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Brain tumors and epilepsy

Expert Rev. Neurother. 8(6), 941–955 (2008)

Christian Brogna,
Santiago Gil Robles
and Hugues Duffau†
† theories of pathological neural networks, especially in low-grade gliomas, can provide the key
Author for correspondence
Department of Neurosurgery,
CNRS UMR 8189 & INSERM
U678, Hôpital Gui de
Chauliac, CHU de
Montpellier, 80 Avenue
Augustin Fliche, 34295
Montpellier Cedex 5, France
Tel.: +33 467 33 6612
Fax: +33 467 33 6912
h-duffau@chu-montpellier.fr
When treating patients harboring a brain tumor, it is mandatory to integrate the dogmas of
epilepsy into a neuro-oncological viewpoint. The frequency of seizures differs widely between
low- and high-grade tumors because of different mechanisms of epileptogenesis. The modern
for an in-depth understanding of the principles of connectionism that underline both seizures,
cognitive impairment and plasticity. It is a consuetude that principles of general management
of patients with nontumor-related epilepsy are applied to neuro-oncology. Nevertheless, since
tumors are complex evolving lesions requiring a multidisciplinary treatment approach (surgery,
radiotherapy and chemotherapy), it is mandatory to have a comprehensive view of the natural
history of each lesion when choosing the best antiepileptic drug. More than two thirds of
patients with brain tumors and medically intractable epilepsy benefit from (sub)total surgical
resection. Therefore, these patients are good surgical candidates both for oncological and
epileptological considerations, in order to change the natural history of the lesion and to
improve the quality of life at the same time. However, 15% of patients still have intractable
medical seizures after surgery. Moreover, the insula may participate more often than usually
considered in (intractable) seizures. Therefore, in these patients, invasive EEG recordings and
eventually a second epilepsy surgery might be proposed.

KEYWORDS: brain tumor • connectivity • epilepsy • glioma • insula • network • plasticity

Approximately 10–15% of adult-onset and of patients harboring glioblastoma multiforme

0.2–6.0% of childhood-onset cases of epilepsy are
caused by CNS neoplasms [1–3]. Conversely, sei-
zure can be the presenting symptom, leading to
diagnosis of the underlying brain tumor in 38% of
primary and 20% of secondary CNS tumors [4].
It is noteworthy that the frequency of seizures
as the first symptom of pathology differs widely
between different histologies and, as a conse-
quence, between tumors with different natural
histories and growth patterns. In fact, while
slow-growing tumors are much more related
with epilepsy [5–7], high-grade tumors are less
related [8–10], probably owing to different mech-
anisms of epileptogenesis involved in each type.
In particular, dysembryoplastic neuroepithelial
tumors can be associated with seizures in up to
100% of patients [3,11–16], and 60–85% of
patients harboring a low-grade glioma (such as
oligodendrogliomas, oligoastrocytomas, mixed
oligoastrocytomas and gangliogliomas) will have
seizures during the course of their disease [17–19].
Instead, the incidence of epilepsy decreases
dramatically in high-grade tumors: only 30–50%
[20–22] and 20–35% with brain metastases [23] will
have seizures during their life. Moreover, focal
neurological deficits instead of seizures are more
likely to be the presenting symptoms of patients
with high-grade tumors [8].
All the data mentioned above are confirmed
by a recent retrospective study, that underlines
the inverse relationship between incidence of
epilepsy as a presenting symptom and histologi-
cal grade of the tumor, with the incidence of sei-
zures in WHO grade II oligodendendroglioma,
grade II astrocytoma, and WHO grade III and
IV astrocytoma being 100, 60, 50 and 25%,
respectively [4]. These differences reflect the dif-
ferent mechanisms of epileptogenesis between
low- and high-grade tumors.
Mechanisms of epileptogenesis
Role of microenvironment
The effects of a mass lesion on the surrounding
brain parenchyma include mechanical compres-
sion, increased pressure, ischemia and specific

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 Review Brogna, Gil Robles & Duffau
trophic factors [24]. Although voltage-gated ion channels con-
trolling cell excitability are involved in epilepsy [25–27], it is not
known whether this is also true for tumor-related epilepsy,
since there is no correlation between the presence of voltage-
gated sodium channels and epileptogenic discharges using
magnetoencephalography (MEG) and EEG [28].
Nevertheless, morphological changes in peritumoral tissue that
may affect epileptogenesis include: aberrant neuronal migration
[15,29], changes in synaptic vesicles [30,31], enhanced intercellular
communication through increased expression of gap junction
channels [32] or an imbalance between inhibitory and excitatory
mechanisms through changes in local concentrations of GABA
[33,34], glutamate and lactate [35,36].
The tumor microenvironment may also affect gene expres-
sion. The occurrence of hypoxic brain regions, as usually occurs
in the core of brain tumors, is associated with changes in gene
expression with negative effects on the stability of DNA repair
mechanisms and on the likelihood of mutations. Under these
conditions, the astrocytic cell membrane becomes prone to
inward sodium currents, leading to risk of epilepsy [37].
The tumor-suppressor gene LGI1, apart from playing a role
in glioma progression probably participating in cell invasion
and migration, is also responsible for the rare syndrome auto-
somal dominant lateral temporal lobe epilepsy, which shows
Mendelian inheritance [38]. Moreover, LGI1 is not expressed in
glioblastoma multiforme cell lines and other high-grade
tumors. Since these considerations support the existence of a
relationship between low-grade gliomas and epilepsy,
Brodtkorb and colleagues have suggested that LGI1 plays a role
in epileptogenesis in patients with brain tumors [39]. Conversly,
a recent study has suggested that it is necessary to reconsider its
role as a tumor suppressor in gliomas [40].
Tumor-associated epilepsy as a deviation of the functional
network topology from the optimal small-world pattern
The modern theories of pathological neural networks provide
the tools for a new in-depth understanding of tumor-related
epilepsy [41–47]. These theories can be well applied to slow-
growing lesions, which determine a continuous middle- and
long-term remodeling of neuronal–synaptic organization bet-
ter than high-grade lesions that are related to an abrupt change
of the microenvironment [48]. Low-grade gliomas are also
responsible for a functional imbalance of the white matter
fibers connecting different cortical networks, since they have a
tendency to spread to adjacent brain structures, migrating
along the main white matter pathways both within the lesional
hemisphere or even contralaterally essentially via the corpus
callosum [49,50].
Traditionally, neurology has considered the brain cortex to be
divided into specific segregated functional areas, specifically ded-
icated to one function. From this assumption derives the consue-
tude to correlate through a basic neurological examination a spe-
cific clinical deficit to a specific anatomical location of the lesion
within the brain. However, especially since neuropsychological
942
assessment before, during and after surgery is more and more
given to the patients in a clinical setting [51–56], it is clear that
those patients harboring a brain tumor often suffer from diffuse
alterations of cognitive functions (attentional deficits, working
memory problems, reduced psychomotor speed and problems
with executive functions [57]) that cannot be explained by the
focal theory.
Conversely, the modern theory of brain networks, which is
derived from the graph theory [58], can explain why a brain
tumor interferes with widespread functional networks in the
brain rather than only the site of the lesion itself [42]. In fact,
cognitive functions in the brain require the functional inter-
actions between multiple distinct neural networks [41,59,60]. In
order to explore the consequences of a lesion on the brain, it is
mandatory to evaluate its impact on the functional connectivity
taking place between different brain regions [61–63]. MEG
recordings and functional MRI seem to be valuable ways of
analyzing the functional connectivity between different brain
regions [64,65], measuring statistical interdependencies between
signals of brain activity and analyzing them with the graph
theory approach [66–68]. In this setting, Bartolomei et al. con-
cluded that brain tumors determine changes in network archi-
tecture of functional connectivity [41,42]. In particular, frontopa-
rietal connections are the most involved in a network’s
disarrangement; in normal subjects, working memory or direct
attentional tasks involve the transient synchronization between
these two regions [42,69,70].
In accordance with the small-world network theory, synchro-
nization of neurons in networks is mandatory for normal func-
tioning and information processing [45,46], but may also reflect
abnormal dynamics related to epilepsy. Excessive synchroniza-
tion owing to compensatory mechanisms after network imbal-
ance from a lesion may be the cause of epilepsy [46,71]. Network
randomization can be a result of general brain damage, caused
by tumors or even surgery. Random networks caused by tumor
infiltration of white matter fibers, and not only infiltration of
the cortex, might have a lower threshold for seizures than
small-world networks [41,71].
Neural networks may develop towards a critical regimen
between local and global synchronization. Seizures would result
if pathology pushes the system beyond this critical state [44,45,72].
In summary, brain tumors probably convert a healthy global
functional network into a pathological network with random
structure, which may be associated with both cognitive prob-
lems and a lower threshold for seizures [73,74]. It is not a coinci-
dence if cognitive impairment and seizures are both the main
issues of low-grade gliomas. This hypothesis must be explored
in further studies.
In favor of the potential modifications of cerebral networks
are all the studies on brain plasticity, namely the continuous
processing allowing short-, middle- and long-term remodeling
of the neuronal-synaptic organization [48]. Several hypotheses
about the pathophysiological mechanisms underlying brain
plasticity and, as a consequence, the modifications of cerebral
Expert Rev. Neurother. 8(6), (2008)

networks, can be considered. At a microscopic scale, these mech-
anisms seem to be essentially represented by: synaptic efficacy
modulations [75], unmasking of latent connections [76], pheno-
typic modifications [77] and neurogenesis [78]. At a microscopic
scale, diaschisis [79], functional redundancies [80], cross-modal
plasticity with sensory substitution [81] and morphological
changes [82] are implicated.
All these studies support the idea that we deal with extremely
complex networks, with a dynamic and not static architecture,
when trying to understand the mechanisms underlying brain
functions. Tumors and probably surgery can modify the natural
balance and synchronization of these networks, leading to a
benefit in terms of plasticity with preservation of functions
and/or to the randomization of networks causing seizure onset.
Nowadays, since it is demonstrated that mechanisms of
epileptogenesis involve not only the microenvironment, but
also the global scale networks and connectivity, in the clinical
setting both aspects must be take into account. A global indi-
vidually based strategy, including antiepileptic drugs, surgery,
radiotherapy and chemotherapy, is mandatory when treating
brain tumor-related epilepsy, both from an oncological and
epileptological viewpoint.
Clinical setting
It is a consuetude that principles of general management of
patients with nontumor-related epilepsy are applied to neuro-
oncology. Nevertheless, since tumors are complex evolving
lesions dealing with a multidisciplinary treatment approach
(surgery, radiotherapy and chemotherapy), it is mandatory to
have a comprehensive view of the natural history of each lesion
in order to incorporate in this scenario the dogmas of general
epilepsy treatment.
In addition, there are several theoretical and practical issues
to be considered when giving antiepileptic drugs to patients
with brain tumors, including pharmacokinetics, pharmaco-
dynamics, and the potential for drug interactions and side
effects [11].
Clinical manifestations of tumor-related seizures
Complex partial seizures and complex partial seizures with sec-
ondary generalization are relatively frequent in patients with
chronic seizures (seizure duration >1 year), whereas simple par-
tial seizures and simple partial seizures with secondary generali-
zation are relatively common in patients with acute seizures
(seizure duration <1 year) [83]. Moreover, secondary generaliza-
tion may occur so quickly that, in certain patients, the focal
phase passes unnoticed [84,85].
Several patients with temporal lobe tumors also report only
isolated auras [86]. Somatosensory signs, experimental phenom-
ena with mnemonic components, language disturbances, vis-
ceromotor and/or viscerosensitive manifestations, olfactory or
gustatory hallucinations, and oroalimentary automatisms can
be related both to temporal and insular lesions.
www.expert-reviews.com
Brain tumors & epilepsy Review
Classification of epilepsy outcome
Clinically, there are two main frequency-based classifications of
the outcome of patients with seizures that are widely used in
the literature. The Engel’s classification is based on four classes
[87,88]: class I: free of disabling seizures; class II: rare disabling
seizures (almost seizure-free); class III: worthwhile improve-
ment; and class IV: no worthwhile improvement. The recently
proposed International League Against Epilepsy classification
(ILAE) is based on six classes: class 1: completely seizure free,
no auras; class 2: only auras, no other seizures; class 3: 1–3 sei-
zure days per year ± auras; class 4: At least 4 seizure days per
year to 50% reduction of baseline seizure days ± auras; class 5:
less than 50% reduction of baseline seizure days to 100%
increase of baseline seizure days ± auras; class 6: more than
100% increase of baseline seizure days ± auras [89].
Monotherapy
For partial seizures, the anticonvulsants carbamazepine or
lamotrigine are recommended as first-line treatments [90]. Valp-
roic acid [91–93] and levetiracetam [94–96] are broad-spectrum
anticonvulsants both for partial and generalized seizures.
It is interesting that side effects associated with levetiracetam
[97], gabapentin [98,99], tiagabine [100] and topiramate [101] are
infrequent. Nevertheless, it is of importance to make some
considerations.
Although carbamazepine alone is one of the most effective
antiepileptic drugs for treatment of partial epilepsy, in
patients with cancer it has the drawback of being an enzyme-
inducer and thus might compromise the effectiveness of con-
comitantly administered chemotherapy [11,102]. Further-
more, carbamazepine is associated with a small risk of bone-
marrow depression, which needs careful consideration in
patients receiving chemotherapy [103]. Although the use of
lamotrigine is well established for the treatment of sympto-
matic localization-related epilepsy, it has a somewhat pro-
tracted prescription formulation (i.e., it can take several
weeks to achieve a therapeutic dose) [104]. Although topiram-
ate is a nonenzyme-inducer and can be chosen as immuno-
therapy, it might have lower tolerability compared with
newer antiepileptic drugs [105,106].
Valproic acid has a sound reputation as a broad-spectrum
anticonvulsant for the treatment of generalized and partial epi-
lepsy; it has mild toxic effects and has the advantage that it can
be started at therapeutic dosages immediately [93,95,107]. How-
ever, combined with chemotherapy, the enzyme-inhibiting
effects of valproic acid might increase the risk of bone-marrow
toxicity [92,108]. Nevertheless, findings on this drug further
corroborate its use in patients with brain tumors [109]. In fact,
valproic acid was suggested to have also inherent antitumor
effects through inhibition of histone deacetylase, which leads
to cell differentiation, growth arrest and apoptosis of cancer
cells [110–112]. Moreover, valproic acid might also suppress for-
mation of MDR-1, which possibly diminishes the chances of
refractoriness [113].
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 Review Brogna, Gil Robles & Duffau
A double-blind, randomized trial showed that levetiracetam
as immunotherapy was as effective as carbamazepine for the
treatment of de novo partial epilepsy, and was associated with
fewer or about the same amount of side effects [114]. Moreover,
a retrospective study showed that phenytoin was the most com-
mon anticonvulsant medication to be discontinued in favor of
levetiracetam [4,97].
Polytherapy
Unfortunately, 70% of patients with low-grade gliomas who
take carbamazepin, 51% who take phenytoin and 44% who
receive valproic acid still have recurrent seizures. Thus, if a first-
line agent is insufficient, levetiracetam or gabapentin can be
added, both of which do not interact with other agents
[95,107,115]. Studies suggest levetiracetam has greater efficacy
than gabapentin [105,106]. Add-on levetiracetam can lead to
some patients becoming seizure-free or having fewer seizure
than before the treatment [4,97,105,115,116]. In a retrospective
study of 147 patients harboring brain tumors treated at one
institution, levetiracetam was the most common additional
medication used when polytherapy was required: 95% of
patients on polytherapy were seizure free or had only occasional
breakthrough seizures [4].
These results suggest that add-on treatment with levetira-
cetam seems to be well tolerated, and that further assessment of
these drugs in patients with brain tumors is warranted [3].
Interactions between antiepileptic &
chemotherapeutic agents
Once again, it is mandatory to have a global viewpoint on the
management of brain tumors when choosing the most appro-
priate antiepileptic drug for one patient, according to the spe-
cific phase of the natural history of the tumor, and in particular
to the concomitant administration of chemotherapeutic agents
as adjuvant or neoadjuvant therapies both in high- and low-
grade gliomas [105,117,118]. In fact, interactions between anti-
epileptic drugs and antineoplastic agents may lead to insuffi-
cient control of the tumor or epilepsy, or to toxic effects of one
or both of the agents.
Table 1. First-line treatment antiepileptic drug
interactions with chemotherapy and corticosteroids.
Drug Chemotherapy Corticosteroids
Phenytoin Yes (decreasing chemotherapy Yes (interfering
plasma concentrations) with hepatic
metabolism)
Carbamazepin Yes (decreasing chemotherapy No
plasma concentrations)
Valproic acid Yes (increasing chemotherapy No
plasma concentrations)
Levetiracetam No No
944
Low levels of antiepileptic drugs have been reported in
60–70% of patients [21]. In patients with brain tumors, thera-
peutic antiepileptic drug levels are difficult to maintain because
of frequent pharmacodynamic and pharmacokinetic inter-
actions with concomitant medications, as changes in plasma
protein (especially albumin) levels [11]. In particular, pharmaco-
kinetic interactions can affect drug uptake, metabolism in the
liver or elimination of the drug. Furthermore, drug–drug inter-
actions can change the volume of drug distribution and affect
protein binding. Several antiepileptic drugs (e.g., phenobarbi-
tal, primidone, carbamazepine and phenytoin) induce cyto-
chrome P450 coenzymes, such as 3A4, 2C9 or 2C19, which
leads to faster metabolism and lower plasma concentrations of
agents given concomitantly that share the same metabolic
isoenzyme [119].
As a proof, enzyme-inducing antiepileptic drugs decrease the
effectiveness of several chemotherapeutic agents, such as nitro-
sureas, paclitaxel, cyclophosphamide, etoposide, topotecan, iri-
notecan, thiotepa, doxorubicin and methotrexate [8,11,120,121].
As a consequence, the enzyme-inducing antiepileptic drugs
might negatively impact on the overall survival of patients with
gliomas [109]. Conversely, valproic acid, which is a broad-
spectrum enzyme-inhibiting antiepileptic drug, can enhance
the toxic effects of nitrosureas given either alone or with cis-
platin and etoposide [108], by raising plasma concentrations of
these chemotherapeutic agents (TABLE 1).
On the contrary, it is also true that some chemotherapeutic
agents can change plasma concentration of concomitantly pre-
scribed antiepileptic drugs, leading to seizures or toxic effects,
inducing coenzymes of the cytochrome P450 pathway.
Methotrexate, cisplatin and doxorubicin can reduce the
plasma concentration and toxic effects of valproic acid
[21,108,122]. Combination of phenytoin with fluoropyrimidines
(i.e., fluorouracil, tegafur and capecitabine) increases the toxic
effects of phenytoin [123].
Therefore, for patients harboring a brain tumor, it is advisa-
ble to administrate the new antiepileptic drugs, such as gabap-
entin, levetiracetam, and pregabalin, that do not interact with
other agents, since they do not influence the cytochrome P450
or other metabolic pathways and few side effects have been
reported [97,107,115,121].
Interactions between antiepileptics & dexamethasone
In neuro-oncological practice, dexamethasone is frequently
given mainly for the treatment of peritumoral edema associated
with brain tumors. Phenytoin and phenobarbital shorten the
half-life, and thus activity, of dexamethasone and prednisone
(TABLE 1) [124]. However, phenytoin plasma levels, given the small
therapeutic window, should always be carefully analyzed with
or without concomitant corticosteroids.
Since steroids enhance the GABA inhibitory effect and
could protect from epilepsy, it is mandatory to never abruptly
interrupt the corticosteroid treatment, but to withdraw them
progressively [125].
Expert Rev. Neurother. 8(6), (2008)

Epilepsy prophylaxis in neuro-oncology
While initiation of an antiepileptic treatment is generally justi-
fied after a first single seizure in patients harboring a brain
tumor, it not clear whether an antiepileptic drug should be
prescribed to patients who have never had a seizure.
Two meta-analyses of antiepileptic drugs in patients with brain
tumors who did not have seizures suggested no efficacy as proph-
ylaxis [21,126]. A consensus statement from the Quality Standards
Subcommittee of the American Academy of Neurology recom-
mends not to use antiepileptic drugs routinely as prophylaxis in
patients with brain tumors, and to withdraw these drugs in the
first week after surgery if patients have never had seizures [21].
Nevertheless, it is mandatory to integrate these recommenda-
tions into a neuro-oncological setting for the following reasons.
First, even if epilepsy is not the presenting symptom of the
tumor, 20–45% of these patients have a risk of developing sei-
zures later on, depending on tumor type, location, patient age
and previous cancer treatment [21]. Second, since the natural
history of low-grade gliomas differs dramatically from high-
grade tumors, we must take into consideration the difference in
prognosis, treatment modalities and the adjunct risk of epilepsy
between them [127–129].
Thus, in patients harboring a low-grade glioma with at least
subtotal resection and no decision of adjuvant oncological
treatment modalities (until a recurrence or anaplastic transfor-
mation), when no seizures occur after surgery, as happens in
more than 85% of cases [18,84], it is reasonable to follow the
available guidelines [21] and to try to withdraw antiepileptic
drugs if possible. However, as physicians, we must respect the
will of patients who wish to continue to take their daily anti-
epileptic drugs. In fact, some patients find a good psychological
balance between the assumption of antiepileptic drugs, their
certainty that “everything is going on well” and their self-confi-
dence. A good psychological balance has a great impact on the
patient’s quality of life.
Conversly, in patients harboring a high-grade glioma, consid-
ering the poor prognosis and the certainty of a recurrence in a
few months [130], it is reasonable to withdraw antiepileptic
drugs only in a subset of patients after radiotherapy, with gross
total resection, good performance status, absence of seizures or
in case of intolerance. Once again, as physicians we must take
into account the will and psychology of our patients.
Multidrug resistance-related proteins in refractory epilepsy
A clinically useful definition of medical refractory epilepsy is the
presence of seizures so frequent or severe that they limit daily
life, despite the use of antiepileptic drugs at adequate serum
concentrations [131]. Patients with refractory epilepsy are com-
monly resistant to many antiepileptic drugs despite different
mechanisms of action, which suggests nonspecific mechanisms
of resistance [132].
In fact, MDR in brain tumor proteins is a major cause of
refractoriness [90,132–135]. While in healthy brains MDR1
(ABCB1, P-glycoprotein) and multidrug resistance-related
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Brain tumors & epilepsy Review
protein (MRP, ABCC1) contribute to the function of the BBB
and blood–cerebrospinal fluid barrier [115,132,136,137], brain
tumors can diminish antiepileptic drugs’ transport into the
brain parenchyma [138].
Therefore, insufficient concentrations of antiepileptic drugs
in the blood can be the result of an active defense mechanism
by MDR1, which restricts the penetration of lipophilic sub-
stances into the brain. To support this hypothesis, overexpres-
sion of MDR1 was founded in samples of brain tissue from
patients with focal cortical dysplasia and ganglioglioma [16,139].
Valproic acid, carbamazepin, phenytoin, phenobarbital and
lamotrigine are substrates for this gene product [132,137], but
recent data do not support the hypothesis that MRP1 or MRP2
are involved in the efflux of valproic acid from the brain [140]. In
preclinical studies it has been demonstrated that levetiracetam
is not a substrate for MRPs [141]. Theoretically, blockers of
MDR might overcome drug resistance [97,105,142].
Tumor location
Tumor location affects the risk of medically intractable epilepsy.
A tumor invading the cortex is the main predictive factor for
development of epilepsy [3,143], and lesions in the frontal, tem-
poral and parietal lobes are more commonly associated with sei-
zures than occipital lesions [4,126]. Moreover, low-grade gliomas
are situated more frequently in eloquent corticosubcortical
areas compared with de novo glioblastoma multiforme [143]. It is
of importance that low-grade gliomas, which are highly associ-
ated with medically refractory seizures, are also located signifi-
cantly more often within the supplementary motor area (SMA)
and insula regions [143], both of which have been shown to have
a functional role in epilepsy [88,144]. In fact, the insula and SMA
share similar transitional structural and functional profiles
[145–149]. Therefore, it can be hypothesized that particular inter-
actions may exist between neurons and glial cells in these
regions [143] due to the fact that glial cells play a role in neuro-
nal migration [150]. It may explain the existence of migration
disorders in some cortical epilepsies [151], including the
extratemporal epilepsy that often originates from the SMA [152]
and insula [153] in the regulation of synaptic transmission [154],
and in the energy metabolism of the neuron, explaining the
neurovascular and metabolic decoupling in gliomas [155].
In the temporal lobe region, mass lesions might induce sec-
ondary epileptogenicity in the mesiotemporal structures lead-
ing to refractory epilepsy after surgery with lesionectomy alone
[156]. The relation between epilepsy and tumors might be
stronger than we think. In neuropathological series of en bloc
temporal resections for surgically treated temporal lobe epi-
lepsy, focal lesions other than hippocampal sclerosis have been
reported in a substantial number of specimens, ranging from
30 to 71% [157,158]. In a recent series of en bloc temporal lobe
resections for temporal lobe epilepsy, neoplasms were seen in
25.6% of the patients [156]. Two comparable publications of an
Indian group reported only 8.3 and 13.8% of neoplasms
accounting for temporal lobe epilepsy [159].
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 Review Brogna, Gil Robles & Duffau
Brain tumor surgery & epilepsy
Functional brain mapping
An essential advance in surgery of intrinsic brain tumors is the
use of intraoperative direct corticosubcortical stimulation
(DCS), under general or local anesthesia due to the frequent
location of these tumors, in particular low-grade gliomas, in elo-
quent areas and their infiltrative feature [51,143,59,160–163]. DCS
allows the mapping of motor function (possibly under general
anesthesia, by inducing involuntary motor response if stimula-
tion at the level of an eloquent site), somatosensory function (by
eliciting dysesthesia described by the patient intraoperatively)
and also the mapping of cognitive functions, such as language
(e.g., spontaneous speech, object naming and comprehension),
calculation, memory and reading or writing, performed in these
cases on awake patients, by generating transient disturbances if
the electrical stimulation is applied at the level of a functional
epicenter. Thus, DCS is able to identify in real-time the cortical
sites and subcortical white matter fibers essential for function
that must be preserved.
Intraoperative mapping also allows a better understanding of
brain functioning [160,164–166] and, above all, the study of
anatomo–functional connectivity, through the detection of
bundles for subcortical, motor, somatosensory and language
pathways, and those for other cognitive functions [59,167–169],
namely the principles of connectionism underlying both sei-
zures, and cognitive impairment and plasticity. Moreover, grad-
ual repetition of electrical stimulation during resection allows
the existence of reorganization phenomena of the functional
cortical maps to be documented over the short and long term,
making it possible to consider a second surgical intervention
with the addition of resecting lesions located in the eloquent
zones that could not be removed during the first intervention
[80,166,167,170–172].
The integration of a systematic functional mapping, of the
online study of the effective connectivity and of the individual
plastic potential during each surgical procedure has enabled
an extension of the indications for surgery of gliomas, espe-
cially low grade, to maximize the quality of the resection and
to minimize the risk of inducing permanent postoperative
neurological deficit.
Impact of brain tumor surgery on epilepsy
Several authors have studied the surgical and epileptological
outcome of tumor-associated epilepsy [86,173–175]. Favorable
results have been reported for complete lesionectomies, with
the percentage of seizure-free patients ranging from 65 to 80%
[86,159,173,175,176]. In these cases, the cortex surrounding the
tumor probably loses the ability to independently initiate and
propagate seizures once the tumor itself has been removed [174].
In low-grade gliomas, the extent of surgery favorably influ-
ences the immediate functional outcome in terms of seizure fre-
quency [177], not solely when it allows the alleviation of signs of
raised intracranial pressure or focal deficits (rarely) due to a
946
compressive mechanism. After surgical resection of low-grade
gliomas in the right and even in the left insula, seizure control
with the patient being in Engel class I is achieved in 80% of
cases [84].
Epilepsy benefits from surgery in the majority of cases, even
without the use of specialized approaches/techniques of corti-
cectomy (with improvement of quality of life), even in eloquent
areas and more so with subtotal or total resections [84].
However, there is evidence to support the concept of separate
seizure foci surrounding a tumor. After resection of temporal
lobe tumors, residual spikes can be observed with intraoperative
electrocorticography monitoring over the hippocampus and
amygdala in 86.4 and 63.6% of cases, respectively [28,178]. In
the surgical series of Sugano et al., seizure control was better if
the zone of seizure origin and the zone of maximal interictal
spiking were completely excised [178]. In a comparative study of
anterior temporal lobectomy incorporating the lesion and
lesionectomy, 90% of lobectomy patients compared with 50%
of lesionectomies patients were seizure free [179].
Therefore, there are circumstances where electrophysiological
changes presumably do not reach the stage of independent sec-
ondary epileptogenicity, and effective seizure control is possible
with lesionectomy alone. In other cases, residual spikes can be
true independent secondary foci of epileptogenicity and the
surgical treatment of independent secondary epileptic spikes
can improve seizure outcome [178].
It has been suggested that intraoperative electrocorticography
under local anesthesia could be a sensible tool to enable the
neurosurgeon to decide whether or not to continue to resect
potential epileptic foci originating in the amygdala and/or
hippocampus, while the posterior limit of surgical resection in
the temporal lobe, especially within the dominant hemisphere,
is found according to functional boundaries (for instance, until
language disturbances are induced by cortical and subcortical
mapping in awake patients) [160,167,178,180–182].
Early surgical intervention showed a strong tendency to pre-
dict better seizure outcome [175]. The seizure-free rate after sur-
gery of gliomas is 82.9% in patients with acute onset of seizures
(mostly high-grade tumors) and 62.5% in patients with
chronic seizures (mostly low-grade gliomas). This supports
early operation not only regarding oncological considerations,
but also to avoid the risk of chronic epilepsy and optimize the
patient’s quality of life [84,86,178]. This can be hypothesized also
in gangliogliomas, which are associated with intractable seizures
in up to 100% of cases. However, even in glioneuronal tumors,
which represent and indication for a true epilepsy surgery [183],
oncological considerations are important, since gangliogliomas
might progress to high-grade tumors [184].
Brain tumor surgery & refractory epilepsy
Despite the fact that more than 80% of brain tumor-related
epilepsies benefit from surgery, 15–20% of patients still suffer
from medically intractable seizures, even after (sub)total tumor
resection [84,86,159,173,175,176].
Expert Rev. Neurother. 8(6), (2008)

It is reasonable that chronic preoperative epileptic patients
might develop aberrant networks, even far from the location of
the lesion. In fact, the possible coexistence of multiple epileptic
foci and dual pathology is well demonstrated, even contralaterally,
in patients with a long history of epilepsy [185].
Interestingly, the majority of reports studied seizures associ-
ated with gliomas involving the limbic system (essentially the
mesiotemporal structures) and/or neocortex [176], but very few
described the epilepsy outcome after surgery of glial tumors
invading the insular mesocortex [186–189]. Moreover, none of
these rare series except one [186] report of two cases detailed the
results concerning medically intractable epilepsy [84].
Conversly, recent studies demonstrated that insular epilepsy
may share many clinical and EEG features with temporomesial
and opercular seizures [153,190,191], probably owing to the rich
connections between the insular cortex and the limbic/neo-
cortical regions via the uncinate fasciculus [145,192]. Thus, it is
possible that the insula may participate more often than usually
considered in (intractable) seizures [153,190].
Penfield noted the similarity between many of the symptoms
of medial temporal lobe epilepsy and those he found with insu-
lar stimulations, indicating that, in theory, insula seizures could
be confused with medial temporal lobe epilepsy seizures (cited
from [88]).
Ictal symptoms related to insula onset are: somatosensory
signs, experimental phenomena with mnemonic component,
language disturbances, visceromotor and/or viscerosensitive
manifestations, olfactory or gustatory hallucinations, and oro-
alimentary automatisms [84], and sensations of unreality of
body movement [88]. If seizures spread to the insula from the
mesial temporal lobe, patients’ reports of their symptoms are
inconsistent and unreliable because their consciousness is
affected [88]. Thus, only patients with seizures arising in the
insula (10%) can provide such information. A fully conscious
patient with laryngeal discomfort, unpleasant perioral or
somatic paresthesias, and dysarthric speech, following hemi-
sensory paresthesias, is quite specific for insular involvement.
Thus, the participation of insular cortex in refractory epilepsy
remains poorly understood [84,88].
First, the difficulty in studying this complex structure
accounted for the incomplete knowledge of its precise func-
tionality for many decades. The new developments in non-
invasive functional neuroimaging methods have recently
allowed a better analysis of the physiopathology of this entity,
which seems to constitute an interface between the limbic system
and the neocortex.
Second, the insular lobe lesions were consequently poorly
studied, particularly concerning insular gliomas and/or seizures,
with few series in several decades [153,170,191,193,194]. Indeed, for
epileptological investigations, due to its location deep within the
sylvian fissure, scalp EEG is relatively insensitive to electrical
activity in the insula, and chronic invasive electrographic studies
of the region have not been reported for a long time that take
account of a dense wall of arteries running on the insular surface.
www.expert-reviews.com
Brain tumors & epilepsy Review
Third, because of the technical complexity in approaching
and dissecting this region, very few neurosurgeons attempted
surgery of the insula structure [170,188,193,194].
Independent epileptogenicity of the insula cortex was diffi-
cult to prove. It has been extremely challenging to differentiate
seizures arising from the mesial temporal lobe and rapidly
spread to the insula versus those that originate in the insula and
consequently spread to the temporal lobe. Although the former
might still be cured with a temporal lobectomy, the latter likely
requires insular resection for successful outcome.
Owing to recent technological improvements of stereo-EEG,
in particular the smaller size of the electrode diameter and the
greater accuracy of localization of the cortical targets using MRI,
chronic recording of the insular cortex with transopercular elec-
trodes is now possible [88]. Indeed, only two observations in the
literature were reported before these developments: a chronically
implanted depth EEG strip electrode in the Sylvian fissure, in a
case of surgical resection of insular glioma, with recording of the
seizures in the insular cortex [186]; and a study in 1985 on stereo-
EEG activity recording in 11 patients with low-grade gliomas
and severe partial epilepsy, which demonstrated that while back-
ground activity is never found in the core of the tumor, it could
be found in the infiltrating white matter fibers [195]. Interest-
ingly, using the new technical progress of stereo-EEG, Isnard
et al. showed that all the recorded spontaneous seizures in a
series of 21 patients with intractable temporal lobe epilepsy were
found to invade the insula, most often after a relay in the ipsilat-
eral hippocampus (19 of 21 cases), but for two patients with
seizures directly originating in the insular cortex itself [153,196].
All these new data suggest that the insula may play an impor-
tant role in the genesis of ictal symptoms, which may sometimes
be wrongly attributed to the temporal lobe [84]. In fact, the
insula has long been implicated in the 30% failure rate after
temporal resections for medial temporal lobe epilepsy [88]. More-
over, 15% of patients harboring a low-grade glioma within the
insula, even after (sub)total surgical resection, still have intracta-
ble medical seizures that deeply affect the quality of life [84]. In
these cases, the invasion by the tumor into functional areas, as
frequently occurs in low-grade gliomas [143,197], probably leads
to a structural remodeling of the optimal small-world network
and to aberrant axonal sprouting [41,42,71,71,198–200].
For all these reasons, the authors suggest invasive recordings
with stereo-EEG in patients with total resection of tumors
within the temporal or insula lobes, who still have intractable
medical seizures. Second epilepsy surgery may be proposed to
these patients, depending on the pathways involved in current
spreading (surgical interruption of these pathways), with the
aim of improving the patient’s quality of life.
Impact of radiotherapy & chemotherapy on epilepsy
Cranial radiotherapy might have a long-term positive effect on
epilepsy in brain tumors [201,202]. It can induce a reduction in
seizure frequency of more than 75% with a median follow-up
947
 Review Brogna, Gil Robles & Duffau
of 12 months or more after this procedure [203]. Interstitial radio-
surgery might lower the incidence of seizures by increasing ben-
zodiazepine receptor density [204]. Gamma-knife radiosurgery for
mesiotemporal tumor-related epilepsy, with the aim to also irra-
diate the presumed epileptic foci surrounding the tumor volume,
might determine an improvement in seizure outcome [205].
Nevertheless, seizure frequency increases occasionally after
surgery or radiotherapy, secondary to complications such as
edema, bleeding or radiation necrosis [206].
The alkylating chemotherapeutic agent temozolomide
reduces seizure frequency in 50–60% of patients with glioma,
and 20–40% of patients become seizure free [207,208]. Therefore,
in patients with partially resected WHO grade II gliomas and
refractory epilepsy, the administration of temozolomide for
oncological reasons might also positively influence the seizure
activity, leading to an improvement in the quality of life.
Expert commentary
When treating patients harboring a brain tumor, it is mandatory
to integrate the dogmas of epilepsy into a neuro-oncological
viewpoint, according to the natural history of the tumor and the
multiple oncological treatments given to these patients. It must
be noted that frequency of seizures, as the first symptom of
pathology, differs widely between low- and high-grade tumors.
Thus, in patients harboring a low-grade glioma with at least
subtotal resection and no decision of adjuvant oncological
treatment modalities (until a recurrence or anaplastic transfor-
mation), when no seizures occur after surgery, as happens in
more than 85% of cases [18,84], it is reasonable to follow the
guidelines available [21] and to try to withdraw antiepileptic
drugs if possible.
Conversly, in patients harboring a high-grade glioma, consid-
ering the necessity to maintain a good performance status after
surgical resection in order to receive radiotherapy and chemo-
therapy, and considering the poor prognosis and the certainty of
a recurrence in a few months, it seems reasonable to maintain
the antiepileptic coverage through the patient’s lifetime.
The ideal antiepileptic drug should be effective in avoiding
both partial and generalized seizures and should not interfere
with other treatments. New antiepileptic drugs, such as leveti-
racetam, are of interest in neuro-oncology, since they have a
broad-spectrum efficacy, few side effects, are not substrates for
MDR proteins and are not enzyme inducers.
Mechanisms of epileptogenesis act at different levels: on gene
expression; on the microenvironment of the surrounding brain
parenchyma; and on global scale networks.
Nowadays, we know that the brain’s functions are shadowed
in highly complex, time-based, well-balanced small-world net-
works. The modern theories of pathological neural networks
explain that brain tumors determine an imbalance in network
architecture of functional connectivity [41,42]. Therefore, exces-
sive synchronization owing to compensatory mechanisms after
network imbalance may be the cause of epilepsy [43,46,71].
948
Low-grade gliomas seem to be highly involved in network
randomization, since they not only infiltrate the cortex, but
also spread along the white matter fibers (cables) that connect
different cortices.
More than two thirds of patients with brain tumors and med-
ically intractable epilepsy benefit from (sub)total surgical resec-
tion. Therefore, these patients are good surgical candidates,
both for oncological (impact on time to progression disease and
overall survival) and epileptological considerations. Moreover,
early surgical intervention shows a strong tendency to predict
better seizure outcome
Nevertheless, in approximately 20% of patients, surgery fails
the goal to reduce seizures and they are still intractable after the
resection of the tumor. The longer we wait to operate on
patients with brain tumors and medically intractable seizures,
the greater the risk of developing aberrant networks even far
from the location of the lesion.
We can also speculate about which treatment to propose to
these patients after the first surgery has failed in terms of seizure
reduction. Invasive EEG recordings could answer the question:
where are the epileptic foci far beyond the surgical cavity, and
how does the current spread along white matter pathways? If
the distribution of the epileptic foci is clear, we could propose
to these patients a second epilepsy surgery, aiming to improve
their quality of life.
Five-year view
In 5 years, several developments could be predicted in the
treatment of tumor-related epilepsy.
• First, in patients with brain tumors, large prospective studies
are mandatory to understand whether new antiepileptic
drugs are effective, free of side effects and free of interactions
with other drugs.
• Second, the great interest about new theories of pathological
brain networks will translate in a new in-depth understanding
of global neural network imbalance leading to epilepsy.
• Third, the modern theories of neural networks will be a unique
mathematical model to correlate at the same time epilepsy,
cognitive impairment and plasticity in brain tumors.
• Fourth, using preoperative diffusion tensor MRI (subcortical
anatomical information), MEG (temporal data), functional
MRI (functional data) and stereo-EEG (electrophysiological
data) will enable elaboration of the individual and predictive
models of the functioning of neuronal synaptic circuits, and
then to tailor the surgical strategy in term of oncological,
functional and seizure results.
• Fifth, invasive EEG recordings will help to localize seizure
foci far from the lesion, in patients with sub(total) surgical
resection, but still medically refractory epilepsy, especially in
cases where the insula seems to be involved, and to eventually
propose to the patients a second epilepsy surgery in order to
improve their quality of life.
Expert Rev. Neurother. 8(6), (2008)
 Brain tumors & epilepsy Review

with the subject matter or materials discussed in the manuscript. This

Financial & competing interests disclosure includes employment, consultancies, honoraria, stock ownership or options,
The authors have no relevant affiliations or financial involvement with expert testimony, grants or patents received or pending, or royalties.
any organization or entity with a financial interest in or financial conflict No writing assistance was utilized in the production of this manuscript.

Key issues
• Slow-growing brain tumors, such as dysembryoplastic neuroepithelial tumors, gangliogliomas and WHO grade II gliomas, are highly
associated with seizures (and no neurological deficit), while high-grade brain tumors are less associated with seizures.
• Different mechanisms of epileptogenesis are involved in low- and high-grade tumors. Epileptogenesis in brain tumors can be explained
at different levels: gene expression, changes in microenvironment and imbalance and/or hypersynchronization of complex brain
networks underlying higher order functions.
• The ideal antiepileptic drug, given to patients harboring a brain tumor, should be effective both in partial and generalized seizures,
should not interfere with neurocognitive status, with other chemotherapeutic agents administered during the natural history of disease
or with radiotherapy. In patients with no history of seizures, withdrawal of antiepileptic drugs is possible in low-grade gliomas, while it
is not recommended in high-grade tumors because of the immediate adjuvant treatments and the certainty of recurrence within
months to years. Moreover, despite the guidelines, we must consider the psychological balance of those patients who do not wish to
withdraw antiepileptic drugs and respect them.
• More than two thirds of patients with brain tumors and medically intractable epilepsy benefit from (sub)total surgical resection.
Therefore, in these patients, indications for surgery are both the impact on the oncological natural history of the lesion and the
improvement of tumor-related seizure outcome. Nevertheless, approximately 15% of patients still have medically refractory epilepsy
after surgery.
• Invasive EEG recordings have demonstrated that the insula cortex plays an important role, not only in seizure spreading, due to its
multiple connections, especially with the temporal lobe, but also in the initiation of seizures.
• Invasive EEG recording might be a valuable tool for studying patients with (sub)total resections and still medically refractory epilepsy.
• As now widely recommended in oncological surgery, namely to extend the quality of tumor removal while preserving the functions by
performing resection according to individual functional boundaries using brain mapping, we suggest to also tailor the resection on the
basis of functional mapping when performing a second surgery in patients with a brain tumor, not only for oncological, but even for
epileptological reasons.

6 Stieber VW. Low-grade gliomas. antiepileptic and chemotherapeutic agents.

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Review
Affiliations
• Christian Brogna, MD
Department of Neuroscience – Neurosurgery,
“Sapienza” University of Rome, Viale del
Policlinico, 155, 00185 Rome, Italy
Tel.: +39 064 940 942
Fax: +39 064 940 941
christian.brogna@tin.it
• Santiago Gil Robles, MD
Department of Neurosurgery,
Hôpital Gui de Chauliac, CHU de
Montpellier, 80 Avenue Augustin Fliche,
34295 Montpellier Cedex 5, France
Tel.: +33 467 33 6612
Fax: +33 467 33 6912
santigilrob@yahoo.es
• Hugues Duffau, MD, PhD
Department of Neurosurgery,
CNRS UMR 8189 and INSERM U678,
Hôpital Gui de Chauliac, CHU de
Montpellier, 80 Avenue Augustin Fliche,
34295 Montpellier Cedex 5, France
Tel.: +33 467 33 6612
Fax: +33 467 33 6912
h-duffau@chu-montpellier.fr
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