Epileptic Disord 2023 Jun 29

SEMINAR IN EPILEPTOLOGY
Accepted Article
The pharmacological treatment of epilepsy in adults
Torbjörn Tomson1, Johan Zelano2-4, Yew Li Dang5,6, Piero Perucca5,6,7,8,9
1. Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden

2. Institute of neuroscience and physiology, Department of clinical neuroscience, Sahlgrenska
Academy, Gothenburg University, Sweden
3. Department of Neurology, Sahlgrenska University Hospital, Gothenburg, Sweden
4. Wallenberg Center of Molecular and Translational Medicine, Gothenburg University, Sweden
5. Bladin-Berkovic Comprehensive Epilepsy Program, Austin Health, Melbourne, Victoria, Australia
6. Epilepsy Research Centre, Department of Medicine (Austin Health), The University of Melbourne,
Melbourne, Victoria, Australia.
7. Department of Neuroscience, Central Clinical School, Monash University, Melbourne, Victoria,
Australia
8. Department of Neurology, The Royal Melbourne Hospital, Melbourne, Victoria, Australia
9. Department of Neurology, Alfred Health, Melbourne, Victoria, Australia
ORCID
Perucca 0000-0002-7855-7066
Dang 0000-0002-0570-5398
Tomson 0000-0003-0554-5352
Zelano 0000-0001-9445-4545
Corresponding author:
Torbjörn Tomson
Department of Clinical Neuroscience
Karolinska Institutet
Stockholm, Sweden
e-mail: torbjorn.tomson@regionstockholm.se
Running title: Pharmacological treatment of epilepsy
Received May 3rd, 2023; Accepted June 24th, 2023
This article has been accepted for publication and undergone full peer review but has not been
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Abstract
Accepted Article
The pharmacological treatment of epilepsy entails several critical decisions that need to be based on
an individual careful risk-benefit analysis. These include when to initiate treatment and with which
antiseizure medication (ASM). With more than 25 ASMs on the market, physicians have opportunities
to tailor the treatment to the individual patients´ needs. ASM selection is primarily based on the
patient’s type of epilepsy and spectrum of ASM efficacy, but several other factors must be considered.
These include age, sex, comorbidities, and concomitant medications to mention the most important.
Individual susceptibility to adverse drug effects, ease of use, costs and personal preferences should
also be taken into account. Once an ASM has been selected, the next step is to decide on an individual
target maintenance dose and a titration scheme to reach this dose. When the clinical circumstances
permit, a slow titration is generally preferred since it is associated with improved tolerability. The
maintenance dose is adjusted based on the clinical response aiming at the lowest effective dose.
Therapeutic drug monitoring can be of value in efforts to establish the optimal dose. If the first
monotherapy fails to control seizures without significant adverse effects, the next step will be to
gradually switch to an alternative monotherapy, or sometimes to add another ASM. If add-on is
considered, combining ASMs with different modes of action is usually recommended.
Misdiagnosis of epilepsy, non-adherence and suboptimal dosing are frequent causes of treatment
failure and should be excluded before a patient is regarded as drug-resistant. Other treatment
modalities, including epilepsy surgery, neuromodulation, and dietary therapies, should be considered
for truly drug-resistant patients. After some years of seizure freedom, the question of ASM withdrawal
often arises. Although successful in many, withdrawal is also associated with risks and the decision
needs to be based on careful risk-benefit analysis.
Key words
Epilepsy, antiseizure medication, pharmacotherapy
ILAE Learning objectives

3.1.1 Identify the spectrum of action for antiseizure medications
3.1.3 Demonstrate knowledge regarding the adverse effects of antiseizure medications
3.2 Recommend appropriate therapy based on epilepsy presentation
3.2.1 Recommend appropriate therapy according to seizure type
3.2.2 Recommend appropriate therapy according to epilepsy syndrome
3.2.3 Recommend individualized titrations of optimal dosing for patients including starting and
discontinuing medication
3.2.4 Communicate information regarding the antiseizure medication regimen
3.4 Demonstrate knowledge about the risks and opportunities associated with drug discontinuation
and methodologies for individualized implementation
2
Introduction
Pharmacological treatment has been a cornerstone in the management of epilepsy ever since the
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introduction of bromide in the 19th century. After a long period of slow development with the
availability of only a few new antiseizure medications (ASMs), the situation has changed dramatically
during the last few decades and we now have a plethora of different ASMs to choose from [1]. With
more than 25 marketed ASMs, prescribers have new opportunities to tailor the treatment to individual
patient needs but also face challenges in keeping up with this development.
The aim of this Seminar is to provide physicians with knowledge and support relevant for the
pharmacological treatment of adults with epilepsy. Many of the principles of treatment are the same
in children, but there are also features that are specific to their age group that will not be covered
here. Below, we will discuss basic key issues including when to start treatment, drug selection, what
to do when first treatment fails, and when ASM withdrawal should be considered in seizure-free
patients.
General principles of pharmacological treatment of epilepsy

Antiseizure medications (ASMs) are used prophylactically in patients with epilepsy with the aim to
reduce the risk of further seizures. The goal is seizure freedom without significant adverse effects. The
treatment is symptomatic in nature, meaning that during treatment the ASMs suppress the tendency
to have seizures, but they are not expected to impact on the underlying epileptogenic disease process.
Thus, the current medications cannot prevent the development of epilepsy. This is why the old term
“antiepileptic drugs” has been considered a misnomer and “antiseizure medications” now is the
favored term [2].
Individualization is a key concept in the pharmacological treatment of epilepsy. Epilepsy is a

heterogeneous disease with different seizure manifestations, and ASMs differ in their efficacy against
different types of seizures and epilepsies. Hence, the ASM needs to be selected based on the patients’
type of seizures, but other individual characteristics such as age, sex, comorbidities, and concurrent
medications should also be considered. Once the appropriate ASM has been selected the next step is
to decide on the first target dosage and on the titration rate to reach this dosage. Depending on the
clinical response adjustments may be needed over the course of the treatment, e.g. reduction of the
dosage or treatment cessation if the patient suffers from adverse effects, or a gradual dosage increase
if patients continue to have seizures. When an ASM has been tried to its full potential without
satisfactory effects, attempts are made to switch to a different ASM or to add another ASM.
When to start
While most patients with epilepsy will come under treatment in regions of the world where ASMs are
accessible, a diagnosis of epilepsy does not necessarily mean that treatment is indicated [3].
The decision to initiate treatment needs to be based on an individual risk-benefit analysis, as once
started, treatment is likely to be maintained for years. The analysis should include an estimation of the
likelihood of further seizures without treatment as well as of the personal risks (e.g. injuries, mortality,
restrictions) associated with further seizures should these occur. The likelihood of obtaining seizure
control with treatment and the risks of adverse drug effects must also be considered. Hence, this
important decision should be made within an evidence-based framework while at the same time taking
patients’ preferences into account.
Randomized studies have compared outcomes in patients receiving treatment already after a first
unprovoked seizure (early treatment) vs. initiated only after recurrence (deferred treatment) [4-6].
While early treatment with ASMs reduced the risk of recurrence by about 50%, the chance of long-
3
term remission was found the same irrespective of whether treatment was initiated early or deferred
[4-6]. Hence, by demonstrating that early initiation of treatment does not affect long-term prognosis,
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these studies confirmed the symptomatic nature of ASM therapy.
In general terms, ASMs are indicated when, in the opinion of the informed patient or if appropriate
their caregivers, the benefits of treatment outweigh the disadvantages. This is usually the case after
two unprovoked seizures occurring >24 hours apart provided that their severity or consequences are
significant for the individual. Some specific situations that may justify deviation from these general
rules are listed in Box 1.
Treatment with ASMs is best withheld if there is reasonable doubt that the events are truly epileptic
or if seizures are likely to be acute symptomatic.
Box 1
A. Situations when it may be reasonable to withhold treatment despite recurrent seizures

a. Subtle seizure manifestations, e.g. mild focal aware somatosensory seizures in
particular if occurring exclusively in non-embarrassing situations (night time, at home)
b. Long interval (years) between seizures
c. If seizures appear to be provoked by circumstances that can be avoided
d. If patient expresses a clear preference to withhold treatment
e. When poor adherence to treatment is very likely
B. Situations when it may be reasonable to consider treatment already after a single seizure
a. When recurrence risk is high, e.g. after a previous stroke or severe head injury; in fact
fulfilling the current criteria for epilepsy [3].
b. When consequences of a recurrence are severe, e.g. elderly fragile person
Which ASM to choose for initial treatment

The choice of initial ASM depends on epilepsy and patient characteristics. The seizure/epilepsy type
defines the range of useful ASMs, among which the most suitable drug for the particular patient is
selected. Important patient factors guiding the choice are comorbidities, concomitant medications,
reproductive plans in women, and presumed adverse effect sensitivity because of age, genetic
predisposition, or other medical conditions. In most settings, ASM cost is also a factor. For the initial
ASM, the risk-benefit analysis almost always favors a well-established ASM, approved as monotherapy
for the patient’s seizure or epilepsy type, and for which substantial clinical evidence has accumulated,
rather than a recently introduced drug where unknown adverse effects could still emerge post-
marketing.
Spectrum of effect by seizure type

Different ASMs are often described as suitable for different seizure types, but it is important to
recognize limitations in our current knowledge. Most ASMs are developed by screening in animal
models of different seizure types, followed by clinical evaluation and licensing in the circumstances
that are deemed most promising from both a medical and commercial perspective [7]. In most cases,
the types of seizures for which an ASM is frequently used is not only a function of the mechanism of
action, but also of the results of clinical research performed to date. As more evidence accumulates,
the spectrum for several of the newer ASMs may be widened. Importantly, some ASMs can aggravate
certain seizure types, a knowledge which also is likely to expand with growing experience.
The spectrum of effect of common ASMs by seizure type is shown in Table 1,[7-9] but note that the
spectrum of newer ASMs could expand as a result of studies in additional populations. Almost all ASMs
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are effective for focal seizures. For generalized tonic-clonic seizures, a smaller range of drugs with
different mechanisms of action can be used. Ethosuximide is instead specifically effective against
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absence seizures, but not other seizure types.
At a first glance, the overlap in effectiveness with regard to seizure type may wrongly give the
impression that a correct seizure classification is not important. To the contrary, a frequent reason for
treatment failure is error in the seizure classification. The risk of error is greatest in young individuals
as they often present with either focal or generalized epilepsy. In cases of juvenile myoclonic epilepsy
(JME, a generalized epilepsy syndrome), aggravation of myoclonus may occur after initiation of
sodium-channel blockers like carbamazepine or lamotrigine. Young men with JME who are
misdiagnosed with focal epilepsy may not be offered valproate, which remains the most effective ASM
for their syndrome. Misclassification of a focal-onset seizures as generalized may in contrast
unnecessarily lead to several ASM options being withheld. The importance of EEG for the correct
classification of the patient’s seizure and epilepsy type, and thus choice of ASM, cannot be over-
estimated.
Spectrum of adverse effects of antiseizure medications

Adverse effects are an important factor in ASM selection. They account for up to 20% of
discontinuations of the initial ASM [10] and prevent attainment of fully effective dosages.
Furthermore, they negatively impact on health-related quality of life, and can lead to substantial
disability, morbidity and even mortality [11].
ASMs can affect any organ or system, accounting for the wide spectrum of ASM toxicity (Table 2).
Building on a WHO framework, adverse ASM effects can be classified into five types (A-E) [11]. Type A
effects can be attributed to the known mechanism(s) of action of the drug, are common or very
common, typically emerge shortly after ASM commencement or dose escalation, and can abate or
resolve spontaneously over time or following dose reduction. Typical examples are drowsiness,
fatigue, dizziness, blurred vision, cognitive impairment, and psychiatric problems. Many of these
effects are shared by most, if not all, ASMs (Table 2). Type B effects are related to individual
vulnerability, be that genetic, immune, or accounted by other mechanisms. These effects are rare or
uncommon, develop over the first few weeks of treatment, and can resolve after discontinuation of
the ASM. Some of these can be life-threatening, particularly if recognition and intervention are
delayed. Examples include skin rashes, severe mucocutaneous reactions (e.g. Stevens-Johnson
syndrome), pancreatitis, and hepatic failure. Type C effects are ascribed to cumulative ASM exposure
and, as such, develop gradually over time, often after many years of drug intake. They are common
and while some can resolve after ASM discontinuation, others are irreversible. Typical examples
include weight changes, decreased bone mineral density, and hair loss. Type D effects include
teratogenic and carcinogenic effects. Overall, ASMs carry a two- to three-fold increased risk of birth
defects. However, the risk varies across different ASMs, being highest with valproate, and for several
ASMs, it increases with higher doses [12]. Prenatal exposure to valproate or topiramate has also been
associated with dose-dependent adverse post-natal neurobehavioral outcomes, including intellectual
impairment and autism spectrum disorder [13]. For many ASMs, including most new agents, data on
teratogenicity is either scarce or lacking. The reader is referred to the section on women of child-
bearing potential for further details. There is no compelling evidence to suggest that ASMs increase
the cancer risk in humans. Type E effects are adverse drug interactions, which are accounted by
pharmacokinetic and pharmacodynamic mechanisms. These interactions will be discussed in a
separate section below.
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HLA alleles/genotyping for ASM certain patient populations
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Genetic factors can increase the risk of adverse ASM effects. The prototypical example is the HLA-
B*1502 allele which was found to be strongly associated with carbamazepine-induced Stevens-
Johnson syndrome and toxic epidermal necrolysis in Han Chinese and other South-East Asian ethnic
groups [14]. This has led the FDA and other regulatory agencies to recommend that individuals of at-
risk ancestry be screened for HLA-B*1502 before commencing carbamazepine [14]. Other HLA alleles
can raise the risk of ASM-induced idiosyncratic reactions, including HLA-A*3101 which has been linked
with carbamazepine-induced cutaneous reactions in Chinese, Japanese, and European populations
[14]. However, the cost-effectiveness of screening for these alleles is unproven.
Drug interactions
ASM selection warrants careful consideration of potential drug interactions, which can be
pharmacokinetic or pharmacodynamic. Pharmacokinetic interactions involve changes in drug
metabolism or, less frequently, drug absorption, distribution, or excretion, ultimately leading to
changes in the serum concentrations of the affected drug. Pharmacodynamic interactions occur
instead at the site of action and are not associated with changes in drug serum concentrations.
Most clinically relevant interactions involving ASMs result from induction or inhibition of drug-
metabolizing enzymes [15]. Among first-line ASMs, carbamazepine, phenytoin and phenobarbital are
strong inducers of the cytochrome P450 and glucuronizing enzymes and can stimulate the metabolism
of a wide range of drugs (Table 3). This leads in turn to a reduction in the serum concentrations of the
affected drug and consequently to its reduced efficacy (unless efficacy is mediated by active
metabolites). The newer ASMs oxcarbazepine, eslicarbazepine acetate, lamotrigine, and topiramate
(at doses ≥200 mg/day) are weaker enzyme inducers and thus have a lower propensity for causing drug
interactions mediated by enzyme induction. Valproate is instead an enzyme-inhibiting ASM and its
introduction can result in elevation of the serum concentrations of a number of concomitant drugs,
increasing the risk for drug toxicity. Co-medications can also induce or inhibit the metabolism of ASMs.
For example, the ethinylestradiol component of combined oral contraceptives can induce lamotrigine
glucuronidation, leading to ≥50% reduction in lamotrigine serum concentrations and thus to a
potential deterioration in seizure control [16]. The CYP3A4 inhibitor erythromycin can increase by two-
to three-fold the serum concentrations of carbamazepine, a CYP3A4 substrate, with increased risks for
carbamazepine-induced toxicity [17].
Pharmacodynamic interactions between ASMs and other drugs can also occur, exemplified by the
aggravation of adverse metabolic effects when combining valproate with olanzapine [18].
Other considerations of relevance for ASM selection

A patient’s preference for an ASM over another can be influenced by other factors. One is daily dosing
frequency, with less frequent doses per day being associated with better patient adherence. A study
of 26 patients with epilepsy on different ASM regimens found that, on average, 87% of the once daily,
81% of the twice daily, 77% of the three times daily, 39% of the four times daily dosages were taken
as prescribed [19]. Another factor influencing ASM selection is cost. Higher costs are a barrier to
accessing newer ASMs not only in resource-poor countries, where phenobarbital might be the only
available ASM in certain settings, but also among low-income groups in industrialized countries [20].
Patients may also elect to take generic rather than the branded products, as the former are generally
cheaper. Of note, in countries with strict regulations for product bioequivalence, multiple studies have
shown that generics are a safe and effective alternative to branded ASMs [21].
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ASM selection by seizure/epilepsy type
From the principles outlined above, ASMs that are suitable for the individual patient - based on their
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efficacy and tolerability profile - can usually be defined. Clinical practice may also be influenced by
licensing, guidelines, or reimbursement. A specific problem in the epilepsy field is that because of the
requirements of regulatory authorities, registration-purpose clinical trials have strived to demonstrate
reasonable short-term anti-seizure effect rather than explore exact spectrum of effect. Trial designs
and the ability to extrapolate findings across populations have varied over time and continents, with
the US allowing historic-control comparators and the EU requiring an active comparator (often
carbamazepine-controlled release) for monotherapy license. Non-inferiority has been the preferred
outcome in EU, while superiority is required by the FDA [9]. Overall, these trials have demonstrated
that several of the newer generation ASMs (lamotrigine, levetiracetam, zonisamide) have an efficacy
similar to first generation ASMs in focal epilepsy [22]. Subsequent reviews and network-metanalyses
suggest that some additional newer ASMs (eslicarbazepine acetate, lacosamide) are as effective
[9,23,24]. Comparative data on long-term effectiveness has been provided by the SANAD studies, in
which patients with new-onset epilepsy of different types were randomized to different open-label
treatments [25-28], however not including some newer ASMs such as eslicarbazepine and lacosamide
In focal epilepsy, first monotherapy choices often recommended by experts are lamotrigine,
oxcarbazepine, and levetiracetam [9]. The SANAD studies found lamotrigine to be the most efficacious
choice [25,27]. The slow titration required for lamotrigine is a drawback that sometimes favor the
other alternatives. As mentioned above, several other newer ASMs could be as efficacious, there
among eslicarbazepine acetate, lacosamide, and zonisamide. Differences in cost and clinical tradition
could explain differences between countries regarding the range of ASMs that are considered
appropriate first monotherapy choices. The substantial accumulated experience with lamotrigine and
levetiracetam and the evaluation of these drugs in large pragmatic trials like SANAD is considered
important in some countries, whereas a wider selection of modes-of-action and dosing regimens that
comes with a wider range of ASMs is more important in others. Involvement of the patient in the
selection is key.
Carbamazepine is as effective but less used today, because of its enzyme-inducing effect and concerns
about chronic toxicity, including increased risk of long-term cardiovascular disease.
In generalized epilepsy with tonic-clonic seizures, valproate, levetiracetam or lamotrigine are common
first choices, but zonisamide, topiramate, and lacosamide are also mentioned in expert reviews [9].
The SANAD study found valproate to be more efficacious than lamotrigine and better tolerated than
topiramate [26], and in SANAD II levetiracetam was less efficacious than valproate [28]. An individual
data Cochrane review also favored valproate, for patient groups where it is a safe choice [24]. An
important limitation for valproate is the teratogenic potential, which has led to both the FDA and EMA
issuing strict regulations [29], in practice eliminating this as an option for initial therapy in women of
childbearing age, leaving clinicians with few alternatives to lamotrigine and levetiracetam in this
patient group. In absence seizures, the first choice is often ethosuximide or valproate [30].
The intricacies of selecting the optimal ASM as first monotherapy have led to expert panel-based ASM
selection tools to assist clinicians, e.g. Epipick [31].
ASM selection by epilepsy syndrome

As most epilepsy syndromes have onset in early life or childhood, their management in adulthood
typically involves adjustments rather than initiation of ASM therapy. Current recommendations on the
pharmacological treatment of epilepsy syndromes rely on expert-consensus opinions, which are
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mostly influenced by results from a few randomised controlled trials (RCTs), case series, and clinical
experience (Table 4).
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While epilepsy syndrome diagnosis can inform ASM selection (Table 4), considerations on ASMs to be
avoided are warranted. For example, sodium-channel blocking ASMs are widely recommended to be
avoided in Dravet syndrome due to the risk of seizure aggravation. However, the sodium channel-
blocker phenytoin can be useful in the management of status epilepticus [32] or even in the chronic
treatment of these patients [33]. Similar considerations apply to another sodium channel-blocker,
lamotrigine, which can be beneficial in some cases with Dravet syndrome [34].
In the same syndrome, ASMs that can control selected seizure types can also exacerbate other types.
This is the case for carbamazepine in Lennox-Gastaut Syndrome, where it can improve tonic seizure
control but also precipitate atypical absence seizures [35]. Intravenous benzodiazepines can control
most seizures in Lennox-Gastaut Syndrome but can also occasionally precipitate tonic seizures [36].
Epilepsy aetiology and ASM selection

Genetic epilepsies
In monogenic epilepsies, understanding the functional effect of the pathogenic variant can guide ASM
selection. In epilepsies caused by loss-of-function mutations in SCN1A, sodium channel blockers should
be avoided due to the risk of seizure aggravation and poor long-term cognitive outcomes [43].
Conversely, these agents can improve seizure control in epilepsies due to SCN1A, SCN2A and SCN8A
gain-of-function mutations [44].
There are also cases where the functional effect caused by a pathogenic variant may not be corrected
by existing ASMs; however, they can be countered by medications approved for other conditions (drug
repurposing). The best example is provided by the mechanistic target of rapamycin (mTOR) inhibitor
everolimus, an immunosuppressant for prevention of organ transplant rejection and antitumour
agent, which has been found to be effective as add-on therapy for focal seizures associated with
tuberous sclerosis complex where mutations in TSC1 or TSC2 genes result in hyperactivation of the
mTOR pathway [45].
Other etiologies
For focal epilepsies, there is some data suggesting that certain ASMs may be preferable to others in
different etiologies. Examples include sodium-channel blockers being more effective in immune-
mediated epilepsies [46] and lamotrigine and levetiracetam being better tolerated than
carbamazepine in poststroke epilepsy [47,48]. Retention rates vary in other epilepsy etiologies as well,
but it is currently unknown whether this reflects anti-seizure effect or tolerability [49]. For two large
adult etiological groups – patients with posttraumatic epilepsy and those with epilepsy in the setting
of dementia - there is only observational data and expert opinion; 1-year retention based from Swedish
prescription data was highest for second generations ASMs levetiracetam and lamotrigine, and the
latter is also recommended in the European guidelines for seizures in dementia based on its tolerability
in the elderly [9,50]. In the absence of etiology-specific evidence, the best practice is generally to select
the initial ASM based on other patient characteristics like age and comorbidities.
Considerations in special populations
Women of childbearing potential

The treatment of female patients that are of childbearing potential requires special considerations
regarding choice of ASMs as well as the overall treatment management [51]. Research during the last
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decades has revealed major differences between ASMs in teratogenic risks [51,52]. Although our
understanding of the risks with many newer generation ASMs is insufficient, exposure to valproate is
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clearly associated with a higher prevalence of major congenital malformations (MCM) in the offspring
than other ASMs such as lamotrigine, levetiracetam, carbamazepine, and oxcarbazepine [12,51-53]. A
recent population-based register study has indicated a level of risk for MCMs after exposure to
topiramate similar to that with valproate [53]. In addition to the increased risk of birth defects, prenatal
exposure to valproate has been associated with adverse neurodevelopmental and behavioral
outcomes, including reduced IQ, increased risk of autism and autism spectrum disorders, as well as
intellectual disabilities [13,54,55]. Again, a recent population-based register study suggests a similar
increased risk for autism spectrum disorders and intellectual disabilities with exposure to topiramate
[13].
For these reasons, the EMA [56]and FDA [57] have issued restrictions regarding the use of valproate in
female patients of childbearing potential. Valproate is now contraindicated for treatment of epilepsy
during pregnancy unless there is no other effective treatment available. Further, according to the EMA,
valproate must not be used in any woman or girl able to have children unless the conditions of a
specific pregnancy prevention program are met.
Although the regulatory bodies have not yet issued formal restrictions regarding use of topiramate,
the recent data [13,53] suggest that topiramate should be used with similar caution as valproate to
female patients of childbearing potential.
Given that the majority of pregnancies of women with epilepsy are unplanned [58], the teratogenic
potential should be considered already at the stage when treatment with ASMs is initiated in girls and
young women. Valproate and probably also topiramate should be avoided whenever possible. Based
on our current knowledge, lamotrigine and levetiracetam appear to be the safest in this regard [52].
There are women that have failed on all appropriate ASMs and become seizure free first on ASMs with
insufficient data on safety during pregnancy. These women have a right to be informed about the
uncertainties. If they wish to become pregnant it is probably best to continue on their effective
medication given the maternal and fetal risks with uncontrolled seizures. They should be encouraged
to report to a pregnancy register should they become pregnant.
Ongoing ASM treatment should be reassessed regularly considering the possibility of future,
unplanned or planned, pregnancies. Pre-pregnancy counselling should be offered aiming among other
things to ensure that the woman enters pregnancy on the lowest effective ASM dose given that the
teratogenic risks appear to be dose-dependent for many ASMs [12,52,54]. It is recommended that the
individual optimal pre-pregnancy serum concentration of the medication is determined. Serum
concentrations of many ASMs decline significantly during pregnancy. The extent varies between ASMs
and also between individual women but often to levels where deterioration in seizure control can
occur [59]. Hence, drug level monitoring is recommended during pregnancy from monthly to less
frequently depending on the type of ASM (in particular but not limited to lamotrigine), the woman’s
epilepsy, and previous sensitivity to changes in serum concentrations [51]. The pre-pregnancy serum
concentration can serve as a reference for dose adjustments during pregnancy.
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Box 2.
A. Actions before conception aiming to improve pregnancy outcomes

a. Consider teratogenic risk when initiating ASM treatment in women of childbearing
potential
b. Whenever possible, avoid valproate and topiramate
c. Reassess ASM indication and selection regularly and in particular before pregnancy
d. Establish lowest effective dose regardless of type of ASM
e. Recommend folate supplementation; Optimal dose not established, but at least 0.4
mg/day
B. Actions during pregnancy aiming to improve pregnancy outcomes
a. Avoid seizure provoking factors
b. Monitor ASM levels and adjust dose to maintain effective serum concentrations where
appropriate (e.g. lamotrigine)
Elderly
When treating epilepsy in the elderly, important considerations include certainty of diagnosis, titration
to adequate dose, changes in pharmacokinetics, increased sensitivity to adverse effects, and avoidance
of drug-drug interactions. Regarding diagnostic certainty, focal seizures with little semiological clues
can present a clinical challenge in advanced age [60]. Stereotypic events, preservation of tone, and
imaging findings suggesting a structural (often stroke) etiology can be important clues. Old age as such
does not seem to be a risk factor for seizure recurrence after a first unprovoked seizure, so the decision
when to start treatment should be governed by similar principles as in a younger population [61].
Successful epilepsy treatment in older patients often involves particular care in finding the appropriate
dose. In general, elderly people attain seizure control at lower ASM doses, and serum concentrations,
than younger patients. A lower target dose is therefore often sufficient, which also reduces the risk of
adverse effects. Focal seizures with mild semiology may allow slower dose titration to find the
minimally effective dose, which can be lower than in younger individuals, thereby avoiding
unnecessary adverse effects. Reduced renal and metabolic elimination of ASMs may also be another
important reason to use low or moderate doses. Naturally, exceptions are relatively common and a
low initial target dose may not be possible in cases of frequent tonic-clonic seizures or status
epilepticus. Tolerability is a very important issue in older persons with epilepsy. Non-enzyme-inducing
drugs are often preferable, because of the lower risk of some adverse effects [62,63]. ASMs with
enzyme-inducing properties are the most prone to cause bone disease [9], and fractures in patients
with long-standing ASM therapy should prompt suspicion and work-up for osteoporosis. Medication
for other health conditions is also more common with advancing age, again making ASMs with little
potential for drug-drug interactions more attractive.
Comorbid conditions
Common comorbid conditions often encountered in epilepsy practice includes psychiatric conditions,
neuropsychiatric disorders, intellectual disability, vascular disease, and dementia. Of particular
concern is the potential for ASMs to aggravate depressive symptoms or anxiety. An increased risk of
suicidal ideation or behavior is debated, but mentioned in the Summary of Product Characteristics
(SmPC) for most ASMs. Regarding the most commonly used ASMs, an ILAE expert panel found evidence
for treatment-emergent suicidal behavior with topiramate and zonisamide, and that levetiracetam can
increase emotional liability or depression [64]. Although there is little evidence to guide practice, it is
advisable to warn persons with epilepsy of potential aggravation of psychiatric symptoms when
10
starting or adjusting ASMs. Conversely, dose reduction or tapering of ASMs may unmask psychiatric
symptoms [9]. Close contact with an epilepsy nurse or psychiatric services can prevent or mitigate
Accepted Article
most problems. For psychiatric and neuropsychiatric conditions, epilepsy should be treated just as
ambitiously as in other patients. In autism or severe intellectual disability, an important caveat to avoid
is misinterpretation of stereotypic behaviors as seizures – which can lead to unnecessary dose
increases and adverse effects. Video-EEG monitoring can be of great help. The relationship between
vascular risk factors and late-onset epilepsy is just beginning to unravel, but hypertension and other
modifiable risk factors seem to increase the risk of epilepsy [65]. Conversely, epilepsy is associated
with increased risks of vascular events [66], Particularly enzyme-inducing ASMs may have negative
effects on serum lipids or interactions with statins and are best avoided in those at-risk [67]. In
dementia, lamotrigine or levetiracetam are recommended as initial monotherapy because of their
favorable tolerability [68].
Titration and target dose

Unless a prompt antiseizure effect is sought, it is generally recommended to commence the selected
ASM at a low dose and up-titrate gradually. This approach can minimize adverse effects of the central
nervous system, such as drowsiness, fatigue, dizziness, and incoordination, owing to the development
of pharmacodynamic tolerance [11]. Low starting doses and gradual up-titration can also reduce the
risk for idiosyncratic reactions. A pooled analysis of lamotrigine monotherapy trials showed that the
risk of rash leading to treatment discontinuation was 1.9% when the dose of lamotrigine in the first
week of treatment was <31 mg/day, 9% when the dose was 31 to <62.5 mg/day, and 12% when the
dose was 62.5 to 125 mg/day [69]. In adults commencing ASM therapy following a new diagnosis of
epilepsy, the optimal speed of up-titration varies according to the type of ASM, the initial target
maintenance, and patient response (Table 5).
It is also recommended initially targeting the lowest effective maintenance dose, which can achieve
the desirable goal of ASM therapy of ‘no seizures, no adverse effects’ in many patients. Indeed, about
two-thirds of individuals with newly diagnosed epilepsy attain seizure freedom on low doses of the
first prescribed ASM [70]. Initial low target maintenance doses can inherently maximize ASM
tolerability, as the most common adverse ASM effects are dose-dependent. A case-control study of
new-onset seizures found very low rates of complaints suggestive of ASM toxicity among individuals
mostly on low-dose ASM monotherapy; furthermore, these rates did not differ from untreated
controls [71]. Importantly, the selection of the initial target dose should also consider other factors,
including patient characteristics (see section on ‘special populations /considerations’) and seizure
recurrence risk.
Treatment monitoring, dose adjustments and Therapeutic Drug Monitoring (TDM)

Regardless of type of ASM, the dosage needs to be individualized and the initial target maintenance
dosage modified in many patients in order to achieve the optimal outcome (seizure freedom without
significant adverse effects) [25]. Decisions on adjustments are mainly based on clinical follow-up.
Admittedly, clinical monitoring of treatment outcome has its limitations. Adverse effects may be
difficult to detect without use of screening tools [11], and also the occurrence of seizures can be
underestimated since some may be unnoticed by patients despite use of seizure calendars [72].
Furthermore, given the prophylactic nature of ASM treatment, and the unpredictable intermittent
occurrence of seizures, it may take a long time before a treatment failure becomes obvious.
Nevertheless, a reduction in the dose should be considered in patients with apparent dose-dependent
adverse effects that outlast the first few weeks of treatment. For patients who tolerate the medication
but continue to have seizures, the dosage is gradually increased.
11
Some of the differences in response to an ASM can be explained by individual pharmacokinetic
variability resulting in serum concentrations that vary widely between patients [73]. Therapeutic drug
Accepted Article
monitoring (TDM) seeks to optimize patient outcome by managing the medication regimen with the
assistance of information on the serum concentration of ASMs, thus providing a tool to control for
pharmacokinetic variability. Although reference ranges of serum levels associated with an optimal
response have been proposed for many ASMs, these are of limited value since the optimal serum
concentration varies between patients [74]. A more rational way of using TDM is to try to determine
the individual patient’s optimal serum concentration when the patient is doing well. This individual
optimal concentration can be used as a reference to adjust dosage when pharmacokinetic changes are
anticipated, e.g. due to drug-drug interactions or during pregnancy. It can also be used to help clarify
if a treatment failure is caused by a change in serum concentrations (e.g. due to non-adherence) or if
other explanations should be sought.
In most cases, samples should be drawn at steady-state and before the morning dose. However, if the
indication is suspected intermittent adverse effects, a sample could be drawn at the time of the
symptoms.
Box 3
Indications for measuring serum concentrations of ASMs
A. When a patient appears clinically to be treated optimally

a. To establish the individual optimal serum concentration for future reference
B. When changes in serum concentrations can be anticipated (e.g. children, elderly, pregnancy,
drug-drug interactions, ASMs with dose-dependent pharmacokinetics especially phenytoin)
a. To enable proactive dose adjustments
C. In case of treatment failures (adverse effects, loss of seizure control)
a. To clarify if failure is due to change in serum concentration
Considerations when 1st monotherapy fails
Excluding pseudo-resistance
Should the first ASM fail to control seizures, it is important to exclude ASM pseudo-resistance, defined
as ongoing seizures due to inadequate or inappropriate treatment leading to apparent ‘resistance’ to
ASMs (Figure 1).
If the diagnosis of epilepsy is confirmed, the next step is to review the seizure type and epilepsy
type/syndrome classifications to ensure that an appropriate ASM has been selected.
Occasionally, ASM pseudo-resistance can result from inadequate ASM dosing, which in some cases,
may be attributable to pharmacokinetic drug interactions resulting in reduced serum concentrations
of the affected ASM. For example, co-administration of combined oral contraceptives and lamotrigine
can result in a reduction of lamotrigine serum concentrations by >50%, accounting for apparently
uncontrolled seizures [16].
Other causes of ASM pseudo-resistance include poor adherence to ASM or unhealthy lifestyle choices,
such as alcohol abuse and exposure to sleep deprivation. These factors are particularly common in
adolescent-onset epilepsies. In a study of 170 individuals with juvenile myoclonic epilepsy, 10% were
recognised as having ASM pseudo-resistance due to both non-adherence and lifestyle factors [75].
12
Accepted Article
Treatment strategy in true 1st failures: alternative monotherapy or add-on
The first ASM renders approximately 50% of individuals with newly diagnosed epilepsy seizure-free
[76]. Where the first ASM was not an appropriate selection for the person’s epilepsy or if its failure
was due to lack of tolerability, switching to an alternative ASM is recommended. In the remaining
cases, either an alternative monotherapy or combination therapy with another ASM (add-on
treatment) may be considered.
Two RCTs in patients with focal epilepsy who had uncontrolled seizures on their first ASM or serial ASM
monotherapies failed to detect differences in efficacy and tolerability between alternative
monotherapy and add-on treatment [77,78]. In a recent single-centre study of 498 patients with
epilepsy who were prescribed a second ASM regimen after failure of the first ASM, the proportion of
individuals who attained seizure freedom for ≥1 year did not differ between patients switched to
substitution monotherapy (30/152, 20%) and those treated with combination therapy (74/346, 21%)
[79].
Ultimately, the decision to adopt one strategy over the other is guided by a number of factors
comprising: patient preference and adherence; epilepsy type/syndrome and aetiology; and potential
drug interactions, including synergistic ASM combinations (e.g., valproate and lamotrigine)[80].
Management of drug-resistant epilepsy

Epilepsy is considered to be drug-resistant if seizure freedom is not achieved with two trials of
tolerated and appropriate ASMs [81]. In such cases, the suitability of non-pharmacological treatment
options, such as epilepsy surgery, should be considered [9]. The definition of drug-resistant epilepsy is
based on the observation that the likelihood of seizure control declines with the number of failed ASM
treatment. However, drug-resistance does not exclude seizure freedom with further trials of ASMs [81-
83]. If epilepsy surgery is not suitable, systematic trials of drug combinations should continue. ASMs
are selected for combination therapy much in the same way as for the first monotherapy; based on
epilepsy factors such as seizure types, syndrome and etiology, and individual factors such as age, co-
morbidity, concomitant medication, pregnancy, and presumed susceptibility to adverse effects. There
is no evidence for differences in effect between suitable ASMs. Rational polypharmacy denotes use of
ASMs with complementary mechanisms of action. The concept is theoretically appealing, but the
scientific support is limited [84,85]. However, most expert will recommend trials of ASMs with different
modes of action since concomitant use of drugs with similar mechanisms of action can increase the
risk of adverse effects. Interactions between ASMs need to be considered in combination treatment,
for example, enzyme induction or enzyme inhibition. In general, ASMs devoid of pharmacokinetic
interaction potential are easier to use in combination therapy. Slow titration and vigilance with regard
to adverse effects is recommended. Although sometimes polytherapy with more than two ASMs can
improve seizure control, combining more than two ASMs increases the risk of adverse events and is
only rarely justified.
ASM withdrawal in seizure free patients

Two-thirds of people with epilepsy become seizure-free on ASM treatment [86]. In some of these
cases, ASM withdrawal may be considered. Several risk factors for seizure recurrence after ASM
withdrawal have been identified (Table 6). Several of these factors have been incorporated into a web-
based predictive model that allows estimation of the risk of seizure recurrence post-ASM withdrawal
(http://epilepsypredictiontools.info) [87].
13
Reasons for ASM withdrawal
Accepted Article
Toxicity is the main reason for ASM withdrawal. Other reasons include medication costs and
accessibility (the latter particularly in resource-poor countries), the burden of and perceived
stigmatisation around the need for daily medication, and the possibility of resumption of an
unconditional private vehicle license.
Risks with ASM withdrawal
In non-epilepsy surgery patients, 30-50% of seizure-free individuals experience recurrent seizures after
ASM withdrawal, and the risk is highest in the first year post-withdrawal [89]. Seizure recurrence can
result in potential injuries and occupational, lifestyle and driving restrictions. Furthermore, ASM
withdrawal may be associated with a risk of potential treatment refractoriness upon ASM
reintroduction, with up to 18% of patients being unable to achieve seizure freedom despite ASM
reinstitution [87].
Timing of ASM withdrawal
In adults, ASM withdrawal may be considered after at least 2 years of seizure freedom. In a
retrospective study of 133 patients with epilepsy, a short seizure-free period (<2 years) before ASM
withdrawal was the strongest risk factor for seizure recurrence, identified in 45% of patients [90].
Additionally, no difference in seizure relapse rate was found when early ASM withdrawal (after 2-3
years of seizure freedom) was compared with delayed ASM withdrawal in a prospective observational
study of 86 epilepsy patients [91].
Although there is no optimal rate established for ASM withdrawal [92], it is reasonable that this be
performed slowly - often over months - for certain ASMs, such as benzodiazepines and barbiturates,
to minimise the risk of seizure recurrence. If >1 ASMs are planned to be withdrawn, it is advisable for
discontinuation to be sequential. A tapering schedule should be provided to the patient with advice
to monitor for potential seizure recurrence.
Most importantly, ASM withdrawal should be attempted only in situations where according to the
informed patient the potential benefits outweigh the risks.
ASM withdrawal after epilepsy surgery
Up to 50% of adults experience seizure freedom after epilepsy surgery [93]. In adults who become
seizure-free after epilepsy surgery, ASM withdrawal may be attempted as early as 1-2 years post-
surgery as more than 75% of seizure recurrences occur within the first 12 months after epilepsy surgery
[94]. Although the optimal timing for ASM withdrawal after epilepsy surgery is unknown, an
individualised decision incorporating the other risk factors for seizure recurrence (Table 7) is required
[95,96,97]. After epilepsy surgery, the ASM burden may be reduced by withdrawing 1 ASMs, but
patients often remain on at least one ASM.
14
Conclusions
Accepted Article
For most patients with epilepsy, ASM treatment can lead to complete seizure control and for a
substantial proportion of these, the treatment can be successfully withdrawn without relapse after
some years of seizure freedom. However, ASMs are also associated with adverse effects that can be
disabling. A successful treatment requires careful considerations, where individualization is the key,
taking into account patients´ epilepsy type, spectrum of antiseizure effects and adverse effects of the
available ASMs, individual susceptibility to adverse effects, comorbidities and individual patient
characteristics and preferences. Shared treatment decisions rely on interaction between the
knowledgeable prescriber and the informed patient.
Conflicts of interest
TT reports research support to EURAP, the International Antiepileptic Drugs and Pregnancy Registry
from the following companies: Accord, Angelini, Bial, Eisai, Glenmark, GSK, GW Pharma, Sanofi, Teva,
UCB, Zentiva, EcuPharma, and SF Group; and speaker’s honoraria to his institution from Angelini, Eisai,
GSK and UCB all outside the submitted work.
JZ reports speaker honoraria from UCB and Eisai for non-branded educations, and as an employee of
Sahlgrenska University Hospital being an investigator/ sub investigator in clinical trials sponsored by
GW Pharma, SK life science, UCB and Bial (no personal compensation).
YLD is supported by the National Health and Medical Research Council (NHMRC) (APP2013800) and
the University of Melbourne Research Training Program Scholarship. She has received speaker
honoraria from Eisai and SEER Medical, outside the submitted work.
PP is supported by an Emerging Leadership 2 Investigator Grant from the Australian National Health
and Medical Research Council (APP2017651), the Epilepsy Foundation, The University of Melbourne,
Monash University, the Weary Dunlop Medical Research Foundation, Brain Australia, and the Norman
Beischer Medical Research Foundation. He has received speaker honoraria or consultancy fees to his
institution from Chiesi, Eisai, LivaNova, Novartis, Sun Pharma, Supernus, and UCB Pharma, outside the
submitted work. He is an Associate Editor for Epilepsia Open.
Key points
 The current pharmacological treatment of epilepsy is symptomatic
 The decision to initiate treatment with antiseizure medications (ASMs) should be based on an
individual risk-benefit analysis
 ASMs are selected based on the patient’s type of epilepsy and corresponding spectrum of ASM
efficacy
 Age, sex, childbearing potential, comorbidities, and concurrent medication need to be
considered in ASM selection
 In most cases treatment is initiated as monotherapy
 A slow titration to a low first target dose improves tolerability
 The ASM dose needs to be individualized based on the clinical response; therapeutic drug
monitoring could assist
 Pseudo-resistance (wrong diagnosis, wrong ASM, non-adherence) should be considered in
those not responding to first ASM
15
Epilepsy surgery and other non-pharmacological treatments should be considered for cases
16
Withdrawal of ASM treatment may be considered after some years of seizure freedom, but
must be preceded by careful risk-benefit assessment
with drug-resistant epilepsy.


Accepted Article
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61. Lawn N, Kelly A, Dunne J, Lee J, Wesseldine A. First seizure in the older patient: clinical
features and prognosis Epilepsy Res. 2013;107:109-114.
62. Vu LC, Piccenna L, Kwan P, O'Brien TJ. New-onset epilepsy in the elderly Br J Clin Pharmacol.
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63. Werhahn KJ, Trinka E, Dobesberger J, Unterberger I, Baum P, Deckert-Schmitz M, et al. A
randomized, double-blind comparison of antiepileptic drug treatment in the elderly with
new-onset focal epilepsy Epilepsia. 2015;56:450-459.
64. Mula M, Kanner AM, Schmitz B, Schachter S. Antiepileptic drugs and suicidality: an expert
consensus statement from the Task Force on Therapeutic Strategies of the ILAE Commission
on Neuropsychobiology Epilepsia. 2013;54:199-203.
65. Johnson EL, Krauss GL, Lee AK, Schneider ALC, Dearborn JL, Kucharska-Newton AM, et al.
Association Between Midlife Risk Factors and Late-Onset Epilepsy: Results From the
Atherosclerosis Risk in Communities Study JAMA Neurol. 2018;75:1375-1382.
66. Olesen JB, Abildstrom SZ, Erdal J, Gislason GH, Weeke P, Andersson C, et al. Effects of
epilepsy and selected antiepileptic drugs on risk of myocardial infarction, stroke, and death
in patients with or without previous stroke: a nationwide cohort study Pharmacoepidemiol
Drug Saf. 2011;20:964-971.
67. Mintzer S, Trinka E, Kraemer G, Chervoneva I, Werhahn KJ. Impact of carbamazepine,
lamotrigine, and levetiracetam on vascular risk markers and lipid-lowering agents in the
elderly Epilepsia. 2018;59:1899-1907.
20
68. Frederiksen KS, Cooper C, Frisoni GB, Frolich L, Georges J, Kramberger MG, et al. A European
Academy of Neurology guideline on medical management issues in dementia Eur J Neurol.
Accepted Article
2020;27:1805-1820.
69. Kwan P, Brodie MJ. Effectiveness of first antiepileptic drug. Epilepsia 2001;42(10):1255-60.
70. Messenheimer J, Mullens EL, Giorgi L, Young F. Safety review of adult clinical trial experience
with lamotrigine. Drug Saf. 1998;18(4):281-96.
71. Perucca P, Jacoby A, Marson AG, Baker GA, Lane S, Benn EK, et al. Adverse antiepileptic drug
effects in new-onset seizures: a case-control study. Neurology. 2011;76(3):273-9.
72. Cook MJ, O'Brien TJ, Berkovic SF, Murphy M, Morokoff A, Fabinyi G, et al. Prediction of
seizure likelihood with a long-term, implanted seizure advisory system in patients with drug-
resistant epilepsy: a first-in-man study. Lancet Neurol. 2013 Jun;12(6):563-71. doi:
10.1016/S1474-4422(13)70075-9. Epub 2013 May 2
73. Landmark CJ, Johannessen SI, Tomson T. Dosing strategies for antiepileptic drugs: from a
standard dose for all to individualised treatment by implementation of therapeutic drug
monitoring. Epileptic Disord. 2016 Dec 1;18(4):367-383. doi: 10.1684/epd.2016.0880
74. Patsalos PN, Berry DJ, Bourgeois BF, Cloyed JC, Glauser TA, Johannessen SI, et al.
Antiepileptic drugs—best practice guidelines for therapeutic drug monitoring: a position
paper by the subcommission on therapeutic drug monitoring, ILAE Commission on
Therapeutic Strategies. Epilepsia 2008; 49: 1239–76
75. Gelisse P, Genton P, Thomas P, Rey M, Samuelian JC, Dravet C. Clinical factors of drug
resistance in juvenile myoclonic epilepsy. J Neurol Neurosurg Psychiatry. 2001;70(2):240-243.
doi:10.1136/jnnp.70.2.240
76. Chen Z, Brodie MJ, Liew D, Kwan P. Treatment outcomes in patients with newly diagnosed
epilepsy treated with established and new antiepileptic drugs a 30-year longitudinal cohort
study. JAMA Neurol. 2018;75(3):279-286. doi:10.1001/jamaneurol.2017.3949
77. Beghi E, Gatti G, Tonini C, Ben-Menachem E, Chadwick DH, Nikanorova M, 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):1-13.
doi:10.1016/j.eplepsyres.2003.09.007
78. Semah F, Thomas P, Coulbaut S, Derambure P. Early add-on treatment vs alternative
monotherapy in patients with partial epilepsy. Epileptic Disord. 2014;16(2):165-174.
doi:10.1684/epd.2014.0650
79. Hakeem H, Alsfouk BAA, Kwan P, Brodie MJ, Chen Z. Should substitution monotherapy or
combination therapy be used after failure of the first antiseizure medication? Observations
from a 30‐year cohort study. Epilepsia. 2023;(December 2022):1-11. doi:10.1111/epi.17573
80. 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(8):1141-1146. doi:10.1111/j.1528-
1157.1999.tb00832.x
81. Kwan P, Arzimanoglou A, Berg AT, Brodie MJ, Allen Hauser W, Mathern G, et al. Definition of
drug resistant epilepsy: consensus proposal by the ad hoc Task Force of the ILAE Commission
on Therapeutic Strategies Epilepsia. 2010;51:1069-1077.
82. Hughes DM, Bonnett LJ, Czanner G, Komarek A, Marson AG, Garcia-Finana M. Identification
of patients who will not achieve seizure remission within 5 years on AEDs Neurology.
2018;91:e2035-e2044.
83. Asadi-Pooya AA, Farazdaghi M. Definition of drug-resistant epilepsy: A reappraisal based on
epilepsy types Acta neurologica Scandinavica. 2022;145:627-632.
84. French JA, Faught E. Rational polytherapy Epilepsia. 2009;50 Suppl 8:63-68.
85. Brigo F, Ausserer H, Tezzon F, Nardone R. When one plus one makes three: the quest for
rational antiepileptic polytherapy with supraadditive anticonvulsant efficacy Epilepsy Behav.
2013;27:439-442.
21
86. Shorvon SD, Goodridge DMG. Longitudinal cohort studies of the prognosis of epilepsy:
Contribution of the National General Practice Study of Epilepsy and other studies. Brain.
Accepted Article
2013;136(11):3497-3510. doi:10.1093/brain/awt223
87. Lamberink HJ, Otte WM, Geerts AT, Pavlovic M, Ramos-Lizana J, Marson AG, et al.
Individualised prediction model of seizure recurrence and long-term outcomes after
withdrawal of antiepileptic drugs in seizure-free patients: a systematic review and individual
participant data meta-analysis. Lancet Neurol. 2017;16(7):523-531. doi:10.1016/S1474-
4422(17)30114-X
88. Medical Research Council Antiepileptic Drug Withdrawal Study Group. Randomised study of
antiepileptic drug withdrawal in patients in remission. Lancet. 1991;337(8751):29-36.
doi:10.1016/0140-6736(91)92856-W
89. Schmidt D, Löscher W. Uncontrolled epilepsy following discontinuation of antiepileptic drugs
in seizure-free patients: A review of current clinical experience. Acta Neurol Scand.
2005;111(5):291-300. doi:10.1111/j.1600-0404.2005.00408.x
90. Contento M, Bertaccini B, Biggi M, Magliani M, Failli Y, Rosati E, et al. Prediction of seizure
recurrence risk following discontinuation of antiepileptic drugs. Epilepsia. 2021;62(9):2159-
2170. doi:10.1111/epi.16993
91. Su L, Di Q, Yu N, Zhang Y. Predictors for relapse after antiepileptic drug withdrawal in seizure-
free patients with epilepsy. J Clin Neurosci. 2013;20(6):790-794.
doi:10.1016/j.jocn.2012.07.010
92. Ferlazzo E, Giussani G, Gasparini S, et al. Rapid versus slow withdrawal of antiepileptic
monotherapy in two-year seizure-free adults patients with epilepsy (RASLOW) study: A
pragmatic multicentre, prospective, randomized, controlled study. Neurol Sci.
2022;43(8):5133-5141. doi:10.1007/s10072-022-06121-9
93. De Tisi J, Bell GS, Peacock JL, McEvoy AW, Harkness WFJ, Sander JW, et al. The long-term
outcome of adult epilepsy surgery, patterns of seizure remission, and relapse: A cohort
study. Lancet. 2011;378(9800):1388-1395. doi:10.1016/S0140-6736(11)60890-8
94. Ramesha KN, Mooney T, Sarma PS, Radhakrishnan K. Long-term seizure outcome and its
predictors in patients with recurrent seizures during the first year after temporal lobe
resective epilepsy surgery. Epilepsia. 2011;52(5):917-924. doi:10.1111/j.1528-
1167.2010.02891.x
95. Ferreira-Atuesta C, de Tisi J, McEvoy AW, Miserocchi A, Khoury J, Yardi R, et al. Predictive
models for starting antiseizure medication withdrawal following epilepsy surgery in adults.
Brain. Published online 2022. doi:10.1093/brain/awac437
96. Menon R, Rathore C, Sarma SP, Radhakrishnan K. Feasibility of antiepileptic drug withdrawal
following extratemporal resective epilepsy surgery. Neurology. 2012;79(8):770-776.
doi:10.1212/WNL.0b013e3182644f7d
97. Park K Il, Lee SK, Chu K, et al. Withdrawal of antiepileptic drugs after neocortical epilepsy
surgery. Ann Neurol. 2010;67(2):230-238. doi:10.1002/ana.21884
98. Stevelink R, Al-Toma D, Jansen FE, et al. Individualised prediction of drug resistance and
seizure recurrence after medication withdrawal in people with juvenile myoclonic epilepsy: A
systematic review and individual participant data meta-analysis. eClinicalMedicine.
2022;53:1-13. doi:10.1016/j.eclinm.2022.101732
Legend to figure 1
Approach to antiseizure medication (ASM) pseudo-resistance
22
TEST YOURSELF
Accepted Article
1. Which of the following statements is correct regarding treatment with antiseizure
medications (ASMs)?
A. Early initiation of treatment improves long-term prognosis
B. Early initiation of treatment is associated with better quality of life
C. Deferred initiation of treatment (until seizure recurrence) is associated with major risks
D. ASM treatment is symptomatic
2. Which of the following factors can influence choice of initial ASM

A. Age
B. Sex
C. Epilepsy type
D. Seizure Frequency
E. All of the above.
3. What would be a suitable first ASM in a 25-year-old woman with genetic generalized
epilepsy?
A. Carbamazepine
B. Valproic acid
C. Lamotrigine
D. Vigabatrin
E. Clobazam
4. Which of the following is incorrect regarding ASM treatment in older patients?

A. Lower doses than in younger individuals can suffice for seizure control.
B. Recurrence risk after a first seizure is much higher, so ASMs should always be started.
C. Drug-drug interactions need to be considered.
D. Reduced metabolism and elimination may affect dosing of ASMs
5. ASM pseudo-resistance can be caused by the following, except:

A. Incorrect diagnosis of epilepsy.
B. Pharmacodynamic drug interactions resulting in reduced serum concentrations of the
affected ASM.
C. Non-adherence to ASM treatment.
D. Alcohol and recreational drug use.
6. Which of the ASMs should be avoided in Dravet syndrome?

A. Valproate
B. Clobazam
C. Fenfluramine
D. Oxcarbazepine
E. Topiramate
7. Which of the following is an established risk factor for seizure recurrence after ASM
withdrawal?
A. Long duration of epilepsy before remission.
23
B. Diagnosis of Juvenile absence epilepsy.
C. History of generalized or focal-to-bilateral tonic-clonic seizures
Accepted Article
D. Epileptiform discharges on EEG before ASM withdrawal.
E. All of the above.
8. Type C adverse effects:

A. Are a synonym for adverse drug interactions
B. Typically arise shortly after commencing treatment with antiseizure medications
C. Comprise Stevens-Johnson syndrome, Toxic epidermal necrolysis, and Drug Reaction with
Eosinophilia and Systemic Symptoms
D. Can develop after years of treatment with antiseizure medications
E. Are related to stimulation of the Cytochrome P450 3A4
9. Which of the following statement is correct:

A. Carbamazepine can increase the serum concentrations of warfarin due to enzyme
induction, resulting in increased risk of bleeding
B. Topiramate, at any dose, can reduce the effectiveness of combined oral contraceptives
C. Valproate is a more potent enzyme-inducing antiseizure medication than phenytoin
D. Lamotrigine is a weak enzyme-inhibiting antiseizure medication and only at doses >200
mg/day
E. Oxcarbazepine can reduce the effectiveness of combined oral contraceptives
10. In individuals with newly epilepsy who are not already on other antiseizure medications,
the recommended starting dose of lamotrigine during the first 2 weeks is:
A. 12.5 mg/day
B. 25 mg/day
C. 50 mg/day
D. 75 mg/day
E. 100 mg/day
24
Table 1. Overview of clinical use and monotherapy indication for focal or generalized seizure types by
the European Medical Agency (EMA) or U.S. Food and Drug Administration (FDA). F = focal onset
seizure, G = generalized onset seizure, A = absence seizures
Clinical use Monotherapy indication in adults

Focal-onset seizures and most generalized-onset EMA FDA
seizures
• Valproate F, G F, G
• Lamotrigine F, G F
• Levetiracetam F F
• Topiramate F, G F, G
• Zonisamide F
Mainly focal-onset but also generalized-onset tonic-

clonic seizures
• Carbamazepine F, G F, G
• Phenytoin F, G F, G
•Phenobarbital F, G F, G
•Perampanel F
Focal-onset seizures
• Lacosamide F F
• Oxcarbazepine F F
•Eslicarbazepine acetate F F
•Gabapentin F
•Brivaracetam F
Absence seizures
•Ethosuximide A A
25
Table 2. Adverse effects of common initial ASM monotherapies in adults with newly diagnosed
epilepsy.
ASM Common adverse effects Selected rare adverse effects

with important clinical relevance
Brivaracetam Drowsiness, fatigue, dizziness, Psychosis
irritability, depression
Carbamazepine Drowsiness, dizziness, unsteadiness, Hypersensitivity reactions
blurred vision, diplopia,
hyponatremia, cardiac conduction
abnormalities, decreased bone
mineral density
Eslicarbazepine Dizziness, abnormal coordination, Hypersensitivity reactions
acetate blurred vision, diplopia, nausea,
drowsiness
Ethosuximide Nausea, abdominal discomfort, Hypersensitivity reactions,
vomiting, diarrhea, drowsiness, psychosis
dizziness
Gabapentin Drowsiness, dizziness, vertigo, Respiratory depression
nystagmus, diplopia, nausea, weight (particularly when used with CNS
gain depressants and in people with
respiratory impairment)
Lacosamide Dizziness, vertigo, blurred vision, Hypersensitivity reactions
diplopia, nausea
Lamotrigine Dizziness, blurred vision, diplopia, Hypersensitivity reactions (risk
insomnia higher than for other ASMs)
Levetiracetam Drowsiness, fatigue, dizziness, Psychosis
irritability, aggression, depression
Oxcarbazepine Drowsiness, dizziness, unsteadiness, Hypersensitivity reactions
blurred vision, diplopia, nausea,
vomiting, hyponatremia
Perampanel Fatigue, drowsiness, dizziness, Psychosis
blurred vision, weight gain,
irritability, agitation, aggression
Phenobarbital* Fatigue, drowsiness, lethargy, Hypersensitivity reactions, birth
cognitive impairment, depression, defects
dizziness, cognitive tissue disorders,
decreased bone mineral density
Phenytoin Nystagmus, dizziness, unsteadiness, Hypersensitivity reactions,
blurred vision, diplopia, hirsutism, pseudo-lymphoma
gingival hypertrophy, decreased
bone mineral density
Topiramate Cognitive impairment, concentration Angle closure glaucoma,
difficulties, speech problems, oligohidrosis, hyperthermia,
drowsiness, fatigue, depression, psychosis, birth defects, postnatal
weight loss, paresthesia, neurodevelopmental disorders
nephrolithiasis after prenatal exposure
Valproate Tremor, drowsiness, nausea, Hepatotoxicity, pancreatitis, birth
abdominal discomfort, defects and postnatal
hyperammonemia, weight gain, hair neurodevelopmental disorders
loss, polycystic ovary syndrome,
26
decreased mineral density, after prenatal exposure (higher
thrombocytopenia risk than for other ASMs)
Zonisamide Drowsiness, fatigue, dizziness, Hypersensitivity reactions
concentration difficulties, oligohidrosis, hyperthermia, birth
depression, weight loss, defects
nephrolithiasis
*only available antiseizure medication in certain resource-poor countries.
27
Table 3. Examples of drugs the metabolism of which can be accelerated by enzyme-inducing ASMs.
Modified from Zaccara & Perucca [15], with permission.
Drug class* Specific drugs*

Analgesics Buprenorphine, Fentanyl, Methadone, Paracetamol (Acetaminophen),
Pethidine (Meperidine), Tramadol
Antimicrobials Albendazole, Chloramphenicol, Doxycycline, Efavirenz,
Hydroxychloroquine, Indinavir, Itraconazole, Lopinavir, Metronidazole,
Nevirapine, Nirmatrelvir, Posiconazole, Praziquantel, Rifampicin,
Ritonavir, Saquinavir, Voriconazole
Antineoplastic drugs 9-Aminocampthotecin, Busulfan, Cyclophosphamide, Etoposide,
Ifosfamide, Imatinib, Irinotecan, Methotrexate, Misonidazole,
Nitrosureas, Paclitaxel, Procarbazine, Tamoxifen, Teniposide, Thiotepa,
Topotecan, Vinca Alkaloids
Cardiovascular drugs Acenocoumarol, Alprenolol, Amiodarone, Apixaban, Atorvastatin,
Dicoumarol, Digoxin, Diltiazem, Disopyramide, Felodipine, Isradipine,
Lovastatin, Metoprolol, Mexiletine, Nifedipine, Nimodipine, Nisoldipine,
Propranolol, Quinidine, Simvastatin, Talinolol, Timolol, Verapamil,
Warfarin
Immunosuppressants Cyclosporin A, sirolimus, tacrolimus
Psychoactive drugs Amitriptyline, Aripiprazole, Benzodiazepines, Bupropion, Citalopram,
Chlorpromazine, Clomipramine, Clozapine, Desipramine,
Desmethylclomipramine, Doxepin, Flupenthixol, Haloperidol,
Imipramine, Mesoridazine, Mianserin, Mirtazepine, Nefazodone,
Nortriptyline, Olanzapine, Paroxetine, Protriptyline, Quetiapine,
Sertraline, Risperidone, Trazodone, Ziprasidone, Zuclopenthixol
Steroids Cortisol, Contraceptive Steroids, Dexamethasone, Hydrocortisone,
Methylprednisolone, Prednisone, Prednisolone
Other drugs Metyrapone, Theophylline, Thyroxine, Vecuronium
*The interactions listed in this table should be interpreted with a few disclaimers. First, not all of the
above drug interactions are clinically relevant. Second, the metabolism of the listed drugs may not be
stimulated by all enzyme inducing ASMs. Third, although in most cases the stimulation of a drug’s
metabolism results in its decreased efficacy, in others it may actually lead to potentiation of its effects
due to accumulation of its active metabolites. For additional information on each of the drugs listed in the
table, please refer to the corresponding prescribing information.
28
Table 4. ASMs to be considered or avoided in specific epilepsy syndromes based on expert-
consensus opinions and evidence from randomised controlled trials.
Epilepsy Syndrome ASM choices ASMs to avoid

(references to expert
consensus opinions)
Dravet syndrome  Valproate  Carbamazepine
[32,37,38]  Clobazam  Oxcarbazepine
 Stiripentol#  Lamotrigine*
 Fenfluramine#  Phenytoin*
 Cannabidiol#  Tiagabine
 Topiramate  Vigabatrin
 Gabapentin
 Pregabalin
Lennox-Gastaut syndrome  Valproate  Carbamazepine*
[37,39]  Lamotrigine#  Oxcarbazepine
 Topiramate#  Eslicarbazepine acetate
 Rufinamide#  Tiagabine
 Clobazam#  Phenytoin
 Cannabidiol#
 Felbamate
 Fenfluramine
Childhood Absence  Ethosuximide#  Oxcarbazepine

Epilepsy [40-42]  Valproatea#  Carbamazepine
 Lamotrigine#  Phenytoin
 Levetiracetam  Phenobarbital
 Tiagabine
 Vigabatrin
#
ASMs with RCT evidence for effectiveness in the corresponding epilepsy syndrome.
*Phenytoin has been shown to be effective in the management of status epilepticus [32] and long-term
management of epilepsy in Dravet syndrome in case series [33]. Lamotrigine has been found to reduce seizures
in patients with Dravet syndrome [34]. Carbamazepine is effective in the management of tonic seizures in
Lennox-Gastaut syndrome but may precipitate atypical absence seizures [35].
a
Valproate as 1st ASM of choice for absence and tonic-clonic seizures [41].
29
Table 5. Suggested up-titration schedules and maintenance dosing regimens for common initial ASM
monotherapies in adults with newly diagnosed epilepsy. Please note that the information below
reflects the authors’ experience and may differ from an ASM’s prescribing information sheet.
ASM Suggested up-titration rate to initial target Maintenance dosea Number of

maintenance dose daily doses
Brivaracetam Commence with 50 mg/day and, if 50-200 mg/day 2
appropriate, increase after 1-2 weeks to 100
mg/day. The usual initial target dose is 50-
100 mg/day.
Carbamazepine Commence with 100 or 200mg/day and 400-1600 mg/day 2-3b
increase over 1-4 weeks to 400-600 mg/day
Eslicarbazepine Commence with 400 mg/day and after 1-2 800-1600 mg/day 1
acetate weeks to 800 mg/day
Ethosuximide Commence with 250 mg/day and increase 500-1500 mg/day 2-3
over 1-3 weeks to 500-750 mg/day
Gabapentin Commence with 300-900 mg/day and 900-3600 mg/day 2-3
increase over 5-10 days to 900-1800 mg/day
Lacosamide Commence with 100 mg/day and increase 200-400 mg/day 2
after 1-2 weeks to 200 mg/day
Lamotrigine Commence with 25 mg/day for 2 weeks, 100-500 mg/day 1-2
then increase to 50 mg/day for 2 weeks;
further increases by 50 mg/day every 2
weeks to 100-150 mg/day
Levetiracetam Commence with 500 mg/day and increase 1000-3000 mg/day 2
after 2 weeks to 1000 mg/day, or
commence directly with 1000 mg/day
Oxcarbazepine Commence with 300 mg/day and increase 600-2400 mg/day 2-3
over 1-3 weeks to 600-900 mg/day
Perampanel Commence with 2 mg/day and increase over 4-12 mg/day 1
2-4 weeks to 4 mg/day
Phenobarbital Commence with 30-50 mg/day and, if 50-200 mg/day 1
appropriate, increase after 10-15 days. The
usual initial target dose is 50-100 mg/day
Phenytoin Commence with 100 mg/day and increase 200-500 mg/day 1-2
over 3-7 days to 200-300 mg/day
Topiramate Commence with 25 mg/day and increase 100-500 mg/day 2
over 3-6 weeks to 100 mg/day
Valproate Commence with 400 or 500 mg/day and, if 400-2500 mg/day 2b
appropriate, increase after 1-2 weeks. The
usual initial target dose is 400-1000 mg/day
Zonisamide Commence with 50 mg/day and increase 200-600 mg/day 2
after 1 week to 100 mg/day; further
increases by 50 mg/day every 1-2 weeks or
by 100 mg/day after 2 weeks to 200 mg/day
a
dose adjustments may be required with concomitant medications; b 2 daily doses with sustained-release
formulations; c 1 daily dose possible with some sustained-release formulations.
30
Table 6. Risk factors for seizure relapse after ASM withdrawal in seizure-free individuals. Data based
on Medical Research Council Antiepileptic Drug Withdrawal Study Group, 1991 and Lamberink et al,
2017 [87,88].
 History of febrile seizures

 Developmental delay
 Older age of onset of epilepsy
 History of generalised or focal-to-bilateral tonic-clonic
seizures
 Epilepsy syndromes that are not self-limiting
 Longer duration of epilepsy before remission
 10 seizures or more before remission
 Shorter seizure freedom duration before ASM withdrawal
 Epileptiform abnormality demonstrated on EEG before
ASM withdrawal
 Seizures after starting treatment
31
Table 7. Predictors of seizure recurrence post-ASM withdrawal after epilepsy surgery [95-97]
 History of focal to bilateral tonic-clonic seizures

 Longer duration of epilepsy prior to surgery
 Normal MRI (“non-lesional” epilepsy)
 Higher number of ASMs at time of surgery
 Cortical dysplasia on histopathology
 Early postoperative seizure (1 week to 3 months post-surgery)
 Persistent auras
 Interictal epileptiform discharges on postoperative EEG
 Early ASM tapering
32
33

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SEMINAR IN EPILEPTOLOGY

Torbjörn Tomson1, Johan Zelano2-4, Yew Li Dang5,6, Piero Perucca5,6,7,8,9

1. Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden

Running title: Pharmacological treatment of epilepsy

Received May 3rd, 2023; Accepted June 24th, 2023

ILAE Learning objectives

General principles of pharmacological treatment of epilepsy

Individualization is a key concept in the pharmacological treatment of epilepsy. Epilepsy is a

A. Situations when it may be reasonable to withhold treatment despite recurrent seizures

Which ASM to choose for initial treatment

Spectrum of effect by seizure type

Spectrum of adverse effects of antiseizure medications

Other considerations of relevance for ASM selection

ASM selection by epilepsy syndrome

Epilepsy aetiology and ASM selection

Considerations in special populations

Women of childbearing potential

A. Actions before conception aiming to improve pregnancy outcomes

Titration and target dose

Treatment monitoring, dose adjustments and Therapeutic Drug Monitoring (TDM)

Indications for measuring serum concentrations of ASMs

A. When a patient appears clinically to be treated optimally

Considerations when 1st monotherapy fails

Management of drug-resistant epilepsy

ASM withdrawal in seizure free patients

Risks with ASM withdrawal

Timing of ASM withdrawal

ASM withdrawal after epilepsy surgery

2. Which of the following factors can influence choice of initial ASM

4. Which of the following is incorrect regarding ASM treatment in older patients?

5. ASM pseudo-resistance can be caused by the following, except:

6. Which of the ASMs should be avoided in Dravet syndrome?

8. Type C adverse effects:

9. Which of the following statement is correct:

Clinical use Monotherapy indication in adults

Mainly focal-onset but also generalized-onset tonic-

ASM Common adverse effects Selected rare adverse effects

*only available antiseizure medication in certain resource-poor countries.

Drug class* Specific drugs*

Epilepsy Syndrome ASM choices ASMs to avoid

Childhood Absence  Ethosuximide#  Oxcarbazepine

ASM Suggested up-titration rate to initial target Maintenance dosea Number of

 History of febrile seizures

 History of focal to bilateral tonic-clonic seizures

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