Approach to the Medical REVIEW ARTICLE


Treatment of Epilepsy C O N T I N U UM A U D I O
I NT E R V I E W A V A I L AB L E
ONLINE
By Francesco Brigo, MD; Anthony Marson, MBChB, MD, FRCP

ABSTRACT
PURPOSE OF REVIEW: This article discusses the use of antiseizure medications
in the treatment of focal and generalized epilepsies using an evidence-
based approach.

RECENT FINDINGS: In recent years, several new antiseizure medications with

differing mechanisms of action have been introduced in clinical practice,
and their efficacy and safety has been evaluated in randomized controlled
clinical trials. Currently, all antiseizure medications can prevent seizure
occurrence, but they have no proven disease-modifying or
antiepileptogenic effects in humans. The choice of therapy should
integrate the best available evidence of efficacy, tolerability, and
effectiveness derived from clinical trials with other pharmacologic
considerations, the clinical expertise of the treating physicians, and
patient values and preferences. After the failure of a first antiseizure
medication, inadequate evidence is available to inform policy. An
alternative monotherapy (especially if the failure is because of adverse
effects) or a dual therapy (especially if failure is because of inadequate
seizure control) can be used.

SUMMARY: Currently, several antiseizure medications are available for the

treatment of focal or generalized epilepsies. They differ in mechanisms of CITE AS:
action, frequency of administration, and pharmacologic properties, with a CONTINUUM (MINNEAP MINN)
2022;28(2, EPILEPSY):483–499.
consequent risk of pharmacokinetic interactions. Major unmet needs
remain in epilepsy treatment. A substantial proportion of patients with Address correspondence to
epilepsy continue to experience seizures despite two or more antiseizure Dr Francesco Brigo, Department
of Neurology, Hospital of
medications, with a negative impact on quality of life. Therefore, more Merano, Via Rossini 5-39012,
antiseizure medications that could provide higher seizure control with Merano-Meran, Italy,
good tolerability and that could positively affect the underlying disease dr.francescobrigo@gmail.com.

are needed. RELATIONSHIP DISCLOSURE:

Dr Brigo reports no disclosure.
Dr Marson has received
publishing royalties from Oxford
University Press.
INTRODUCTION

T
his article discusses the use of antiseizure medications in the UNLABELED USE OF
treatment of focal and generalized epilepsies. An evidence-based PRODUCTS/INVESTIGATIONAL
USE DISCLOSURE:
approach is used, focusing where possible on the results of high- Drs Brigo and Marson report no
quality randomized controlled clinical trials and systematic reviews of disclosures.
randomized controlled trials. Priority is given to results of randomized
controlled trials, since their study design minimizes the risk of bias, enabling a © 2022 American Academy
more reliable inference of treatment effect associated with an intervention. of Neurology.

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Where high-quality randomized trials are not available, information from

nonrandomized trials and observational studies is used. Evidence from
nonrandomized studies is particularly important when assessing harms (such
as teratogenicity) and longer-term effects that occur outside the time frame
of what is deliverable in randomized controlled trials.
The practice of evidence-based medicine includes the integration of the best
available research evidence with clinical expertise and patient values and
preferences in making decisions about the care of individuals1; therefore, every
clinical decision should always consider these three components. The clinical
experience of the authors is also reflected in this article.
The use of a drug in clinical practice requires rigorous evidence that it
positively affects a health outcome (ie, has efficacy) and is safe. In epilepsy, if an
antiseizure medication reduces the risk of seizure occurrence without
unacceptable adverse effects, it may be considered for use in clinical practice.
Clinical practice is best informed by evidence about the comparative efficacy
and safety of treatment options generated from head-to-head randomized
controlled trials; however, most epilepsy trials are placebo controlled, and few
head-to-head trials have been undertaken, especially for treating
refractory epilepsy.
The initial focus of antiseizure medication development is to meet the
requirements of the regulatory authorities (eg, the US Food and Drug
Administration [FDA] in the United States and the European Medicines Agency
in Europe) to gain a licensed indication.2 Antiseizure medications will typically
be tested first as adjunctive treatments in adults with drug-resistant focal
epilepsy in placebo-controlled trials that assess efficacy and safety over a 12- to
16-week period. This is usually followed by assessment in other scenarios, such as
in children with drug-resistant focal epilepsy, as adjunctive treatment in
generalized epilepsies or specific epilepsy syndromes, or as monotherapy.
Monotherapy licenses for new antiseizure medications therefore lag behind
licenses for add-on treatment.3
The regulatory adjunctive trials in drug-resistant epilepsy provide evidence of
efficacy by testing whether the drug works under ideal conditions. These trials
are usually conducted in a selected population with a high seizure frequency,
which limits their generalizability to those with drug-resistant epilepsy and to
other patient groups (eg, children). Being placebo controlled, they do not
provide direct evidence about the relative efficacy of antiseizure medications.
Furthermore, they are conducted over a limited time frame and hence do not
provide information on longer-term outcomes, which are vital to inform
treatment decisions for long-term conditions such as epilepsy. Although these
studies have high internal validity, having been designed to minimize the risk of
bias and provide an accurate evaluation of the causal relationship between
exposure to the drug and the selected outcome, they have poor external validity
(ie, low or poor generalizability of results) because of the strict and narrow
inclusion criteria, outcomes used, and short time frame over which they are
measured; they therefore have limited value in informing clinical practice.
To gain a license for monotherapy, the regulatory authorities have differing
requirements for trial design2: in Europe, the European Medicines Agency
requires head-to-head trials designed to show noninferiority against a standard
treatment for achieving 6 months’ remission from seizures. Conversely, the
FDA will not accept noninferiority designs because of concerns about assay

484 APRIL 2022

sensitivity.4 Instead, they require the demonstration of superiority, which has led KEY POINTS
to trials of doubtful ethical conduct and trials using historical controls.5
● The practice of evidence-
After regulatory requirements have been met, the drug is marketed. However, based medicine integrates
at this stage, the real-world clinical effectiveness is unknown and requires further the best available research
assessment. Ideally, this should be done in pragmatic randomized controlled evidence with clinical
trials, which are usually unblinded, include a broad population, and select the expertise and patient values
and preferences in making
outcomes that patients and clinicians are most interested in and are assessed over
decisions about the care of
a number of years. Although pragmatic trials can provide information that can individuals.
inform every clinical practice, because of the lack of blinding they can be more
prone to bias (lower internal validity with higher external validity). ● Evaluating and integrating
Evaluating and integrating data on efficacy and safety is essential to conclude data on efficacy, safety, and
effectiveness is essential to
whether a certain drug can improve a health outcome and, therefore, to obtain obtain the best information
the best information upon which to make treatment decisions.6 upon which to make
treatment decisions.
FIRST UNPROVOKED SEIZURE
● Estimating the risk of
Currently, all medications available for the treatment of epilepsy can prevent seizure recurrence for an
seizure occurrence but have no significant impact on the underlying disease individual and the effect of
process.7 Thus, they should be regarded as antiseizure medications rather than antiseizure medication on
antiepileptic drugs.8 Estimating the risk of seizure recurrence for an individual as that recurrence risk is
crucial to inform the
well as the effect of antiseizure medication on that recurrence risk is therefore
decision on whether to start
crucial to help inform the decision on whether to start antiseizure medication antiseizure medication
treatment. According to the current International League Against Epilepsy treatment.
(ILAE) definition,9 it is possible to make a diagnosis of epilepsy even after a
single unprovoked seizure, provided that the risk of seizure recurrence for an ● Antiseizure medication
treatment following a first
individual can be reliably predicted. Some evidence from observational studies unprovoked seizure reduces
and clinical trials identifies subgroups of patients at a higher risk of seizure the risk of a seizure
recurrence, but the ability to precisely predict seizure recurrence risk for recurrence with no impact
individual patients is limited. Important risk factors include elements of the on longer-term seizure
remission rates.
history, physical examination, and findings on EEG and neuroimaging
investigations.10 For example, an EEG showing generalized 3-Hz spike-and-wave
discharges in a patient with a first-ever generalized tonic-clonic seizure indicates
idiopathic generalized epilepsy and a higher seizure recurrence risk. Individual
patient data from a large randomized trial of immediate versus deferred
antiseizure treatment11 have been used to develop predictive models to enable
identification of patients at low, medium, or high risk of seizure recurrence.10
The risk of recurrence for unprovoked seizures is mainly determined by their
etiology.12 For example, a single seizure occurring more than 1 week after a stroke
is associated with a risk of seizure recurrence of 71.5% (95% confidence interval,
59.7% to 81.9%; P=.001) over 10 years of follow-up. Conversely, the risk of
seizure recurrence following a single unprovoked seizure with other etiologies
(eg, dementia, traumatic brain injury, or central nervous system infection) can
vary and depends on individual factors.12,13 In these conditions, more studies
are needed for individualized prediction of recurrence risk (CASE 9-1).
Randomized controlled trials have shown that antiseizure medication
treatment following a first unprovoked seizure reduces the risk of a seizure
recurrence14 but has no impact on longer-term seizure remission rates.11 In
addition, antiseizure medications are associated with adverse effects that can
diminish quality of life.15 The impact of antiseizure medications on seizure
recurrence risk is, however, modest; prognostic modeling10 has indicated that the
risk of seizure recurrence at 3 years is reduced from 50% to 35% in those at

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medium risk (unprovoked seizure and abnormal EEG) and from 67% to 46% for
those at high risk of recurrence (abnormal EEG and neurologic deficit). In
practice, it is those at high risk of seizure recurrence who are likely to opt for
antiseizure medication, although in the authors’ experience, many would prefer
to await another seizure before doing so. It is important, therefore, to consider
each case separately and disconnect the fact that that some individuals might be
given a diagnosis of epilepsy following a single seizure with the need to start
antiseizure medications.

CLASSIFICATION OF EPILEPSIES
The current classification of epilepsies was proposed by the ILAE in 2017.16 It is a
multilevel classification that starts by classifying the type of seizure (first level)
and then the patient’s type of epilepsy (second level) based on the history, results

CASE 9-1 A 68-year-old man was admitted for sudden onset of a left hemiparesis.
Initial investigations revealed atrial fibrillation and a hypodensity in the
right middle cerebral artery territory. Twenty hours later, he had a focal
motor clonic seizure (left hand and arm jerks). Levetiracetam up to
1000 mg/d and warfarin were initiated, and the patient was discharged
with a residual left hemiparesis. Four weeks after the stroke, the
levetiracetam was tapered off and discontinued. Six months after
levetiracetam discontinuation, the patient had a focal motor seizure
evolving to a bilateral tonic-clonic seizure. Levetiracetam was restarted,
and no further seizures occurred.

COMMENT This case illustrates the importance of evaluating the risk of seizure
recurrence to inform the decision on whether to start antiseizure
medication treatment. This patient had a first seizure occurring in close
temporal association with ischemic stroke. Such a seizure can be
considered as an acute symptomatic (provoked/reactive) seizure. Acute
symptomatic seizures occur at the time of a systemic insult or in close
temporal correlation with a documented brain insult and are not suggestive
of an enduring predisposition of the brain to generate epileptic seizures.
Acute symptomatic seizures occurring within 7 days of a stroke are
associated with a low risk of long-term recurrence, although they can
increase the risk of developing poststroke epilepsy with recurrent
unprovoked seizures. Consequently, it was decided to stop the initial
antiseizure medication therapy. The patient later had a second seizure
occurring some months after the stroke (unprovoked seizure). The risk of
seizure recurrence after an unprovoked late-onset seizure occurring more
than 1 week after a stroke is associated with a risk of recurrence of 71.5%
(95% confidence interval, 59.7% to 81.9%; P=.001) over 10 years of follow-up.
Therefore, levetiracetam was reintroduced and maintained as long-term
treatment. Levetiracetam, an antiseizure medication devoid of
pharmacokinetic interactions with other drugs, was chosen considering the
concomitant treatment with warfarin.

486 APRIL 2022

of the EEG, neuroimaging studies, and other investigations of the underlying KEY POINTS
etiology. If sufficient information is available, a specific epilepsy syndrome
● According to the
diagnosis is made (third level). According to the classification, every attempt International League Against
should be made to consider and incorporate etiology, as it often has relevant Epilepsy classification,
treatment implications. Seizure types can be classified as focal onset, generalized every attempt should be
onset, or unknown onset. According to the seizure types experienced by the made to consider and
incorporate etiology when
patient, epilepsies can hence be classified as focal, generalized, combined
classifying epilepsies, as it
generalized and focal, or unknown. The underlying etiology of seizures, often has relevant treatment
epilepsies, and epilepsy syndromes can be classified as structural, genetic, implications.
infectious, metabolic, immune, or unknown.
Generalized epilepsies include a range of seizure types, including absence, ● The choice of initial
antiseizure medication
myoclonic, atonic, tonic, and tonic-clonic seizures. The diagnosis of generalized therapy should integrate the
epilepsy is based on the clinical features and is supported by the finding of best available evidence
characteristic interictal EEG discharges typically showing generalized spike-and- from clinical trials, other
wave activity. In patients with a normal EEG despite generalized tonic-clonic pharmacologic
considerations, the clinical
seizures, supportive evidence is required for a diagnosis of generalized epilepsy, expertise of the treating
such as myoclonic jerks or positive family history.16 Idiopathic generalized physicians, and patient
epilepsies are a well-defined subgroup of generalized epilepsies and encompass values and preferences.
four specific syndromes: childhood absence epilepsy, juvenile absence epilepsy,
juvenile myoclonic epilepsy, and generalized tonic-clonic seizures alone.16
Focal epilepsies include a range of seizure types that involve one hemisphere.
They can be classified as focal aware seizures, focal impaired awareness seizures,
focal motor seizures, focal nonmotor seizures, and focal to bilateral tonic-
clonic seizures.16
Finally, the 2017 ILAE classification has introduced the new group of
combined generalized and focal epilepsies in which both seizure types can occur,
such as in Dravet syndrome and Lennox-Gastaut syndrome.16

INITIAL MONOTHERAPY TREATMENT CHOICE

The choice of initial therapy should integrate the best available evidence of
efficacy, safety, and tolerability derived from clinical trials and take into account
other pharmacologic considerations, such as drug interaction and teratogenicity,
the clinical expertise of the treating physicians, and patient values and
preferences. Furthermore, the selection of the most suitable initial monotherapy
should take into consideration the presence of comorbidities. For example, in
a patient with obesity, antiseizure medications associated with weight gain
(eg, valproic acid) are not advisable and the use of drugs with no effect on weight
(eg, lamotrigine) or even drugs associated with weight loss (eg, zonisamide or,
less likely, topiramate because of its poor tolerability) could be considered
(CASE 9-2).

Focal Epilepsy
Carbamazepine has been used as a first-line antiseizure medication for
monotherapy of focal epilepsy for many years. In a seminal multicenter
double-blind trial, carbamazepine, phenobarbital, phenytoin, and primidone
were compared in the treatment of focal-onset seizures and focal-onset seizures
evolving to bilateral tonic-clonic seizures in 622 adults who were predominantly
male military veterans.17 Patients were followed for 2 years or until the drug
failed to control seizures or caused unacceptable side effects. The proportion of
patients remaining on treatment (retention rate) was highest with carbamazepine

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and phenytoin, intermediate with phenobarbital, and lowest with primidone

( P<.002). This difference was mainly because of poorer tolerability of primidone.
No significant difference was found in control of focal-onset seizures evolving to
bilateral tonic-clonic seizures, whereas for focal-onset seizures that did not evolve
to bilateral tonic-clonic seizures, carbamazepine was associated with a higher
seizure freedom rate than primidone or phenobarbital ( P<.03).
In a subsequent study, carbamazepine was compared to valproate in 480
adults with focal impaired awareness seizures (206 patients) or focal-onset
seizures evolving to bilateral tonic-clonic seizures (274 patients).18 No difference
was found in the control of focal-onset seizures evolving to bilateral tonic-clonic
seizure, whereas in focal seizure with impaired awareness, carbamazepine was
more effective than valproate and had fewer long-term adverse effects.
Based on these studies, carbamazepine became the first-line treatment for
focal epilepsy and has also been used as a standard active comparator in
regulatory trials evaluating the efficacy and tolerability of newer-generation
antiseizure medications as monotherapy.19-22 These randomized double-blind
trials demonstrated that a number of antiseizure medications (eg, levetiracetam,
lacosamide) are noninferior to carbamazepine for 6-month seizure remission
rates. However, these trials do not adequately inform treatment decisions as they
measure outcomes over too short a time for a chronic condition such as epilepsy
and have strict inclusion and exclusion criteria limiting their generalizability.
The longer-term comparative effectiveness of newer antiseizure medications
compared to older antiseizure medications has been evaluated in two
randomized controlled trials that have tried to answer the question of whether
carbamazepine should still be considered a first-line agent for the treatment of
focal-onset epilepsy and whether valproate should still be considered a first-line
agent for the treatment of generalized/unclassified epilepsy.23,24

CASE 9-2 A 65-year-old woman was in a severe car accident that resulted in head
trauma and subsequently developed posttraumatic focal epilepsy. Her
past medical history was notable for bipolar disorder treated with
lithium. Treatment with valproic acid was recommended. After reaching
the total daily dose of valproic acid of 1500 mg/d, her concomitant
therapy with lithium was gradually reduced and eventually withdrawn. On
follow-up, the patient had achieved seizure freedom and maintained
mood stability.

COMMENT This case illustrates the importance of integrating the best available
evidence from clinical trials, other pharmacologic and clinical
considerations (including comorbidities), the clinical expertise of the
treating physicians, and patient values and preferences. The selection of
valproic acid as initial therapy appears to be an advisable option for the
presence of bipolar disorder. Eventually, the patient reduced and
suspended the prior therapy with lithium, receiving only valproic acid, a
drug effective against both bipolar disorder and epilepsy. In this case, the
strategy of “killing two birds with one stone” proved effective.

488 APRIL 2022

 The SANAD (Standard and New Antiepileptic Drugs) trial was a pragmatic
unblinded randomized controlled trial conducted in the United Kingdom that
compared the effectiveness and cost-effectiveness of standard and new
antiseizure medications available as monotherapy options. Arm A recruited 1721
patients for whom carbamazepine was considered by the treating physician to
be standard treatment (ie, patients with focal-onset epilepsy).23 Participants
were then randomly assigned to carbamazepine, gabapentin, lamotrigine,
oxcarbazepine, or topiramate. Lamotrigine performed significantly better than
carbamazepine, gabapentin, and topiramate for time to treatment failure, with a
nonsignificant trend compared with oxcarbazepine. For time to 12-month
remission, carbamazepine performed significantly better than gabapentin, with a
nonsignificant trend compared to lamotrigine, topiramate, and oxcarbazepine.
Based on this pragmatic trial, lamotrigine proved better than carbamazepine for
time to treatment failure outcomes and as a cost-effective drug for initial
monotherapy of focal epilepsy.
A second study, SANAD-II, adopted a similar design and compared
lamotrigine with levetiracetam or zonisamide in patients with newly diagnosed
focal epilepsy.24 For time to treatment failure, lamotrigine performed
significantly better than levetiracetam or zonisamide. The per-protocol analysis
for time to 12-month remission also found lamotrigine to be significantly superior
to levetiracetam or zonisamide.
Overall, results from the literature suggest that lamotrigine is clinically more
effective than carbamazepine for time to treatment failure and noninferior to
it for 12-month remission.24 Neither levetiracetam nor zonisamide appears to be
a clinically or cost-effective alternative.24
However, the choice of the initial monotherapy should not rely only on
possible differences in efficacy and tolerability but should also take into
consideration other issues, such as the intervals of administration, the
pharmacokinetic properties with the consequent risk of drug interactions, and
patient preferences. For example, in patients with poor adherence, antiseizure
medications that can be administered once daily at bedtime (eg, eslicarbazepine
acetate, perampanel, phenobarbital, zonisamide) are preferred. Patients at
increased risk of prolonged seizures or status epilepticus or who are temporarily
unable to swallow can benefit from antiseizure medications that also have an IV
formulation (eg, brivaracetam, lacosamide, phenytoin). Furthermore, in some
circumstances the time required to achieve the target dose should also be
considered (although it may vary between individuals and can be difficult to
know it in advance). For example, in patients requiring rapid seizure control
because of high seizure frequency, the use of lamotrigine is not advisable as it
requires a slow titration to minimize the risk of serious skin rashes.

Generalized Epilepsy
Evaluating the overall evidence for the use of antiseizure medications as first-line
monotherapy for generalized epilepsy is complicated by the intrinsic clinical
heterogeneity of generalized epilepsy, with only very few studies having been
conducted in specific epilepsy syndromes. Merging evidence from randomized
controlled trials conducted in specific syndromes (eg, idiopathic generalized
epilepsy with typical absence seizures) and studies conducted in various other
generalized epilepsies carries the risk of making specific conclusions in the face of
considerable clinical heterogeneity.

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MEDICAL TREATMENT OF EPILEPSY
KEY POINT
● Despite the increased
availability of antiseizure
medications, the prognosis
of patients with newly
diagnosed epilepsy has not
significantly improved.
490
Childhood absence epilepsy is the generalized epilepsy syndrome that has
most commonly been assessed in randomized controlled trials, which indicate
that ethosuximide and valproate have similar efficacy when used as first-line
monotherapy for children and adolescents.25 Both drugs have higher seizure
freedom rates at 12 months than lamotrigine. Because of better tolerability,
ethosuximide is preferred in patients with only typical absence seizures.
However, ethosuximide is probably ineffective against generalized tonic-clonic
seizures and should be regarded as a narrow-spectrum antiseizure medication
(TABLE 9-1); thus, if generalized tonic-clonic seizures occur together with typical
absences, valproate should be preferred or, as a second-line option, lamotrigine.25
Valproate has long been considered the first-line treatment for generalized
seizures, irrespective of the specific generalized epilepsy syndrome, because of
its broad-spectrum efficacy (TABLE 9-1). Its comparative effectiveness with
newer antiseizure medications has been evaluated in two pragmatic randomized
controlled trials. The unblinded pragmatic randomized controlled SANAD
study compared the longer-term effectiveness of valproate, lamotrigine, and
topiramate for the treatment of generalized-onset seizures or seizures that are
difficult to classify (arm B).23 The study recruited 716 patients for whom
valproate was considered to be standard treatment and randomly assigned
participants to one of the three antiseizure medications. Valproate was found to
be more effective than lamotrigine and topiramate in patients with idiopathic
generalized epilepsy as assessed by time to treatment failure. Valproate was
found to be significantly better than topiramate for time to treatment failure and
significantly better than lamotrigine for time to 12-month remission in the whole
study group and in the subgroup of patients with idiopathic generalized epilepsy.
SANAD-II compared sodium valproate with levetiracetam in 520 patients
with generalized and unclassifiable epilepsy (arm B).24 For time to 12-month
remission, levetiracetam did not meet the criteria for noninferiority in the
intention-to-treat analysis, whereas the per-protocol analysis showed valproate
was superior to levetiracetam. Valproate was also superior for time to treatment
failure. Adverse reactions were reported by 37% of the participants receiving
valproate and 42% of the participants assigned to levetiracetam.
Based on these results, sodium valproate is an effective first-line treatment for
generalized tonic-clonic seizures (with or without other generalized seizure
types). However, the use of valproate is limited by the serious concerns about its
teratogenic potential, particularly for spina bifida as well as for cardiac, craniofacial,
skeletal, and limb defects.26,27 Furthermore, prenatal exposure to valproate is
associated with an increased prevalence of neurodevelopmental disorders.28
Consequently, lamotrigine and levetiracetam appear suitable, although less
effective, alternatives as first-line treatment for women of childbearing
potential20; these drugs carry the lowest risk of overall congenital malformation.27
PROGNOSIS
In recent years, several new antiseizure medications with different mechanisms
of action have been introduced in clinical practice. However, despite the increased
availability of antiseizure medications, the prognosis of patients with newly
diagnosed epilepsy has not significantly improved over time. It is also important
to highlight that although antiseizure medications suppress seizures, they have no
proven disease-modifying or antiepileptogenic effects. Most patients achieve seizure
freedom with the first or second antiseizure medication, and the probability of
APRIL 2022
complete seizure control decreases sharply with each subsequent medication
regimen administered.
A 2018 observational cohort study of 1795 patients showed that among those
achieving 1-year seizure freedom (1144 patients), 993 (86.8%) were taking
monotherapy and 1028 (89.9%) achieved seizure freedom with the first or second
medical regimen.29 If the initial antiseizure medication was ineffective, the
second regimen provided an additional 11.6% likelihood of achieving complete

Efficacy Spectrum of Antiseizure Medications TABLE 9-1

Broad-spectrum antiseizure medications (effective against both focal and generalized-onset

seizures)
◆ Brivaracetam
◆ Clobazam
◆ Felbamate
◆ Lamotriginea
◆ Levetiracetam
◆ Perampanel
◆ Rufinamide
◆ Topiramate
◆ Valproate
◆ Zonisamide
Narrow-spectrum antiseizure medications (effective primarily against focal-onset seizures
and focal evolving to bilateral tonic-clonic seizures)
◆ Carbamazepineb
◆ Cenobamate
◆ Eslicarbazepine acetate
◆ Ethosuximidec
◆ Gabapentin
◆ Lacosamide
◆ Oxcarbazepine
◆ Phenobarbitalb
◆ Phenytoinb
◆ Pregabalin
◆ Primidoneb
◆ Stiripentol
◆ Tiagabine
◆ Vigabatrin

a
May worsen myoclonic seizures.
b
Some efficacy also against generalized onset tonic-clonic seizures but may aggravate other generalized
seizures (particularly absence seizures).
c
Active only against absence seizures.

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FIGURE 9-1
Treatment strategy after failure of the first antiseizure medication.
" = increase; # = decrease.
Modified with permission from Zaccara G, et al, Epilepsy Behav.34 © 2021 Elsevier Inc.

seizure control, and the third regimen provided an additional 4.4% likelihood of
achieving complete seizure control, whereas subsequent antiseizure medications
led to seizure freedom in a further 2.12% of patients.
Subgroup analyses of data from the SANAD trial have identified some clinical
factors (sex, age, treatment history, time from first seizure, EEG results, seizure
type, neurologic insult, total number of seizures before randomization) that
could affect the probability of treatment failure and the likelihood of achieving
12 months of remission.30 If validated, these variables could lead to outcome
prediction models aimed at identifying patients at risk of a poor treatment
outcome who may benefit from more regular follow-up.

TREATMENT OPTIONS AFTER FAILURE OF THE FIRST ANTISEIZURE

MEDICATION
After the failure of a first antiseizure medication because of adverse effects,
switching to an alternative monotherapy is the most common treatment decision.
When an antiseizure medication fails because of inadequate seizure control, the
main options are an alternative monotherapy or a dual therapy that adds a second
antiseizure medication to the first medication. Both of these alternatives are also
available for therapies that fail because of a combination of inadequate seizure
control and adverse effects; dual therapy is possible if the dose of the first drug
can be reduced to eliminate the adverse effects. Post hoc analyses of the first
SANAD trial showed that, following the failure of a first antiseizure medication,
70% of patients had achieved a 12-month remission at 5 years (65% of those with a

492 APRIL 2022

first treatment failure due to inadequate seizure control and 80% of those with a KEY POINTS
first failure due to adverse events).31 Risk factors for not achieving 12-month seizure
● After monotherapy failure
remission included tonic-clonic seizure, focal epilepsy, younger age, and female sex. because of inadequate
Alternative monotherapy and dual therapy have been compared in two seizure control, the main
randomized controlled trials, which did not find significant differences in options are an alternative
efficacy and tolerability.32,33 Both these studies were conducted in patients with monotherapy or a dual
therapy.
focal epilepsy and were open label; in one study, neurologists were randomly
assigned to prescribe either alternative monotherapy or dual therapy (cluster ● Several antiseizure
trial).33 These were small studies, and it is therefore possible that the lack of medications are available
significant results is attributable to inadequate statistical power. for treating focal epilepsy
Because of the lack of differences in efficacy and tolerability between these with seizures refractory to a
first or alternative
two strategies, other aspects should be taken into consideration when choosing monotherapy.
the appropriate therapy (FIGURE 9-134). An alternative monotherapy appears
preferable and advisable for patients with poor adherence. Similarly, if the failure
of the first antiseizure medication is because of lack of tolerability, an alternative
monotherapy with a different drug also seems advisable. In patients for whom
the initial monotherapy was effective but not tolerated because of dose-related
adverse effects, the target dose should be evaluated to determine whether it
was too high; potential pharmacokinetic interactions with concomitant
enzyme-inhibiting drugs that could lead to an increased antiseizure medication
level should also be evaluated. In these scenarios, the dose could be reduced
before opting for an alternative monotherapy.
Conversely, if the failure of the first monotherapy is because of lack of
efficacy, it is important to first exclude causes of pseudoinefficacy, such as use of
an inappropriate drug for the patient´s epilepsy or seizure type with worsening
of seizures or lack of seizure control, poor treatment adherence, initial target
dose too low to provide adequate antiseizure control, and pharmacokinetic
interactions with concomitant enzyme-inducing drugs leading to reduced
antiseizure medication level. After these issues have been ruled out, a dual
therapy with an adjunctive drug is an advisable choice (CASE 9-3).

DRUG-RESISTANT EPILEPSY
The following sections summarize the add-on treatments for drug-resistant focal
and generalized epilepsies, discuss the limitations of the evidence for these
treatments, and briefly discuss the issue of rational polytherapy.

Focal Epilepsy
Several antiseizure medications are currently available for the treatment of focal
epilepsy with seizures refractory to a first or alternative monotherapy, all of
which have been shown superior to placebo in regulatory randomized controlled
trials. Antiseizure medications that are commonly used in clinical practice as
adjunctive treatments for drug-resistant focal epilepsy include brivaracetam,
clobazam, eslicarbazepine acetate, gabapentin, lacosamide, lamotrigine,
levetiracetam, oxcarbazepine, perampanel, pregabalin, topiramate, valproate,
vigabatrin, and zonisamide.

Generalized Epilepsy
Although most patients with idiopathic generalized epilepsies achieve seizure
freedom with monotherapy, 35% to 40% of patients may continue to experience
seizures, requiring the use of adjunctive antiseizure medications.35,36 In a study of

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162 patients aged 12 years and older with drug-resistant primary generalized
tonic-clonic seizures due to idiopathic generalized epilepsy, adjunctive
perampanel reduced the seizure frequency by 76.5% (compared to 38.4% with
placebo; P<.0001).37
Lamotrigine, levetiracetam, perampanel, and topiramate have demonstrated
efficacy as adjunctive treatments for primary generalized tonic-clonic seizures
not controlled by a first or alternative monotherapy. Their efficacy has been
evaluated in randomized double-blind placebo-controlled trials adopting
different methodologies. The size of the full analysis sets in these studies ranged
from 45 to 164 patients, whereas the median reduction in the frequency of
primary generalized tonic-clonic seizures ranged from 56.7% with topiramate
(compared to 9.0% with placebo; P=.019) to 77.6% with levetiracetam
(compared to 44.6% with placebo; P<.001).37

Combining Antiseizure Medications

In patients for whom first or alternative monotherapy fails to control seizures,
adding a second antiseizure medication is required. Evidence on the efficacy
and tolerability of adjunctive treatments in focal drug-resistant epilepsy has
traditionally relied on the results of randomized controlled trials showing
superiority over add-on placebo. It is extremely unlikely that substantive
head-to-head randomized controlled trials of adjunctive antiseizure medications

CASE 9-3 A 34-year-old man was diagnosed with focal epilepsy due to right-sided
hippocampal sclerosis. He was initially treated with controlled-release
carbamazepine, which was gradually increased up to a maximum total
daily dose of 1400 mg/d. Although the therapy was well tolerated and the
patient took the drug regularly, he continued experiencing three to four
focal impaired awareness seizures per month. Levetiracetam was added
to the carbamazepine and gradually increased to a total daily dose of
1500 mg/d. The patient continued having seizures, although less
frequently. The levetiracetam was increased to a total daily dose of
3000 mg/d, and the patient eventually achieved seizure freedom.

COMMENT In this patient, the failure of the first monotherapy was not because of poor
tolerance but lack of efficacy. Causes of pseudoinefficacy were ruled out:
carbamazepine was an appropriate antiseizure medication for the patient’s
epilepsy type and was administered at an adequate dose, and the patient
had a good treatment adherence and received no other concomitant drugs
(no risk of drug interactions leading to increased metabolism and
consequent reduced efficacy of carbamazepine). Therefore, levetiracetam
was added to carbamazepine (dual therapy). Considering the optimal
efficacy of the combination and the patient’s high seizure frequency under
carbamazepine monotherapy, it was decided to maintain both drugs rather
than opting for an alternative monotherapy with levetiracetam by gradually
reducing and eventually withdrawing carbamazepine.

494 APRIL 2022

will ever be conducted; the industry is unlikely to fund them as they are not KEY POINTS
required by regulators and significant challenges exist with design and
● When choosing the add-
interpretation, particularly for noninferiority trials in which a finding of on treatment, several
noninferiority requires a distinction between similar efficacy and lack of efficacy. aspects need to be
These are challenges the international community has so far failed to address. considered in addition to its
Add-on studies using placebo as a comparator carry several methodologic and efficacy and tolerability,
including frequency of
ethical issues, including the high number of seizures at baseline and during
administration;
titration and the increased risk of sudden unexpected death in epilepsy (SUDEP) pharmacokinetic properties,
among patients randomly assigned to placebo.38 Furthermore, although add-on including the risk of drug
studies using placebo as a comparator provide evidence of efficacy to inform interactions; and patient
preferences.
regulatory and licensing decisions, they do not inform clinical practice as they do
not provide data on the relative effects of different alternative antiseizure ● The ideal rational
medications. Randomized controlled trials evaluating the efficacy and safety of polytherapy should have
add-on antiseizure medications have been conducted across an extended time supraadditive or synergistic
period. These studies differ substantially both methodologically and clinically, effects in efficacy (ie, their
combined efficacy should
including in the number and type of concurrent antiseizure medications used be greater than the sum of
and other patient characteristics. For example, participants recruited to more efficacy of each antiseizure
recently completed trials could be more drug-resistant than those included in medication alone) with
earlier trials,39 and this reduces the comparability of study results. infraadditive toxicity (ie,
their combined toxicity
When choosing an add-on treatment, it is thus important to consider other should be less than the sum
aspects in addition to efficacy and tolerability, including frequency of of the toxicity of each
administration, pharmacokinetic properties with the risk of drug interactions, antiseizure medication
and patient preferences. In the absence of reliable evidence from randomized alone).
controlled trials to inform practice, one proposal has been “rational polytherapy,”40
which largely focuses on antiseizure medication mechanisms of action. Although
theoretically attractive, the evidence supporting rational polytherapy is sparse
and based primarily on animal models and preclinical studies. The clinical studies
available are small, provide only imprecise results and low-level evidence, and
are usually observational studies or post hoc or subgroup analyses of randomized
controlled trials, which can be affected by confounding; these results should be
interpreted with caution.
Combining two or more antiseizure medications is aimed at maximizing efficacy
and minimizing side effects. The ideal rational polytherapy should therefore have
supraadditive or synergistic effects in efficacy (ie, their combined efficacy should
be superior to the sum of efficacy of each antiseizure medication alone), with
infraadditive toxicity (ie, their combined toxicity should be less than the sum of the
toxicity of each antiseizure medication alone).41 Favorable combinations are mainly
those between antiseizure medications with different mechanisms of action or
between antiseizure medications with multiple mechanisms of action.42 Combining
antiseizure medications with different mechanisms of action is considered useful
to achieve optimal outcomes, such as higher retention of treatment and lower
risks for hospitalization and emergency department visits.43
Some antiseizure medication combinations appear to be particularly effective in
focal drug-resistant epilepsy (eg, phenobarbital and phenytoin for tonic seizures;
lamotrigine and valproate for various epilepsy/seizure types).42 Cannabidiol (used
as an add-on treatment for Lennox-Gastaut syndrome, Dravet syndrome, and
tuberous sclerosis complex) is an enzyme-inhibiting drug that can increase serum
concentrations of the active metabolite of clobazam. This could synergically
potentiate the antiseizure efficacy of the combined drugs41,42 but may also explain the
increased risk of somnolence among patients using these combination therapies.44

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The clinical evidence supporting rational polytherapy for the treatment of

generalized epilepsies is scarce. The combination with the highest evidence for
synergistic efficacy is valproic acid and lamotrigine; patients who have not
responded to a maximally tolerated dose of either lamotrigine or valproic acid
can achieve seizure control with a combination of the two.45 This supraadditive
efficacy is due to a pharmacodynamic interaction and could prove useful in
treating seizures in patients with generalized epilepsy.
So far, no clear evidence-based recommendations can be made to inform
physicians in the choice of a specific drug association for treating focal drug-
resistant epilepsy. Specific antiseizure medication combinations represent a sort
of “irrational polytherapy” characterized by infraadditive antiseizure effect
(ie, their combined efficacy is less than the sum of the efficacy of each antiseizure
medication alone) and synergistic toxicity and thus should be avoided or
considered very carefully. An example is the pharmacodynamic interactions
between lacosamide and other sodium channel blockers, which can lead to
increased risk of central nervous system adverse effects (CASE 9-4).46 However,
even in this case, the evidence available so far is not robust enough to inform
clinical decisions.

CONCLUSION
Currently, several antiseizure medications are available for the treatment of focal
or generalized epilepsies. They differ in terms of mechanisms of action,

CASE 9-4 A 64-year-old man with focal structural epilepsy due to a hemorrhagic
stroke was initially treated with controlled-release carbamazepine
(1200 mg/d). His past medical history was also notable for hypertension
and type 2 diabetes.
The treatment with carbamazepine was well tolerated, but because he
had persistent focal seizures, lacosamide was added (dual therapy) and
gradually uptitrated to 200 mg/d. Shortly after starting lacosamide, the
patient reported dizziness and drowsiness, with increasing asthenia and
without a relevant improvement in seizure control. Lacosamide was thus
replaced with levetiracetam (up to a total daily dose of 1500 mg/d), which
resulted in disappearance of the adverse effects and satisfactory seizure
control.

COMMENT This patient’s seizures were uncontrolled with a first monotherapy and
were therefore treated with a dual therapy by adding a second antiseizure
medication. However, the combination of carbamazepine and lacosamide,
both sodium channel blockers, led to neurotoxic adverse effects. The
combination of lacosamide and other sodium channel blockers represents
an example of “irrational polytherapy,” characterized by infraadditive
antiseizure effect (ie, their combined efficacy is less than the sum of
efficacy of each antiseizure medication alone) and synergistic toxicity
(increased risk of central nervous system adverse effects).

496 APRIL 2022

frequency of administration, and pharmacologic properties, with a consequent
risk of pharmacokinetic interactions. Major unmet needs in epilepsy treatment
remain. A substantial proportion of patients with epilepsy continue to experience
seizures despite two or more antiseizure medications, with a negative impact on
quality of life. More antiseizure medications that can provide higher seizure
control with good tolerability and that could positively affect the underlying
disease are needed.
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