Epilepsy & Behavior 21 (2011) 331–341

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Epilepsy & Behavior

j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / ye b e h

Review

Antiepileptic drug therapy: Does mechanism of action matter?

Martin J. Brodie a,⁎, Athanasios Covanis b, Antonio Gil-Nagel c, Holger Lerche d, Emilio Perucca e, f,
Graeme J. Sills g, H. Steve White h
a
Epilepsy Unit, Western Infirmary, Glasgow, UK
b
Neurology Department, Agia Sophia Children's Hospital, Thivon and Levadias, Goudi, Athens, Greece
c
Epilepsy Programme, Hospital Ruber Internacional, Madrid, Spain
d
Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University Hospital Tübingen, Tübingen, Germany
e
Clinical Pharmacology Unit, Department of Internal Medicine and Therapeutics, University of Pavia
f
National Institute of Neurology IRCCS C Mondino Foundation, Pavia, Italy
g
Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK
h
Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, UT, USA

a r t i c l e i n f o a b s t r a c t

Article history: This article represents a synthesis of presentations made by the authors during a scientific meeting held in
Received 10 March 2011 London on 7 June 2010 and organized by GlaxoSmithKline. Each speaker produced a short précis of his lecture
Revised 19 May 2011 to answer a specific question, resulting in an overview of what we know about the relevance of the
Accepted 24 May 2011
mechanisms of action of antiepileptic drugs in determining appropriate combination therapies for the
Available online 16 July 2011
treatment of drug-resistant epilepsy.
Keywords:
© 2011 Elsevier Inc. All rights reserved.
Antiepileptic drugs
Mechanism of action
Epileptogenesis
Antiepileptogenesis
Disease modification
Epilepsy
Pharmacokinetics
Pharmacodynamics
Interactions
Treatment

1. Introduction potentially useful combinations that require investigation—too many

The past two decades have witnessed an unprecedented expan-
sion in pharmacological treatment options for epilepsy [1], but there
is limited evidence to suggest that clinical outcomes have substan-
tially improved for people with epilepsy over that period [2–4]. This is
perhaps not surprising as the placebo-corrected efficacy of adjunctive
treatment with modern antiepileptic drugs (AEDs) in double-blind,
dose-ranging trials in adults with refractory focal epilepsy has been
disappointingly small [5], with very few patients becoming seizure
free, even for the relatively short period of these trials [6]. The
situation seems no better for childhood epilepsies [7–9]. With 20
currently recognized AEDs, there are, in theory, 190 possible
partnerships of two drugs and 1140 possible combinations of three
drugs. Although a significant proportion of these are not likely to be
used in clinical practice, there remains a substantial number of
⁎ Corresponding author at: Epilepsy Unit, Western Infirmary, Glasgow G11 6NT,
Scotland, UK. Fax: + 44 141 211 2072.
E-mail address: mjb2k@clinmed.gla.ac.uk (M.J. Brodie).
for a doctor and his or her patient to try in a single lifetime.
Accordingly, a more focused approach to treating drug-resistant
epilepsy is needed [10]. It is logical to suggest that this should be
based on the mechanisms of action of the available therapeutic
armamentarium. Although we have a reasonable idea of how the
majority of AEDs act, little is known about the pathophysiology of
most epilepsies or the neurobiologies underpinning drug response
and pharmacoresistance in the individual patient.
A rational approach to combination therapy has been adopted
in other complex, multifaceted diseases in which a single agent is
ineffective in a substantial proportion of patients. Examples
include migraine [11], neuropathic pain [12], hypertension [13],
and human immunodeficiency virus infection [14]. In addition,
rational polytherapy is used increasingly in oncology as agents
are developed that target specific pathogenic mechanisms
[15,16].
In this review we consider the theory and practice of combining
AEDs in the treatment of epilepsies as approaches to a number of
relevant questions.

1525-5050/$ – see front matter © 2011 Elsevier Inc. All rights reserved.
doi:10.1016/j.yebeh.2011.05.025
332 M.J. Brodie et al. / Epilepsy & Behavior 21 (2011) 331–341
2. Does what we know about mechanisms of action match what
we know about seizure generation?
Ion channels, which form the basis of neuronal excitability and
synaptic transmission, are membrane-spanning proteins that form
selective pores with gates that open and close in response to stimuli
such as membrane voltage or ligand binding. Recordings from
epileptic foci typically show a paroxysmal depolarizing shift, in
which glutamate receptors and calcium channels are implicated in the
depolarizing and plateau phases. These feature recurrent action
potentials, during which GABA receptors and potassium channels
are involved in the hyperpolarizing and terminating phases, respec-
tively. Similarly, rhythmic discharges in thalamocortical loops, which
play an important role in generalized seizures, are determined by the
interplay of depolarizing and repolarizing ionic conductances.
The most common target among AEDs is the sodium channel,
which is responsible for the upstroke of the action potential in
neurons and other excitable cells [17]. The majority of sodium
channels expressed in the mammalian brain belong to four subtypes,
two of which have been found to be mutated in genetic forms of
epilepsy. NaV1.1 (SCN1A) mutations cause a spectrum of epileptic
disorders ranging from simple febrile seizures to Dravet syndrome
[18]. Of the more than 200 NaV1.1 mutations that have been
described, most cause loss of function, with complete loss of function
of one allele in Dravet syndrome [18]. At first, it seems paradoxical
that a loss of sodium channel function would produce epileptic
seizures. However, knockout mouse models have revealed that NaV1.1
seems to be the main sodium channel in inhibitory interneurons
[19,20], which may explain the pathophysiology of neuronal network
hyperexcitability. Furthermore, the sodium channel-blocking drug
lamotrigine may aggravate epileptic seizures in patients with NaV1.1
mutations [21]. This observation could be explained by a block of the
remaining functional sodium channels which are generated by the
healthy allele in inhibitory interneurons. In contrast, mutations in
NaV1.2 (SCN2A) cause a benign epilepsy syndrome of neonates and
infants through a gain of function in sodium channels expressed in the
axon initial segment of excitatory principal neurons in the hippo-
campus and cortex [22,23]. The transient high expression of these
channels during development and their subsequent partial replace-
ment with NaV1.6 channels may explain the remission of seizures at
later ages in patients with NaV1.2 mutations [22,23].
Mutations in KV7.2 and KV7.3 potassium channels (KCNQ2/KCNQ3)
lead to a decrease in functional potassium channels in the axon initial
segment and cause neonatal seizures [24]. These benign seizures provide
a useful model of disturbed excitability in epileptogenesis. Other genetic
potassium channel defects have been described including KV1.1, related
to episodic ataxia with focal epilepsy [25], and KCa1.1, related to
paroxysmal dyskinesia with generalized epilepsy [26]. The involvement
of potassium channel defects in the generation of focal epilepsies is
supported by the observation that KV4.2 channels are reduced in
principal neurons in an animal model of temporal lobe epilepsy [27].
Traditional sodium channel blockers, such as phenytoin, carbamaz-
epine and derivatives, and lamotrigine, bind to the fast-inactivated state
of sodium channels and cause a use-dependent blockade following
opening and inactivation. In contrast, lacosamide binds to the slow-
inactivated state of sodium channels that predominates during
prolonged depolarization and, in so doing, extends the latency period
between action potentials to a greater extent than traditional sodium
channel blockers [28]. However, none of these drugs has only one
mechanism of action. For example, some sodium channel blockers also
block presynaptic calcium channels [29], and lamotrigine enhances the
activity of hyperpolarization-activated cyclic nucleotide-gated (HCN)
cation channels [30].
Other AEDs enhance GABA-mediated inhibitory activity, classically
benzodiazepines and barbiturates, but also tiagabine, which blocks
synaptic GABA reuptake, and vigabatrin, which inhibits GABA transam-
inase [31]. However, none of the currently marketed drugs primarily
targets the brain's main excitatory neurotransmitter, glutamate, or
potassium channels, which hyperpolarize neural membranes. The
glutamate pathway is targeted by the developmental agent perampanel,
an AMPA-type glutamate receptor antagonist, which has now completed
a phase III program as an add-on treatment in focal epilepsy; full results
are awaited [32]. The investigational agent retigabine (also known as
ezogabine), which was recently approved by the FDA and the CHMP,
enhances the activity of KV7.2/KV7.3 potassium channels by binding
within the pore region [33,34]. These channels generate the M current, a
non-inactivating potassium conductance that regulates the neuronal
firing rate at subthreshold voltages between −60 and −40 mV [35].
Enhancing the M current with retigabine hyperpolarizes the cell
membrane toward the potassium equilibrium potential [36]. This drug
has been shown to be effective in phase III add-on trials in refractory
focal epilepsies [37,38].
The literature on AED pharmacology is vast, and our current
understanding of the mechanisms of action of drugs used in the treatment
of epilepsy is undoubtedly incomplete [31,39]. Nevertheless, it is possible
to categorize current AEDs into discrete pharmacological groups based on
their most prominent mechanism of action at therapeutic concentrations
(Table 1). This categorization includes a group of drugs known to possess
multiple prominent cellular effects, giving a total of five broad and nine
more specific mechanistic categories of AEDs.
3. Does mechanism of action predict antiepileptic drug efficacy or
side effects?
Animal models of seizures, epilepsy, and drug-related neurotox-
icity are widely used in the identification of novel antiseizure agents,
and many of them have been in routine laboratory use for decades
[40]. Together, these models offer an opportunity to characterize the
efficacy and toxicity of single drugs and combinations of drugs in large
groups of genetically homogeneous animals and have been instru-
mental in the identification of almost all current AEDs, providing
valuable surrogates in the search for optimal combination therapies
[41]. The models most commonly used for AED screening are maximal
electroshock (MES), pentylenetetrazol (PTZ), spike–wave models and
kindling models for efficacy purposes, and the rotarod, horizontal
screen, and chimney tests for neurotoxicity [42].
Table 1
Mechanistic categorization of current antiepileptic drugs based on foremost targets at
therapeutic concentrations.
Target and mechanism Antiepileptic drug
Sodium channel actions
Blockade by stabilizing fast-inactivated state Phenytoin, carbamazepine,
lamotrigine, oxcarbazepine,
rufinamide, eslicarbazepine
acetate
Blockade by stabilizing slow-inactivated state Lacosamide
Calcium channel actions
Blockade of high voltage-activated Gabapentin, pregabalin
channel (P/Q type)
Blockade of low voltage-activated Ethosuximide
channel (T type)
GABA-related actions
Activation of GABAA receptor Phenobarbital, benzodiazepines
Blockade of GABA transporter Tiagabine
(GAT1a selective)
Inhibition of GABA transaminase Vigabatrin
SV2A actions
Modulation of SV2A Levetiracetam
Multiple actions
Various actions on multiple targets Valproic acid, felbamate,
topiramate, zonisamide
Potassium channel activity
Opens Kv7 potassium channels Retigabine/ezogabine
a
GAT1, GABA transporter 1; SV2A, synaptic vesicle protein 2A.
 M.J. Brodie et al. / Epilepsy & Behavior 21 (2011) 331–341
The kindling model, in which electrical or chemical stimulation
induces a progressive decrease in seizure threshold and a corresponding
increase in seizure severity and afterdischarge duration, is considered a
valuable model for studying epileptogenesis [43] and the efficacy of
AEDs against focal seizures [44]. Inhibition of hind-leg extension in the
MES test suggests that an agent is able to prevent seizure propagation
and, therefore, may be effective against generalized tonic–clonic (GTC)
seizures [42]. Drugs that inhibit voltage-gated sodium channels, such as
phenytoin, carbamazepine, lamotrigine, and oxcarbazepine, are usually
effective in this model. In the PTZ test, clonic seizures are blocked by
AEDs acting on the GABAA neurotransmitter system, such as barbitu-
rates, benzodiazepines, valproic acid, and tiagabine, and by ethosux-
imide through its action on T-type calcium channels [45]. Drugs effective
in the PTZ test are considered to be likely to suppress myoclonic and/or
absence seizures [46]. Prediction based on these tests correlates with
clinical results for most AEDs, but there are striking exceptions.
Clonazepam is not effective in the MES test, but has clinical efficacy
against GTC seizures. Similarly, levetiracetam is not effective in the MES
and PTZ tests, but is useful in some idiopathic generalized epilepsies,
including epilepsies with prominent myoclonic features [47–49].
Furthermore, gabapentin, pregabalin, and tiagabine, which demonstrate
efficacy in the PTZ test, not only fail to control absence and myoclonic
seizures, but can exacerbate these seizure types [50].
Spike–wave seizure models, such as GAERS (Genetic Absence
Epilepsy Rats from Strasbourg), lethargic mouse, and WAG/Rij rat, are
sensitive to benzodiazepines, valproic acid, ethosuximide, lamotri-
gine, and levetiracetam [51], which correlates with the clinical
efficacy of these AEDs against absence seizures. However, although
clinical trials have shown that some AEDs may be more effective than
others in the treatment of childhood absence epilepsy [52], the spike–
wave models so far have not been able to stratify AEDs based on their
degree of efficacy in the treatment of this syndrome.
For practical reasons, clinical trials are conducted using relatively
standard patient selection, which is almost always limited to adults with
focal epilepsies [53]. Occasionally, an AED approved for focal epilepsy
will later show efficacy against idiopathic generalized epilepsies, but it is
probable that many compounds potentially effective against general-
ized epilepsies but not active against focal epilepsies are rejected during
development. It is notable that add-on and monotherapy trials often
show little differences in efficacy among drugs [54,55], which may be
related to the fact that all of these agents went through the same
assessment and development processes. Despite this, some studies have
been able to demonstrate the efficacy of AEDs on epilepsies other than
those of focal onset, including levetiracetam in juvenile myoclonic
epilepsy [56], rufinamide in Lennox–Gastaut syndrome [57], vigabatrin
in infantile spasms [58], and stiripentol in Dravet syndrome [59].
However, it was clinical observation rather than prediction of efficacy
based on mechanism of action that led to these observations.
Analysis of adverse-effect profiles based on mechanism of action
shows few differences among approved AEDs. Adverse effects consis-
tently noted in randomized trials include dizziness, lethargy, diplopia,
vertigo, and unsteadiness. This is probably related to the trial design, in
which new compounds are added to one, two, or three background
AEDs regardless of their dosage or mechanisms of action. Clinical
observation, however, indicates that sodium channel blockers are most
often associated with cerebellar adverse effects [60]. In line with this,
analysis of patient subgroups in some clinical trials has shown that
neurotoxic effects can be more prominent when two traditional sodium
channel blockers are combined, compared with the addition of a sodium
channel blocker to AEDs with different mechanisms of action [61–64].
Similarly, clinical observations indicate that headache can be
associated with lamotrigine [65], depression with levetiracetam [66],
anhydrosis with AEDs that inhibit carbonic anhydrase (topiramate
and zonisamide) [67–69], and psychosis with the GABAergic drug
vigabatrin [70]. However, the evidence for these associations was not
always obtained from placebo-controlled, randomized studies.
333
To avoid this lack of predictability of efficacy and adverse effects, a
different approach is needed in AED development, including trials on
epilepsy syndromes other than focal epilepsies, genetic testing of
large patient populations, and development of novel animal models.
Such changes are beginning to take effect: some AEDs are being tested
in idiopathic and symptomatic generalized epilepsies; most clinical
trials now include genetic analysis of the population studied; and the
number of animal models of refractory epilepsy used to evaluate AED
efficacy is expanding. In addition, clinical experience is being applied
in trial design, providing more specific analyses of efficacy and better
detection of adverse effects. The regular use of depression scales and
adverse-event questionnaires in modern clinical trials is encouraging.
However, adverse effects such as depression, anxiety, and psychosis,
and effects on cognition probably also need to be better defined. The
predictability of efficacy and toxicity would be enhanced by improved
testing of larger populations in head-to-head monotherapy trials.
4. What are the pharmacological issues in treating children
with epilepsy?
Almost all of the evidence for the safety and efficacy of AEDs
discussed above is based on studies in adults. Children, particularly
infants, differ from adults not only in the clinical expression of their
seizures, but also in the unique age-dependent EEG abnormalities
characteristic of childhood self-limited epileptic syndromes as well as
epileptic encephalopathies. Diffuse epileptic activity interferes with
the development and organization of the immature brain and with
cognition [71]. This is most conspicuous in infancy, in which 40% of
epilepsies can be classified as epileptic encephalopathies and only a
few respond to pharmacological, nonpharmacological, or neurosur-
gical approaches. In this age group, epileptic activity and seizures may
become persistent, thereby perpetuating hyperexcitability and alter-
ing networks in seizure-prone regions. This can affect the outcome by
producing changes in seizure semiology (focal or generalized) and
possibly reduced responsiveness to treatment [72]. To avoid or
minimize such consequences, the correct diagnosis of seizures and
syndromes is mandatory.
The recognition of seizure type and syndrome gives us valuable
information regarding treatment strategies and prognosis. The
decision to treat a child after the first unprovoked seizure has an
impact on the recurrence risk over a short, but not over a longer,
period [73–75]. There are “good epilepsies,” such as “benign” focal
epilepsy syndromes, that may not need any treatment. Subsequent
management, however, will depend on the type of seizures,
recurrence frequency, and the way in which the parents perceive
and manage the episodes. There are also “bad epilepsies,” such as
Landau–Kleffner syndrome and continuous spike–waves during sleep,
for which children often need aggressive treatment from the outset.
Parents should be instructed on how to identify these seizures early
and to act quickly to abort them, for example, with buccal midazolam
or rectal diazepam.
Misdiagnosis is common in children and occurs in 18–30% of
patients, mainly through misinterpretation of clinical and nonepilepto-
genic paroxysmal interictal EEG activity [76]. An EEG obtained using the
correct methodology relevant to the clinical event is the most important
diagnostic test in evaluating children with suspected epilepsy. Once the
underlying etiology has been identified, the decision will be made
whether to treat or not to treat, and, if necessary, the first-choice
medication selected. The short-term aim is seizure freedom with
minimal or no adverse effects, and the long-term goal is optimal motor,
social, cognitive, and developmental evolution, coupled with good
quality of life for the child and the family. In choosing the appropriate
AED, the type of seizure or syndrome, pharmacodynamic and
pharmacokinetic properties of the drug(s), the patient's age, gender,
activities, and body weight, and also the preference of parents should, if
possible, be taken into account.
334 M.J. Brodie et al. / Epilepsy & Behavior 21 (2011) 331–341
In patients with primarily generalized seizures (absence, myoclonic,
tonic–clonic, tonic, atonic), particularly in those with idiopathic
generalized epilepsies and syndromes with or without a positive
response to intermittent photic stimulation, valproic acid can be
regarded as a possible drug of first choice for all types of seizures [77].
Valproic acid is a particularly suitable first choice in syndromes in which
myoclonic seizures are the only or predominant seizure type and in
syndromes in which absence and myoclonic seizures are the main
seizure types.
In cases of obesity, and in girls from the prepubertal phase onward,
an alternative to valproic acid should be sought. The increased risk of
congenital malformations when this agent is used, compared with
other traditional AEDs, particularly when the daily dose exceeds
1000 mg, dictates that valproic acid should be avoided, if possible, in
girls and women of childbearing potential [78,79]. Cognitive and
behavioral abnormalities have also been observed in children exposed
to valproic acid in utero [80–82]. Serious adverse reactions to valproic
acid, such as hepatic failure and acute pancreatitis, occur mainly in
children receiving polytherapy and in infants with organic brain
(metabolic) disease. For some girls and young women with idiopathic
generalized epilepsy syndromes, there may be no suitable alternative
to valproic acid, in which case doses under 1000 mg/day should be
employed.
Potential alternatives to valproic acid include ethosuximide,
lamotrigine, levetiracetam, topiramate, zonisamide, and benzodiaze-
pines [83]. Ethosuximide is effective against absences, and a recent
study found it to be less likely to cause cognitive impairment than
valproic acid [52], but it does not protect against GTC seizures.
Lamotrigine, primarily a sodium channel blocker, can be effective for
primary GTC seizures, but can worsen myoclonic seizures [21,84] and
is less effective than ethosuximide or valproic acid for absences [52].
Levetiracetam is particularly effective in juvenile myoclonic epilepsy
[85], whereas topiramate can cause cognitive dysfunction in some
children.
Useful combinations that have been identified clinically in patients
not responding to monotherapy include valproic acid with ethosux-
imide for absence seizures [86,87], valproic acid with levetiracetam
for myoclonic seizures, and valproic acid with lamotrigine for a variety
of seizure types.
Gabapentin and pregabalin can worsen myoclonic and, possibly,
absence seizures [88,89]. Vigabatrin and tiagabine are inactive against
absence seizures and may exacerbate generalized spike-and-wave
discharges (GSWDs). Tiagabine may also induce nonconvulsive status
epilepticus [90]. Classic AEDs that bind to the fast-inactivated state of
sodium channels such as phenytoin, carbamazepine, oxcarbazepine,
and eslicarbazepine acetate should be avoided in idiopathic general-
ized epilepsy syndromes associated with absence and myoclonic
seizures [89].
In focal seizures and syndromes with or without secondary
generalization, drugs with activity in either MES or kindling models are
typically effective, including phenobarbital, phenytoin, carbamazepine,
oxcarbazepine, valproic acid, lamotrigine, levetiracetam, lacosamide,
topiramate, zonisamide, gabapentin, pregabalin, felbamate, tiagabine,
vigabatrin, and benzodiazepines [41]. However, some of these drugs have
not been adequately tested in children. Carbamazepine, lamotrigine, and
oxcarbazepine can be regarded as first-choice AEDs for monotherapy for
all types of focal seizures in children with or without secondary
generalization. Lamotrigine and oxcarbazepine may be preferable to
carbamazepine in infancy and early childhood because they may be
better tolerated inasmuch as they are not broad-spectrum enzyme
inducers. Lamotrigine, however, carries an increased risk of serious skin
rashes [91]. Levetiracetam has a favorable pharmacokinetic profile and
can be used as monotherapy or in polytherapy in all focal or generalized,
idiopathic or symptomatic epilepsy syndromes in children, without
clinically significant pharmacokinetic drug interactions [83,92]. Slow
titration is advisable to minimize the risk of skin rashes, particularly with
lamotrigine, and other early adverse effects, such as sedation and
aggression. Useful AED combinations in focal seizures include carbamaz-
epine, or preferably oxcarbazepine, with a broad-spectrum drug such as
valproic acid or levetiracetam [93]. Carbamazepine, however, may
aggravate seizures or precipitate continuous spike-and-waves during
sleep in children with Landau–Kleffner syndrome [94] and idiopathic
focal epilepsies [95]. Additionally, in benign childhood epilepsy with
centrotemporal spikes and minor atypical features, carbamazepine can
aggravate epileptic negative myoclonus and precipitate almost contin-
uous central spike-and-wave activity. Seizure exacerbation has also been
reported in Panayiotopoulos syndrome [96]. Alternative choices for
treatment of these syndromes are levetiracetam [97–99], valproic acid
[100], and sulthiame [101,102].
Epileptic encephalopathies are severe brain disorders, in which the
underlying electrical activity significantly contributes to progressive
cognitive dysfunction [103]. Treatment is aimed not only at preventing
seizures, but also at abolishing ictal and interictal EEG abnormalities.
Vigabatrin, a GABA transaminase inhibitor, may be a first-choice agent
for infantile spasms [104]. Adrenocorticotropin can be added if
vigabatrin fails to prevent seizures and abolish the hypsarrhythmic
pattern within 5 days. Additional treatment can include levetiracetam,
topiramate, valproic acid, benzodiazepines, zonisamide, pyridoxine (in
pyridoxine dependency cases in which a prompt EEG response is
observed after intravenous infusion of 100–200 mg), or intravenous
immunoglobulin G.
In Dravet syndrome, the main genetic defect is loss of function in
voltage-gated sodium channels and traditional sodium channel-
blocking AEDs are not recommended [105]. Stiripentol, a direct
allosteric modulator of GABA receptors [106], combined with valproic
acid and clobazam has given encouraging results [59]. Topiramate
may also be of value in some children [107].
The majority of AEDs are ineffective in encephalopathies with
continuous spike-and-waves during sleep; some benefit with
sulthiame has been reported [108].
Specific clinical trials are needed in children and infants with
epileptic encephalopathies because early and successful prevention of
seizure activity will lead to better outcomes with regard to cognition
and quality of life. In addition, mechanisms underlying drug resistance
in infancy and childhood need to be better understood to develop
novel therapies. The consequences of inadequate seizure control are
different for each child, depending on age, type of seizure, diurnal
variation of seizures, lifestyle, and quality-of life-issues. New genetic
approaches to mechanisms of epileptogenesis will enhance progress
toward more effective treatment for these challenging epilepsy
syndromes.
5. How can experimental studies on drug combinations inform
clinical practice?
The systematic investigation of all possible AED combinations is
scientifically and economically unrealistic. As an alternative, it is
reasonable to investigate combinations of mechanisms rather than
drugs. There are a total of 32 possible combinations from nine
mechanistic categories (Table 1), a figure that can be substantially
reduced as clinical experience dictates that some combinations can be
ignored. Even excluding combinations that are not used clinically,
undertaking a robust clinical evaluation of the remaining mechanistic
combinations would be impractical because it would require
assessment of efficacy and dose-related adverse effects of both
drugs applied singly and in combination in sufficiently large and
homogeneous groups of patients with careful consideration of dose
ratios and drug loads [109]. As an initial and potentially cost-effective
alternative, animal models can be used to identify the most effective
mechanistic combinations prior to detailed clinical evaluation.
Experimental drug combination studies should incorporate efficacy
and toxicity models in which both drugs are at least minimally effective
 M.J. Brodie et al. / Epilepsy & Behavior 21 (2011) 331–341
and use drug ratios that reflect those employed clinically. Drug
concentrations in both plasma and the brain should be measured to
rule out confounding pharmacokinetic interactions, and an appropriate
method of analysis should be applied, such as isobolography or
comparison of protective indices [110]. Isobolographic analysis is
preferable as it provides a robust measure of effectiveness and affords
a definitive determination of infra-additive (antagonistic), additive, or
supra-additive (synergistic) interactions [111]. The ideal AED combi-
nation would demonstrate pharmacological synergism, defined as
improved efficacy with similar toxicity, similar efficacy with reduced
toxicity, or, ideally, improved efficacy with reduced toxicity.
Experimental investigations of AED combinations have appeared
in the literature since the 1950s [112]. Early studies explored
combinations of established drugs, such as phenobarbital, phenytoin,
and carbamazepine, and were performed without any knowledge of
their mechanisms of action. Interestingly, combinations were com-
monly reported to have superior efficacy, reduced toxicity, or both,
compared with either constituent drug alone irrespective of the drugs
under investigation [113]. However, this was most evident when two
drugs with what we now know to have different mechanisms of
action were combined [114]. Combinations of AEDs with similar
mechanisms were less successful [115]. These studies set the
benchmark for the concept of “rational polypharmacy” as it evolved
throughout the 1990s with new knowledge about the pharmacology
of AEDs and the advent of modern drugs, which are invariably
introduced as adjunctive therapy for refractory focal epilepsy [116].
Arguably, the laboratory of Czuczwar and colleagues has contrib-
uted more data to the study of AED combinations than all others
[117,118]. Some common themes have emerged in the literature,
most notably that combining drugs with differing mechanisms of
action appears to be superior to combining those with the same or
similar cellular effects [113]. This observation is exemplified by the
consistent demonstration of synergism between lamotrigine and
valproic acid in multiple efficacy models [119,120] and the repeated
failure to demonstrate synergism between lamotrigine and either
carbamazepine or phenytoin [120,121]. Other combinations produced
less consistent results; for example, gabapentin with carbamazepine
is synergistic in the MES model but not in the DBA/2 audiogenic
seizure susceptible mouse [122,123]. Overall, however, the message is
relatively clear: reinforcement on a single pharmacological pathway is
less effective than a combined effect on two distinct pathways.
Relatively few studies contradict this intuitive hypothesis [124].
Some of the most successful two-drug combinations in laboratory
studies appear to involve a single-mechanism drug combined with an
AED known to possess multiple mechanisms of action [113].
Combinations of drugs that selectively target sodium channels appear
to offer only additive improvements in efficacy and often supra-
additive enhancement of neurotoxicity [118]. Unfortunately, because
of variability in experimental methodology and problems comparing
results across multiple studies, it is difficult to conduct an objective
assessment of the available data. Many published investigations are
also incomplete: neurotoxicity testing is often not reported, which
undermines any suggestion of synergism in terms of efficacy, and
pharmacokinetic analysis is rarely performed, which is necessary to
rule out the potential for altered drug absorption, clearance, or brain
penetration.
6. What is the relevance of pharmacokinetics when combining
antiepileptic drugs?
When two or more AEDs are used together, pharmacokinetic
interactions may influence their combined effects and result in
alterations in the absorption, distribution, or elimination of the
affected drug, influencing the concentration of the active molecule(s)
at the site of action. An understanding of these interactions allows a
335
more rational approach to combination therapy, with potential
advantages in terms of efficacy and minimization of adverse effects.
Interactions whereby an AED affects the gastrointestinal absorp-
tion of another AED are uncommon [125]. It has been suggested that
the fall in plasma phenytoin concentration that occurs in some
patients started on combination therapy with vigabatrin may involve
an interaction at the absorption level, but an ad hoc study failed to
provide any evidence for this, and the mechanism underlying this
interaction remains unclear [126].
Plasma protein binding interactions are relevant only for highly
protein-bound AEDs, such as phenytoin and valproic acid. Contrary to
common belief, these interactions are usually of little or no clinical
significance, because the displaced drug becomes diluted in a large
volume of distribution and is also eliminated more rapidly as a result of
an increase in clearance. The usual consequence of these interactions is a
fall in the total plasma concentration of the displaced drug, without any
significant change in the concentration of the unbound, pharmacolog-
ically active molecule [125]. For example, when protein-bound
phenytoin is displaced by valproic acid, the total plasma phenytoin
concentration falls, but the unbound phenytoin concentration is not
affected and the phenytoin response is generally unaltered [127]. In
some cases, unbound phenytoin levels may increase moderately, but
this is due to a concurrent inhibitory effect of valproic acid on phenytoin
metabolism rather than displacement from plasma proteins. The
important message for physicians is that, despite the fall in total plasma
phenytoin levels, the phenytoin dosage does not need to be increased
when valproic acid is given concomitantly.
The most common pharmacokinetic interactions in AED therapy
are those resulting in changes in the rate of drug metabolism.
These interactions can be very important clinically [128]. Carba-
mazepine, phenytoin, and phenobarbital, in particular, markedly
stimulate the activity of most cytochrome P450 (CYP) enzymes, as
well as enzymes involved in glucuronidation (uridine 5'-diphospho-
glucuronosyltransferases [UGTs]). Enzyme-inducing AEDs interact
with many other medications that are metabolized in the liver, as
well as other AEDs (Table 2). Although the reduction in the steady-
state plasma concentration of the affected AED may be compensated
by the efficacy of the added drug, in many cases the dosage will need
to be increased to optimize efficacy. This decrease in plasma
concentration can be particularly marked (N50%) when the affected
AED depends almost entirely on metabolic clearance for its
elimination, as is the case with lamotrigine, valproic acid, tiagabine,
and carbamazepine [125]. Caution is also required when an enzyme-
inducing AED is withdrawn as the plasma concentration of the
previously induced drug may rise, leading to toxicity.
Some AEDs have the potential to inhibit drug-metabolizing enzymes,
thereby increasing the plasma concentration of concomitant medications
that are substrates of those enzymes. Among these interactions, those
Table 2
Antiepileptic drugs for which clearance is enhanced by concomitant administration of
carbamazepine, phenytoin, and barbiturates.
Benzodiazepines
Carbamazepine
Ethosuximide
Felbamate
Lamotrigine
Levetiracetam
Oxcarbazepinea
Primidone
Rufinamide
Tiagabine
Topiramate
Valproic acid
Zonisamide
a
Interaction leads to decreased plasma concentration of the active monohydroxy-
lated metabolite, for which oxcarbazepine is a prodrug.
336 M.J. Brodie et al. / Epilepsy & Behavior 21 (2011) 331–341
occurring most commonly in combination AED therapy include
inhibition of the metabolism of lamotrigine and phenobarbital by
valproic acid [125]. These interactions usually require a reduction in
the dosage of the affected drug to avoid the risk of toxicity. In the case of
lamotrigine, a slower than normal dose titration is also required to
minimize the risk of idiosyncratic toxicity when treatment is initiated in
patients who are taking valproic acid [129].
Most drug–drug interactions can be predicted from knowledge of
the effect of the added agent on the CYP and/or UGT enzymes
responsible for the metabolism of the concomitant medications [130];
such information is now largely retrievable online (http://www.
druginteractioninfo.org/, http://www.micromedex.com/products/
drugdex/, http://www.pdr.net/, http://www.pubmed.gov/).
7. Is there clinical evidence that mechanism of action matters
when combinations of antiepileptic drugs are used?
It seems reasonable to use a drug possessing a different mechanism
of action when an AED fails as a result of poor tolerability or, perhaps
more persuasively, lack of efficacy [93]. There are arguments in the
literature for combining a sodium channel blocker with a drug
possessing GABAergic properties [113] or one known to have multiple
mechanisms of action [131], but what hard clinical evidence do we have
in support of rational polytherapy based on combining drugs with
different mechanisms of action?
7.1. Valproic acid with lamotrigine
The best evidence for a synergistic interaction between AEDs is
with valproic acid and lamotrigine for focal-onset and generalized
seizures. Brodie and his European colleagues undertook a pragmatic
trial during which an attempt was made to substitute lamotrigine as
monotherapy in patients suboptimally controlled with carbamaze-
pine, phenytoin, or valproic acid [63]. Patients were initially stabilized
on combination therapy, and adjustment was made in the lamotrigine
dosing schedules for the well-known pharmacokinetic interactions
among these drugs, resulting in similar plasma lamotrigine concen-
trations in all three treatment groups. When these patients were
established on both drugs, it was noted that responder rates were
significantly higher for the valproic acid group than for the patients
taking lamotrigine with carbamazepine or phenytoin (Fig. 1). Fol-
lowing up on this observation, Pisani and colleagues performed a
well-designed crossover study in 20 patients with focal seizures [132].
70
64%
60
50
*
Percentage
41% *
40 38%
30
20
10
0 blockers [64].
LTG+VPA LTG+CBZ LTG+PHT
(n=115) (n=129) (n=92)
*p<0.001 VPA vs CBZ and PHT
Fig. 1. Responder rates in patients with uncontrolled epilepsy established on
duotherapy following the addition of lamotrigine (LTG) to monotherapy with valproic
acid (VPA), carbamazepine (CBZ), or phenytoin (PHT). Data taken from Brodie and
Yuen [63].
Among the 13 patients who did not respond to the consecutive
addition of valproic acid or lamotrigine to their existing regimen, four
became seizure free and an additional four experienced N50% seizure
reductions when both drugs were given in combination despite lower
doses and lower plasma drug concentrations than occurred during
their separate administration.
7.2. Other combinations
Other recommended combinations are based largely on anecdotal
reports in small groups of patients or studies with modest sample
sizes. These include valproic acid with ethosuximide for absence
seizures [87], phenobarbital with phenytoin for GTC seizures [133],
carbamazepine with valproic acid or vigabatrin for focal seizures
[134], vigabatrin with tiagabine for focal seizures [135], and
lamotrigine with topiramate for a range of seizure types [136].
Although none of these reports can be regarded as any more than
observational evidence in support of the mechanistic hypothesis, it is
interesting to note that combinations with different modes of action
were universally employed in these studies [137].
7.3. Negative combinations
There are now multiple drugs (phenytoin, carbamazepine,
oxcarbazepine, lamotrigine, lacosamide, eslicarbazepine acetate)
that act primarily by blocking voltage-gated sodium channels. Most
of these were licensed following positive adjunctive, dose-ranging,
placebo-controlled regulatory trials, many with patients already
established on another sodium blocker. Subanalyses have often failed
to show a difference in response between patients already taking or
not taking sodium channel blockers, but the details are not widely
available and such post hoc analyses are not always able to generate
useful information about combination strategies.
Lacosamide appears to be pharmacologically distinct from the
other drugs in that it influences the slow- rather than fast-inactivated
state of sodium channels [138]. This drug can be used successfully in
patients established on traditional sodium channel blockers (carba-
mazepine, lamotrigine, oxcarbazepine, and phenytoin derivatives)
[64]. However, although no formal comparisons were performed
between subgroups of patients taking or not taking traditional sodium
channel blockers, a post hoc analysis of these data suggested that
tolerability profiles and responder rates may be better when
lacosamide is combined with AEDs other than traditional sodium
channel blockers [64].
Another interesting compound is rufinamide, which is licensed for
use in Lennox–Gastaut syndrome [57], but not for focal seizures because
the trial results for the latter indication were disappointing [139,140]. In
a double-blind, placebo-controlled, randomized, parallel-group, multi-
center trial of rufinamide 1600 mg twice daily in adults and adolescents
with refractory focal seizures, there was a 12% reduction in monthly
seizure frequency in the 96 patients established on carbamazepine
compared with a 29% seizure reduction (P = 0.05) in the 60 patients
taking a regimen that did not contain carbamazepine [139].
There is additional evidence that combining two drugs that block
voltage-dependent sodium channels is more likely to produce neuro-
toxic side effects, such as dizziness, diplopia, and ataxia [61–63,141].
Similarly, a dose-dependent increase in dizziness was demonstrated
with lacosamide in patients already established on traditional sodium
7.4. Combination strategy
Drug-resistant epilepsy has recently been defined by an Interna-
tional League Against Epilepsy Task Force as “failure of adequate trials
of two tolerated, appropriately chosen and used, antiepileptic drug
schedules (whether as monotherapy or in combination) to achieve
 M.J. Brodie et al. / Epilepsy & Behavior 21 (2011) 331–341
sustained seizure freedom” [142]. Thus, drug-resistant epilepsy can
now be readily recognized, sometimes within 1 year of the diagnosis
being made. This should allow earlier referral to specialist centers, and
may be used to justify initiation of combination therapy and, most
importantly, early evaluation of nonpharmacological treatment
options and, specifically, feasibility of epilepsy surgery [143].
It is increasingly considered appropriate to treat patients estab-
lished on a sodium channel blocker with a drug or drugs that possess
different mechanisms of action, such as levetiracetam and pregabalin,
or drugs that have multiple mechanisms of action, such as valproic
acid, levetiracetam, topiramate, and zonisamide, which may be added
in the hope of producing a beneficial effect in drug-resistant epilepsy
by focusing on multiple pharmacological targets [93,143]. Drugs with
multiple mechanisms of action also tend to have a broad efficacy
spectrum across a range of seizure types [144]. Thus, if a patient
tolerates the first or second drug well with a useful but suboptimal
response, combination therapy could be considered, particularly if
there is a high seizure density and demonstrable underlying
pathology, such as mesial temporal sclerosis or cortical dysplasia
[145]. Several duotherapy combinations should be tested before
considering the addition of a third drug. Larger numbers of drugs
should be avoided as it is unlikely that this strategy will produce a
useful seizure reduction [144].
There are reasons for combining AEDs other than seeking
synergistic or adjunctive efficacy in controlling seizures. It has been
suggested that combinations of two drugs at low dosage may be
better tolerated and, therefore, more effective than a high dose of a
single agent [146], although there is no sound evidence that this is
consistently the case. Also, an additional AED may be used not just to
treat the epilepsy, but to benefit comorbid conditions such as
neuropathic pain (e.g., gabapentin, pregabalin); trigeminal neuralgia
(e.g., carbamazepine, oxcarbazepine); migraine (e.g., topiramate,
valproic acid); bipolar disorder (e.g., lamotrigine, valproic acid); and
anxiety (e.g., pregabalin, clobazam) [147,148]. There is increasing
interest and knowledge concerning the common mechanisms of
action responsible for the broader range of therapeutic effects
possessed by many AEDs [149,150].
A personalized treatment plan should be formulated once a patient
fulfills the criteria for drug-resistant epilepsy to limit cognitive
deterioration and psychosocial dysfunction, while taking into consid-
eration seizure type(s) and syndrome classification [145]. Special
attention should be paid to drug load to avoid adverse effects [151],
even though a recent large observational study did not provide
evidence for adverse effects being associated with higher drug loads
[152]. Combinations using modest doses of each AED have a higher
chance of being tolerated and, therefore, effective [145]. At this stage,
it would also be worthwhile to raise the possibility that seizure
freedom may not be attainable, paving the way for a palliative
strategy if this proves to be necessary [153].
8. What are the emerging targets and novel strategies for future
treatment?
Identifying a new generation of AEDs that better serve patients
with uncontrolled seizures may necessitate a paradigm-shift in drug
development strategies. Indiscriminate screening of compound
libraries should be superseded by rational drug design based on
recently acquired knowledge of the pathophysiological mechanisms
of ictogenesis and the genetics of the epilepsies. In this way, novel
compounds could be specifically targeted to known defects in the
epileptic brain, providing direct modulation of causative pathways
while sparing normal neuronal function. There also needs to be
greater utilization of model systems that display one or more
attributes of human pharmacoresistance and an integration of models
of epileptogenesis to help identify potential disease-modifying
therapies [154]. Understanding the molecular causes and conse-
337
quences of epilepsy and designing drugs to manipulate, circumvent,
or overcome those insidious processes should lead to identification of
more effective therapies for adults with refractory epilepsy, children
suffering from catastrophic seizures, and perhaps even individuals
with a predisposition toward the development of epilepsy. A selection
of emerging targets and strategies for new AED development are
briefly described below.
8.1. Voltage-gated sodium channel subtypes
Blockade of voltage-gated sodium channels is a mechanism shared
by several existing AEDs, but current drugs are relatively nonselective
and do not exploit individual characteristics of the channels in the
brain. These channels are differentially expressed during develop-
ment, at different sites on neuronal membranes, and on different
neuronal populations [155], with distinctive conductance properties
and multiple biophysical states. In addition, it is increasingly
recognized that seizures can influence the expression of sodium
channel subtypes and/or alter their structural conformation [156].
Designing a subtype-selective sodium channel blocker might offer
advantages over existing AEDs. For example, a selective NaV1.6
blocker should inhibit both transient and persistent sodium currents
in excitatory neurons while sparing inhibitory interneurons, which
express predominantly the NaV1.1 subtype. Other compounds might
be designed to specifically target sodium channel subtypes and
conformations known to be upregulated in epileptic tissue, thus
leaving normal neuronal function unperturbed. A novel sodium
channel blocker with unique characteristics in terms of selectivity
for a specific subunit or biophysical state (cf. effects of lacosamide on
slow inactivation [28]) might represent a significant improvement on
an already successful pharmacological strategy.
8.2. GABAA receptor subunits
The GABAA receptor is a ligand-gated ion channel comprising five
independent protein subunits arranged around a central anion pore
that is permeable to chloride and bicarbonate ions. Nineteen GABAA
receptor subunits have been identified to date, and subunit compo-
sition affects the physiology and pharmacology of the receptor [157].
Seizures can influence the subunit composition of the GABAA receptor,
with a consequent effect on the biophysical properties of the
receptor–channel complex and altered sensitivity to pharmacological
manipulation [158]. Current GABAA receptor drugs, such as the
barbiturates, are relatively nonselective. The development of subunit-
specific drugs could potentially avoid undesirable effects associated
with nonselective GABAA modulation and might allow targeting of
drugs to channels in epileptic neurons or at extrasynaptic sites. There
is already a precedence for subunit-specific AEDs: stiripentol
preferentially activates α3-β3-γ2-containing receptors [106], and
other such compounds are in development. ELB139, for example, is a
specific α3 agonist that is anxiolytic and anticonvulsant, but not
sedative [159], and neurosteroid analogs (such as ganaxolone)
selectively target receptors containing δ subunits [160]. Selective
GABAA compounds, targeted to subunits known to be overexpressed
in epileptic brain tissue, may prove effective against seizures, with
limited adverse effects.
8.3. GABA transporters
On release from the presynaptic terminal, GABA is actively
removed from the synaptic and extrasynaptic space by various
GABA transporters (GATs). Tiagabine is thought to exert its anti-
seizure effect by blocking GAT1-mediated reuptake into neurons and
astrocytes [31]. With the exception of tiagabine, none of the currently
available AEDs targets the other GATs, betain-GAT1, GAT2, and GAT3.
Given their broad cellular (neuronal and astrocytic) and anatomical
338 M.J. Brodie et al. / Epilepsy & Behavior 21 (2011) 331–341
(synaptic and extrasynaptic) distribution in the central nervous
system, coupled with the diverse stoichiometry of extrasynaptic
versus synaptic GABAA receptors, non-GAT1 GATs have the potential
to exert control over neuronal excitability and could potentially
offer some unique advantages in efficacy and tolerability over
tiagabine [161].
8.4. Potassium channels
Potassium channels are the most heterogeneous of all brain-
expressed ion channel families and arguably represent one of the last
major unexplored targets in neuropharmacology [162]. Voltage-gated
potassium channels (of which more than 40 are known) display a
multiplicity of functions associated with membrane hyperpolarization
including: (1) regulation of the resting potential; (2) repolariation of
the membrane after action potential generation; and (3) determina-
tion of action potential duration [163]. Mutations in the genes
encoding KV7.2 and KV7.3 channels have been observed in inherited
forms of human epilepsy, confirming the role of voltage-gated
potassium channels in neuronal excitability and their potential as
targets for AEDs [164]. Indeed, the successful development of
retigabine, an activator of KV7.2 and KV7.3 channels [165], un-
derscores the importance of the KV7 family as a molecular target
worthy of pharmacological manipulation. Efforts to develop further
potassium channel activators (such as those targeting KV1–KV4
subunits, which carry the delayed rectifier current) are justified on
the basis of current experimental and clinical data [166].
8.5. Gap junctions
Gap junctions provide a mechanism for rapid, nonsynaptic
communication between adjacent neurons and astrocytes [167].
They are believed to underlie the synchronization of epileptiform
activity and the generation of high-frequency oscillations which
precede the onset of ictal discharges in temporal lobe epilepsies [168].
Gap junctions are formed from two hemichannels (one in each cell),
each comprising six connexin proteins with a central pore permeable
to ions and small molecules [169]. Eleven connexins have been
identified in brain tissue, with differential expression depending on
the cell type and stage of development. Connexin 43 is the major
isoform in astrocytes, whereas connexin 36 and connexin 45
predominate in hippocampal and neocortical neurons [170]. The
11β-hydroxysteroid dehydrogenase inhibitor carbenoxolone blocks
gap junctions at high concentrations. It reduces epileptiform
discharges in hippocampal slices, and is effective in the tetanus
toxin model of temporal lobe epilepsy and against experimental
absence seizures in WAG/Rij rats and lethargic mice [171,172].
Tonabersat is a gap junction blocker currently in early-stage
development for epilepsy. Identification of further gap junction
blockers with selectivity for individual brain-expressed connexins is
warranted.
8.6. HCN channels
HCN channels contribute to neuronal pacemaker currents, such as
Ih, and comprise four subunits (HCN1–4) arranged in homomeric or
heteromeric tetramers around a central pore that is permeable to
sodium and potassium [173]. Differential expression of HCN subunits
in the brain (HCN1 in hippocampus and cortex, HCN2 in thalamus)
makes them an attractive target, with the potential for HCN1 agents to
be effective in limbic and neocortical epilepsies and HCN2 agents in
absence seizures [166]. Changes in HCN subunit expression and in Ih
currents have been observed in models of absence seizures and
epileptogenesis, and HCN2 knockout mice have an absence-like
phenotype [174,175]. Evidence to support the pharmacological
manipulation of HCN channels as an antiseizure mechanism remains
controversial. Lamotrigine activates Ih in the dendrites of hippocam-
pal pyramidal cells [30], whereas ZD-7288, a putative HCN blocker,
has been shown to inhibit epileptiform activity in hippocampal slices
[176]. Dissecting the anatomical, cellular, and subcellular localizations
and the functions of individual HCN channels and their relative
contributions to overall neuronal excitability is required before their
full potential as AED targets can be realized.
8.7. Overcoming pharmacoresistance
Two major hypotheses to explain pharmacoresistance in epilepsy
have arisen in the past decade; the so-called “transporter hypothesis”
and the “target hypothesis.” The latter proposes that traditional AED
targets are disrupted in epileptic brain tissue to the extent that their
sensitivity to pharmacological manipulation is lost [177]. Overcoming
this situation would require the development of compounds that
selectively target those proteins (or subunits thereof) that are
differentially expressed or disrupted in the epileptic brain. The
“transporter hypothesis” offers a more immediate opportunity for
therapeutic intervention. It is based on the premise that drug efflux
transporters are upregulated in the blood–brain barrier at epileptic
foci, thereby preventing AEDs from reaching their intended site of action
[177]. In theory, this could be circumvented by co-administration of
efflux transport inhibitors (currently being developed in oncology),
which would restore the brain penetration capability of AEDs. An
alternative approach might be the development of focal drug delivery
systems that bypass the blood–brain barrier.
8.8. Disease modification and antiepileptogenesis
Available evidence suggests that current AEDs are antiseizure and
not antiepileptogenic; they control the symptoms but not the initial
development or subsequent progression of the epilepsy [178]. The
ultimate aim for the treatment of epilepsy should be the identification
of a therapeutic agent that will halt or reverse the neurological and
neuropsychological decline associated with chronic seizures or,
perhaps, even prevent epilepsy in “at risk” individuals. This concept
represents an enormous challenge to both preclinical and clinical
researchers, but recent advances in our understanding of epilepsy at
the genetic, molecular, cellular, and network levels suggest that this
aspiration may eventually become a reality. Some of the therapeutic
targets and strategies that have already attracted attention as
potential disease modifiers are listed in Table 3. In the postgenomic
era and with new integrative systems biology approaches to
biomedical science, tackling the causes of epilepsy and not simply
one of its consequences (i.e., seizures) may be within reach.
Conflict of interest statement
M.J. Brodie serves on the scientific advisory boards of Pfizer, UCB
Pharma, Eisai Pharmaceuticals, GlaxoSmithKline, Novartis, Valeant
Pharmaceuticals, ICVRx, and Medtronic. He has accepted honoraria for
Table 3
Novel targets and emerging strategies to modify disease progression and prevent
epileptogenesis.
Mammalian target of rapamycin (mTOR)
Inflammatory modulators (cf. interleukins, high-mobility group protein
1 [HMGB1])
Neuropeptide modulators (cf. galanin, neuropeptide Y)
Gene therapy (cf. galanin, neuropeptide Y)
Gene silencing techniques (i.e., small interfering RNA [siRNA])
Stem cell therapy (cf. medial ganglionic eminence [MGE] precursors in KV1.1
knockout mice)
Modulators of growth factors (i.e., brain-derived neurotrophic factor
[BDNF]) or transcription factors (i.e., neuron-restrictive silencer factor [NRSF])
 M.J. Brodie et al. / Epilepsy & Behavior 21 (2011) 331–341
speaking on behalf of Pfizer, UCB Pharma, Eisai Pharmaceuticals,
GlaxoSmithKline, and Valeant Pharmaceuticals, and has received
research grants from Pfizer, UCB Pharma, and Eisai Pharmaceuticals
within the past 3 years.
A. Covanis has received speaker/consultancy fees from
GlaxoSmithKline, Actelion, and Biocodex. He does not have any
other professional or personal relationship with pharmaceutical
companies.
A. Gil-Nagel serves on the scientific advisory boards of Bial, Eisai
Pharmaceuticals, GlaxoSmithKline, and UCB Pharma, and has received
honoraria for Grand Rounds and Symposia from Bial, Eisai Pharma-
ceuticals, GlaxoSmithKline, Sepracor, and UCB Pharma. He serves as a
consultant to Bial, Eisai Pharmaceuticals, GlaxoSmithKline, Medtronic,
UCB Pharma, and Valeant Pharmaceuticals, and has received research
support from UCB Pharma.
H. Lerche has received speaker/consultancy fees, and/or travel
funding from Desitin Pharmaceuticals, GlaxoSmithKline, Eisai Inc.,
Pfizer, UCB Pharma, and Valeant Pharmaceuticals. He has received
research support from Sanofi–Aventis and UCB Pharma.
E. Perucca has received speaker/consultancy fees and/or research
grants from Bial, Eisai Pharmaceuticals, GlaxoSmithKline, Johnson and
Johnson, Novartis, Pfizer Inc., Sanofi–Aventis, Sepracor, SK Holdings,
UCB Pharma, and Valeant Pharmaceuticals. He has also received
research grants from the European Union, the Italian Medicines
Agency (AIFA), the Italian Ministry of Health, and the Italian Ministry
for University and Scientific Research.
G.J. Sills has received speaker/consultancy fees and support
for conference attendance from Alapis, Eisai Pharmaceuticals,
GlaxoSmithKline, Janssen–Cilag Ltd, Pfizer, and UCB Pharma.
H. Steve White has served as a paid consultant to Johnson and
Johnson Pharmaceutical Research and Development, GlaxoSmithKline,
Valeant Pharmaceuticals, Eli Lilly & Company, and Upsher–Smith
Laboratories, Inc. He is a member of the UCB Pharma Speakers Bureau
and a member of the NeuroTherapeutics Scientific Advisory Board, and
has received research funding from NeuroAdjuvants, Inc. He is also one
of two scientific co-founders of NeuroAdjuvants, Inc., Salt Lake City, UT,
USA.
Acknowledgments
The scientific meeting on which this article is based (Antiepileptic
Drug Therapy: Does Mechanism of Action Matter? 7 June 2010,
London, UK) was initiated and supported by GlaxoSmithKline (GSK).
Members of the Scientific Committee who developed the meeting
program were selected by the Chairman, Professor Martin Brodie, in
consultation with GSK. Scientific Committee members and presenters
who were not members of the Scientific Committee were paid an
honorarium for their participation in the meeting. Editorial support in
the form of editing and formatting of the article, collation of author
comments, and coordination of submission requirements was
provided by Janet M. Brandon of Caudex Medical Ltd. and was funded
by GSK. A draft of the article was reviewed by GSK for factual accuracy.
References
[1] Chong DJ, Bazil CW. Update on anticonvulsant drugs. Curr Neurol Neurosci Rep
2010;10:308–18.
[2] Brodie MJ, Bamagous G, Kwan P. Improved outcomes in newly diagnosed
epilepsy. Epilepsia 2009;50:411–2.
[3] Callaghan BC, Anand K, Hesdorffer D, Hauser WA, French JA. Likelihood of seizure
remission in an adult population with refractory epilepsy. Ann Neurol 2007;62:
382–9.
[4] Luciano AL, Shorvon SD. Results of treatment changes in patients with apparently
drug-resistant chronic epilepsy. Ann Neurol 2007;62:375–81.
[5] Beyenburg S, Stavem K, Schmidt D. Placebo-corrected efficacy of modern
antiepileptic drugs for refractory epilepsy: systematic review and meta-analysis.
Epilepsia 2010;51:7–26.
[6] Gazzolla DM, Balcer LJ, French JA. Seizure-free outcome in randomized add-on
trials of the new antiepileptic drugs. Epilepsia 2007;48:1303–7.
339
[7] Berg AT, Shinnar S, Levy SR, Testa FM. Status epilepticus in children with newly
diagnosed epilepsy. Ann Neurol 1999;45:618–23.
[8] Geerts A, Arts WF, Stroink H, et al. Course and outcome of childhood epilepsy: a 15-
year follow-up of the Dutch Study of Epilepsy in Childhood. Epilepsia 2010;51:
1189–97.
[9] Sillanpaa M, Schmidt D. Early seizure frequency and aetiology predict long-term
medical outcome in childhood-onset epilepsy. Brain 2009;132:989–98.
[10] Kwan P, Schachter SC, Brodie MJ. Drug-resistant epilepsy. N Engl J Med, in press.
[11] Krymchantowski AV, Bigal ME. Polytherapy in the preventive and acute
treatment of migraine: fundamentals for changing the approach. Expert Rev
Neurother 2006;6:283–9.
[12] Dworkin RH, O'Connor AB, Audette J, et al. Recommendations for the
pharmacological management of neuropathic pain: an overview and literature
update. Mayo Clin Proc 2010;85:S3–S14.
[13] Epstein BJ. Improving blood pressure control rates by optimizing combination
antihypertensive therapy. Expert Opin Pharmacother 2010;11:2011–26.
[14] Thompson MA, Aberg JA, Cahn P, et al. Antiretroviral treatment of adult HIV
infection: 2010 recommendations of the International AIDS Society—USA panel.
JAMA 2010;304:321–33.
[15] Cheung MC, Haynes AE, Meyer RM, Stevens A, Imrie KR. Rituximab in lymphoma:
a systematic review and consensus practice guideline from Cancer Care Ontario.
Cancer Treat Rev 2007;33:161–76.
[16] Engstrom PF. Systemic therapy for advanced or metastatic colorectal cancer:
National Comprehensive Cancer Network guidelines for combining anti-vascular
endothelial growth factor and anti-epidermal growth factor receptor monoclonal
antibodies with chemotherapy. Pharmacotherapy 2008;28:18-22S.
[17] Meisler MH, Kearney JA. Sodium channel mutations in epilepsy and other
neurological disorders. J Clin Invest 2005;115:2010–7.
[18] Catterall WA, Kalume F, Oakley JC. NaV1.1 channels and epilepsy. J Physiol
2010;588:1849–59.
[19] Ogiwara I, Miyamoto H, Morita N, et al. Na(v)1.1 localizes to axons of
parvalbumin-positive inhibitory interneurons: a circuit basis for epileptic
seizures in mice carrying an Scn1a gene mutation. J Neurosci 2007;27:5903–14.
[20] Yu FH, Mantegazza M, Westenbroek RE, et al. Reduced sodium current in
GABAergic interneurons in a mouse model of severe myoclonic epilepsy in
infancy. Nat Neurosci 2006;9:1142–9.
[21] Guerrini R, Dravet C, Genton P, Belmonte A, Kaminska A, Dulac O. Lamotrigine
and seizure aggravation in severe myoclonic epilepsy. Epilepsia 1998;39:508–12.
[22] Liao Y, Deprez L, Maljevic S, et al. Molecular correlates of age-dependent seizures
in an inherited neonatal-infantile epilepsy. Brain 2010;133:1403–14.
[23] Vacher H, Mohapatra DP, Trimmer JS. Localization and targeting of voltage-
dependent ion channels in mammalian central neurons. Physiol Rev 2008;88:
1407–47.
[24] Maljevic S, Wuttke TV, Seebohm G, Lerche H. KV7 channelopathies. Pfluegers
Arch 2010;460:277–88.
[25] Zuberi SM, Eunson LH, Spauschus A, et al. A novel mutation in the human
voltage-gated potassium channel gene (Kv1.1) associates with episodic ataxia
type 1 and sometimes with partial epilepsy. Brain 1999;122(Pt. 5):817–25.
[26] Du W, Bautista JF, Yang H, et al. Calcium-sensitive potassium channelopathy in
human epilepsy and paroxysmal movement disorder. Nat Genet 2005;37:733–8.
[27] Bernard C, Anderson A, Becker A, Poolos NP, Beck H, Johnston D. Acquired
dendritic channelopathy in temporal lobe epilepsy. Science 2004;305:532–5.
[28] Errington AC, Stohr T, Heers C, Lees G. The investigational anticonvulsant
lacosamide selectively enhances slow inactivation of voltage-gated sodium
channels. Mol Pharmacol 2008;73:157–69.
[29] Kito M, Maehara M, Watanabe K. Antiepileptic drugs: calcium current interaction
in cultured human neuroblastoma cells. Seizure 1994;3:141–9.
[30] Poolos NP, Migliore M, Johnston D. Pharmacological upregulation of H-channels
reduces the excitability of pyramidal neuron dendrites. Nat Neurosci 2002;5:767–74.
[31] Kwan P, Sills GJ, Brodie MJ. The mechanisms of action of commonly used
antiepileptic drugs. Pharmacol Ther 2001;90:21–34.
[32] Stephen LJ, Brodie MJ. Pharmacotherapy of epilepsy: newly approved and
developmental agents. CNS Drugs 2011;25:89–107.
[33] Rundfeldt C, Netzer R. The novel anticonvulsant retigabine activates M-currents
in Chinese hamster ovary-cells tranfected with human KCNQ2/3 subunits.
Neurosci Lett 2000;282:73–6.
[34] Wuttke TV, Seebohm G, Bail S, Maljevic S, Lerche H. The new anticonvulsant
retigabine favors voltage-dependent opening of the Kv7.2 (KCNQ2) channel by
binding to its activation gate. Mol Pharmacol 2005;67:1009–17.
[35] Delmas P, Brown DA. Pathways modulating neural KCNQ/M (Kv7) potassium
channels. Nat Rev Neurosci 2005;6:850–62.
[36] Main MJ, Cryan JE, Dupere JR, Cox B, Clare JJ, Burbidge SA. Modulation of KCNQ2/3
potassium channels by the novel anticonvulsant retigabine. Mol Pharmacol
2000;58:253–62.
[37] Brodie MJ, Lerche H, Gil-Nagel A, et al. Efficacy and safety of adjunctive ezogabine
(retigabine) in refractory partial epilepsy. Neurology 2010;75:1817–24.
[38] French JA, Abou-Khalil BW, Leroy R, on behalf of the RESTORE 1/Study 301
investigators. Randomized double-blind placebo-controlled trial of ezogabine
(retigabine) in partial epilepsy. Neurology 2011;76:1555–63.
[39] Rogawski MA, Loscher W. The neurobiology of antiepileptic drugs. Nat Rev
Neurosci 2004;5:553–64.
[40] Löscher W, Schmidt D. Which animal models should be used in the search for
new antiepileptic drugs? A proposal based on experimental and clinical
considerations. Epilepsy Res 1988;2:145–81.
[41] Bialer M, White HS. Key factors in the discovery and development of new
antiepileptic drugs. Nat Rev Drug Discov 2010;9:68–82.
340 M.J. Brodie et al. / Epilepsy & Behavior 21 (2011) 331–341
[42] White HS, Woodhead JH, Wilcox KS, Stables JP, Kupferberg HJ, Wolf HH.
Discovery and preclinical development of antiepileptic drugs. In: Levy RH,
Mattson RH, Meldrum BS, Perucca E, editors. Antiepileptic drugs. Philadelphia:
Lippincott Williams & Williams; 2002. p. 36–48.
[43] Stables JP, Bertram E, Dudek FE, et al. Therapy discovery for pharmacoresistant
epilepsy and for disease-modifying therapeutics: summary of the NIH/NINDS/
AES Models II Workshop. Epilepsia 2003;44:1472–8.
[44] McNamara JO. Development of new pharmacological agents for epilepsy: lessons
from the kindling model. Epilepsia 1989;30(Suppl. 1):S13–8.
[45] Sills GJ, Brodie MJ. Preclinical drug development in epilepsy. In: Schwartzkroin
PA, editor. Encyclopedia of basic epilepsy research. London: Elsevier; 2009.
p. 97–103.
[46] Kupferberg HJ, Schmutz M. Screening of new compounds and the role of the
pharmaceutical industry. In: Engel J, Pedley TA, editors. Epilepsy: a comprehen-
sive textbook. Philadelphia: Lippincott–Raven; 1997. p. 1417–34.
[47] Berkovic SF, Knowlton RC, Leroy RF, Schiemann J, Falter U. Placebo-controlled study
of levetiracetam in idiopathic generalized epilepsy. Neurology 2007;69:1751–60.
[48] Krauss GL, Bergin A, Kramer RE, Cho YW, Reich SG. Suppression of post-hypoxic
and post-encephalitic myoclonus with levetiracetam. Neurology 2001;56:411–2.
[49] Noachtar S, Andermann E, Meyvisch P, Andermann F, Gough WB, Schiemann-Delgado
J. Levetiracetam for the treatment of idiopathic generalized epilepsy with myoclonic
seizures. Neurology 2008;70:607–16.
[50] Perucca E, Gram L, Avanzini G, Dulac O. Antiepileptic drugs as a cause of
worsening seizures. Epilepsia 1998;39:5–17.
[51] Smith M, Wilcox KS, White HS. Discovery of antiepileptic drugs. Neurotherapeutics
2007;4:12–7.
[52] Glauser TA, Cnaan A, Shinnar S, et al. Ethosuximide, valproic acid, and
lamotrigine in childhood absence epilepsy. N Engl J Med 2010;362:790–9.
[53] Schmidt D, Holmes GL. Commentary: novel delivery approaches for antiepileptic
drugs: hope and hurdles. Neurotherapeutics 2009;6:381–2.
[54] Brodie MJ, Perucca E, Ryvlin P, Ben-Menachem E, Meencke HJ. Comparison of
levetiracetam and controlled-release carbamazepine in newly diagnosed
epilepsy. Neurology 2007;68:402–8.
[55] Marson AG, Al-Kharusi AM, Alwaidh M, et al. The SANAD study of effectiveness of
carbamazepine, gabapentin, lamotrigine, oxcarbazepine, or topiramate for
treatment of partial epilepsy: an unblinded randomised controlled trial. Lancet
2007;369:1000–15.
[56] Specchio LM, Gambardella A, Giallonardo AT, et al. Open label, long-term,
pragmatic study on levetiracetam in the treatment of juvenile myoclonic
epilepsy. Epilepsy Res 2006;71:32–9.
[57] Glauser T, Kluger G, Sachdeo R, Krauss G, Perdomo C, Arroyo S. Rufinamide for
generalized seizures associated with Lennox–Gastaut syndrome. Neurology
2008;70:1950–8.
[58] Elterman RD, Shields WD, Mansfield KA, Nakagawa J. Randomized trial of
vigabatrin in patients with infantile spasms. Neurology 2001;57:1416–21.
[59] Chiron C, Marchand MC, Tran A, et al, for the STICLO Study Group. Stiripentol in
severe myoclonic epilepsy in infancy: a randomised placebo-controlled syndrome-
dedicated trial. Lancet 2000;356:1638–42.
[60] Toledano R, Gil-Nagel A. Adverse effects of antiepileptic drugs. Semin Neurol
2008;28:317–27.
[61] Barcs G, Walker EB, Elger CE, et al. Oxcarbazepine placebo-controlled, dose-
ranging trial in refractory partial epilepsy. Epilepsia 2000;41:1597–607.
[62] Besag FM, Berry DJ, Pool F, Newbery JE, Subel B. Carbamazepine toxicity with
lamotrigine: pharmacokinetic or pharmacodynamic interaction? Epilepsia
1998;39:183–7.
[63] Brodie MJ, Yuen AW, for the 105 Study Group. Lamotrigine substitution study:
evidence for synergism with sodium valproate? Epilepsy Res 1997;26:423–32.
[64] Saké J-K, Herbert D, Isojarvi J, et al. A pooled analysis of lacosamide clinical trial
data grouped by mechanisms of action of concomitant antiepileptic drugs. CNS
Drugs 2010;24:1055–68.
[65] Holmes GL, Frank LM, Sheth RD, et al. Lamotrigine monotherapy for newly
diagnosed typical absence seizures in children. Epilepsy Res 2008;82:124–32.
[66] Labiner DM, Ettinger AB, Fakhoury TA, et al. Effects of lamotrigine compared with
levetiracetam on anger, hostility, and total mood in patients with partial
epilepsy. Epilepsia 2009;50:434–42.
[67] Arcas J, Ferrer T, Roche MC, Martinez-Bermejo A, Lopez-Martin V. Hypohidrosis
related to the administration of topiramate to children. Epilepsia 2001;42:1363–5.
[68] Ohtahara S, Yamatogi Y. Safety of zonisamide therapy: prospective follow-up
survey. Seizure 2004;13(Suppl. 1):S50–5.
[69] Ohtahara S, Yamatogi Y. Erratum to "Safety of zonisamide therapy: prospective
follow-up survey.". Seizure 2007;16:87–93.
[70] Sander JW, Hart YM. Vigabatrin and behaviour disturbances. Lancet 1990;335:57.
[71] Marsh ED, Brooks-Kayal AR, Porter BE. Seizures and antiepileptic drugs: does
exposure alter normal brain development? Epilepsia 2006;47:1999–2010.
[72] Cohen I, Navarro V, Clemenceau S, Baulac M, Miles R. On the origin of interictal
activity in human temporal lobe epilepsy in vitro. Science 2002;298:1418–21.
[73] First Seizure Trial Group. Randomized clinical trial on the efficacy of antiepileptic
drugs in reducing the risk of relapse after a first unprovoked tonic–clonic seizure.
Neurology 1993;43:478–83.
[74] Leone MA, Solari A, Beghi E. Treatment of the first tonic–clonic seizure does not
affect long-term remission of epilepsy. Neurology 2006;67:2227–9.
[75] Musicco M, Beghi E, Solari A, Viani F, for the First Seizure Trial Group. Treatment of
first tonic-clonic seizure does not improve the prognosis of epilepsy. Neurology
1997;49:991–8.
[76] Schachter SC, LaFrance WC, eds. Gates and Rowan's: Nonepileptic seizures. Third
Edition. Cambridge: Cambridge University Press; 2010.
[77] Covanis A, Gupta AK, Jeavons PM. Sodium valproate: monotherapy and
polytherapy. Epilepsia 1982;23:693–720.
[78] Jentink J, Loane MA, Dolk H, et al. Valproic acid monotherapy in pregnancy and
major congenital malformations. N Engl J Med 2010;362:2185–93.
[79] Tomson T, Battino D. Teratogenic effects of antiepileptic medications. Neurol Clin
2009;27:993–1002.
[80] Banach R, Boskovic R, Einarson T, Koren G. Long-term developmental outcome of
children of women with epilepsy, unexposed or exposed prenatally to
antiepileptic drugs: a meta-analysis of cohort studies. Drug Saf 2010;33:73–9.
[81] Bromley RL, Mawer G, Love J, et al. Early cognitive development in children born
to women with epilepsy: a prospective report. Epilepsia 2010;51:2058–65.
[82] Meador KJ, Baker GA, Browning N, et al. Cognitive function at 3 years of age after
fetal exposure to antiepileptic drugs. N Engl J Med 2009;360:1597–605.
[83] Chung AM, Eiland LS. Use of second-generation antiepileptic drugs in the
pediatric population. Paediatr Drugs 2008;10:217–54.
[84] Crespel A, Genton P, Berramdane M, et al. Lamotrigine associated with
exacerbation or de novo myoclonus in idiopathic generalized epilepsies.
Neurology 2005;65:762–4.
[85] Sharpe DV, Patel AD, Abou-Khalil B, Fenichel GM. Levetiracetam monotherapy in
juvenile myoclonic epilepsy. Seizure 2008;17:64–8.
[86] Covanis A, Skiadas K, Loli N, Lada C, Theodorou V. Absence epilepsy: early
prognostic signs. Seizure 1992;1:281–9.
[87] Rowan AJ, Meijer JW, de Beer-Pawlikowski N, van der Geest P, Meinardi H.
Valproate–ethosuximide combination therapy for refractory absence seizures.
Arch Neurol 1983;40:797–802.
[88] Modur PN, Milteer WE. Adjunctive pregabalin therapy in mentally retarded,
developmentally delayed patients with epilepsy. Epilepsy Behav 2008;13:554–6.
[89] Sazgar M, Bourgeois BF. Aggravation of epilepsy by antiepileptic drugs. Pediatr
Neurol 2005;33:227–34.
[90] Kellinghaus C, Dziewas R, Ludemann P. Tiagabine-related non-convulsive status
epilepticus in partial epilepsy: three case reports and a review of the literature.
Seizure 2002;11:243–9.
[91] Guberman AH, Besag FM, Brodie MJ, et al. Lamotrigine-associated rash: risk/
benefit considerations in adults and children. Epilepsia 1999;40:985–91.
[92] Kaminski RM, Matagne A, Patsalos PN, Klitgaard H. Benefit of combination
therapy in epilepsy: a review of the preclinical evidence with levetiracetam.
Epilepsia 2009;50:387–97.
[93] Kwan P, Brodie MJ. Combination therapy in epilepsy: when and what to use.
Drugs 2006;66:1817–29.
[94] Marescaux C, Hirsch E, Finck S, et al. Landau–Kleffner syndrome: a pharmacologic
study of five cases. Epilepsia 1990;31:768–77.
[95] Fejerman N, Di Blasi AM. Status epilepticus of benign partial epilepsies in
children: report of two cases. Epilepsia 1987;28:351–5.
[96] Kikumoto K, Yoshinaga H, Oka M, et al. EEG and seizure exacerbation induced by
carbamazepine in Panayiotopoulos syndrome. Epileptic Disord 2006;8:53–6.
[97] Bello-Espinosa LE, Roberts SL. Levetiracetam for benign epilepsy of childhood
with centrotemporal spikes: three cases. Seizure 2003;12:157–9.
[98] Coppola G, Franzoni E, Verrotti A, et al. Levetiracetam or oxcarbazepine as
monotherapy in newly diagnosed benign epilepsy of childhood with centrotemporal
spikes (BECTS): an open-label, parallel group trial. Brain Dev 2007;29:281–4.
[99] Garcia C, Rubio G. Efficacy and safety of levetiracetam in the treatment of
Panayiotopoulos syndrome. Epilepsy Res 2009;85:318–20.
[100] Wheless JW, Clarke DF, Arzimanoglou A, Carpenter D. Treatment of pediatric
epilepsy: European expert opinion, 2007. Epileptic Disord 2007;9:353–412.
[101] Bast T, Volp A, Wolf C, Rating D. The influence of sulthiame on EEG in children
with benign childhood epilepsy with centrotemporal spikes (BECTS). Epilepsia
2003;44:215–20.
[102] Engler F, Maeder-Ingvar M, Roulet E, Deonna T. Treatment with sulthiame
(Ospolot) in benign partial epilepsy of childhood and related syndromes: an
open clinical and EEG study. Neuropediatrics 2003;34:105–9.
[103] Engel J. Report of the ILAE classification core group. Epilepsia 2006;47:1558–68.
[104] Wohlrab G, Boltshauser E, Schmitt B. Vigabatrin as a first-line drug in West syndrome:
clinical and electroencephalographic outcome. Neuropediatrics 1998;29:133–6.
[105] Escayg A, Goldin AL. Sodium channel SCN1A and epilepsy: mutations and
mechanisms. Epilepsia 2010;51:1650–8.
[106] Fisher JL. The anti-convulsant stiripentol acts directly on the GABA(A) receptor as
a positive allosteric modulator. Neuropharmacology 2009;56:190–7.
[107] Grosso S, Franzoni E, Iannetti P, et al. Efficacy and safety of topiramate in
refractory epilepsy of childhood: long-term follow-up study. J Child Neurol
2005;20:893–7.
[108] Wirrell E, Ho AW, Hamiwka L. Sulthiame therapy for continuous spike and wave
in slow-wave sleep. Pediatr Neurol 2006;35:204–8.
[109] Reife R. Assessing pharmacokinetic and pharmacodynamic interactions in clinical
trials of antiepileptic drugs. In: French J, Leppik I, Dichter MA, editors. Antiepileptic
drug development. Advances in Neurology. Philadelphia: Lippincott–Raven; 1998.
p. 95–103.
[110] Jonker DM, Voskuyl RA, Danhof M. Synergistic combinations of anticonvulsant
agents: what is the evidence from animal experiments? Epilepsia 2007;48:412–34.
[111] Tallarida RJ. An overview of drug combination analysis with isobolograms.
J Pharmacol Exp Ther 2006;319:1–7.
[112] Weaver LC, Swinyard EA, Woodbury LA, Goodman LS. Studies on anticonvulsant
drug combinations: phenobarbital and diphenylhydantoin. J Pharmacol Exp Ther
1955;113:359–70.
[113] Deckers CL, Czuczwar SJ, Hekster YA, et al. Selection of antiepileptic drug
polytherapy based on mechanisms of action: the evidence reviewed. Epilepsia
2000;41:1364–74.
 M.J. Brodie et al. / Epilepsy & Behavior 21 (2011) 331–341
[114] Bourgeois BF. Antiepileptic drug combinations and experimental background: the
case of phenobarbital and phenytoin. Naunyn Schmiedebergs Arch Pharmacol
1986;333:406–11.
[115] Morris JC, Dodson WE, Hatlelid JM, Ferrendelli JA. Phenytoin and carbamazepine,
alone and in combination: anticonvulsant and neurotoxic effects. Neurology
1987;37:1111–8.
[116] Stafstrom CE. Mechanisms of action of antiepileptic drugs: the search for
synergy. Curr Opin Neurol 2010;23:157–63.
[117] Czuczwar SJ, Borowicz KK. Polytherapy in epilepsy: the experimental evidence.
Epilepsy Res 2002;52:15–23.
[118] Luszczki JJ, Czuczwar SJ. Preclinical profile of combinations of some second-
generation antiepileptic drugs: an isobolographic analysis. Epilepsia 2004;45:
895–907.
[119] Cuadrado A, de las Cuevas I, Valdizan EM, Armijo JA. Synergistic interaction
between valproate and lamotrigine against seizures induced by 4-aminopyridine
and pentylenetetrazole in mice. Eur J Pharmacol 2002;453:43–52.
[120] De Sarro G, Nava F, Aguglia U, De Sarro A. Lamotrigine potentiates the antiseizure
activity of some anticonvulsants in DBA/2 mice. Neuropharmacology 1996;35:
153–8.
[121] Luszczki JJ, Czuczwar M, Kis J, et al. Interactions of lamotrigine with topiramate
and first-generation antiepileptic drugs in the maximal electroshock test in mice:
an isobolographic analysis. Epilepsia 2003;44:1003–13.
[122] Borowicz KK, Swiader M, Luszczki J, Czuczwar SJ. Effect of gabapentin on the
anticonvulsant activity of antiepileptic drugs against electroconvulsions in mice:
an isobolographic analysis. Epilepsia 2002;43:956–63.
[123] De Sarro G, Spagnolo C, Gareri P, Gallelli L, De Sarro A. Gabapentin potentiates the
antiseizure activity of certain anticonvulsants in DBA/2 mice. Eur J Pharmacol
1998;349:179–85.
[124] Klitgaard H, Knudsen ML, Jackson HC. Synergism between drugs with different
mechanisms of action against audiogenic seizures in DBA/2 mice. Epilepsia
1993;34:93–4.
[125] Patsalos PN, Perucca E. Clinically important drug interactions in epilepsy: general
features and interactions between antiepileptic drugs. Lancet Neurol 2003;2:347–56.
[126] Gatti G, Bartoli A, Marchiselli R, et al. Vigabatrin-induced decrease in serum
phenytoin concentration does not involve a change in phenytoin bioavailability.
Br J Clin Pharmacol 1993;36:603–6.
[127] Mattson RH, Cramer JA, Williamson PD, Novelly RA. Valproic acid in epilepsy:
clinical and pharmacological effects. Ann Neurol 1978;3:20–5.
[128] Perucca E. Clinically relevant drug interactions with antiepileptic drugs. Br J Clin
Pharmacol 2006;61:246–55.
[129] Messenheimer J, Mullens EL, Giorgi L, Young F. Safety review of adult clinical trial
experience with lamotrigine. Drug Saf 1998;18:281–96.
[130] Obach RS, Walsky RL, Venkatakrishnan K, Houston JB, Tremaine LM. In vitro
cytochrome P450 inhibition data and the prediction of drug–drug interactions:
qualitative relationships, quantitative predictions, and the rank-order approach.
Clin Pharmacol Ther 2005;78:582–92.
[131] Kwan P, Brodie MJ. Epilepsy after the first drug fails: substitution or add-on?
Seizure 2000;9:464–8.
[132] Pisani F, Oteri G, Russo MF, Di Perri R, Perucca E, Richens A. The efficacy of
valproate–lamotrigine comedication in refractory complex partial seizures:
evidence for a pharmacodynamic interaction. Epilepsia 1999;40:1141–6.
[133] Cereghino JJ, Brock JT, Van Meter JC, Penry JK, Smith LD, White BG. The efficacy of
carbamazepine combinations in epilepsy. Clin Pharmacol Ther 1975;18:733–41.
[134] Brodie MJ, Mumford JP, for the 012 Study Group. Double-blind substitution of
vigabatrin and valproate in carbamazepine-resistant partial epilepsy. Epilepsy
Res 1999;34:199–205.
[135] Leach JP, Brodie MJ. Synergism with GABAergic drugs in refractory epilepsy.
Lancet 1994;343:1650.
[136] Stephen LJ, Sills GJ, Brodie MJ. Lamotrigine and topiramate may be a useful
combination. Lancet 1998;351:958–9.
[137] Sills GJ, Brodie MJ. Update on the mechanisms of action of antiepileptic drugs.
Epileptic Disord 2001;3:165–72.
[138] Beydoun A, D'Souza J, Hebert D, Doty P. Lacosamide: pharmacology, mechanisms
of action and pooled efficacy and safety data in partial-onset seizures. Expert Rev
Neurother 2009;9:33–42.
[139] Brodie MJ, Rosenfeld WE, Vazquez B, et al. Rufinamide for the adjunctive
treatment of partial seizures in adults and adolescents: a randomized placebo-
controlled trial. Epilepsia 2009;50:1899–909.
[140] Elger CE, Stefan H, Mann A, Narurkar M, Sun Y, Perdomo C. A 24-week
multicenter, randomized, double-blind, parallel-group, dose-ranging study of
rufinamide in adults and adolescents with inadequately controlled partial
seizures. Epilepsy Res 2010;88:255–63.
[141] Wong IC, Mawer GE, Sander JW, Lhatoo SD. A pharmacoepidemiologic study of
factors influencing the outcome of treatment with lamotrigine in chronic
epilepsy. Epilepsia 2001;42:1354–8.
[142] Kwan P, Arzimanoglou A, Berg AT, et al. Definition of drug resistant epilepsy:
consensus proposal by the ad hoc Task Force of the ILAE Commission on
Therapeutic Strategies. Epilepsia 2010;51:1069–77.
[143] Kwan P, Brodie MJ. Definition of refractory epilepsy: defining the indefinable?
Lancet Neurol 2010;9:27–9.
[144] Stephen LJ, Brodie MJ. Seizure freedom with more than one antiepileptic drug.
Seizure 2002;11:349–51.
341
[145] Brodie MJ, Kwan P. Staged approach to epilepsy management. Neurology
2002;58:S2–8.
[146] Beghi E, Gatti G, Tonini C, et al. Adjunctive therapy versus alternative monotherapy
in patients with partial epilepsy failing on a single drug: a multicentre, randomised,
pragmatic controlled trial. Epilepsy Res 2003;57:1–13.
[147] Ettinger AB, Argoff CE. Use of antiepileptic drugs for nonepileptic conditions:
psychiatric disorders and chronic pain. Neurotherapeutics 2007;4:75–83.
[148] Spina E, Perugi G. Antiepileptic drugs: indications other than epilepsy. Epileptic
Disord 2004;6:57–75.
[149] Johannessen LC, Johannessen SI. Pharmacological management of epilepsy:
recent advances and future prospects. Drugs 2008;68:1925–39.
[150] Rogawski MA, Loscher W. The neurobiology of antiepileptic drugs for the
treatment of nonepileptic conditions. Nat Med 2004;10:685–92.
[151] Deckers CL, Hekster YA, Keyser A, Meinardi H, Renier WO. Reappraisal of
polytherapy in epilepsy: a critical review of drug load and adverse effects.
Epilepsia 1997;38:570–5.
[152] Canevini MP, De SG, Galimberti CA, et al. Relationship between adverse effects of
antiepileptic drugs, number of coprescribed drugs, and drug load in a large
cohort of consecutive patients with drug-refractory epilepsy. Epilepsia 2010;51:
797–804.
[153] Devinsky O. Patients with refractory seizures. N Engl J Med 1999;340:1565–70.
[154] Stables JP, Bertram EH, White HS, et al. Models for epilepsy and epileptogenesis:
report from the NIH workshop, Bethesda, Maryland. Epilepsia 2002;43:1410–20.
[155] Mantegazza M, Curia G, Biagini G, Ragsdale DS, Avoli M. Voltage-gated sodium
channels as therapeutic targets in epilepsy and other neurological disorders.
Lancet Neurol 2010;9:413–24.
[156] Remy S, Gabriel S, Urban BW, et al. A novel mechanism underlying drug
resistance in chronic epilepsy. Ann Neurol 2003;53:469–79.
[157] Johnston GA. GABA(A) receptor channel pharmacology. Curr Pharm Des 2005;11:
1867–85.
[158] Brooks-Kayal AR, Shumate MD, Jin H, Rikhter TY, Coulter DA. Selective changes in
single cell GABA(A) receptor subunit expression and function in temporal lobe
epilepsy. Nat Med 1998;4:1166–72.
[159] Langen B, Egerland U, Bernoster K, Dost R, Unverferth K, Rundfeldt C. Character-
ization in rats of the anxiolytic potential of ELB139 [1-(4-chlorophenyl)-4-
piperidin-1-yl-1,5-dihydro-imidazol-2-on], a new agonist at the benzodiazepine
binding site of the GABAA receptor. J Pharmacol Exp Ther 2005;314:717–24.
[160] Stell BM, Brickley SG, Tang CY, Farrant M, Mody I. Neuroactive steroids reduce
neuronal excitability by selectively enhancing tonic inhibition mediated by delta
subunit-containing GABAA receptors. Proc Natl Acad Sci USA 2003;100:14439–44.
[161] Madsen KK, Clausen RP, Larsson OM, Krogsgaard-Larsen P, Schousboe A, White
HS. Synaptic and extrasynaptic GABA transporters as targets for anti-epileptic
drugs. J Neurochem 2009;109(Suppl. 1):139–44.
[162] Wulff H, Castle NA, Pardo LA. Voltage-gated potassium channels as therapeutic
targets. Nat Rev Drug Discov 2009;8:982–1001.
[163] Benarroch EE. Potassium channels: brief overview and implications in epilepsy.
Neurology 2009;72:664–9.
[164] Wickenden AD, Roeloffs R, McNaughton-Smith G, Rigdon GC. KCNQ potassium
channels: drug targets for the treatment of epilepsy and pain. Expert Opin Ther
Patents 2004;14:457–69.
[165] Wickenden AD, Yu W, Zou A, Jegla T, Wagoner PK. Retigabine, a novel anti-
convulsant, enhances activation of KCNQ2/Q3 potassium channels. Mol
Pharmacol 2000;58:591–600.
[166] Meldrum BS, Rogawski MA. Molecular targets for antiepileptic drug develop-
ment. Neurotherapeutics 2007;4:18–61.
[167] Nemani VM, Binder DK. Emerging role of gap junctions in epilepsy. Histol
Histopathol 2005;20:253–9.
[168] Timofeev I, Steriade M. Neocortical seizures: initiation, development and
cessation. Neuroscience 2004;123:299–336.
[169] Nakase T, Naus CC. Gap junctions and neurological disorders of the central
nervous system. Biochim Biophys Acta 2004;1662:149–58.
[170] Venance L, Rozov A, Blatow M, Burnashev N, Feldmeyer D, Monyer H. Connexin
expression in electrically coupled postnatal rat brain neurons. Proc Natl Acad Sci
USA 2000;97:10260–5.
[171] Gareri P, Condorelli D, Belluardo N, et al. Antiabsence effects of carbenoxolone in
two genetic animal models of absence epilepsy (WAG/Rij rats and lh/lh mice).
Neuropharmacology 2005;49:551–63.
[172] Nilsen KE, Kelso AR, Cock HR. Antiepileptic effect of gap-junction blockers in a rat
model of refractory focal cortical epilepsy. Epilepsia 2006;47:1169–75.
[173] Herrmann S, Stieber J, Ludwig A. Pathophysiology of HCN channels. Pfluegers
Arch 2007;454:517–22.
[174] Ludwig A, Budde T, Stieber J, et al. Absence epilepsy and sinus dysrhythmia in
mice lacking the pacemaker channel HCN2. EMBO J 2003;22:216–24.
[175] Shah MM, Anderson AE, Leung V, Lin X, Johnston D. Seizure-induced plasticity of h
channels in entorhinal cortical layer III pyramidal neurons. Neuron 2004;44:495–508.
[176] Arias RL, Bowlby MR. Pharmacological characterization of antiepileptic drugs and
experimental analgesics on low magnesium-induced hyperexcitability in rat
hippocampal slices. Brain Res 2005;1047:233–44.
[177] Schmidt D, Löscher W. Drug resistance in epilepsy: putative neurobiologic and
clinical mechanisms. Epilepsia 2005;46:858–77.
[178] Walker MC, White HS, Sander JW. Disease modification in partial epilepsy. Brain
2002;125:1937–50.