-4-yl)propanoic acid)], N-methyl-D-aspartate and kainate
receptors.
The efficacy of antiepileptic drugs has been investigated in the
general epilepsy population and there are extensive guidelines on
treatment in this population. Unfortunately, large randomized studies of the efficacy of antiepileptic drugs in patients with a brain
tumour are scarce, although with the development of newer antiepileptic drugs, more studies on the efficacy of these drugs have
been carried out. The majority of research has focused on levetiracetam, both as add-on therapy as well as monotherapy (Patsalos,
| 1003
Table 1 Proposed mechanisms of action of anti-epileptic

drugs and associated epilepsy syndromes
Mechanisms of action
Associated
epilepsy
syndromes
Voltage-gated ion channels

Sodium channels
GEFS
Calcium channels
L-type
P/Q type
N-type
T-type
Potassium channels
Kv
PHT, CBZ, TPM,

LTG, OCBZ, FBM,
VPA, ZNS
AEA
Absence
PB, FBM
LTG, OCBZ, LEV
LTG, GBP, PG
ESM
Absence,
ADLTLE,
EAT1-MK-PS
Retigabine
Kir 4.1
HCN channels
HCN-2
Absence
Ligand-gated ion channels
GABAA receptor
JME, GEFS
Nicotinic cholinergic
receptors
Glutamate receptors
AMPA receptors
NMDA receptors
Kainate receptors
Synaptic vesicle proteins
SV2A
Enzymes
GABA-transaminase
Carbonic anhydrase
GABA metabolism
Increase synthesis
Dexrease metabolism
Prevent reuptake
Anti-epileptic
drugs
LEV,TPM
LTG
ADNFLE
PB, BZD, FBM,

TPM, propofol
CBZ
PB, TPM
FBM
TPM
LEV, brivaracetam
Vigabatrin
TPM, ZNS
VPA, GBP
VPA
TGB
ADLTLE = autodominant lateral temporal lobe epilepsy; ADNFLE = autosomal

dominant nocturnal frontal lobe epilepsy; AEA = absence epilepsy with ataxia;
CBZ = carbamazepine; EAT1-MK-PS = episodic ataxia type 1 wih myokomia and
partial seizures; ESM = ethosuximide; BZD = benzodiazepines; FBM = felbamate;
GBP = gabapentin; GE = generalized epilepsy; GEFS = generalized epilepsy with
febrile seizures; HCN = hyperpolarization-activated cyclic nucleotide-gated cation;
JME = juvenile myoclonic epilepsy; LEV = levetiracetam; LTG = lamotrigine;
OCBZ = oxcarbazepine; PB = phenobarbital; PHT = phenytoin; TGB = tiagabine;
TPM = topiramate; VPA = valproin acid; ZNS = zonisamide.
2000). In an early report, Wagner et al. (2003), prospectively

followed 26 patients with a brain tumour and found that a seizure
reduction of 450% was achieved with levetiracetam in 65% of
the patients, whereas seizure freedom was seen in 20%. In other
studies with levetiracetam, e.g. by Maschio et al. (2006) and
Newton et al. (2006) in 19 and 41 patients with a brain tumour,
respectively, a reduction in seizure frequency of 450% was found in
72% and 90%, respectively. More recent studies showed similar
percentages (Dinapoli et al., 2009; Maschio et al., 2010a; Rosati
et al., 2010; Usery et al., 2010). Other drugs investigated in patients
with a brain tumour are topiramate, pregabalin, gabapentin,
The specific events that occur in a lesion and lead to seizures are
unknown. Many studies have assessed the efficacy of antiepileptic
drugs, but relatively few have investigated the mechanisms that
underlie epileptogenesis. Altogether, little progress has been made
in recent years and many patients with a brain tumour with epilepsy suffer from ongoing seizures due to pharmacoresistance. In a
large cohort study, complete seizure control was achieved in only
20 of 158 (12.6%) patients with a brain tumour (Hildebrand
et al., 2005). In 1558% of cases of low-grade glioma, the epilepsy appears to be intractable (Duffau et al., 2002).
Understanding the mechanisms that underlie epileptogenesis in
brain tumours is essential to identify new treatment targets and
to develop effective treatment. In this review we will comment
on the current state regarding the treatment of both epilepsy
and tumour, and review the current knowledge on underlying
mechanisms of epileptogenesis in patients with a brain tumour.
Further, we provide suggestions for optimal treatment and
future research.
Brain 2012: 135; 10021016
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| Brain 2012: 135; 10021016
of older antiepileptic drugs without a specific choice of agent

and the ILAE guidelines recommend the use of phenytoin and
carbamazepine as first line choices. Two large trials have been
published since then. A large randomized double blind trial
found similar effectiveness of levetiracetam and carbamazepine
in patients with focal seizures (Brodie et al., 2007). The large
randomized and controlled, but not double-blind standard and
new antiepileptic drugs (SANAD) trial (Marson et al., 2007a, b)
reported lamotrigine to be more effective than carbamazepine,
oxcarbazepine, topiramate and gabapentin in patients with
focal seizures, and valproic acid to be superior to lamotrigine
and topiramate in generalized epilepsy. A comparison with
this literature on patients with a brain tumour is difficult since
research reports on antiepileptic drug treatment in the general
epilepsy population are often restricted to populations with specific
seizure types or epilepsy syndromes, while patients with a brain
tumour are rarely stratified according to seizure type for study
purposes.
Since many different types of antiepileptic drugs with similar
efficacy exist, selection criteria to choose a specific antiepileptic
drug in an individual patient are needed. The safety profile will
play an important part in this decision. However, with a similar
tolerability profile, specific selection criteria would be helpful. We
investigated the correlation between the efficacy of levetiracetam
in 34 patients with glioma and the expression of the synaptic
vesicle protein (SV2A), the target of levetiracetam (de Groot
et al., 2011). We found that the amount of SV2A expression in
tumour and peritumoral tissue was a predictor for the efficacy of
levetiracetam. Similar predictors for other antiepileptic drugs are
not known (Kinirons et al., 2006). In the future, identification of
such predictors would be of great help in the choice of antiepileptic drugs for individual patients.
Since systemic treatment with antiepileptic drugs may induce
many side-effects (see Issues associated with antiepileptic drugs
in patients with a brain tumour section), the possibility of focal
drug treatment could be an interesting option. Focal treatment has
been mainly investigated in animal models and methods include:
intraparenchymal injection (bolus deposition), application via the
epidural or subdural spaces, injection through a self-contained implanted device and convection-enhanced delivery. All these methods have a theoretical advantage over systemic therapy in that
systemic side-effects are avoided, but there are many technical
hurdles (Barcia and Gallego, 2009; Rogawski, 2009). The majority
of clinical trials that use convection-enhanced delivery comprise
small trials in patients with glioma (Rogawski, 2009). The reason
is that patients with glioma are being operated on anyway with
the epileptogenic focus coming within reach of the neurosurgeon.
Thus far, the analysis of this technique for the treatment of
focal epilepsy consists mainly of anticonvulsant toxins delivered
locally in an experimental mouse model; this can produce
long-lasting elevations in seizure threshold. The specific practical
ways in which this technique should be used, however, have
yet to be determined. Although some of these trials give promising results, optimal drug delivery may be achieved in only
20% of patients since there is often leakage into CSF subarachnoid spaces.
zonisamide and lacosamide. Topiramate, as add-on and as monotherapy, was studied prospectively in a cohort of 47 patients
with a brain tumour; 55.6% achieved seizure freedom and another 20% of the patients experienced a seizure reduction of
450% (Maschio et al., 2008). Novy et al. (2008) studied the
effects of add-on and monotherapy with pregabalin in nine patients with a brain tumour. Fifty per cent of the patients became
seizure free and 50% had a reduction in seizure frequency of
450%. Gabapentin was explored in a series of 14 patients and
the authors reported that all patients had a reduction of 450%
whereas 8 of 14 patients achieved seizure freedom (Perry and
Sawka, 1996). The responder rate for zonisamide as add-on therapy
was 83.3% (Maschio et al., 2009a). Lacosamide was studied in 14
patients with a mean follow-up of 5.4 months (Maschio et al.,
2011). The responder rate to lacosamide was 78.6%. For the
newer antiepileptic drugs: eslicarbazepine acetate, perampanel and
retigabine, no studies in patients with a brain tumour have been
performed.
A few studies have compared the efficacy of newer versus older
antiepileptic drugs in the brain tumour population. In three studies, levetiracetam was compared to phenytoin (Milligan et al.,
2008; Lim et al., 2009; Merrell et al., 2010). Two of the three
were retrospective studies (Milligan et al., 2008; Merrell et al.,
2010) that showed a similar efficacy in both groups. In the
third, a prospective study, Lim et al. (2009) found that 75% of
the eight patients treated with phenytoin were seizure free versus
87% of 15 patients on levetiracetam therapy. In one study, the
efficacy of oxcarbazepine and traditional antiepileptic drugs was
compared (Maschio et al., 2009b). The authors found a similar
efficacy, but also showed that traditional antiepileptic drugs
caused more side-effects. Finally, valproic acid and levetiracetam
were compared as monotherapy or in combination with other
antiepileptic drugs in a group of 140 patients (van Breemen
et al., 2009). Seizure freedom was achieved in: 52% of patients
using valproic acid, with or without other antiepileptic drugs; 59%
of patients using valproic acid and levetiracetam with or without
other antiepileptic drugs; 31% of patients using levetiracetam with
or without other antiepileptic drugs; and in 29% of patients treated with other (combinations of) antiepileptic drugs. Overall, in
these studies, none of the antiepileptic drugs provided seizure
freedom in all patients with a brain tumour.
Although large trials with antiepileptic drugs have been performed in the general epilepsy population, the same methodological flaws are met as in the brain tumour population, such as
differences in target dosage between studies, designs that were
primarily aimed at obtaining marketing licences instead of the best
scientific evidence, bias in selection of patients, and short treatment duration. This might be illustrated by the fact that national
guidelines regarding antiepileptic drugs treatment that were published between 2003 and 2006, such as the American Academy of
Neurology guidelines, the UK National Institute for Health and
Clinical Excellence (NICE) guidelines and the International
League Against Epilepsy (ILAE) guidelines, are all based upon
these large trials but differ in their recommendations (Perucca
and Tomson, 2011). The American Academy of Neurology guidelines do not express any preferences among older and newer
antiepileptic drugs, the UK NICE guidelines recommend the use
M. de Groot et al.
Issues associated with antiepileptic

drugs in patients with a brain tumour
Adverse events
epileptic drug therapy rather than seizure burden affects cognitive

function (Klein et al., 2003). Furthermore, cognitive deficits due to
treatment with antiepileptic drugs have been described both in
patients who are seizure free as well as in patients who are not
seizure free (Hamed et al., 2009). As adverse events have a negative influence on the quality of life (Gilliam, 2002), choosing
antiepileptic drugs with a lower chance of adverse events is
preferable.
| 1005
Drugdrug interactions
In general, the second generation antiepileptic drugs are less susceptible to pharmacokinetic interactions, a desirable characteristic
for antiepileptic drugs that are prescribed to patients with glioma
who are often subject to other medical treatment regimens. For
that reason, the use of enzyme-inducing or enzyme-inhibiting
antiepileptic drugs in patients with a brain tumour is discouraged.
Levetiracetam is the optimal choice with regard to pharmacokinetic characteristics compared with other new antiepileptic drugs
(topiramate, zonisamide, clonazepam, lamotrigine and ethosuximide) (Patsalos, 2000, 2002).
Recently, several studies have used first generation antiepileptic drugs to enhance chemotherapy due to their
enzyme-inducing or -inhibiting properties. In a retrospective
study, Oberndorfer et al. (2005) found that patients with glioblastoma on chemotherapy using enzyme-inhibiting antiepileptic
drugs (valproic acid) had longer survival than patients using
enzyme-inducing antiepileptic drugs; 13.8 versus 10.8 months,
respectively. This finding was explained through the inhibition
of P450 enzymes by valproic acid resulting in increased serum
levels, and thus improved efficacy of chemotherapeutic agents
and/or decreased serum levels with subsequent decreased efficacy of chemotherapeutic agents by enzyme-inducing antiepileptic drugs. In contrast to these findings, Jaeckle et al. (2009)
prospectively showed that patients with glioblastoma receiving
enzyme-inducing antiepileptic drugs had longer overall (12.3
versus 10.7 months) and progression-free survival (5.6 versus
4.8 months) than patients not receiving enzyme-inducing antiepileptic drugs. However, the results of this study could have
been biased since only 2% of the patients used non-enzymeinducing antiepileptic drugs. The mechanism behind these observations remains unclear and needs further investigation before
definite conclusions can be drawn.
Apart from these indirect effects of antiepileptic drugs on survival, there are reports that several antiepileptic drugs might
have intrinsic anti-tumour properties. Valproic acid inhibited
tumour cell growth in in vitro and in vivo systems by modulating multiple pathways through its histone deacetylase inhibitor
properties (Eyal et al., 2004; Li et al., 2005; Chavez-Blanco
et al., 2006). Another study (Fu et al., 2010) showed that valproic acid induces autophagy in glioma cells. Autophagy is an
alternative tumour suppressing mechanism to apoptosis. It is a
caspase-independent process characterized by accumulation of
autophagic vacuoles in the cytoplasm accompanied by an extensive degradation of organelles. Manipulation of this mechanism
could provide support for anticancer therapy. Studies of valproic
acid in combination with anti-tumour therapy in patients with
glioma are ongoing (Phase II) (Blaheta et al., 2005;
Duenas-Gonzalez et al., 2008). Other antiepileptic drugs, such
as levetiracetam, have shown to restore the O6methylguanineDNA-methyltransferase inhibitory activity of mutated p53 activity
in glioblastoma cell lines and thereby sensitizing glioblastoma
cells to temozolomide (Bobustuc et al., 2010). O6methylguanine-DNA-methyltransferase is a DNA repair protein and is associated with resistance to alkylating agents, such as temozolomide
and lomustine (CCNU).
Since the targets of antiepileptic drugs are not solely present in the
epileptogenic zone, antiepileptic drugs may cause a broad range of
adverse events, such as liver dysfunction, drowsiness, bonemarrow suppression and skin rashes, etc (Gates, 2000). Patients
with a brain tumour are more sensitive to the side-effects of antiepileptic drugs than other patients with epilepsy (Wen and Marks,
2002; Aguiar et al., 2004). For example, skin rash due to antiepileptic drugs (carbamazepine, phenobarbital and phenytoin) appears to occur more frequently in patients with brain tumours
(Mamon et al., 1999). It has also been suggested that patients
receiving radiotherapy and concomitant oxcarbazepine have a
higher risk of developing serious skin rashes such as Stevens
Johnson syndrome and toxic epidermal necrolysis (Maschio
et al., 2010b).
The frequency (incidence) of adverse events differs considerably
between antiepileptic drugs. Particularly, antiepileptic drugs of earlier generations show more adverse events (Klein et al., 2003). In
addition to these potential adverse events, antiepileptic drugs frequently affect cognitive function. Deficits in cognitive functioning
due to the tumour and anti-tumour treatment are a major concern
in patients with a brain tumour (Douw et al., 2009), and the
prescription of antiepileptic drugs to these patients will increase
the risk for cognitive dysfunction. In the general epilepsy population, much research into the cognitive effects of antiepileptic drugs
has been performed (Loring et al., 2007). Studies comparing the
effect of antiepileptic drugs on cognition in healthy volunteers or
in the epilepsy population showed that first generation antiepileptic drugs cause more cognitive side-effects than second generation
antiepileptic drugs (Park and Kwon, 2008; Cavanna et al., 2010).
Klein et al. (2003) found that patients with low-grade glioma who
used antiepileptic drugs performed worse on cognitive tests than
patients who did not use antiepileptic drugs. It needs to be
emphasized that most patients in this study used first generation
antiepileptic drugs. However, in another study a significant decline
on the Mini-Mental State Examination in glioma patients using
levetiracetam was shown (Maschio et al., 2010a), but this could
also be attributed to tumour progression.
Moreover, seizure burden itself may negatively affect cognition
(Motamedi and Meador, 2003; Carreno et al., 2008).
Distinguishing seizure effects from antiepileptic drugs effects is
very difficult, since antiepileptic drugs in patients with brain
tumour are usually prescribed only to those patients who actually
experienced seizures. However, it has been suggested that anti-
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M. de Groot et al.
Table 2 Molecular (or proposed) targets of known potential relevance to tumour associated epilepsy
Target
Suggested relevance in
(tumour type)
Potential antiepileptic drug
Tumour/ peritumoral
Tumour
Peritumoral
Tumour
Tumour
PB, TPM
TPM
FMT
PB, BZD, FBM, TPM, propofol
Peritumoral
Peritumoral
Peritumoral
Peritumoral
(extracellular)
(extracellular)
(extracellular)
(extracellular)
Tumour
PHT, CBZ, TPM, LTG, OCBZ, FBM, VPA, ZNS
Tumour, peritumoral
Tumour, peritumoral
Tumour
(LEV), (TPM) retigabine
Tumour/ peritumoral
LEV
Tumour/ peritumoral
LEV
Tumour/ peritumoral
Tumour/ peritumoral
Tumour/Peritumoral
Peritumoral (extracellular)
Peritumoral (extracellular)
Peritumoral
Peritumoral
Tumour
VPA, LTG, GBP, vigabatrin, TGB

Vigabatrin, TPM, ZNS, PHT
TPM, ZNS
BZD = benzodiazepines; CBZ = carbamazepine; FMT = felbamate; GBP = gabapentin; GG = ganglioglioma; GN = glioneuronal tumours; LEV = levetiracetam;
LTG = lamotrigine; OCBZ = oxcarbazepine; PB = phenobarbital; PHT = phenytoin; TGB = tiagabine; TPM = topiramate; VPA = valproic acid; ZNS = zonisamide.
Pharmacoresistance
Pharmacoresistance or medically refractory epilepsy is common in
patients with primary brain tumours, especially low-grade tumours. The ILAE Commission on Therapeutic Strategies defines
refractory epilepsy as an epilepsy that is not controlled by two
tolerated and appropriately chosen and used antiepileptic drugs
schedules (whether as monotherapies or in combination) (Kwan
et al., 2010). This definition is currently a matter of debate
(Gomez-Alonso and Gil-Nagel, 2010).
Several hypotheses have been explored to explain drug
pharmacoresistance that could also be applicable to pharmacoresistance in brain tumours. The first hypothesis, the target hypothesis (Remy and Beck, 2006), presumes alterations in drug targets;
targets that antiepileptic drugs normally bind to are possibly
altered in tumour and peritumoral tissue. Table 2 shows possible
targets that are modified in patients with a brain tumour and the
antiepileptic drugs that could bind to these targets. The second
hypothesis is the transporter hypothesis (Kwan and Brodie, 2005;
Loscher and Potschka, 2005): drugs can enter and leave the brain
through carrier-mediated transport. Multi-drug transporters such
as P-glycoprotein, multi-drug resistant protein and breast cancer
resistance protein, and detoxifying enzymes such as glutathione-Stransferase actively remove lipophilic molecules out of the brain
parenchyma. This mechanism contributes to the function of the
bloodbrain barrier, which is to protect the brain from toxic substances. However, upregulation of multi-drug transporters, as may
be found in epileptogenic brain tissue, may restrain access of antiepileptic drugs to the epileptogenic tissue (Schmidt and Loscher,
2005). Overexpression of multi-drug transporters, such as
P-glycoprotein, multi-drug resistance protein and breast cancer
resistance protein, has been reported in brain tumours and may
underlie the drug refractoriness observed in patients with a brain
tumour (Aronica et al., 2003, 2005; Decleves et al., 2006). In
glioma, P-glycoprotein is highly expressed in endothelial cells of
newly formed capillaries, and is not so extensive in the tumour
cells themselves (Toth et al., 1996; Calatozzolo et al., 2005). Also,
Glutamate receptors changes

mGluR
GG, glioma
AMPA receptors
GG
Kainate receptors
Astrocytoma
NMDA receptors
GN
GABA receptors
GG, glioma
Ion level changes
Fe3 +
Glioma
Mg2 +
Glioma
Glioma
Ca2 +
Na2 +
Glioma
Voltage-gated ion channels
Sodium channels
Glioma
Chloride channels
NKCC1
GG, glioma
KCC2
GG, glioma
Potassium channels
GG, glioma
Inflammatory interleukines
IL-1b
GG
Synaptic vesicle proteins
SV2A
GN, glioma
Gap junctions (connexins)
CX32
GN, oligodendroglioma
CX34
GN, astrocytomas
Enzym changes
Adenosine kinase
Glioma
Amino acids
Glutamate
Glioma
GABA
Glioma
Enzym changes
Glioma
PH changes
GN, glioma, meningeoma
Pi3K-mTOR pathway
GG, glioma
Location
| 1007
response to treatment. This is comparable to other diseases, which

often vary from mild to severe and also vary in response to
treatment.
Current state: treatment of

the tumour
Surgery
Surgery focuses on resection of the tumour as radically as possible
in order to delay tumour growth and lengthen survival (Smith
et al., 2008). The extent of resection of the tumour is limited by
functional areas of the brain. Further, removal of the tumour may
also lead to reduction of seizures, and many patients are seizure
free after oncological surgery (Chang et al., 2008).
It is important to note that the percentage of patients with a
significant reduction in seizures after surgery is higher when more
sophisticated surgical techniques are applied. With conventional
oncological surgery the epileptogenic zone is not always resected,
since this zone is often not restricted to the tumour area. In fact,
in one-third of patients the tumour area is not the epileptogenic
zone (Gilmore et al., 1994). With the help of imaging techniques
that are routinely applied in epilepsy surgery in non-tumour patients, the epileptogenic zone can be identified and exactly localized. These imaging techniques are functional MRI, Wada test,
magnetoencephalography, diffusion tensor imaging, interictal electrocorticography and electrostimulation during awake craniotomy.
Subsequently, simultaneous resection of both the tumour and
(if possible) the epileptic focus provides a significantly better control of seizures than oncological surgery alone. The percentage of
patients with oncological surgery alone that achieve seizure freedom ranges from 65% to 77% (Choi et al., 2004; Chang et al.,
2008), whereas that percentage ranges from 82% to 92% after
extended lesionectomy (Lombardi et al., 1997; Duffau et al.,
2002; Zaatreh et al., 2003; Bauer et al., 2007).
Thus, while having to decide whether oncological surgery is
necessary, epilepsy surgery should always be taken into consideration. This is especially so in patients with low-grade (WHO
grades I and II) gliomas, without neurological deficits and low
risk for progression or dedifferentiation, and when epilepsy constitutes the only symptom, surgery should be considered (Iannelli
et al., 2000). This is, however, a constant issue of debate (Langfitt
et al., 2007; Teixidor et al., 2007; Chang et al., 2008; Sanai and
Berger, 2008), since surgery comes with many risks, and may even
increase seizure frequency. Apart from that, for epilepsy surgery
the identification of the epileptogenic zone is pivotal and the
required diagnostic work-up may consume a considerable
amount of time, which may be undesirable in the case of a malignant brain tumour.
Thus, although we advocate considering the application of an
epilepsy surgery strategy in every patient with a brain tumour
suffering from seizure, whether this strategy should be followed
eventually depends on: (i) the grade and prognosis of the tumour
(the higher the tumour grade, the faster or more restricted the
work-up and this might even be impossible); (ii) the localization of
high multi-drug resistance protein 1 expression has been reported

both in tumour cells and in tumour vasculature of gliomas
(Calatozzolo et al., 2005).
Expression of these transporters (breast cancer resistance protein, P-glycoprotein and multi-drug resistance protein 1) has also
been reported in glioneuronal tumours (Aronica et al., 2003,
2005). The overexpression of multi-drug resistant proteins can
be intrinsic or acquired, meaning that the resistance is either present before exposure to antiepileptic drugs, resulting in immediate
resistance or develops during treatment, resulting in tolerance to
antiepileptic drugs (Loscher and Potschka, 2005). In addition, it
has been hypothesized that so-called cancer stem-like cells in glioblastoma multiforme express breast cancer resistance protein and
play a role in therapy resistance and tumour recurrence (Bleau
et al., 2009). Metastatic brain tumours differ in this aspect from
primary brain tumours. The neovasculature of secondary brain tumours express characteristics of the blood vessels of the primary
tumour, with subsequent altered characteristics of the bloodbrain
barrier (Gerstner and Fine, 2007). For instance, melanoma metastases express only 5% of the P-glycoprotein level normally found
in the bloodbrain barrier and non-small cellular lung carcinoma
metastases only 3040% (Gerstner and Fine, 2007). This suggests
pharmacoresistance via an enhanced expression/function of
multi-drug transporters is less of a problem in metastatic brain
tumours.
In order to support the theory of the transporter hypothesis in
pharmacoresistance in patients with a brain tumour, the antiepileptic drugs must be substrates for these transporters. One study
found no measurable directional transport of antiepileptic drugs
(phenytoin, carbamazepine and levetiracetam) by human
P-glycoprotein or multi-drug resistance protein 2 (Baltes et al.,
2007). Recently, the same research group used a different assay
to determine the transport of antiepileptic drugs and found that
several major antiepileptic drugs (phenytoin, phenobarbital, lamotrigine and levetiracetam, but not carbamazepine) are transported
by P-glycoprotein (Luna-Tortos et al., 2008). Even the newer drug
levetiracetam, which has long been thought not to be a
P-glycoprotein substrate, was shown to be a weak substrate for
P-glycoprotein (Luna-Tortos et al., 2008). As far as multi-drug
resistance proteins 1, 2 and 5 are concerned, carbamazepine, valproic acid, levetiracetam, phenytoin, lamotrigine and phenobarbital were not substrates (Luna-Tortos et al., 2010). Correlations
between drug efficacy and expression of multi-drug transporters
have been reported for both animals and humans (Rizzi et al.,
2002; Marchi et al., 2005; van Vliet et al., 2007). The upregulation of multi-drug transporters in the vasculature of primary brain
tumours and the fact that the majority of antiepileptic drugs are
substrates for multi-drug transporters, suggest that multi-drug
transporters have a role in pharmacoresistant epilepsy in patients
with a brain tumour.
The third hypothesis is the intrinsic severity hypothesis
(Rogawski and Johnson, 2008). This model suggests that neurobiological factors, which underlie disease severity, contribute pharmacoresistance. It is based on the observation that patients with
high seizure frequency in the early phase of epilepsy have a poor
outcome of pharmacotherapy. In other words, differences in inherent epilepsy severity have influence on an individual patients
Brain 2012: 135; 10021016
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| Brain 2012: 135; 10021016
Radiotherapy and chemotherapy

Radiotherapy and chemotherapy are frequently applied in the
treatment of patients with a brain tumour in order to prolong
survival or improve quality of life. Although seizure reduction is
not the first priority of chemo- and radiotherapy, these therapies
also have an effect on seizure occurrence. Few studies have addressed this issue. In a small study in five patients with a brain
tumour receiving cranial irradiation, 90% reduction in seizure frequency was found in three patients and 75% reduction in seizure
frequency in one patient (Rogers et al., 1993). In another small
study of nine patients with a brain tumour, five patients achieved
seizure freedom and four patients reported a reduction of 475%
in seizure frequency (Chalifoux and Elisevich, 1996). Stereotactic
radiosurgery with gamma knife resulted in 13 of 24 patients with
seizure control (Schrottner et al., 1998; Quigg and Barbaro, 2008).
Regarding chemotherapy, a few studies suggest a role of temozolomide and the combination of procarbazine, vincristine and
CCNU (lomustine) (PCV scheme) in reducing seizure frequency
(Brada et al., 2003; Pace et al., 2003). Recently, a cohort study
compared the seizure frequency of 39 patients with low-grade
glioma treated with temozolomide to 30 patients with low-grade
patients under observation (and not receiving any form of postoperative chemotherapy) (Sherman et al., 2011). There was a
significant difference in reduced seizure frequency between the
two groups: 59% of the patients using temozolomide and 13%
of patients not using temozolomide showed a reduction of
450%. These findings suggest that chemotherapy and radiotherapy might decrease epilepsy burden significantly. However, larger
prospective studies are needed.
Clinical impact
Treatment of seizures in patients with a brain tumour is complex
and often unsuccessful. Although antiepileptic drugs have many
different modes of action, none of these seem to effectively
modify the epileptogenic nature of brain tumours (Schaller and
Ruegg, 2003). In order to develop more effective therapies without adverse events, it is essential to return to the key question,
why do brain tumours cause epilepsy?
Pathophysiology of tumour-related
epilepsy: what makes brain tumours
epileptogenic?
Epilepsy commonly develops in patients with a brain lesion, but
not all patients with a brain lesion suffer from epilepsy.
Tumour-associated epilepsy can be classified under symptomatic
epilepsy, which is defined as the development of epilepsy caused
by an identifiable injury or lesion (Hauser, 1997). Lesions or injuries such as stroke, contusions, abscesses, vascular malformations
and malformations of cortical development, may all trigger a succession of events that sets off epilepsy. However, the cellular
mechanisms underlying the epileptogenesis of those lesions are
not clear. Given the fact that both intracerebral and extracerebral
tumours can cause epilepsy and differences in seizure frequency
exist between tumours of the same histopathological tumour type,
it is likely that in tumour-related epilepsy multiple mechanisms are
involved, including tumour-related factors (histological type, location), environment-related factors and functional changes (Fig. 1).
Although any tumour type can cause seizures, low-grade tumours are more frequently associated with epilepsy than
high-grade tumours (van Breemen et al., 2007). High-grade tumours that present with seizures are usually smaller in size than
high-grade tumours that present with other symptoms such as
focal neurological deficits. In contrast, low-grade tumours that
present with epilepsy are usually larger tumours than the tumours
without epilepsy (Lee et al., 2010). This suggests that the slow
growth rate allows time to develop functional changes. Patients
with temporal or frontal located low-grade tumours, are more
likely to present with seizures or develop seizures during the
course of their disease (Sirven et al., 2004; van Breemen et al.,
2007) than patients with deeply located tumours (e.g. pericallosal
region). Also, patients with tumours in the insular cortex are more
likely to present with seizures (Lee et al., 2010). In temporal lobe
epilepsy, the insular region is associated with seizure spread. This
could implicate that tumours located near or in the cortex are
more likely to affect neuronal tissue and thus present with
seizures.
Tumours also share a number of similar histopathological features suggesting that a common set of primary mechanisms of
epileptogenesis could predominate. Some tumours consist of a
mixture of dysplastic neurons and neoplastic glial cell (e.g. ganglioglioma), while others display neoplastic glial cells (e.g. astrocytes
and oligodendrocytes). Cellular composition and neurochemical
profile of glioneuronal tumours may be relevant for epileptogenesis (e.g. the presence of a hyperexcitable neuronal component).
the tumour (the more difficult to achieve gross total or subtotal

resection, the more elaborate the work-up if there is a considerable chance that this will improve resectability); and (iii) the severity of epilepsy if tumour surgery should be combined with
epilepsy surgery (the more refractory the epilepsy is, the lower
the chance that a patient becomes seizure free postoperatively).
The latter would imply that pre-surgical evaluation includes functional MRI, magnetoencephalography etc. in order to enable the
patient and the physician to make a reasoned decision considering
both the risks of surgery as well as the chances of seizure freedom. If there is an urgent oncological reason for interventionfor
example in case of a rapidly growing high-grade gliomaa full
work-up for epilepsy surgery is undesirable due to the fact that it
delays surgical treatment. For patients in the inbetween grey area,
informed consent must be the defining featurethe potential
benefits of completing full pre-surgical epilepsy evaluation
weighed up against the theoretical risks of delaying surgical treatment in that individual. Important considerations in planning surgical treatment in patients with glioma are variables that predict
seizure freedom and show a requirement for pre-surgical evaluation for epilepsy surgery. For example, duration of seizures of
51 year predicts a good outcome after surgery whereas medically
refractory epilepsy and simple partial seizures predict a bad outcome after surgery in patients with a brain tumour (Englot et al.,
2011). This supports the integration of the epileptologist as early
as possible in the decision process.
M. de Groot et al.
Brain 2012: 135; 10021016
| 1009
moral tissue and brain networks.
Possibly, more neuronal involvement is associated with epileptogenicity. On the other hand, an astrocytic basis for epilepsy
has been proposed previously (Boison, 2010), since astrocytes
support neuronal synapses and contribute to the regulation of
neurotransmission.
A number of other hypotheses regarding pathophysiology have
been put forward, such as bloodbrain barrier disruption, pH imbalance and metabolic changes due to vascular disturbance and
hypoxia. Such hypotheses have been previously summarized by
Beaumont and Whittle (2000), Schaller and Ruegg (2003) and
Shamji et al. (2009). In this review, specific aspects of epileptogenesis in patients with a brain tumour are discussed. These include neurotransmitter and receptor expression, since these
alterations may provide targets for drug therapy, but also genetic
seizure susceptibility. Tumour growth not only leads to structural
changes, but also to functional changes of tumour cells and the
surrounding tissue. Brain tumour tissue and the peritumoral tissue
are both known to express altered levels of receptors and neurotransmitters. However, it is generally thought that the peritumoral
regions may be most relevant for the generation and propagation
of seizure activity (Baayen et al., 2003; Kohling et al., 2006).
Three key questions exist: (i) which epileptogenic processes develop in the tumour; (ii) what is the influence of the tumour on
the epileptogenic properties of the surrounding brain tissue; and

(iii) what is the effect of the tumour on brain networks? All three
questions begin with the tumour and all three have clinical implications, both for surgical approaches and for antiepileptic drug
therapy.
What happens in the tumour?

For glioneuronal tumours, several studies have suggested an intrinsic epileptogenicity, indicating the presence of a hyperexcitable
neuronal component. Electrocorticographic studies show that epileptiform activity is associated with a high neuronal density within
the lesion (Ferrier et al., 2006). Regarding tumours of glial origin,
abrupt tissue damage leading to necrosis and haemosiderin deposition and to oedema has been proposed as pathophysiological
factor within the tumour (Riva, 2005). This theory is mainly applicable to high-grade glioma. Low-grade tumours are thought to
slowly cause functional changes. These changes can be subdivided
in categories used below.
Gap junctions
One hypothesis is that a disturbed communication between cells
contributes to epileptogenesis. Intercellular communication
Figure 1 Schematic illustration of epileptogenesis in brain tumours. Multiple mechanisms are involved regarding tumour tissue, peritu-
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| Brain 2012: 135; 10021016
between glial cells takes place through gap junction channels:

connexins. Low-grade gliomas demonstrate overexpression of
connexin 43 both in the tumour as well as in the peritumoral
cortex, and oligodendroglioma and glioneuronal tumours show
overexpression of connexin 32 (Aronica et al., 2001a).
Voltage-gated ion channels and transporters

Experimental data in vitro and in vivo have shown a high density
of voltage-gated sodium channels in tumour cells (Patt et al.,
1996; Labrakakis et al., 1997) suggesting that tumour cells can
generate action potentials. Increase of the sodiumpotassium
chloride cotransporter (NKCC1) expression and reduced expression
of the potassiumchloride cotransporter (KCC2) has also been reported in glioneuronal tumours (Aronica et al., 2007a, 2008). The
dysregulation of these transporters can contribute to epileptogenicity in ganglioglioma by modulation of GABA receptors (Yamada
et al., 2004).
Dysplastic glial cells in glioma also express compounds normally

not present in glial cells, such as synaptic vesicle proteins (De
Groot et al., 2010). The function of these proteins is not understood, but they might play a role in epileptogenicity. Glial tumour
cells express synaptic vesicle protein 2A (SV2A) (De Groot et al.,
2010). Dysfunction of SV2A leads to calcium accumulation during
repeated action potential generation and might play an important
role in epileptogenesis. Both gliomas and gangliogliomas express
specific glutamate receptor subtypes including both ionotropic and
metabotropic receptors (Aronica et al., 2001b; Maas et al., 2001;
Samadani et al., 2007). This implies a specific role of glutamatergic
neurotransmission in the epileptogenicity of these lesions. In glioblastoma, a downregulation and mislocalization of AMPA receptors compared to normal non-neoplastic brain and low-grade
gliomas was reported, suggesting that downregulation of ionotropic glutamate receptors in a glutamate rich environment allows
glioblastoma to be less excitable than low-grade tumours (van
Vuurden et al., 2009). Also, a decreased expression of glial glutamate transporters has been found that may increase extracellular
glutamate resulting in high excitability (Samadani et al., 2007;
de Groot and Sontheimer, 2010). A downregulation of several
GABAa receptor subunits (1, 5, b1, b3 and ) was detected in
ganglioglioma suggesting an impairment in inhibitory neurotransmission (Samadani et al., 2007; Aronica et al., 2008).
Genetics and molecular pathways

Low expression of potassium channel genes has been found in
ganglioglioma indicating a disturbed ion homeostasis that could
lead to epilepsy (Aronica et al., 2008). The leucine-rich, glioma
inactivated gene 1 (LGI1) is a possible tumour suppressor gene of
glioma and mutations in this gene are associated with autosomal
dominant lateral temporal lobe epilepsy (Gu et al., 2005). Low
expression of leucine-rich, glioma inactivated gene 1 in glioma
tissue has been observed, suggesting a role for this gene in the
epileptogenesis (Gu et al., 2005). In ganglioglioma, several components of the phosphatidylinositol-3 kinase mammalian target of
rapamycin (Pi3K-mTOR) signalling pathways are activated (Boer
et al., 2010). Activation of this pathway might contribute to
epileptogenesis and is a potential target for mTOR inhibitors,

such as rapamycin (Zeng et al., 2008). In glioblastoma and
low-grade glioma, the pi3K-mTOR pathway plays a role in the
development of the tumours (McBride et al., 2010; Sunayama
et al., 2010), suggesting common genetic pathways for
tumour-associated epilepsy and glioma (Berntsson et al., 2009).
Glutamate hypothesis
Calcium (Ca2 + ) permeable AMPA receptors are activated due to
glutamatergic stimulation in high-grade glioma. The transport of
glutamate through Na + dependent glutamate uptake is almost
absent in glioma, leading to excess amounts of glutamate.
Furthermore, gliomas use the xc cystine glutamate system. It
transports cystine in the cell and, in exchange, glutamate is
released. The high glutamate release and low uptake suggest
overactivation of neuronal glutamate receptors. Excessive amounts
of glutamate also lead to excitotoxicity and cellular oedema, subsequently leading to seizures (de Groot and Sontheimer, 2010).
What is the influence of brain tumours

on the peritumoral area?
The epileptogenicity of the peritumoral zone is supported by findings of functional and immunocytochemical studies. These studies
show network alterations and reveal cytoarchitectural and neurochemical changes in the perilesional cortex resected from patients
with epilepsy associated with different types of focal brain lesions,
including glial tumours (Goel et al., 2003; Shamji et al., 2009). It is
likely that peritumoral cells (both neuronal and glial) have a distorted function. Rapidly progressive tumours infiltrate neighbouring tissue, resulting in excitability (Kohling et al., 2006).
Peritumoral neurons show downregulation of inhibitory synapses
and upregulation of excitatory synapses (McNamara, 1999) and
demonstrate abnormal electrophysiological properties (Steriade
and Amzica, 1999). Peritumoral ischaemia (mainly induced by
high-grade tumours) could play a role in epileptogenicity, but
does not explain why low-grade tumours more frequently present
with seizures than high-grade tumours. Low-grade tumours cause
chronic functional changes in peritumoral cortex more often than
high-grade tumours. These changes can be subdivided into the
following categories.
Gap junctions
Alterations in gap-junctions (connexins) have been observed in the
peritumoral tissue of both glial and glioneuronal tumours (Aronica
et al., 2001a).
Voltage-gated ion channels and transporters

Peritumoral tissue of patients with glioma and epilepsy show an
increased expression of NKCC1 and a modest expression of KCC2
compared to non-epileptic control tissue (Conti et al., 2011). It
has been shown that altered neuronal expression of NKCC1 and
KCC2 in peritumoral tissue of glial tumours leads to a positive shift
of EGABA (depolarized reversal potential) (Conti et al., 2011). This
might lead to an inhibition of GABAergic function.
Receptor and synaptic vesicle changes
M. de Groot et al.
Receptor changes
Peritumoral astrocytes express an increased amount of kainate
receptors (Aronica et al., 2001b). These receptors downregulate
GABAergic inhibition and may predispose to epilepsy. Furthermore, multiple metabotropic glutamate receptors are overexpressed in the peritumoral cortex (Aronica et al., 2001b).
Ion level changes

Macro- or microhaemorrhage may lead to injury to the neuronal
membrane resulting in higher peritumoral extracellular levels of
iron (Fe3 + ) (Shamji et al., 2009), which may change the membrane potential of neurons. Extracellular ion level changes are also
reported for magnesium (Mg2 + ) and calcium (Ca2 + ), probably
released from oedema and haemorrhage. Decreased extracellular
levels of magnesium (Mg2 + ) lead to spontaneous epileptiform discharges (Schaller and Ruegg, 2003).
Extracellular amino acid changes have also been reported in peritumoral tissue. Higher levels of extracellular glutamate have been
found in peritumoral brain parenchyma of tumour patients with
epilepsy compared to non-tumour patients with epilepsy (de Groot
and Sontheimer, 2010). Abnormal levels of glutamate can result in
higher neuronal excitability. Several studies have shown alterations
in the levels of GABA, but the studies are contrasting. One study
reports a higher level of GABA, while the other reports a lower
level of GABA (Beaumont and Whittle, 2000; Shamji et al., 2009).
Altered concentrations of other amino acids have also been
shown, though the pathological significance remains unclear.
Enzyme changes
Enzymatic changes have been demonstrated in peritumoral tissue
(Shamji et al., 2009). These changes may impair neurotransmitter
synthesis and storage leading to alterations in signalling, processing and neuronal excitation.
Inflammation
An epileptogenic role has also been suggested for inflammation
(Vezzani and Granata, 2005; Vezzani et al., 2011). Brain tumours
often show a prominent immune response. Upregulation of inflammatory interleukins (such as IL-1b) in ganglioglioma, have
been suggested to play a role in epileptogenicity (Aronica et al.,
2008; Vezzani et al., 2011). Inflammation activates a cascade of
proinflammatory cytokines and induces alterations in the blood
brain barrier possibly leading to epilepsy.
What is the effect of brain tumours

on the whole brain (brain networks)?
The human brain can be interpreted as a highly complex neural
network. In order to function properly, a network requires several
concepts such as segregation and integration. It has been proposed by Watts and Strogatz (1998) that an optimal network
holds a balance between these characteristics and may be
described as a small-world network. The features of small-world
networks areat least partlygenetically determined (Smit et al.,
2008). Functional connectivity is a measure that is used to express
| 1011
the degree of communication between brain areas and one of the

parameters that are used to describe networks (Reijneveld et al.,
2007). Brain tumours are thought to disrupt functional connectivity, thus interfering with normal brain function. Dysfunctional
tissue disturbs dynamic interactions that normally occur between
intact brain areas and therefore causes changes in connectivity.
Magnetoencephalography studies demonstrate altered functional
connectivity in patients with a brain tumour compared to healthy
controls (e.g. low-frequency theta band connectivity is increased
and the small-world configuration is disturbed) (Bartolomei et al.,
2006). Loss of functional connectivity in patients with a brain
tumour affects not only the tumour area, but also other brain
areas (Bartolomei et al., 2006). The mechanisms underlying the
alteration of functional connectivity are unclear.
Studies in patients with temporal lobe epilepsy suggest that the
small-world configuration is more disrupted in patients with a
longer history of seizures (van Dellen et al., 2009). Moreover, in
patients with epilepsy, increased connectivity has been reported
(Douw et al., 2010a), and patients with a brain tumour with more
severe epilepsy (higher number of seizures) display a stronger increase of functional connectivity in the theta band (Douw et al.,
2010b). This suggests that alterations in functional connectivity
can contribute to tumour-related epilepsy.
Both structural changes and functional deficits caused by the
tumour have been proposed to alter functional connectivity. It
has been shown that changes in membrane ion permeability directly lead to changes in functional network properties. For instance, blockade of GABA receptors alters theta band activity
(Mackenzie et al., 2002). In an in vitro model of stroke-induced
epilepsy, glutamate-injured hippocampal neuronal networks had a
more random network topology than non-injured neuronal networks, and became hyperexcitable (Srinivas et al., 2007). In another study it has been demonstrated that dysfunction of the
inhibitory GABAergic neuronal network and a reduced number
of inhibitory interneurons in perilesional tissue surrounding
low-grade glioma contribute to the generation and propagation
of epileptic seizures through the induction of abnormally functioning neuronal networks in these highly epileptogenic lesions
(Aronica et al., 2007b).
As mentioned before, not only neurons but also astrocytes surrounding the lesion undergo reorganization (Hatten et al., 1991;
Landis, 1994; Norenberg, 1994; Zhang and Olsson, 1995).
Increased coupling between astrocytes in perilesional tissue of patients with low-grade glioma with epilepsy reflected by connexin
43 (Aronica et al., 2001a), is thought to contribute to the (local)
hypersynchronization of neuronal firing at the epileptic focus (Lee
et al., 1995; OConnor et al., 1998). Gap junctions may also play
a role in synchronizing neocortical networks and may lead to characteristic neocortical firing patterns in focal cortical dysplasias
(Gigout et al., 2006). Recently, increased expression of lynx1 protein has been identified to prevent plasticity in the visual cortex in
adults (Morishita et al., 2010). Removal of this protein led to
enhanced signalling of nicotinic acetylcholine receptors. This suggests that the stability of cortical networks can be modulated by
proteins.
Taken together, these findings suggest that (peri-)lesional
changes may induce alterations in local neuronal network
Amino acids
Brain 2012: 135; 10021016
1012
| Brain 2012: 135; 10021016
topological features. We suggest that a focal lesion leads to local

imbalance between inhibition and excitation at the receptor, neuronal and astrocytic level. This causes brain networks to be disorganized. Eventually, patients develop seizures. However, structural
changes and cellular deficits might not necessarily lead to affection
of networks, and other, until now unknown factors, might contribute to epileptogenesis.
Future directions
Conclusion
Brain tumours often cause epilepsy and therapy is far from perfect.
Epileptogenesis is not well understood, but presumably comprises
structural and cellular/molecular changes induced by the tumour
that leads to changes in the surrounding tissue and at further
distance, eventually resulting in alterations in functional connectivity. Therapy should aim at eliminating the epileptic focus and
decrease epileptic activity of the focus. Research is warranted
both for optimizing anti-tumour treatment and its effects on
epilepsy and for elucidation of the underlying pathophysiology

of tumour-related epilepsy to provide targets for new therapies.
Funding
UCB Pharma (unrestricted grant to M.d.G.); Dutch Epilepsy
Foundation, Stichting Kinderen Kankervrij (KIKA) (research support
to E.A.); Dutch Epilepsy Foundation (NEF), Dutch Cancer Society
(KWF Kankerbestrijding), Foundation NutsOhra and Foundation
STOPHersentumoren.nl (research support to J.J.H. and J.C.R.)
and UCB Pharma and Sanofi Aventis (unrestricted grants). These
sponsors were not involved in the writing of this manuscript.
The authors have no relevant affiliations or financial involvement
with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in
the manuscript apart from those disclosed.
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Brain 2012: 135; 10021016

Epilepsy in patients with a brain tumour: focal

Correspondence to: Marjolein de Groot, MD,

Keywords: epilepsy; brain tumour; antiepileptic drugs; epileptogenesis

and 100% and depends on the tumour type, with slow-growing

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Epilepsy in patients with a brain tumour

Current state: treatment

Table 1 Proposed mechanisms of action of anti-epileptic

Voltage-gated ion channels

PHT, CBZ, TPM,

PB, BZD, FBM,

ADLTLE = autodominant lateral temporal lobe epilepsy; ADNFLE = autosomal

2000). In an early report, Wagner et al. (2003), prospectively

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Brain 2012: 135; 10021016

| Brain 2012: 135; 10021016

of older antiepileptic drugs without a specific choice of agent

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Epilepsy in patients with a brain tumour

Issues associated with antiepileptic

epileptic drug therapy rather than seizure burden affects cognitive

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Brain 2012: 135; 10021016

| Brain 2012: 135; 10021016

Potential antiepileptic drug

PHT, CBZ, TPM, LTG, OCBZ, FBM, VPA, ZNS

(LEV), (TPM) retigabine

VPA, LTG, GBP, vigabatrin, TGB

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Glutamate receptors changes

Epilepsy in patients with a brain tumour

response to treatment. This is comparable to other diseases, which

Current state: treatment of

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high multi-drug resistance protein 1 expression has been reported

Brain 2012: 135; 10021016

| Brain 2012: 135; 10021016

Radiotherapy and chemotherapy

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the tumour (the more difficult to achieve gross total or subtotal

Epilepsy in patients with a brain tumour

Brain 2012: 135; 10021016

moral tissue and brain networks.

the epileptogenic properties of the surrounding brain tissue; and

What happens in the tumour?

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| Brain 2012: 135; 10021016

between glial cells takes place through gap junction channels:

Voltage-gated ion channels and transporters

Dysplastic glial cells in glioma also express compounds normally

Genetics and molecular pathways

epileptogenesis and is a potential target for mTOR inhibitors,

What is the influence of brain tumours

Voltage-gated ion channels and transporters

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Receptor and synaptic vesicle changes

Epilepsy in patients with a brain tumour

Ion level changes

What is the effect of brain tumours

the degree of communication between brain areas and one of the

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