Optimal Seizure Management in
Brain Tumor Patients
Melanie S.M. van Breemen, MD, and Charles J. Vecht, MD, PhD*
Address
*Department of Neurology, Medical Center The Hague, 2501 CK
The Hague, The Netherlands.
E-mail: c.vecht@mchaaglanden.nl
Current Neurology and Neuroscience Reports 2005, 5:207–213
Current Science Inc. ISSN 1528-4042
Copyright © 2005 by Current Science Inc.
The mechanism of epilepsy in brain tumor patients is proba-
bly multifactorial, and its incidence depends on tumor type
and location. Refractory epilepsy is common in patients
with a structural brain lesion, and a role for multidrug resis-
tance proteins has been suggested. Until now, the medical
treatment of epilepsy in brain tumor patients has only been
studied retrospectively. Therefore, the optimal seizure
management by antiepileptic drugs (AEDs) in this patient
category is essentially unsure. Choices depend on the out-
come of retrospective studies, a few nonrandomized series,
extrapolation from other studies in symptomatic epilepsy,
and anticipated interactions, most notably between AEDs
and anticancer agents. The newly developed AEDs levetirac-
etam and gabapentin are recommended because of good
results in preliminary studies and because they do not
show interactions with anticancer agents. The use of pro-
phylactic AEDs in brain tumor patients is disputable and
generally not advised.
Introduction
Epilepsy is a common neurologic disorder. Cerebrovascular
diseases (21%), brain tumors (11%), and trauma (7%) are
frequent causes of symptomatic epilepsy [1].
This article focuses on the incidence, mechanisms,
and medical treatment of epilepsy associated with brain
tumors and reviews the outcome of antiepileptic drugs
(AEDs) in brain tumor patients. The prophylactic use of
AEDs in brain tumor patients and interactions of AEDs
with antineoplastic drugs is also discussed. Guidelines for
optimal treatment of epilepsy in brain tumor patients are
also suggested.
Incidence of Seizures in Brain Tumor Patients
The incidence of brain tumors in patients with epilepsy
varies from 3.5% (before the advent of computed tomo-
graphy and magnetic resonance imaging) to 35%. However,
selection bias influences these figures, as many reports
focus on patients with refractory epilepsy in tertiary care
facilities. In the general population, the incidence of brain
tumors in patients with epilepsy is approximately 4%.
With an average of 30% or more, the incidence of epilepsy
in patients with brain tumors is much higher [2,3]. The
greatest frequency is seen with parietal lesions, and the
smallest risk is observed in occipital tumors [4,5].
The risk of developing seizures in brain tumor patients
is related to tumor type (Table 1). Low-grade gliomas such
as grade II astrocytomas and gangliogliomas are more
frequently associated with seizures than high-grade brain
tumors, and an incidence up to 100% has been reported in
patients with dysembryoblastic neuroepithelial tumors
(DNET) [1,2,4]. In high-grade tumors, the incidence of
epilepsy varies between 29% and 69% [1,6], and in meta-
static brain lesions 35% of patients develop seizures [1].
The location of the tumor seems to be related to seizure
development, and epilepsy is much more frequent with
cortical lesions than with (deep) white matter lesions [6].
Infratentorial and sellar lesions rarely cause seizures unless
there is extension into the cerebral hemispheres.
Epileptogenesis in Brain Tumors
The question of why brain tumors cause epilepsy is
intriguing, and the answer is probably multifactorial
because several mechanisms may cause epilepsy in brain
tumors. The epileptogenic activity probably arises in the
adjacent cortex, although most lesions are electrically inert
[7]. Most likely, the mechanism of epileptogenesis is
related to the type of the tumor. Developmental tumors
with a high seizure incidence are often associated with
cortical dysplasia or other structural abnormalities with
epileptogenic properties. Secondly, developmental tumors
are composed of well-differentiated cells with the poten-
tial to release neurotransmitters or modulators involved in
epileptogenesis. Developmental and slow growing tumors
may, by means of mechanic or vascular mechanisms,
partially isolate brain regions. Relative deafferentation of
circumscribed cortical areas is known to cause intrinsic
epileptogenic properties [6,7]. Low-grade lesions are
more often associated with seizures than their malignant
counterpart, as a longer time interval is needed for the
development of focal or remote cell changes involved in
epileptogenesis [9]. Rapidly progressive brain tumors,
208 Neoplasms
Table 1. Association between tumor type and
seizure frequency
Seizure
Tumor type frequency, % Study
DNET 100 Fish [6], Morrell and
Toldeo-Morrell [7]
Ganglioglioma 80–90 Herman [1], Villemure
and De Tribolet [8]
Low-grade 75 Cascino [42••], Villemure
astrocytoma and De Tribolet [8]
Meningioma 29–60 Herman [1], Villemure
and De Tribolet [8]
Glioblastoma 29–49 Herman [1], Cascino
multiforme [42••], Villemure and
De Tribolet [8]
Metastasis 20–35 Herman [1], Villemure
and De Tribolet [8]
DNET—dysembryoplastic neuroepithelial tumor.
such as metastases or glioblastoma multiforme (GBM),
may cause epilepsy due to more abrupt ways of tissue
damage (eg, necrosis, edema, or hemosiderin deposits).
Increased epileptogenesis develops as the distance of
tumor cells to the cortex diminishes, most clearly seen with
Rolandic lesions [6]. Also, tumor location is associated
with the clinical type of epilepsy. Complex partial, sensory
partial, and motor partial seizures are usually seen when
lesions are respectively located in temporal, primary
sensory motor cortex, or mesial frontal areas. When a
tumor is present in parietal or occipital regions, seizures
are often simple or complex partial. In general, the aura
provides a clue to the site of seizure onset. However,
in almost one third of patients with brain tumors and
epilepsy, the epileptogenic focus would not correspond to
tumor location. This phenomenon is called secondary
epileptogenesis, implying that an actively discharging
epileptogenic region induces similar paroxysmal activity in
regions distant to the original site [6,10]. This process is
mostly seen with temporal lesions [3], and the secondary
focus seems directly connected with the site of the primary
lesion. The risk of developing a secondary focus seems
related to younger age and to duration of the illness. Early
treatment of the primary focus may be warranted because
over time a secondary focus can become irreversible [9].
Tumors might also be located in or near the hippocam-
pus, a well-recognized epileptogenic area. Hippocampal
sclerosis is described in patients with developmental and
acquired tumors, mainly with temporally located tumors.
Morphologic changes in peri-tumoral brain tissue, like
aberrant neuronal migration, changes in synaptic vesicles,
persistent neurons in white matter, or imbalance between
incitatory and excitatory mechanisms, are all likely to be
involved in seizure development in brain tumor patients [8].
It is known that peri-tumoral pH is slightly alkaline, leading
to epileptogenesis by inducing excitatory pathways
and diminishing inhibitory ones. Glutamate, an excitatory
neurotransmitter, is probably also related to the develop-
ment of seizures in brain tumor patients. Bateman et al. [11]
reported increased concentrations of this neurotransmitter in
gliomas associated with epilepsy. Schaller and Rüegg [12]
described the possibility of increased excitability resulting
from abnormal glutamatergic transmission, involving altered
receptor subunit expression in brain tumors. Wolf et al. [9]
reported altered perilesional immunoreactivity patterns for
glutamate decarboxylase and for the gamma aminobutyric
acid receptor in patients with focal lesions and refractory
epilepsy, suggesting a possible relation of a disturbed balance
of incitatory and excitatory mechanisms. Increased inter-
cellular communication through increased expression of
gap-junction channels has also been implicated in the patho-
genesis of epilepsy in peri-tumoral brain tissue. Aronica et al.
[13] observed high expression of connexin, a gap-junction
protein, in low-grade tumors and in perilesional astrocytes,
suggesting a possible relation between increased cellular
communication and epileptogenesis.
In summary, these observations suggest that the
mechanism of epileptogenesis in brain tumor patients
seems to be multifactorial, related to tumor type and
location, and to mechanical, vascular, biochemical, or
morphologic peri-tumoral changes.
Epilepsy As a Presenting Sign
Overall, 30% to 50% of patients with brain tumors present
with epilepsy as the presenting sign of the cerebral tumor
[1,14,15•,16,17], and they can be divided in two groups of
patients. The first are children and adolescents presenting
with epilepsy without neurologic deficits, often in low-
grade tumors. The second are the middle aged and elderly
who present with epilepsy and commonly have high-grade
tumors associated with neurologic deficits. Slow-growing
tumors present in 60% to 85% with seizures [1], malignant
gliomas in 20% to 40% [18], and brain metastasis in 15%
to 19% [14]. The highest risk for developing epilepsy
exists when the tumor is located in the temporal, primary
sensory motor cortex, or supplementary areas [1].
Refractory Seizures
Epilepsy in brain tumors is often of a refractory type; the
reported incidence of treatment-resistant epilepsy varies
from 12% to 50% [3,6]. In the overall epilepsy population,
refractory seizures occur in approximately 20% of patients
with primary generalized epilepsy and in 35% of those
with partial epilepsy [19]. Patients with a structural brain
lesion are prone to refractory epilepsy [20]. The basis of
resistance to drug treatment is unknown. It is striking that
refractory patients are often resistant to many AEDs, in
spite of the different mechanisms of action of AED sub-
groups, which indicates nonspecific mechanisms of resis-
tance [21]. Different studies mention the importance of
 Optimal Seizure Management in Brain Tumor Patients • van Breemen and Vecht
overexpression of proteins involved in a multidrug resis-
tance pathway in brain tumors, augmenting the risk on
developing refractory epilepsy. In cancer multidrug resis-
tance, these proteins reduce the intracellular concentra-
tiong of many antineoplastic agents. Multidrug resistance
gene-1 P-glycoprotein (MDR1) and multidrug resistance-
associated protein 1 (MRP1) contribute in the normal
brain to the function of the blood-brain barrier and blood-
cerebrospinal fluid barrier [20,22–24]. There is evidence
that several AEDs, such as phenytoin, phenobarbital,
carbamazepine, lamotrigine, and felbamate, are substrates
of P-glycoprotein and might actively be transported out of
the brain, resulting in insufficient antiepileptic blood lev-
els [20,22]. Overexpression of MDR1 has been reported in
brain tissue specimens of patients with intractable epi-
lepsy. Theoretically, MDR1 blockers could help overcome
drug resistance, and presently the efficacy of third-genera-
tion MDR1 blockers are being studied [25]. Probably not
all AEDs are substrates of this pathway, so drug resistance
in epilepsy most likely is multifactorial. When the brain
tumor is accessible for neurosurgical treatment in patients
with medical refractory epilepsy, surgery is an important
type of treatment to consider. In selected patients, many
studies indicate that epilepsy surgery can control seizures
in more than two third of patients [19,26].
Treatment
Before reviewing AED treatment in brain tumor patients,
we discuss general brain tumor management. The
prophylactic use of AEDs in brain tumor patients is
discussed as well.
General management of brain tumors
Discussing the treatment of brain tumors in general would
exceed the scope of this article because it is a broad topic
with ongoing improvements in diagnostic and treatment
options. In general, treatment decisions in brain tumor
patients depend on patient and tumor characteristics
including age, performance status, clinical manifestations
of the tumor, and location, size, histology, grading, and
spread of the tumor.
Treatment modalities depend on these criteria and
may differ from more symptomatic management to treat-
ments with a curative intent. In low-grade gliomas, radia-
tion therapy is often withheld in patients younger than
40 years of age, whereas in high-grade lesions adjuvant
radiotherapy and chemotherapy will be applied after sur-
gical excision. Recurring gliomas can be treated, depen-
dent on age, performance status, previously administered
treatment, tumor type, and location of the tumor by
means of neurosurgery, re-irradiation, chemotherapy, or
a combination of these modalities. Also, treating patients
with brain tumors is not a purely medical affair, but
requires emotional support as well, preferably in a multi-
disciplinary setting.
209
Antiepileptic drugs in brain tumor patients
Remarkably, despite their huge prevalence, only a few
studies describe the efficacy of AEDs in epilepsy associated
with brain tumors. Most reports are mainly devoted to the
effects of brain tumor surgery on refractory epilepsy. This
article reviews the available papers on the efficacy of AED
treatment on the epilepsy in brain tumors and discusses
the results of neurosurgery in refractory epilepsy in this
patient category.
Moots et al. [18] studied retrospectively the course of
seizure disorders in 65 patients with malignant gliomas
(Table 2). They report a high incidence of seizures in
patients with bilateral or multifocal neoplasms and lesions
located in frontal or parietal regions. Seizures were pre-
dominantly partial. All patients underwent tumor surgery
and received AED treatment, followed by adjuvant therapy
in up to 95% of the patients. Patients who presented
with seizures as the first manifestation of their illness
almost always had recurrent seizures. Also, the likelihood
of experiencing a status epilepticus and the need for
AED polypharmacy was greater in the group with
epilepsy as presenting sign. Because of the high number of
patients with recurrent seizures (72%) and late-onset
seizures in 10% of patients despite prophylaxis with AEDs,
Moots et al. [18] concluded limited efficacy of anti-
convulsants in patients with malignant gliomas. However,
the reported seizure frequency is probably confounded
by several factors. The operation and adjuvant treatment
will influence brain characteristics and probably epilepto-
genesis as well. The existence of interactions between
chemotherapeutics and AEDs may be another confound-
ing factor in this study. Third, this study only evaluated
patients with malignant gliomas; low-grade tumors are
probably more resistant to therapy with AEDs. Fourth, the
exact type of anticonvulsants used in this patient group
was not specified.
Stephen et al. [27] studied the response of 550 patients
with localization-related epilepsy to AEDs. Two thirds
(66%) of patients showed structural abnormalities on brain
imaging, of which only 6% constituted primary brain
tumors. Of these 34 patients (with a median follow-up
of 5 years), 60% became seizure free, of whom 25% of
these required more than one AED. Because of the small
group of brain tumor patients and the absence of informa-
tion about the type of AED treatment, no firm conclusions
can be drawn.
Wagner et al. [28], Siddiqui et al. [29], and Perry and
Sawka [30] studied the effects of third-generation AEDs in
patients with brain tumors (Table 3).
Wagner et al. [28] investigated the effect of levetiracetam
encouraged by the absence of potential interference with
other drugs such as chemotherapeutic agents metabolized
by the hepatic cytochrome P-450 system. They studied 26
patients with a primary brain tumor who received add-on
levetiracetam because of persisting seizures, adverse side
effects of other AEDs, or potential drug interactions. In 65%
210 Neoplasms

Table 2. Treatment in brain tumor patients

Presenting sign, % (n/n) Late onset, % (n/n) All patients, % (n/n)
Recurrent seizures 72 (21/29) NA NA
Refractory seizures 62 (13/21) 10 (1/10) 22 (14/65)
Surgery NA NA 100
Chemotherapy NA NA 95
Radiotherapy NA NA 89
AEDs NA NA 97
Polypharamacy 28 (8/29) 10 (1/10) NA
Partial motor status 31 (9/29) 10 (1/10) 15 (10/65)
AED toxicity NA NA 26 (rash)*, 14 (other)

*Especially for carbamazepine and phenytoin.

AED—antiepileptic drug; NA—not available.
(Data from Moots et al. [18].)

Table 3. Effects of specific AEDs on seizure frequency in brain tumor patients

Siddiqui et al. [29] Wagner et al. [28] Perry and Sawka [30]
Study design Retrospective Prospective Prospective
Patients, n 41 26 14
Tumor Brain Primary brain Brain
AED studied Levetiracetam Levetiracetam Gabapentin
Dosage, mg/d 1000–3000 2000–4000 300–2400
Monotherapy, % 39 46 0
Seizure reduction, % 27 65 100
Seizure free, % 51 20 57
No improvement, % 5 NA 0
Other treatment NA Corticosteroids, chemotherapy, Corticosteroids, radiotherapy
previous surgery, radiotherapy

AED—antiepileptic drug; NA—not available.

of patients, a seizure reduction of more than 50% was
observed and a substantial part of patients eventually
received monotherapy with levetiracetam. Siddiqui et al.
[29] retrospectively studied the effect of levetiracetam in 41
patients with brain tumors. Indications for starting levetirac-
etam were similar to Wagner et al. [28]. Compared with the
latter, more patients became seizure free but fewer patients
experienced seizure reduction (27% vs 65%). Both studies
reported few side effects of levetiracetam treatment.
Perry and Sawka [30] studied the effect of add-on gaba-
pentin in patients with intractable seizures associated with
brain neoplasms. In this small prospective study, gaba-
pentin was added to phenytoin, carbamazepine, or cloba-
zam. In all patients, reduction in seizure frequency was
seen, and more than 50% became seizure free. Of course,
in these studies we have to take into account their small
size, so conclusions are hard to make. Thus, treatment with
add-on levetiracetam or gabapentin seems well tolerated
in brain tumor patients, but further clinical investigations
in larger series are certainly needed.
Antiepileptic drug prophylaxis in brain tumor patients
The high risk of developing seizures in brain tumor patients
makes prophylactic AEDs a feasible option. Indeed, in
patients undergoing brain tumor surgery this has been
examined, although with conflicting results [5,31–33]. In a
retrospective study of 195 patients with intracerebral
metastases, the prophylactic use of diphenylhydantoin
proved to be ineffective [34]. A meta-analysis on 12 studies
examined the effectiveness of prophylactic anticonvulsants
to prevent a first seizure in patients with brain tumors.
None of these studies provided convincing evidence of
efficacy of prophylactic AEDs. Wide effects of AEDs, how-
ever, were more frequently seen in patients with brain
tumors (20% to 40%) than in a more general population
with epilepsy receiving anticonvulsants [15•,17]. Taphoorn
[35•] discussed the results of a large cross-sectional study in
the Netherlands that involved 195 patients with low-grade
gliomas. Not only the presence and severity of epilepsy, but
also the use of AEDs, were more frequently associated with
cognitive deficits.
Another reason to be more reserved in prescribing
prophylactic AEDs is the fact that older patients are more
prone to develop side effects of AED treatment because
of changing pharmacokinetics. Aging, gastric mucosal
atrophy, declining hepatic and renal function, decreasing
serum albumin concentration, and increase in ratio of fat
to lean body mass may all result in changing pharmaco-
 Optimal Seizure Management in Brain Tumor Patients • van Breemen and Vecht
kinetics [36]. A consensus statement has been published
recommending discontinuing AEDs or not applying pro-
phylactic AEDS in patients who have not had a previous
seizure [15•,17].
Interactions between antiepileptic drugs and
antineoplastic agents
An important issue is the appreciable risk on serious inter-
actions with simultaneous use of AEDs and anticancer
therapy. For example, phenytoin, carbamazepine, and
phenobarbital reduce the efficacy of corticosteroids, a
frequently used medication in cancer patients. Secondly,
many AEDs influence the cytochrome P-450 enzyme system
of the liver in either an excitatory or inhibiting way, and thus
are designated as either enzyme-inducing antiepileptic drugs
(EIAEDs) or enzyme-inhibiting antiepileptic drugs. The
classic AEDs phenobarbital, phenytoin, and carbamazepine
are all enzyme-inducers, as is the recently developed topira-
mate. As expected, many chemotherapeutic agents are also
being metabolized by the cytochrome P-450 enzyme
system. Theoretically, EIAEDs can result in an accelerated
metabolism of chemotherapeutics, leading to a diminished
plasma concentration and anticancer activity. Indeed,
EIAEDs have been observed to reduce the effects of taxanes,
vinca alkaloids, methotrexate, teniposide, and camptothecin
analogues [37,38]. However, the interaction of EIAEDs and
chemotherapeutics is double-sided. Grossman et al. [39]
described diminished phenytoin concentration in patients
with brain tumors receiving a combination of cisplatin and
carmustin. Later, they also described drug interactions
between 9-aminocamptothecin and anticonvulsants [39].
Neef et al. [40] reported lower levels of carbamazepine and
valproate in patients receiving adriamycin and cisplatin.
Poor seizure control has also been reported in patients
using a combination of phenytoin and corticosteroids or a
combination of valproic acid and methotrexate.
Increased toxicity of AEDs or chemotherapeutics may,
however, develop when enzyme-inhibiting agents are
being prescribed. Toxicity of phenytoin is described when
it is combined with 5-fluorouracil [41]. Valproic acid, an
enzyme-inhibiting anticonvulsant, has been reported to
induce toxicity of chemotherapy by means of inhibition of
the metabolism of nitrosoureas or etoposide [17].
Some of the newer AEDs not metabolized by the P-450
enzyme system may better suited for use in combination
with anticancer agents. Few side effects by levetiracetam
have been reported in brain tumor patients receiving con-
comitant chemotherapeutic drugs [23,28]. However, these
observations were made in small studies with a relatively
short follow-up and warrant further testing.
Surgical treatment of refractory epilepsy in brain
tumor patients
The frequency and type of seizures, comorbidity, under-
lying pathology, and the psychologic effect of the disease
all are important factors in selecting proper candidates for
211
neurosurgical treatment. Favorable prognostic indicators
include early age of seizure onset, a foreign tissue lesion,
and medial temporal lobe seizure onset. Following a total
excision of the epileptogenic zone, more than 80% to 90%
of patients with lesional epilepsy or medial temporal lobe
epilepsy may be rendered seizure free [42••].
Zentner et al. [43] studied the effect of surgical treat-
ment of neoplasms in 146 patients with intractable
epilepsy (incomplete seizure control for at least 1 year at
maximum serum levels of at least two first-line AEDs)
and a mean follow-up of 3 years (Table 4). The extent of
resection included both the tumor and the epileptogenic
zone. Most tumors were located temporally (116 of 146)
and 98% were low-grade tumors (ganglioglioma, DNET,
pilocytic astrocytoma). Overall, 95% of patients showed
improvement after surgical treatment, and in this group
71% became seizure free (Engel class I), 11% experienced
less than two seizures per year, and 13% reported post-
o p e r a t i ve s e i z u r e r e d u c t i o n o f m o r e t h a n 7 5 % .
Most favorable results were seen with gangliogliomas
(78% vs 64% in the glioma group).
Morris et al. [44] retrospectively studied the effect of
surgery in 38 patients with ganglioglioma and intractable
epilepsy. Resected areas were similar to those described by
Zentner et al. [43]. After a 3-year follow-up period, 66%
of patients became seizure free. A good postoperative
outcome was associated with the absence of secondary
generalized seizures, shorter duration of epilepsy prior to
surgical treatment, younger age at operation, and absence
of epileptogenic activity on interictal electroencephalo-
gram at 6 months postoperatively. It seems that early oper-
ative intervention in patients with ganglioglioma and
intractable epilepsy is associated with the greatest change
of relief of the epilepsy.
Luyken et al. [45] discussed 207 patients with medical
refractory epilepsy–associated brain tumors. Median follow-
up was 8 years. Most tumors were low-grade (99%) and
located in temporal areas (83%). At 1 year after the opera-
tion, 82% of the population was seizure free, and overall
95% of patients showed remarkable improvement. Of
patients who were not seizure free after surgery, 29% did
improve to Engel class I after a median follow-up of 3 years.
Factors associated with improved seizure outcome included
shorter duration of epilepsy, a single EEG focus, no addi-
tional hippocampal sclerosis, histology other than grade II
or III astrocytomas, and no postoperative residual tumor.
They conclude that improvement of seizure outcome is
possible when a tumor is diagnosed and removed early.
A small retrospective study from Brazil on 32 patients
with a brain tumor and intractable epilepsy showed com-
parable results of neurosurgical treatment of the tumor
together with the epileptogenic zone [46].
Because there may be a substantial risk of developing
secondary epileptogenesis, early treatment of the primary
focus may be warranted because over time the secondary
focus can become irreversible [9]. Another argument for
212 Neoplasms

Table 4. Effect of neurosurgery on tumor-related intractable epilepsy

Zentner et al. [43] Morris et al. [44] Luyken et al. [45] Brainer-Lima et al. [46]
Study design Retrospective Retrospective Retrospective Retrospective
Patients, n 146 38 207 32
Tumor grade, %
Low 98 100 99 94
High 2 0 1 6
Resection Tumor, EZ Tumor Tumor, EZ Tumor, EZ
Engel class, %*
I 71 66 87 90
II/III 24 NA 10 10

*Engel class I refers to patient being seizure free or having only auras after surgery; class II indicates rare seizures (≤ 2/y); and class III indicates
reduction of seizure frequency of 75% or more.
EZ—epileptogenic zone; NA—not available.

treating brain tumor patients with intractable epilepsy
early by means of neurosurgery is neurocognitive decline
as reported in patients using AEDs [35•]. Thus, it seems
sensible to consider early neurosurgical intervention in
patients with treatment-resistant epilepsy secondary to
brain tumors.
Conclusions
Prophylactic use of AEDs is not recommended based on
the absence of proven efficacy for preventing seizures as
observed in randomized studies. Following brain sur-
gery, AEDS can be discontinued after 1 week in patients
who had no prior seizures. In patients with refractory
epilepsy and brain tumors, surgery has to be considered
in an early phase in tumors accessible for neurosurgical
excision [15•]. Given the scarcity of reports on medical
treatment of epilepsy in brain tumors, recommenda-
tions rather than firm guidelines can be given on opti-
mal prescription of AEDs.
In general, the use of EIAEDS is discouraged. Valproic
acid can be considered as a first-line agent, although one
should be aware of enhanced toxicity of concomitant use
with agents sharing the same P-450 coenzyme of metabo-
lism. If valproic acid alone is ineffective, levetiracetam can
be added given its observed efficacy in combination with
valproic acid, and also its absence of interactions. Alterna-
tively, gabapentin can be given because it shows no appar-
ent drug interactions, even with chemotherapeutic agents,
and it can also be used as a single agent. Further studies are
warranted to evaluate the effects of specific AEDs in deter-
mining optimal regimens for epilepsy in brain tumors.
References and Recommended Reading
Papers of particular interest, published recently, have been
highlighted as:
• Of importance
•• Of major importance
1. Herman ST: Epilepsy after brain insult. Neurology 2002,
599(Suppl 5):S21–S26.
2. Hauser WA, Annegers JF, Kurland LT: Incidence of epilepsy and
unprovoked seizures in Rochester, Minnesota: 1935-1984.
Epilepsia 1988, 34:453–468.
3. Morris HH, Estes ML: Brain tumors and epilepsy. In The
Treatment of Epilepsies. Principles & Practice. Edited by Wyllie E.
Cleveland: Lippincott Williams & Wilkins; 2001: 615–626.
4. Cascino GD: Epilepsy and brain tumors: implications for
treatment. Epilepsia 1990, 31(Suppl 3):S37–S44.
5. Mahaley MS, Dudka L: The role of anticovulsant medications
in the management of patients with anaplastic gliomas. Surg
Neurol 1981, 16:399–401.
6. Fish DR: How do tumors cause epilepsy? In The Epilepsies.
Etiologies and Prevention. Edited by Kotagal P, Lüders HO.
Cleveland: Academic Press; 1999:301–314.
7. Morrell F, Toledo-Morell L: Secondary epileptogenesis and
brain tumors. In The Epilepsies. Etiologies and Prevention. Edited
by Kotagal P, Lüders HO. Cleveland: Academic Press;
1999:357–363.
8. Villemure JG, De Tribolet N: Epilepsy in patients with central
nervous system tumors. Curr Opin Neurol 1996, 9:424–428.
9. Wolf HK, Roos D, Blümcke I, et al.: Perilesional neurochemical
changes in focal epilepsies. Acta Neuropathologica 1996,
91:376–384.
10. Gilmore R, Morris H, Van Ness PC, et al.: Mirror focus: function
of seizure frequency and influence on outcome after surgery.
Epilepsia 1994, 35:258–263.
11. Bateman DE, Hardy JA, McDermott JR, et al.: Amino acid trans-
mitter levels in gliomas and their relationship to the incidence
of epilepsy. Neurol Res 1988, 10:112–114.
12. Schaller B, Rüegg S: Brain tumor and seizures: pathophysiol-
ogy and its implications for treatment revisited. Epilepsia
2003, 44:1223–1232.
13. Aronica E, Gorter JA, Jansen GH, et al.: Expression of connex-
ion 43 and connexion 32 gap-junction proteins in epilepsy-
associated brain tumors and in the perilesional epileptic
cortex. Acta Neuropathol 2001, 101:449–459.
14. Bourekas EC, Perl J: Imaging tumors in epilepsy. In The Epilepsies.
Etiologies and Prevention. Edited by Kotagal P, Lüders HO.
Cleveland: Academic Press; 1999:315–335.
 Optimal Seizure Management in Brain Tumor Patients • van Breemen and Vecht
15.• Glantz MJ, Cole BF, Forsyth PA, et al.: Practice parameter: anti-
convulsant prophylaxis in patients with newly diagnosed
brain tumors: report of quality standards subcommittee of
the American Academy of Neurology. Neurology 2000,
54:1886–1893.
A clear guideline on the use of prophylactic AED treatment in patients
with primary and metastatic brain tumors.
16. Morris HH, Estes ML, Gilmore R, et al.: Chronic intractable
epilepsy as the only symptom of primary brain tumor. Epilepsia
1993, 34:1038–1043.
17. Wen PY, Marks PW: Medical management of patients with
brain tumors. Oncology 2002, 14:299–307.
18. Moots PL, Maciunas RJ, Eisert DR, et al.: The course of seizure
disorders in patients with malignant gliomas. Arch Neurol
1995, 52:717–724.
19. Devinsky O: Patients with refractory seizures. N Engl J Med
1999, 20:1565–1570.
20. Sisodiya SM, Lin WR, Harding BN, et al.: Drug resistance in
epilepsy: expression of drug resistance proteins in common
causes of refractory epilepsy. Brain 2002, 125:22–31.
21. Löscher W, Poitschka H: Role of multidrug transporters in
pharmacoresistance to antiepileptic drugs. J Pharmacol Exper
Ther 2002, 301:7–14.
22. Rogawski MA: Does P-glycoprotein play a role in pharma-
coresistance to antiepileptic drugs? Epilepsy Behav 2002,
3:493–495.
23. Siddiqui A, Kerb R, Weale ME, et al.: Association of multidrug
resistance in epilepsy with a polymorphism in the drug-
transporter gene ABCB1. N Engl J Med 2003, 348:1442–1448.
24. Tan B, Piwnica-Worms D, Ratner L: Multidrug resistance trans-
porters and modulation. Curr Opin Oncol 2000, 12:450–458.
25. Goldman B: Multidrug resistance: can new drugs help
chemotherapy score against cancer? J Natl Cancer Inst 2003,
95:255–257.
26. Britton JW, Cascino GD, Sharbrough FW, Kelly PJ: Low-grade
glial neoplasms and intractable partial epilepsy: efficacy of
surgical treatment. Epilespia 1994, 35:1130–1135.
27. Stephen LJ, Kwan P, Brodie MJ: Does the cause of localisation-
related epilepsy influence the response to antiepileptic drug
treatment? Epilepsia 2001, 42:357–362.
28. Wagner GL, Wilms EB, Van Donselaar CA, Vecht CJ: Levetira-
cetam: the preliminary experience in patients with primary
brain tumours. Seizure 2003, 12:585–586.
29. Siddiqui F, Wen P, Dworetzky B, et al.: Use of levetiracetam in
patients with brain tumors. Epilepsia 2002, 43(Suppl 7):297.
30. Perry JR, Sawka C: Add-on Gabapentin for refractory seizures
in patients with brain tumours. Can J Neurol Sci 1996,
23:128–131.
213
31. Franceshetti S, Binelli S, Casazza M, et al.: Influence of surgery
and antiepileptic drugs on seizures symptomatic of cerebral
tumors. Acta Neurochirurg 1990, 103:47–51.
32. North JB, Penhall RK, Hanieh A, et al.: Phenytoin and post-
operative epilepsy. J Neurosurg 1983, 58:672–677.
33. Shaw MDM: Post-operative epilepsy and the efficacy of anti-
consulvant therapy. Acta Neurochirurg 1990, S50:55–57.
34. Cohen N, Strauss G, Lew R, et al.: Should prophylactic
anticonsulvants be administered to patients with newly-
diagnosed cerebral metastases? A retrospective analysis.
J Clin Oncol 1988, 6:1621–1624.
35.• Taphoorn JB: Neurocognitive sequelae in the treatment of
low-grade gliomas. Semin Oncol 2003, 30:45–48.
An interesting article showing us that not only the tumor itself and
radiotherapy, but also the severity of epileptic seizures and the use of
AEDs, are strongly associated with cognitive decline.
36. Rowan AJ, James RA: Reflections on the treatment of seizures
in the elderly population. Neurology 1998, 51:S28–S33.
37. Baker AF, Dorr RT: Drug interactions with the taxanes: clinical
implications. Cancer Treat Rev 2001, 27:221–233.
38. Vecht CJ, Wagner L, Wilms EB: Interactions between antiepi-
leptic and chemotherapeutic drugs. Lancet 2003, 2:404–409.
39. Grossman SA, Hochberg F, Fisher J, et al.: Increase 9-amino-
camtothecin dose requirements in patients on anticonsul-
vants. Cancer Chenother Pharmacol 1998, 42:118–126.
40. Neef C, de Voogd-van der Straaten I: An interaction between
cytostatic and anticonsvulsant drugs. Clin Pharmacol Ther
1998, 43:372–375.
41. Gilber PJ, Brodribb TR: Phenytoin and fluorouracil inter-
action. Ann Pharmacother 2001, 35:1367–1370.
42.•• Cascino GD: Surgical treatment for epilepsy. Epilepsy Res 2004,
60:179–186.
A clear review describing the importance of early and effective
epilepsy surgery looking at seizure frequency and quality of life.
43. Zentner J, Hufnagel A, Wolf HK, et al.: Surgical treatment of
neplasms associated with medically intractable epilepsy.
Neurosurgery 1997, 41:378–386.
44. Morris HH, Matkovic Z, Estes ML, et al.: Ganglioglioma and
intractable epilepsy: clinical and neurophysiologic features
and predictors of outcome after surgery. Epilepsia 1998,
39:307–313.
45. Luyken C, Blümcke I, Fimmers R, et al.: The spectrum of epi-
lepsy-associated tumors: long-term seizure and tumor outcome
and neurosurgical aspects. Epilepsia 2003, 44:822–830.
46. Brainer-Lima PT, Rao S, Cukiert A, et al.: surgical treatment of
refractory epilepsy associated with space occupying lesions.
Arq Neuropsiquiatr 1996, 54:384–392.